ß-catenin/Wnt signaling controls progenitor fate in the developing and regenerating zebrafish retina

ABSTRACT: BACKGROUND: The zebrafish retina maintains two populations of stem cells: first, the germinal zone or ciliary marginal zone (CMZ) contains multipotent retinal progenitors that add cells to the retinal periphery as the fish continue to grow; second, radial glia (Muller cells) occasionally divide asymmetrically to generate committed progenitors that differentiate into rod photoreceptors, which are added interstitially throughout the retina with growth. Retinal injury stimulates Muller glia to dedifferentiate, re-enter the cell cycle, and generate multipotent retinal progenitors similar to those in the CMZ to replace missing neurons. The specific signals that maintain these two distinct populations of endogenous retinal stem cells are not understood. RESULTS: We used genetic and pharmacological manipulation of the beta-catenin/Wnt signaling pathway to show that it is required to maintain proliferation in the CMZ and that hyperstimulation of beta-catenin/Wnt signaling inhibits normal retinal differentiation and expands the population of proliferative retinal progenitors. To test whether similar effects occur during regeneration, we developed a method for making rapid, selective photoreceptor ablations in larval zebrafish with intense light. We found that dephosphorylated beta-catenin accumulates in Muller glia as they re-enter the cell cycle following injury, but not in Muller glia that remain quiescent. Activation of Wnt signaling is required for regenerative proliferation, and hyperstimulation results in loss of Muller glia from the INL as all proliferative cells move into the ONL. CONCLUSIONS: beta-catenin/Wnt signaling is thus required for the maintenance of retinal progenitors during both initial development and lesion-induced regeneration, and is sufficient to prevent differentiation of those progenitors and maintain them in a proliferative state. This suggests that the beta-catenin/Wnt cascade is part of the shared molecular circuitry that maintains retinal stem cells for both homeostatic growth and epimorphic regeneration.     

A case of apathy due to frontotemporal dementia responsive to memantine

Objective: To study the effect of memantine on apathy, a common symptom of behavioral variant frontotemporal dementia (bvFTD). Design: The patient underwent an off-label trial of memantine with behavioral inventories and [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scans performed at baseline, 7 weeks and 6 months. Subject: The patient was a 66-year-old male whose main manifestation of bvFTD was affective, behavioral and cognitive apathy. Intervention: The patient began memantine at an oral dose of 5 mg per morning and titrated up by 5 mg per week to the maintenance dose of 10 mg PO bid. Results: Informants reported reduction of the apathy. The insula and cerebellum, both involved in the salience network, showed improved metabolism. Conclusion: Further study to correlate the effects of memantine on apathy and the salience network in bvFTD are warranted.     

Testing-Related and Geo-Demographic Indicators Strongly Predict COVID-19 Deaths in the United States during March of 2020

The COVID-19 pandemic has wreaked havoc around the globe and caused significant disruptions across multiple domains[1]. Moreover, different countries have been differentially impacted by COVID-19 — a phenomenon that is due to a multitude of complex and often interacting determinants[2]. Understanding such complexity and interacting factors requires both compelling theory and appropriate data analytic techniques. Regarding data analysis, one question that arises is how to analyze extremely non-normal data, such as those variables evidencing L-shaped distributions. A second question concerns the appropriate selection of a predictive modelling technique when the predictors derive from multiple domains (e.g., testing-related variables, population density), and both main effects and interactions are examined.