Investigating the role of CYP26 and retinoic acid signaling regulation in vertebrate cornea and lens regeneration

The larvae of Xenopus laevis can naturally regenerate a lost lens from the outer cornea epithelium after it is triggered to do so by signals from the neural retina. The signals have been widely studied, and FGFs are reported to play a key role in causing the cornea to transform into a lens. However, the factors that make the cornea itself competent to respond to these signals are unknown. Understanding the factors that underlie regeneration competency is the key to granting otherwise ordinary tissues the ability to regenerate, including in our own bodies. Thus, the focus of this work has been on the cornea, in order to unravel the signaling schemes that operate within it. The Retinoic Acid (RA) signaling pathway is a major cellular signaling pathway involved in development, organogenesis, and regeneration. It was strongly implicated in the regeneration of the lens in another model system, the newt, where retinal signals trigger the dorsal region of the iris to differentiate and give rise to a lens. Antagonism of RA signaling was shown to inhibit lens regeneration, demonstrating its necessity. We investigated whether the same was true in Xenopus. We inhibited RA signaling using inhibitors of RA synthesizing enzymes, and of the RAR nuclear receptors. In all cases we found there to be no effect on regeneration. We validated that the drug treatments were meaningful by observing, via qPCR, a decrease in the expression cyp26a1, a well-established marker of RA signaling. We also examined the expression of multiple RA signaling pathway members both in control corneas and in corneas harvested in the first 4 days following lentectomy. In both these normal and regenerating tissues we found the expression of cyp26 genes, which encode the RA metabolizing enzyme CYP26. In light of this finding, we assessed whether CYP26 was necessary for supporting lens regeneration. In contrast to the experiment described above, exogenous addition of an antagonist of CYP26 greatly inhibited lens regeneration. Likewise, a synthetic retinoid that activates RA signaling without being metabolized by CYP26 also inhibited regeneration, as did excess exogenous RA. In all treatments, we observed profound upregulation of the RA signaling marker cyp26a1. Taken together, we demonstrated that the action of CYP26 is necessary for lens regeneration, which implies a necessity to attenuate RA signaling by metabolism in order for lens regeneration to occur in Xenopus. This represents a species-specific difference in the signaling schemes that underlie lens regeneration, and a previously undescribed role for CYP26 in regeneration. Using immunohistochemistry and a whole-cornea mounting technique, we observed the widespread expression of RALDH and CYP26 enzymes within the corneal layers under a confocal microscope. We next investigated the possible mechanistic roles of CYP26 that could explain its necessity in lens regeneration. We assessed whether RA signaling regulated cell proliferation in the cornea by quantifying changes in cell division following various treatments. We found that CYP26 antagonism, but not exogenous retinoids, lead to a significant reduction in cell proliferation. This finding lead us to examine the possibility that CYP26 may actively generate RA-metabolites whose absence would lead to reduced corneal cell division, and therefore stunted regeneration. This would suggest a mechanistic role of CYP26 as a ligand generator, rather than simply an RA signaling attenuator. We tested this by supplementing ex vivo cultures with both Liarozole (a CYP26 antagonist), and 4-oxo-RA (a metabolic product of RA). These co-treated cultures failed to regenerate lenses, just like Liarozole-only controls. Additionally, 4-oxo-RA supplementation does not recover the loss of cell division that occurs from Liarozole. We also documented that 4-oxo- RA causes the upregulation of cyp26a1 in corneas, confirming its transcriptional effects. Taken together, it appears that CYP26 likely plays a role to simply attenuate RA signaling, and does not act to generate novel signaling ligands. We additionally examined the possibility that RA signaling modulates the expression of key corneal stem cell markers like sox2, oct60, and p63. We examined their expression under RA antagonism and stimulation, and found that CYP26 does not likely mediate its effects through such markers. However, we discovered that RA can attenuate the expression of the eye markers fgfr2 and pax6 in the cornea, and CYP26 may prevent this attenuation during regeneration. Lastly, we looked at whether CYP26 was involved in early, late, or all stages of lens regeneration by varying the timepoints at which compounds were added to ex vivo cultures. We discovered that CYP26 activity is only important during hours 12-48 post-lentectomy. This suggests a role in establishing or maintaining lens- competency in the cornea, rather than lens cell differentiation/maturation. In summary, the principal finding of these studies is that CYP26 is important for Xenopus lens regeneration, likely by acting to attenuate RA signaling during early regenerative events

