Timing is everything for compassionate use of delamanid.
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ABSTRACT:
SUBMITTER: Barry CE
PROVIDER: S-EPMC6380361 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:As the molecular mechanisms of vertebrate phototransduction became increasingly clear in the 1980s, a persistent problem was the discrepancy between the slow GTP hydrolysis catalyzed by the phototransduction G protein, transducin, and the much more rapid physiological recovery of photoreceptor cells from light stimuli. Beginning with a report published in 1989, a series of studies revealed that transducin GTPase activity could approach the rate needed to explain physiological recovery kinetics in the presence of one or more factors present in rod outer segment membranes. One by one, these factors were identified, beginning with PDE?, the inhibitory subunit of the cGMP phosphodiesterase activated by transducin. There followed the discovery of the crucial role played by the regulator of G protein signaling, RGS9, a member of a ubiquitous family of GTPase-accelerating proteins, or GAPs, for heterotrimeric G proteins. Soon after, the G protein ? isoform G?5 was identified as an obligate partner subunit, followed by the discovery or R9AP, a transmembrane protein that anchors the RGS9 GAP complex to the disk membrane, and is essential for the localization, stability, and activity of this complex in vivo. The physiological importance of all of the members of this complex was made clear first by knockout mouse models, and then by the discovery of a human visual defect, bradyopsia, caused by an inherited deficiency in one of the GAP components. Further insights have been gained by high-resolution crystal structures of subcomplexes, and by extensive mechanistic studies both in vitro and in animal models.
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Project description:The transcription factor nuclear factor erythroid 2 (NF-E2)-related factor 2 (NRF2) is a central regulator of redox, metabolic, and protein homeostasis that intersects with many other signaling cascades. Although the understanding of the complex nature of NRF2 signaling continues to grow, there is only one therapeutic targeting NRF2 for clinical use, dimethyl fumarate, used for the treatment of multiple sclerosis. The discovery of new therapies is confounded by the fact that NRF2 levels vary significantly depending on physiological and pathological context. Thus, properly timed and targeted manipulation of the NRF2 pathway is critical in creating effective therapeutic regimens. In this review, we summarize the regulation and downstream targets of NRF2. Furthermore, we discuss the role of NRF2 in cancer, neurodegeneration, and diabetes as well as cardiovascular, kidney, and liver disease, with a special emphasis on NRF2-based therapeutics, including those that have made it into clinical trials.
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Project description:BackgroundThe synchrony of an organism with both its external and internal environment is critical to well-being and survival. As a result, organisms display daily cycles of physiology and behavior termed circadian rhythms. At the cellular level, circadian rhythms originate via interlocked autoregulatory feedback loops consisting of circadian clock genes and their proteins. These regulatory loops provide the molecular framework that enables the intracellular circadian timing system necessary to generate and maintain subsequent 24 hr rhythms. In the present study we examine the daily control of circadian clock genes and regulation of the inflammatory response by the circadian clock in the spleen.ResultsOur results reveal that circadian clock genes as well as proinflammatory cytokines, including Tnfά and IL-1β, display rhythmic oscillations of mRNA abundance over a 24 hr cycle. LPS-induced systemic inflammation applied at midday vs. midnight reveals a differential response of proinflammatory cytokine induction in the spleen, suggesting a daily rhythm of inflammation. Exogenous melatonin administration at midday prior to LPS stimulation conveys pleiotropic effects, enhancing and repressing inflammatory cytokines, indicating melatonin functions as both a pro- and anti-inflammatory molecule in the spleen.ConclusionIn summary, a daily oscillation of circadian clock genes and inflammatory cytokines as well as the ability of melatonin to function as a daily mediator of inflammation provides valuable information to aid in deciphering how the circadian timing system regulates immune function at the molecular level. However, further research is needed to clarify the precise mechanisms by which the circadian clock and melatonin have an impact upon daily immune functions in the periphery.
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Project description:Theory suggests that communities should be more open to the establishment of regional species following disturbance because disturbance may make more resources available to dispersers. However, after an initial period of high invasibility, growth of the resident community may lead to the monopolization of local resources and decreased probability of successful colonist establishment. During press disturbances (i.e., directional environmental change), it remains unclear what effect regional dispersal will have on local community structure if the establishment of later arriving species is affected by early arriving species (i.e., if priority effects are important). To determine the relationship between time-since-disturbance and invasibility, we conducted a fully factorial field mesocosm experiment that exposed tundra zooplankton communities to two emerging stressors - nutrient and salt addition, and manipulated the arrival timing of regional dispersers. Our results demonstrate that invasibility decreases with increasing time-since-disturbance as abundance (nutrient treatments) or species richness (salt treatments) increases in the resident community. Results suggest that the relative timing of dispersal and environmental change will modify the importance of priority effects in determining species composition after a press disturbance.
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