Pathogenic Bacteria Target NEDD8-Conjugated Cullins to Hijack Host-Cell Signaling Pathways

The cycle inhibiting factors (Cif), produced by pathogenic bacteria isolated from vertebrates and invertebrates, belong to a family of molecules called cyclomodulins that interfere with the eukaryotic cell cycle. Cif blocks the cell cycle at both the G1/S and G2/M transitions by inducing the stabilization of cyclin-dependent kinase inhibitors p21waf1 and p27kip1. Using yeast two-hybrid screens, we identified the ubiquitin-like protein NEDD8 as a target of Cif. Cif co-compartmentalized with NEDD8 in the host cell nucleus and induced accumulation of NEDD8-conjugated cullins. This accumulation occurred early after cell infection and correlated with that of p21 and p27. Co-immunoprecipitation revealed that Cif interacted with cullin-RING ubiquitin ligase complexes (CRLs) through binding with the neddylated forms of cullins 1, 2, 3, 4A and 4B subunits of CRL. Using an in vitro ubiquitylation assay, we demonstrate that Cif directly inhibits the neddylated CUL1-associated ubiquitin ligase activity. Consistent with this inhibition and the interaction of Cif with several neddylated cullins, we further observed that Cif modulates the cellular half-lives of various CRL targets, which might contribute to the pathogenic potential of diverse bacteria

Cutaneous lesions of the external ear

Skin diseases on the external aspect of the ear are seen in a variety of medical disciplines. Dermatologists, othorhinolaryngologists, general practitioners, general and plastic surgeons are regularly consulted regarding cutaneous lesions on the ear

Prospects for the development of probiotics and prebiotics for oral applications

There has been a paradigm shift towards an ecological and microbial community-based approach to understanding oral diseases. This has significant implications for approaches to therapy and has raised the possibility of developing novel strategies through manipulation of the resident oral microbiota and modulation of host immune responses. The increased popularity of using probiotic bacteria and/or prebiotic supplements to improve gastrointestinal health has prompted interest in the utility of this approach for oral applications. Evidence now suggests that probiotics may function not only by direct inhibition of, or enhanced competition with, pathogenic micro-organisms, but also by more subtle mechanisms including modulation of the mucosal immune system. Similarly, prebiotics could promote the growth of beneficial micro-organisms that comprise part of the resident microbiota. The evidence for the use of pro or prebiotics for the prevention of caries or periodontal diseases is reviewed, and issues that could arise from their use, as well as questions that still need to be answered, are raised. A complete understanding of the broad ecological changes induced in the mouth by probiotics or prebiotics will be essential to assess their long-term consequences for oral health and disease

Multi-functional mechanisms of immune evasion by the streptococcal complement inhibitor C5a peptidase

The complement cascade is crucial for clearance and control of invading pathogens, and as such is a key target for pathogen mediated host modulation. C3 is the central molecule of the complement cascade, and plays a vital role in opsonization of bacteria and recruitment of neutrophils to the site of infection. Streptococcal species have evolved multiple mechanisms to disrupt complement-mediated innate immunity, among which ScpA (C5a peptidase), a C5a inactivating enzyme, is widely conserved. Here we demonstrate for the first time that pyogenic streptococcal species are capable of cleaving C3, and identify C3 and C3a as novel substrates for the streptococcal ScpA, which are functionally inactivated as a result of cleavage 7 amino acids upstream of the natural C3 convertase. Cleavage of C3a by ScpA resulted in disruption of human neutrophil activation, phagocytosis and chemotaxis, while cleavage of C3 generated abnormally-sized C3a and C3b moieties with impaired function, in particular reducing C3 deposition on the bacterial surface. Despite clear effects on human complement, expression of ScpA reduced clearance of group A streptococci in vivo in wildtype and C5 deficient mice, and promoted systemic bacterial dissemination in mice that lacked both C3 and C5, suggesting an additional complement-independent role for ScpA in streptococcal pathogenesis. ScpA was shown to mediate streptococcal adhesion to both human epithelial and endothelial cells, consistent with a role in promoting bacterial invasion within the host. Taken together, these data show that ScpA is a multi-functional virulence factor with both complement-dependent and independent roles in streptococcal pathogenesis