Prevalence of frailty among kidney transplant candidates and recipients in the United States: Estimates from a National Registry and Multicenter Cohort Study

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154612/1/ajt15709.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154612/2/ajt15709_am.pd

Parents’ perceived neighborhood safety and children’s cognitive performance:Complexities by race, ethnicity, and cognitive domain

Background:Aim: To examine racial/ethnic variations in the effect of parents’ subjective neighborhood safety on children’s cognitive performance. Methods: This cross-sectional study included 10,027 children from the Adolescent Brain Cognitive Development (ABCD) study. The exposure variable was parents’ subjective neighborhood safety. The outcomes were three domains of children’s cognitive performance: general cognitive performance, executive functioning, and learning/memory. We used mixed-effects regression models for data analysis. Results: Overall, parents’ subjective neighborhood safety was positively associated with children’s executive functioning, but not general cognitive performance or learning/memory. Higher parents’ subjective neighborhood safety had a more positive influence on the executive functioning of non-Hispanic White than Asian American children. Higher parents’ subjective neighborhood safety was associated with higher general cognitive performance and learning/memory for non-White children relative to non-Hispanic White children. Conclusion: The race/ethnicity of children moderates the association between neighborhood safety and cognitive performance. This becomes more complicated, as the patterns seem to differ across ethnicity and cognitive domains. It is unknown whether the observed racial/ethnic variations in the effect of neighborhood safety on cognitive performance are neighborhood characteristics such as residential segregation. Addressing neighborhood inequalities is needed if we wish to reduce racial/ethnic inequities in the cognitive development of children

Associations Between High-Density Lipoprotein Particles and Ischemic Events by Vascular Domain, Sex, and Ethnicity A Pooled Cohort Analysis

Background: High-density lipoprotein (HDL) cholesterol concentration (HDL-C) is an established atheroprotective marker, in particular for coronary artery disease; however, HDL particle concentration (HDL-P) may better predict risk. The associations of HDL-C and HDL-P with ischemic stroke and myocardial infarction (MI) among women and Blacks have not been well studied. We hypothesized that HDL-P would consistently be associated with MI and stroke among women and Blacks compared with HDL-C. Methods: We analyzed individual-level participant data in a pooled cohort of 4 large population studies without baseline atherosclerotic cardiovascular disease: DHS (Dallas Heart Study; n=2535), ARIC (Atherosclerosis Risk in Communities; n=1595), MESA (Multi-Ethnic Study of Atherosclerosis; n=6632), and PREVEND (Prevention of Renal and Vascular Endstage Disease; n=5022). HDL markers were analyzed in adjusted Cox proportional hazard models for MI and ischemic stroke. Results: In the overall population (n=15 784), HDL-P was inversely associated with the combined outcome of MI and ischemic stroke, adjusted for cardiometabolic risk factors (hazard ratio [HR] for quartile 4 [Q4] versus quartile 1 [Q1], 0.64 [95% CI, 0.52-0.78]), as was HDL-C (HR for Q4 versus Q1, 0.76 [95% CI, 0.61-0.94]). Adjustment for HDL-C did not attenuate the inverse relationship between HDL-P and atherosclerotic cardiovascular disease, whereas adjustment for HDL-P attenuated all associations between HDL-C and events. HDL-P was inversely associated with the individual end points of MI and ischemic stroke in the overall population, including in women. HDL-P was inversely associated with MI among White participants but not among Black participants (HR for Q4 versus Q1 for Whites, 0.49 [95% CI, 0.35-0.69]; for Blacks, 1.22 [95% CI, 0.76-1.98];P-interaction=0.001). Similarly, HDL-C was inversely associated with MI among White participants (HR for Q4 versus Q1, 0.53 [95% CI, 0.36-0.78]) but had a weak direct association with MI among Black participants (HR for Q4 versus Q1, 1.75 [95% CI, 1.08-2.83];P-interactio

Acceptability and feasibility of mobile phone-based ecological momentary assessment and intervention in Uganda: A pilot randomized controlled trial

