No abstract

Gene regulatory networks (GRNs), consisting of transcription factors and their target cis-regulatory sequences, control neurogenesis and cell fate specification in the developing central nervous system, but their organization is poorly characterized. In this study, we performed integrated scRNA-seq and scATAC-seq analysis from both mouse and human retina to profile dynamic changes in gene expression, chromatin accessibility and transcription factor footprinting during retinal neurogenesis. We identified multiple interconnected, evolutionarily-conserved GRNs consisting of cell type-specific transcription factors that both activate expression of genes within their own network and often inhibit expression of genes in other networks. These GRNs control state transitions within primary retinal progenitors that underlie temporal patterning, regulate the transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirmed the prediction of this analysis that the NFI transcription factors Nfia, Nfib, and Nfix selectively activate expression of genes that promote late-stage temporal identity in primary retinal progenitors. We also used GRNs to identify additional transcription factors that selectively promote (Insm1/2) and inhibit (Tbx3, Tcf7l1/2) rod photoreceptor specification in postnatal retina. This study provides an inventory of cis- and trans-acting factors that control retinal development, identifies transcription factors that control the temporal identity of retinal progenitors and cell fate specification, and will potentially help guide cell-based therapies aimed at replacing retinal neurons lost due to disease.

It is well appreciated that the social determinants of health are intimately related with health outcomes. However, there is a paucity of literature that explores these themes comprehensively for the indigenous people within Micronesia. Certain Micronesia-specific factors, such as transitions from traditional diets, the consumption of betel nut, and exposure to radiation from the nuclear bomb testing in the Marshall Islands, have predisposed certain Micronesian populations to an increased risk of developing a variety of malignancies. Furthermore, severe weather events and rising sea levels attributed to climate change threaten to compromise cancer care resources and displace entire Micronesian populations. The consequences of these risks are expected to increase the strain on the already challenged, disjointed, and burdened healthcare infrastructure in Micronesia, likely leading to more expenses in off-island referrals. A general shortage of Pacific Islander physicians within the workforce reduces the number of patients that can be seen, as well as the quality of culturally competent care that is delivered. In this narrative review, we comprehensively underscore the health disparities and cancer inequities faced by the underserved communities within Micronesia.

Conformational changes in a-synuclein (a-syn)a re centralt o its biological function and Parkinson'sd isease pathology.H ere, terminal alkynes( homopropargylglycine) were employed as environmentallys ensitive Ramanp robes at residues 1, 5, 116, and 127 to characterize soluble (disordered), micelle-bound (ahelical), and fibrillar (b-sheet) a-syn. Along with the full-length protein, ad isease-related C-terminal truncation (1-115) was also studied. For the first time, b-sheet a-syn amyloid structure was detected by the amide-I band in N27 dopaminergic rat cells, where ar eciprocal relationship between levels of fibrils and lipids was seen. Site-specific spectral features of the terminal alkynes also revealed the heterogeneity of the cellular environment. This work shows the versatility of Ramanm icrospectroscopya nd the powero fu nnatural amino acids in providing structural and residue-level insights in solution and in cells.