Atmospheric Dispersion at Spatial Resolutions Below Mesoscale for university of Tennessee SimCenter at Chattanooga: Final Report

In Year 1 of this project, items 1.1 and 1.2 were addressed, as well as item 2.2. The baseline parallel computational simulation tool has been refined significantly over the timeline of this project for the purpose of atmospheric dispersion and transport problems; some of these refinements are documented in Chapter 3. The addition of a concentration transport capability (item 1.2) was completed, along with validation and usage in a highly complex urban environment. Multigrid capability (item 2.2) was a primary focus of Year 1 as well, regardless of the fact that it was scheduled for Year 2. It was determined by the authors that due to the very large nature of the meshes required for atmospheric simulations at mesoscale, multigrid was a key enabling technology for the rest of the project to be successful. Therefore, it was addressed early according to the schedule laid out in the original proposal. The technology behind the multigrid capability is discussed in detail in Chapter 5. Also in Year 1, the issue of ground topography specification is addressed. For simulations of pollutant transport in a given region, a key prerequisite is the specification of the detailed ground topography. The local topography must be placed into a form suitable for generating an unstructured grid both on the topography itself and the atmospheric volume above it; this effort is documented in Chapter 6. In Year 2 of this project, items 1.3 and 2.1 were addressed. Weather data in the form of wind speeds, relative humidity, and baseline pollution levels may be input into the code in order to improve the real-world fidelity of the solutions. Of course, the computational atmospheric boundary layer (ABL) boundary condition developed in Year 1 may still be used when necessary. Cloud cover may be simulated via the levels of actinic flux allowed in photochemical reactions in the atmospheric chemistry model. The primary focus of Year 2 was the formulation of a multispecies capability with included chemical reactions (item 2.1). This proved to be a very arduous task, taking the vast majority of the time and personnel allocation for Year Two. The addition of this capability and related verification is documented in Chapter 7. A discussion of available tropospheric chemistry models is located in Chapter 8; and, a technology demonstrator for the full multispecies capability is detailed in Chapter 9. Item 2.3 has been partially addressed, in that the computation of sensitivity derivatives have been incorporated in the Tenasi code [7]. However, it has not been utilized in this project in order to compute probability distribution functions for pollutant deposition. In order to completely address the integration of weather and sensor data into the code (item 1.3) and integrate with existing sensor networks (item 3.1), a customizable interface was established. Weather data is most commonly available via a real database, and as such, support for accessing these databases is present in the solver source code. For integration functionality, a method of dynamic code customization was developed in Year 3, which is documented in Chapter 11

Mixed-Initiative Control of Multiple Heterogeneous Robots for Urban Search and Rescue

This article describes a mixed-initiative system for Urban Search and Rescue, its implementation on a team of heterogeneous robots, and data collected with the NIST USAR Standard Test Course. It contributes to the justification and understanding of heterogeneous robot teams in perceptually and navigationally challenging domains, and to the theory of architectures for mixed-initiative systems. The mixed-initiative control scheme used a novel Three-A#ent Society organization which places an Intelligent Assistant Agent as the middleware between the Physically-Situated (remote robots) and Cognitive (human) Agents. The Intel- ligent Assistant Agent provided perceptual assistance, cueing the teleoperator to the possible presence of victims using a fusion of four affordances: heat, motion, skin color, and color difference. The mixed-initiative system was novel in that the robot took the initiative for perception rather than for navigation. Navigation through the confined space was done cooperatively using collaborative teleoperation. Data collected at the 2000 AAAI Mobile Robot Competition showed that the robot team found four times as many victims under more demanding conditions as any competitor. The robots cooperatively identified 209% (23) more victims than they would have individually (11). In addition, an analysis of the recordings showed that three types of navigation errors were introduced by the teleoperators: iterative course corrections (2 per minute per robot), collisions with the environment (0.13 per minute), and pose errors (0.3 per minute)