Valid, reliable behavioral data and contextually meaningful interventions are necessary for improved health outcomes. Ecological Momentary Assessment and Intervention (EMAI), which collects data as behaviors occur to deliver real-time interventions, may be more accurate and reliable than retrospective methods. The rapid expansion of mobile technologies in low-and-middle-income countries allows for unprecedented remote data collection and intervention opportunities. However, no previous studies have trialed EMAI in sub-Saharan Africa. We assessed EMAI acceptability and feasibility, including participant retention and response rate, in a prospective, parallel group, randomized pilot trial in Rakai, Uganda comparing behavioral outcomes among adults submitting ecological momentary assessments (EMA) versus EMAI. After training, participants submitted EMA data on five nutrition and health risk behaviors over a 90-day period using a smartphone-based application utilizing prompt-based, participant-initiated, and geospatial coordinate data collection, with study coordinator support and incentives for >50% completion. Included behaviors and associated EMAI-arm intervention messages were selected to pilot a range of EMAI applications. Acceptability was measured on questionnaires. We estimated the association between high response rate and participant characteristics and conducted thematic analysis characterizing participant experiences. Study completion was 48/50 participants. Median prompt response rate was 66.5% (IQR: 60.0%-78.6%). Prior smartphone app use at baseline (aPR 3.76, 95%CI: 1.16–12.17, p = 0.03) and being in the intervention arm (aPR 2.55, 95% CI: 1.01–6.44, p = 0.05) were significantly associated with the top response rate quartile (response to >78.6% of prompts). All participants submitted self-initiated reports, covering all behaviors of interest, including potentially sensitive behaviors. Inconsistent phone charging was the most reported feasibility challenge. In this pilot, EMAI was acceptable and feasible. Response rates were good; additional strategies to improve compliance should be investigated. EMAI using mobile technologies may support improved behavioral data collection and intervention approaches in low and middle-income settings. This approach should be tested in larger studies

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Maintenance of Golf Carts by Thomas Pepe (page 1) Why a Golf Course Superintendent Should Play Golf by Stephen Skowronski (2) Tree Pruning by Martin Walsh (3) Golf Course Labor: A Dilemma by Robert Barber (5) Turf Problems by Alexander M. Radko (A-1) 1967 Turfgrass Problems by Lee Record (A-3) Southern Turfgrass Production and Problems by Ralph W. White Jr. (A-5) Canadian Turf Grass Production and Problems by David Moote (A-8) Turf Research Abroad by C.R. Skogley (A-13) Turf Research at Home by Victor B. Younger (A-14) Turfgrass Research - An Industrial Approach by J. A. Simmons (A-16) Cutting Labor Costs in Turfgrass Managemnt by Tom Mascaro (A-24) The Reluctant human by John W. Denison (A-28) The Problem Drinker - Management Responsibility by G.E. Osburn (A-31) Contemporary Design Standards by Geoffrey S. Cornish (A-34) Construction - Superintendents\u27 Viewpoint by Robert E. Grant (A-36) Construction b Contract and the Role of the Superintendent by David Canavan (A-39) Seed Production by Robert J. Peterson (A-41) Cemetery Turf Maintenance on a High and Low Budget by Stanley Sosenski (A-45) Ten Steps to a Good Lawn by John Zak (A-49) Review of Herbicides for Turf Weed Control by Alvin A. Baber (A-53

Status of Muon Collider Research and Development and Future Plans

The status of the research on muon colliders is discussed and plans are outlined for future theoretical and experimental studies. Besides continued work on the parameters of a 3-4 and 0.5 TeV center-of-mass (CoM) energy collider, many studies are now concentrating on a machine near 0.1 TeV (CoM) that could be a factory for the s-channel production of Higgs particles. We discuss the research on the various components in such muon colliders, starting from the proton accelerator needed to generate pions from a heavy-Z target and proceeding through the phase rotation and decay ($\pi \to \mu \nu_{\mu}$) channel, muon cooling, acceleration, storage in a collider ring and the collider detector. We also present theoretical and experimental R & D plans for the next several years that should lead to a better understanding of the design and feasibility issues for all of the components. This report is an update of the progress on the R & D since the Feasibility Study of Muon Colliders presented at the Snowmass'96 Workshop [R. B. Palmer, A. Sessler and A. Tollestrup, Proceedings of the 1996 DPF/DPB Summer Study on High-Energy Physics (Stanford Linear Accelerator Center, Menlo Park, CA, 1997)].Comment: 95 pages, 75 figures. Submitted to Physical Review Special Topics, Accelerators and Beam