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.
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 PDEγ, 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 β isoform Gβ5 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.
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.
Project description:Type Three Secretion Systems (T3SSs) are essential virulence determinants of many Gram-negative bacteria. The T3SS is an injection device that can transfer bacterial virulence proteins directly into host cells. The apparatus is made up of a basal body that spans both bacterial membranes and an extracellular needle that possesses a channel that is thought to act as a conduit for protein secretion. Contact with a host-cell membrane triggers the insertion of a pore into the target membrane, and effectors are translocated through this pore into the host cell. To assemble a functional T3SS, specific substrates must be targeted to the apparatus in the correct order. Recently, there have been many developments in our structural and functional understanding of the proteins involved in the regulation of secretion. Here we review the current understanding of protein components of the system thought to be involved in switching between different stages of secretion.
Project description:There is ample evidence that immune-related processes in humans are under temporal regulation. The circadian variation of humoral and cellular immunity is well documented and appears to be hormonally modulated via the hypothalamic-pituitary-adrenal axis. In advanced melanoma, it has recently been demonstrated that systemic immunity is repolarized toward a global state of chronic inflammation (Th2 dominance) and appears to be governed by infradian biorhythms of cytokines and immune cell subsets, which extend beyond the 24-h circadian variability reported in healthy volunteers. It is suggested that synchronizing administration of lymphodepleting chemotherapy (temozolomide) with these endogenous (individualized) immune dynamics (biorhythms) in patients with advanced/metastatic melanoma improves clinical outcomes compared with temozolomide used in a conventional 'random delivery' fashion.
Project description:IntroductionDamage control strategies in resuscitation and (fracture) surgery have become standard of care in the treatment of severely injured patients. It is suggested that damage control improves survival and decreases the incidence of organ failure. However, these strategies can possibly increase the risk of complications such as infections. Indication for damage control procedures is guided by physiological parameters, type of injury, and the surgeon's experience. We analyzed outcomes of severely injured patients who underwent emergency surgery.MethodsSeverely injured patients, admitted to a level-1 trauma center ICU from 2016 to 2020 who were in need of ventilator support and required immediate surgical intervention ( ≤24 h) were included. Demographics, treatment, and outcome parameters were analyzed.ResultsHundred ninety-five patients were identified with a median ISS of 33 (IQR 25-38). Ninety-seven patients underwent immediate definitive surgery (ETC group), while 98 patients were first treated according to damage control principles with abbreviated surgery (DCS group). Although ISS was similar in both groups, DCS patients were younger, suffered from more severe truncal injuries, were more frequently in shock with more severe acidosis and coagulopathy, and received more blood products. ETC patients with traumatic brain injury needed more often a craniotomy. Seventy-four percent of DCS patients received definitive surgery in the second surgical procedure. There was no difference in mortality, nor any other outcome including organ failure and infections.ConclusionsWhen in severely injured patients treatment is dictated by physiology into either early definitive surgery or damage control with multiple shorter procedures stretched over several days combined with aggressive resuscitation with blood products, outcome is comparable in terms of complications.
Project description:Accurate detection of acute kidney injury (AKI) in clinical trials is important. Using a 'baseline' creatinine from trial enrolment may not be ideal for understanding a participant's true baseline kidney function. We aimed to determine if a 'pre-trial baseline creatinine' resulted in comparable creatinine concentrations to a 'trial baseline creatinine', and how the timing of baseline creatinine affected the incidence of AKI in the Combination Antibiotic therapy for MEthicillin Resistant Staphylococcus aureus (CAMERA2) randomised trial. Study sites retrospectively collected a pre-trial baseline creatinine from up to 1 year before CAMERA2 trial enrolment ideally when the patient was medically stable. Baseline creatinine from CAMERA2 (the 'trial baseline creatinine'), was the highest creatinine measurement in the 24 h preceding trial randomisation. We used Wilcoxon sign rank test to compare pre-trial and trial baseline creatinine concentrations. We included 217 patients. The median pre-trial baseline creatinine was significantly lower than the median trial baseline creatinine (82 μmol/L [IQR 65-104 μmol/L] versus 86 μmol/L [IQR 66-152 μmol/L] p = <0.001). Using pre-trial baseline creatinine, 48 of 217 patients (22%) met criteria for an AKI at CAMERA2 enrolment and only 5 of these patients met criteria for an AKI using the CAMERA2 study protocol (using baseline creatinine from trial entry). Using a baseline creatinine from the time of trial enrolment failed to detect many patients with AKI. Trial protocols should consider the optimal timing of baseline creatinine and the limitations of using a baseline creatinine during an acute illness.
Project description:Wildlife vaccination is an important tool for managing the burden of infectious disease in human populations, domesticated livestock and various iconic wildlife. Although substantial progress has been made in the field of vaccine designs for wildlife, there is a gap in our understanding of how to time wildlife vaccination, relative to host demography, to best protect a population.We use a mathematical model and computer simulations to assess the outcomes of vaccination campaigns that deploy vaccines once per annual population cycle.Optimal timing of vaccination is an important consideration in animals with short to intermediate life spans and a short birthing season. Vaccines that are deployed shortly after the birthing season best protect the host population.The importance of timing is greater in wildlife pathogens that have a high rate of transmission and a short recovery period. Vaccinating at the end of the birthing season best reduces the mean abundance of pathogen-infected hosts. Delaying vaccination until later in the year can facilitate pathogen elimination. Policy Implications. Tuning wildlife vaccination campaigns to host demography and pathogen traits can substantially increase the effectiveness of a campaign. Our results suggest that, for a fluctuating population, vaccinating at, or shortly after, the end of the birthing season, best protects the population against an invading pathogen. If the pathogen is already endemic, delaying vaccination until after the birthing season is over can help facilitate pathogen elimination. Our results highlight the need to better understand and predict host demography in wildlife populations that are targeted for vaccination.
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.