Signaling Signatures and Functional Properties of Anti-Human CD28 Superagonistic Antibodies

Superagonistic CD28 antibodies (CD28SAs) activate T lymphocytes without concomitant perturbation of the TCR/CD3-complex. In rodents these reagents induce the preferential expansion of regulatory T cells and can be used for the treatment of autoimmune diseases. Unexpectedly, the humanized CD28 superagonist TGN1412 caused severe and life threatening adverse effects during a recently conducted phase I clinical trail. The underlying molecular mechanisms are as yet unclear. We show that TGN1412 as well as the commercially available CD28 superagonist ANC28.1 induce a delayed but extremely sustained calcium response in human naïve and memory CD4+ T cells but not in cynomolgus T lymphocytes. The sustained Ca++-signal was associated with the activation of multiple intracellular signaling pathways and together these events culminated in the rapid de novo synthesis of high amounts of pro-inflammatory cytokines, most notably IFN-γ and TNF-α. Importantly, sustained transmembranous calcium flux, activation of Src-kinases as well as activation of PI3K were found to be absolutely required for CD28SA-mediated production of IFN-γ and IL-2. Collectively, our data suggest a molecular basis for the severe side effects caused by TGN1412 and impinge upon the relevance of non-human primates as preclinical models for reagents that are supposed to modify the function of human T cells

Status and Trends of Physical Activity Surveillance, Policy, and Research in 164 Countries: Findings From the Global Observatory for Physical Activity—GoPA! 2015 and 2020 Surveys

Background: Physical activity (PA) surveillance, policy, and research efforts need to be periodically appraised to gain insight into national and global capacities for PA promotion. The aim of this paper was to assess the status and trends in PA surveillance, policy, and research in 164 countries. Methods: We used data from the Global Observatory for Physical Activity (GoPA!) 2015 and 2020 surveys. Comprehensive searches were performed for each country to determine the level of development of their PA surveillance, policy, and research, and the findings were verified by the GoPA! Country Contacts. Trends were analyzed based on the data available for both survey years. Results: The global 5-year progress in all 3 indicators was modest, with most countries either improving or staying at the same level. PA surveillance, policy, and research improved or remained at a high level in 48.1%, 40.6%, and 42.1% of the countries, respectively. PA surveillance, policy, and research scores decreased or remained at a low level in 8.3%, 15.8%, and 28.6% of the countries, respectively. The highest capacity for PA promotion was found in Europe, the lowest in Africa and low- and lower-middle-income countries. Although a large percentage of the world’s population benefit from at least some PA policy, surveillance, and research efforts in their countries, 49.6 million people are without PA surveillance, 629.4 million people are without PA policy, and 108.7 million live in countries without any PA research output. A total of 6.3 billion people or 88.2% of the world’s population live in countries where PA promotion capacity should be significantly improved. Conclusion: Despite PA is essential for health, there are large inequalities between countries and world regions in their capacity to promote PA. Coordinated efforts are needed to reduce the inequalities and improve the global capacity for PA promotion

Calculation of fuel pin failure timing under LOCA conditions

The objective of this research was to develop and demonstrate a methodology for calculation of the time interval between receipt of the containment isolation signals and the first fuel pin failure for loss-of-coolant accidents (LOCAs). Demonstration calculations were performed for a Babcock and Wilcox (B W) design (Oconee) and a Westinghouse (W) 4-loop design (Seabrook). Sensitivity studies were performed to assess the impacts of fuel pin burnup, axial peaking factor, break size, emergency core cooling system (ECCS) availability, and main coolant pump trip on these items. The analysis was performed using a four-code approach, comprised of FRAPCON-2, SCDAP/RELAP5/MOD3, TRAC-PF1/MOD1, and FRAP-T6. In addition to the calculation of timing results, this analysis provided a comparison of the capabilities of SCDAP/RELAP5/MOD3 with TRAC-PF1/MOD1 for large-break LOCA analysis. This paper discusses the methodology employed and the code development efforts required to implement the methodology. The shortest time intervals calculated between initiation of containment isolation and fuel pin failure were 11.4 s and 19.1 for the B W and W plants, respectively. The FRAP-T6 fuel pin failure times calculated using thermal-hydraulic data generated by SCDAP/RELAP5/MOD3 were more conservative than those calculated using data generated by TRAC-PF1/MOD1. 18 refs., 7 figs., 4 tabs

Comparison of SCDAP/RELAP5/MOD3 to TRAC-PF1/MOD1 for timing analysis of PWR fuel pin failures

A comparison has been made of SCDAP/RELAP5/MOD3- and TRAC-PF1/MOD1- based calculations of the fuel pin failure timing (time from containment isolation signal to first fuel pin failure) in a loss-of-coolant accident (LOCA). The two codes were used to calculate the thermal-hydraulic boundary conditions for a complete, double-ended, offset-shear break of a cold leg in a Westinghouse 4-loop pressurized water reactor. Both calculations used the FRAPCON-2 code to calculate the steady-state fuel rod behavior and the FRAP-T6 code to calculate the transient fuel rod behavior. The analysis was performed for 16 combinations of fuel burnups and power peaking factors extending up to the Technical Specifications limits. While all calculations were made on a best-estimate basis, the SCDAP/RELAP5/MOD3 code has not yet been fully assessed for large-break LOCA analysis. The results indicate that SCDAP/RELAP5/MOD3 yields conservative fuel pin failure timing results in comparison to those generated using TRAC-PF1/MOD1. 7 refs., 5 figs