Chromatin remodeling protein HELLS is critical for retinoblastoma tumor initiation and progression.

Retinoblastoma is an aggressive childhood cancer of the developing retina that initiates by biallelic RB1 gene inactivation. Tumor progression in retinoblastoma is driven by epigenetics, as retinoblastoma genomes are stable, but the mechanism(s) that drive these epigenetic changes remain unknown. Lymphoid-specific helicase (HELLS) protein is an epigenetic modifier directly regulated by the RB/E2F pathway. In this study, we used novel genetically engineered mouse models to investigate the role of HELLS during retinal development and tumorigenesis. Our results indicate that Hells-null retinal progenitor cells divide, undergo cell-fate specification, and give rise to fully laminated retinae with minor bipolar cells defects, but normal retinal function. Despite the apparent nonessential role of HELLS in retinal development, failure to transcriptionally repress Hells during retinal terminal differentiation due to retinoblastoma (RB) family loss significantly contributes to retinal tumorigenesis. Loss of HELLS drastically reduced ectopic division of differentiating cells in Rb1/p107-null retinae, significantly decreased the incidence of retinoblastoma, delayed tumor progression, and increased overall survival. Despite its role in heterochromatin formation, we found no evidence that Hells loss directly affected chromatin accessibility in the retina but functioned as transcriptional co-activator of E2F3, decreasing expression of cell cycle genes. We propose that HELLS is a critical downstream mediator of E2F-dependent ectopic proliferation in RB-null retinae. Together with the nontoxic effect of HELLS loss in the developing retina, our results suggest that HELLS and its downstream pathways could serve as potential therapeutic targets for retinoblastoma

The Impact of College Course Offerings on the Supply of Academically Talented Public School Teachers

University of Michigan forthcoming in the Journal of Econometrics This paper identifies the impact of undergraduate teacher certification programs on the likelihood that recent college graduates enter and remain in public school teaching jobs. More selective postsecondary institutions are far less likely to offer teacher certification programs and those that do offer them are less likely to allow students to complete them within their four undergraduate years. First, to examine the overall relationship between the availability of teacher certification programs and the likelihood that academically talented students enter teaching careers, I combine Barron's ratings of college selectivity, detailed data tracking college seniors into the workforce, data on the types of teacher certification programs offered by their colleges, and data on states' certification requirements. Next, to isolate the causal effect of program offerings, I treat the selection issue related to students sorting into colleges based on pre-existing interest in teaching careers as an omitted variable problem. Using another data set that surveys high school seniors' career interests and tracks them into college, I estimate an upper bound for the magnitude of the bias in the baseline coefficient estimates. The results suggest that the addition of teacher certification programs that may be completed within four undergraduate years could increase rates of entry into public school teaching by at least 50% among recent graduates of certain selective colleges. JEL Classification: I20, J45, C2

The banned sunscreen ingredients and their impact on human health: a systematic review

Recent evidence of high systemic absorption of sunscreen ingredients has raised concerns regarding the safety of sunscreen products. Oxybenzone (BP-3) and octinoxate (OMC), two common sunscreen ingredients, were recently banned in Key West and Hawaii owing to their toxic effects on marine ecosystems. Their impact on human health requires a careful assessment. To summarize the current evidence on the association between the systemic level of BP-3 or OMC and its health impact, a primary literature search was conducted using PubMed database in February 2019. There are 29 studies that address the impact of these ingredients on human health. Studies show that elevated systemic level of BP-3 has no adverse effect on male and female fertility, female reproductive hormone level, adiposity, fetal growth, child's neurodevelopment, and sexual maturation. However, the association of BP-3 level on thyroid hormone, testosterone level, kidney function, and pubertal timing has been reported and prompts further investigations to validate a true association. The systemic absorption of OMC has no reported effect on thyroid and reproductive hormone levels. In conclusion, current evidence is not sufficient to support the causal relationship between the elevated systemic level of BP-3 or OMC and adverse health outcomes. There are either contradictory findings among different studies or an insufficient number of studies to corroborate the observed association. To accurately evaluate the long-term risk of exposure to BP-3 and OMC from sunscreen, a well-designed longitudinal randomized controlled trial needs to be conducted

Retinoids in the visual cycle: role of the retinal G protein-coupled receptor.

Driven by the energy of a photon, the visual pigments in rod and cone photoreceptor cells isomerize 11-cis-retinal to the all-trans configuration. This photochemical reaction initiates the signal transduction pathway that eventually leads to the transmission of a visual signal to the brain and leaves the opsins insensitive to further light stimulation. For the eye to restore light sensitivity, opsins require recharging with 11-cis-retinal. This trans-cis back conversion is achieved through a series of enzymatic reactions composing the retinoid (visual) cycle. Although it is evident that the classical retinoid cycle is critical for vision, the existence of an adjunct pathway for 11-cis-retinal regeneration has been debated for many years. Retinal pigment epithelium (RPE)-retinal G protein-coupled receptor (RGR) has been identified previously as a mammalian retinaldehyde photoisomerase homologous to retinochrome found in invertebrates. Using pharmacological, genetic, and biochemical approaches, researchers have now established the physiological relevance of the RGR in 11-cis-retinal regeneration. The photoisomerase activity of RGR in the RPE and Müller glia explains how the eye can remain responsive in daylight. In this review, we will focus on retinoid metabolism in the eye and visual chromophore regeneration mediated by RGR

Precision genome editing in the eye

CRISPR-Cas-based genome editing technologies could, in principle, be used to treat a wide variety of inherited diseases, including genetic disorders of vision. Programmable CRISPR-Cas nucleases are effective tools for gene disruption, but they are poorly suited for precisely correcting pathogenic mutations in most therapeutic settings. Recently developed precision genome editing agents, including base editors and prime editors, have enabled precise gene correction and disease rescue in multiple preclinical models of genetic disorders. Additionally, new delivery technologies that transiently deliver precision genome editing agents in vivo offer minimized off-target editing and improved safety profiles. These improvements to precision genome editing and delivery technologies are expected to revolutionize the treatment of genetic disorders of vision and other diseases. In this Perspective, we describe current preclinical and clinical genome editing approaches for treating inherited retinal degenerative diseases, and we discuss important considerations that should be addressed as these approaches are translated into clinical practice

Genome editing in the treatment of ocular diseases.

Genome-editing technologies have ushered in a new era in gene therapy, providing novel therapeutic strategies for a wide range of diseases, including both genetic and nongenetic ocular diseases. These technologies offer new hope for patients suffering from previously untreatable conditions. The unique anatomical and physiological features of the eye, including its immune-privileged status, size, and compartmentalized structure, provide an optimal environment for the application of these cutting-edge technologies. Moreover, the development of various delivery methods has facilitated the efficient and targeted administration of genome engineering tools designed to correct specific ocular tissues. Additionally, advancements in noninvasive ocular imaging techniques and electroretinography have enabled real-time monitoring of therapeutic efficacy and safety. Herein, we discuss the discovery and development of genome-editing technologies, their application to ocular diseases from the anterior segment to the posterior segment, current limitations encountered in translating these technologies into clinical practice, and ongoing research endeavors aimed at overcoming these challenges