The impact of environmental contaminants on extracellular vesicles and their key molecular regulators: A literature and database-driven review

Exposure to environmental chemicals is now well recognized as a significant factor contributing to the global burden of disease; however, there remain critical gaps in understanding the types of biological mechanisms that link environmental chemicals to adverse health outcomes. One type of mechanism that remains understudied involves extracellular vesicles (EVs), representing small cell-derived particles capable of carrying molecular signals such as RNAs, miRNAs, proteins, lipids, and chemicals through biological fluids and imparting beneficial, neutral, or negative effects on target cells. In fact, evidence is just now starting to grow that supports the role of EVs in various disease etiologies. This review aims to (1) Provide a landscape of the current understanding of the functional relationship between EVs and environmental chemicals; (2) Summarize current knowledge of EV regulatory processes including production, packaging, and release; and (3) Conduct a database-driven analysis of known chemical–gene interactions to predict and prioritize environmentally relevant chemicals that may impact EV regulatory genes and thus EV regulatory processes. This approach to predicting environmentally relevant chemicals that may alter EVs provides a novel method for evidence-based hypothesis generation for future studies evaluating the link between environmental exposures and EVs.     

Molecular basis of cross-species reactivities of human versus porcine CTLA-4

The binding motif of human CTLA-4 is well known to be MYPPPY and for porcine CTLA-4 the binding motif is LYPPPY. Is this single amino acid difference of methionine (M) versus leucine (L) critical for the CTLA-4 binding? Recently, we have reported that the recombinant soluble porcine CTLA-4 was incapable of binding to human CD80. In this study we mutated L to M in the binding motif of the soluble porcine CTLA-4 and mutated M to L in the binding motif of the soluble human CTLA-4. We then analyzed how these mutations affected the binding affinity of the mutants to both porcine and human CD80⁺ cells. The soluble porcine CTLA-4-L97M mutant partially lost its binding affinity to porcine CD80 compared to the wild-type and conferred very weak binding ability to human CD80. These results indicate that the L in the binding motif of porcine CTLA-4 is important for determining its binding ability to porcine CD80. Wild-type soluble human CTLA-4 binds to both human and porcine CD80 with comparable affinity, however, the soluble human CTLA-4-M97L mutant almost lost its binding ability to human CD80 and increased its binding ability to porcine CD80. These results indicate that M in the human CTLA-4 binding motif is extremely critical for its binding to human CD80. Those data suggest that the human CTLA-4 based recombinant protein drugs such as human CTLA-4-Ig can be used and/or tested in a porcine model. Conversely, the use of porcine CTLA-4 based recombinant protein drugs such as porcine CTLA-4-Ig is restricted to swine models. The difference in binding specificity of CTLA-4 observed in this study may be useful for studies such as pig to nonhuman primate xeno-transplantation. Porcine CTLA-4- and human CTLA-4-M97L mutant-based recombinant protein drugs can be used to specifically block the direct presentation by donor antigen presenting cells in pig to nonhuman primate xeno-transplantation. Human CTLA-4-M97L mutant-based recombinant protein drugs will be more ideal as it is without immunogenicity to human being.     

Reductions in functional balance, coordination, and mobility measures among patients with stable chronic obstructive pulmonary disease

PURPOSE: To compare measures of balance, coordination, and mobility between patients with chronic obstructive pulmonary disease (COPD) and healthy control subjects, and to determine whether differences in these measures are associated with measures of disease severity. METHODS: The subjects were divided into three groups: 15 patients with COPD who required the use of supplemental oxygen (WO), 15 patients with COPD who did not require the use of supplemental oxygen (NO), and 21 healthy control subjects (CO). The subjects performed spirometry and several measures of balance, coordination, and mobility including the Community Balance and Mobility Scale, the timed up and go test, the fast-gait speed test, posturography, and both a finger-to-nose test and a toe-tapping coordination test. Significance was set at an alpha less than 0.05. RESULTS: When control was used for age, significant differences were found between the WO group and the CO group for the finger-to-nose test, and for both the sway index and peak sway index for the eyes open, moving-platform test. Differences were found among all three groups for the Community Balance and Mobility Scale overall score. The scores for the WO group were significantly worse than for the NO group on the timed up and go and the fast-gait speed tests. Moderate correlation was found among all of the measures, demonstrating significant differences in forced-expiratory volume in 1 second (FEV1), peak expiratory flow, and forced-expiratory volume. When controls were used for both age and FEV1, between-group differences disappeared. CONCLUSIONS: Patients with COPD exhibit deficiencies in functional balance, coordination, and mobility tasks associated with disease severity or differences in activity levels, but not in the requirement for supplemental oxygen.