Functional inaccessibility of quiescent herpes simplex virus genomes

BACKGROUND: Newly delivered herpes simplex virus genomes are subject to repression during the early stages of infection of human fibroblasts. This host defence strategy can limit virus replication and lead to long-term persistence of quiescent viral genomes. The viral immediate-early protein ICP0 acts to negate this negative regulation, thereby facilitating the onset of the viral replication cycle. Although few mechanistic details are available, the host repression machinery has been proposed to assemble the viral genome into a globally inaccessible configuration analogous to heterochromatin, blocking access to most or all trans-acting factors. The strongest evidence for this hypothesis is that ICP0-deficient virus is unable to reactivate quiescent viral genomes, despite its ability to undergo productive infection given a sufficiently high multiplicity of infection. However, recent studies have shown that quiescent infection induces a potent antiviral state, and that ICP0 plays a key role in disarming such host antiviral responses. These findings raise the possibility that cells containing quiescent viral genomes may be refractory to superinfection by ICP0-deficient virus, potentially providing an alternative explanation for the inability of such viruses to trigger reactivation. We therefore asked if ICP0-deficient virus is capable of replicating in cells that contain quiescent viral genomes. RESULTS: We found that ICP0-deficient herpes simplex virus is able to infect quiescently infected cells, leading to expression and replication of the superinfecting viral genome. Despite this productive infection, the resident quiescent viral genome was neither expressed nor replicated, unless ICP0 was provided in trans. CONCLUSION: These data document that quiescent HSV genomes fail to respond to the virally modified host transcriptional apparatus or viral DNA replication machinery provided in trans by productive HSV infection in the absence of ICP0. These results point to global repression as the basis for HSV genome quiescence, and indicate that ICP0 induces reactivation by overcoming this global barrier to the access of trans-acting factors

Delamination growth in composite materials

The Double Cantilever Beam (DCB) and the End Notched Flexure (ENF) specimens are employed to characterize MODE I and MODE II interlaminar fracture resistance of graphite/epoxy (CYCOM 982) and graphite/PEEK (APC2) composites. Sizing of test specimen geometries to achieve crack growth in the linear elastic regime is presented. Data reduction schemes based upon beam theory are derived for the ENF specimen and include the effects of shear deformation and friction between crack surfaces on compliance, C, and strain energy release rate, G sub II. Finite element (FE) analyses of the ENF geometry including the contact problem with friction are presented to assess the accuracy of beam theory expressions for C and G sub II. Virtual crack closure techniques verify that the ENF specimen is a pure Mode II test. Beam theory expressions are shown to be conservative by 20 to 40 percent for typical unidirectional test specimen geometries. A FE parametric study investigating the influence of delamination length and depth, span, thickness and material properties on G sub II is presented. Mode I and II interlaminar fracture test results are presented. Important experimental parameters are isolated, such as precracking techniques, rate effects, and nonlinear load-deflection response. It is found that subcritical crack growth and inelastic materials behavior, responsible for the observed nonlinearities, are highly rate-dependent phenomena with high rates generally leading to linear elastic response

Delamination growth in composite materials

Research related to growth of an imbedded through-width delamination (ITWD) in a compression loaded composite structural element is presented. Composites with widely different interlaminar fracture resistance were examined, viz., graphite/epoxy (CYCOM 982) and graphite/PEEK (APC-2). The initial part of the program consisted of characterizing the material in tension, compression and shear mainly to obtain consistent material properties for analysis, but also as a check of the processing method developed for the thermoplastic APC-2 material. The characterization of the delamination growth in the ITWD specimen, which for the unidirectional case is essentially a mixed Mode 1 and 2 geometry, requires verified mixed-mode growth criteria for the two materials involved. For this purpose the main emphasis during this part of the investigation was on Mode 1 and 2 fracture specimens, namely the Double Cantilever Beam (DCB) and End Notched Flexure (ENF) specimens

The prevalence and incidence of mental ill-health in adults with autism and intellectual disabilities

The prevalence, and incidence, of mental ill-health in adults with intellectual disabilities and autism were compared with the whole population with intellectual disabilities, and with controls, matched individually for age, gender, ability-level, and Down syndrome. Although the adults with autism had a higher point prevalence of problem behaviours compared with the whole adult population with intellectual disabilities, compared with individually matched controls there was no difference in prevalence, or incidence of either problem behaviours or other mental ill-health. Adults with autism who had problem behaviours were less likely to recover over a two-year period than were their matched controls. Apparent differences in rates of mental ill-health are accounted for by factors other than autism, including Down syndrome and ability level

Instances and connectors : issues for a second generation process language

This work is supported by UK EPSRC grants GR/L34433 and GR/L32699Over the past decade a variety of process languages have been defined, used and evaluated. It is now possible to consider second generation languages based on this experience. Rather than develop a second generation wish list this position paper explores two issues: instances and connectors. Instances relate to the relationship between a process model as a description and the, possibly multiple, enacting instances which are created from it. Connectors refers to the issue of concurrency control and achieving a higher level of abstraction in how parts of a model interact. We believe that these issues are key to developing systems which can effectively support business processes, and that they have not received sufficient attention within the process modelling community. Through exploring these issues we also illustrate our approach to designing a second generation process language.Postprin