T-cell co-stimulatory pathways in autoimmunity

T-cell activation and differentiation depend on the signal strength received by the T-cell receptor and on signals provided by co-stimulatory molecules. The most prominent co-stimulatory molecule is CD28, which controls the activation of naïve and memory T cells by antigen presented on professional antigen-presenting cells. Blocking of the CD28-CD80/86 pathway has been an appealing strategy for inducing tolerance in autoimmune diseases where the disease-inducing autoantigens are not known. Although CD28 has maintained its unique position, the past decade has witnessed the recognition that a large number of regulatory molecules on T cells must be stimulated to generate a fully protective immune response. These regulatory receptors differ in their preferential expression on T-cell subsets, in the ligands that they recognize, and in the signaling pathways that they trigger. They have in common the fact that they provide information on the cellular environment in which the T-cell response occurs. By intercepting these signals, we may be able to influence disease-relevant T-cell responses in autoimmune diseases while potentially minimizing broad immunosuppression

Developments in the scientific understanding of rheumatoid arthritis

Rheumatoid arthritis (RA) is recognized to be an autoimmune disease that causes preclinical systemic abnormalities and eventually leads to synovial inflammation and destruction of the joint architecture. Recently identified genetic risk factors and novel insights from animal models of spontaneous arthritis have lent support to the concept that thymic selection of an autoreactive T-cell repertoire is an important risk factor for this disease. With advancing age, defects in the homeostatic control of the T-cell pool and in the setting of signaling thresholds lead to the accumulation of pro-inflammatory T-effector cell populations and loss of tolerance to neo-antigens, such as citrullinated peptides. As the breakdown of tolerance to modified self-antigens can precede synovitis by decades, repair of homeostatic defects may open a unique window of opportunity for preventive interventions in RA. The end result of RA, destruction of cartilage and bone, appears to be driven by cytokine- and cell contact-induced activation of synoviocytes and monocytic cells, some of which differentiate into tissue-destructive osteoclasts. Targeting mediators involved in this process has greatly improved the management of this chronic inflammatory syndrome

Human Sprint Running Mechanics: Do Right and Left Legs Apply Equal Ground Forces?

Introduction: A growing body of research has focused on between-leg asymmetry as a critical factor for athletic performance and dysfunction. Specifically, various measures of between-leg asymmetry during running have been investigated in both healthy and injured populations. However, while the most important factor for running performance is the magnitude and rate of ground force application, it is not known whether the right and left legs typically apply equal ground forces at faster running speeds. Objective: In a healthy population of athletic female participants, we aimed to: 1) compare the mechanics of ground force application between right and left legs during moderate and top speed running, and 2) evaluate if the right vs. left leg asymmetries observed at intermediate speeds are more pronounced at faster speeds. Hypothesis: We hypothesized that the forces applied by the right and left legs of healthy athletes would agree to within 10% or less at both moderate and top speed. Participants: Nine female intercollegiate soccer players volunteered for the study (age: 19.4 ± 1.0 years, height: 1.72 ± 0.04 m, mass: 69.0 ± 7.2 kg). Data Collection: Ground force data was acquired at 1,000 Hz using a custom high-speed, three-axis force treadmill (AMTI, Watertown, MA). Data was analyzed for trials at 5.0 m•s-1 and each individual’s top speed. Top speed was defined as the fastest speed where the participant could complete eight consecutive steps on the treadmill without drifting backward more than 0.2 m. Outcome Measures: Ground contact time, vertical force, and vertical impulse were analyzed. Vertical force was normalized to body weight (Wb) and vertical impulse was calculated in body weight • seconds (Wb•s). For all trials, these variables were averaged for right vs. left footfalls, and percentage difference was calculated to quantify between-leg asymmetry. Results: Top speeds ranged from 7.21 to 8.26 m•s-1 (7.83 ± 0.38 m•s-1). At 5.0 m•s-1, the mean between-leg asymmetry was 2.3 ± 1.2 % for ground contact time, 1.9 ± 1.3 % for vertical force, and 2.3 ± 1.9 % for vertical impulse. At top speed, the mean between-leg asymmetry was 3.5 ± 2.8 % for ground contact time, 5.5 ± 3.0 % for vertical force, and 8.3 ± 4.8 % for vertical impulse. Conclusions: We conclude that the right and left legs apply ground force similarly during moderate and top-speed sprint running in healthy female athletes

Iridium Coatings for the Protection of Graphite Re-Entry Structures

Because of its high strength-to-weight ratio and other desirable features, graphite is desirable for use as structural components that are to be exposed to a high-temperature environment. At elevated temperatures, however, graphite reacts with oxidizing atmospheres, and smooth surfaces having specific engineering properties are degraded into eroded surfaces of lower efficiency. It has been demonstrated that iridium can be used to protect graphite in air at temperatures to 3600 F for 1 hour or more. Battelle has been conducting a program for the Air Force Materials Laboratory to study the application of iridium and iridium-alloy coatings to graphite, based on a comb ined plasma-arc deposition and gas-pressure bonding process. A comprehensive prog ram involving the development, fabrication, and testing of these coatings is described

A general relationship links gait mechanics and running ground reaction forces

The relationship between gait mechanics and running ground reaction forces is widely regarded as complex. This viewpoint has evolved primarily via efforts to explain the rising edge of vertical force– time waveforms observed during slow human running. Existing theoretical models do provide good rising-edge fits, but require more than a dozen input variables to sum the force contributions of four or more vague components of the body’s total mass (mb). Here, we hypothesized that the force contributions of two discrete body mass components are sufficient to account for vertical ground reaction force– time waveform patterns in full (stance foot and shank, m1=0.08mb; remaining mass, m2=0.92mb). We tested this hypothesis directly by acquiring simultaneous limb motion and ground reaction force data across a broad range of running speeds (3.0–11.1 m s−1 ) from 42 subjects who differed in body mass (range: 43–105 kg) and foot-strike mechanics. Predicted waveforms were generated from our two-mass model using body mass and three stride-specific measures: contact time, aerial time and lower limb vertical acceleration during impact. Measured waveforms (N=500) differed in shape and varied by more than twofold in amplitude and duration. Nonetheless, the overall agreement between the 500 measured waveforms and those generated independently by the model approached unity (R2 =0.95 ±0.04, mean±s.d.), with minimal variation across the slow, medium and fast running speeds tested (ΔR2 ≤0.04), and between rear-foot (R2 =0.94±0.04, N=177) versus fore-foot (R2 =0.95±0.04, N=323) strike mechanics. We conclude that the motion of two anatomically discrete components of the body’s mass is sufficient to explain the vertical ground reaction force–time waveform patterns observed during human running

B cells in rheumatoid synovitis

In rheumatoid arthritis, T cells, B cells, macrophages, and dendritic cells invade the synovial membranes, establishing complex microstructures that promote inflammatory/tissue destructive lesions. B cell involvement has been considered to be limited to autoantibody production. However, recent studies suggest that B cells support rheumatoid disease through other mechanisms. A critical element of rheumatoid synovitis is the process of ectopic lymphoid neogenesis, with highly efficient lymphoid architectures established in a nonlymphoid tissue site. Rheumatoid synovitis recapitulates the pathways of lymph node formation, and B cells play a key role in this process. Furthermore, studies of rheumatoid lesions implanted in immunodeficient mice suggest that T cell activation in synovitis is B cell dependent, indicating the role played by B cells in presenting antigens and providing survival signals