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Allred Ralston posted an update 6 months, 3 weeks ago
Receptor tyrosine kinases (RTKs) play crucial roles in human health, and their misregulation is implicated in disorders ranging from neurodegenerative diseases to cancers. The highly conserved mechanism of activation of RTKs makes them especially appealing candidates for control via optogenetic dimerization methods. This work offers a strategy for using the improved Light-Induced Dimer (iLID) system with a constructed tandem-dimer of its binding partner nano (tdnano) to build light-activatable versions of RTKs. In the absence of light, the iLID-RTK is cytosolic, monomeric and inactive. Under blue light, the iLID + tdnano system recruits two copies of iLID-RTK to tdnano, dimerizing and activating the RTK. We demonstrate that iLID opto-iTrkA and opto-iTrkB are capable of reproducing downstream ERK and Akt signaling only in the presence of tdnano. We further show with our opto-iTrkA that the system is compatible with multi-day and population-level activation of TrkA in PC12 cells. By leveraging genetic targeting of tdnano, we achieve RTK activation at a specific subcellular location even with whole-cell illumination, allowing us to confidently probe the impact of context on signaling outcome. Cell cycle is a highly regulated process that is finely coordinated by a plethora of interconnected regulators. In this paper, we report that post-transcriptional mechanisms mediated by the RNA-binding protein Staufen1 (STAU1) are essential for the proliferation of non-transformed cells (hTERT-RPE1 and IMR90). Cell sorting quantification and time-lapse video microscopy using FUCCI-hTERT-RPE1 cells identified the G1/S and G2/M phase transitions of the cell cycle as crucial steps for STAU1 functions. The level of expression of 35 transcripts coding for cell-cycle regulators is up- or down-regulated following STAU1 depletion. Among others, expression of E2F1, a transcription factor essential for the G1/S transition, is decreased in STAU1 depleted cells, dependent on a STAU1-binding site in the 3′ untranslated region of E2F1 mRNA. Interestingly, E2F1, in turn, increases STAU1 transcription, highlighting a regulatory loop that enhances expression of both STAU1 and E2F1. Our results indicate that a STAU1-mediatedpost-transcriptional mechanism of gene regulation controls an mRNA regulon involved in decision making during cell-cycle phase transitions and that this mechanism is essential for cell-cycle progression in non-tumor cells. PURPOSE To describe the prevalence of vitreomacular interface (VMI) features and their associated risk factors in the Northern Ireland Cohort for the Longitudinal Study of Ageing (NICOLA) Study. DESIGN Cross-sectional population-based study. PARTICIPANTS Noninstitutionalized Northern Irish adults 40 years of age or older. METHODS Using geographic stratification, a representative sample of people in Northern Ireland was invited to participate in the NICOLA Study. Empagliflozin in vitro SD OCT images of participants were graded for vitreomacular traction (VMT), macular hole (MH), and epiretinal membrane (ERM) according to the International Vitreomacular Traction Study Group. A subsample was graded in more detail to estimate the prevalence of VMA and VMA area detailing size and location of VMA. Descriptive analysis and risk factors for each VMI feature were determined using generalized estimating equations. Results were standardized to the Northern Ireland population census (2011). MAIN OUTCOME MEASURES Cohort profile, standardized prdent. Vitreous separation reduced to a greater extent in the horizontal meridians compared with the vertical, differing from previous studies. Future longitudinal studies of the evolution of these VMI changes over time would be of great interest. PURPOSE To review the available literature on the prevalence, incidence, natural history, and exudative conversion rates of subclinical (treatment-naïve) nonexudative macular neovascularization (MNV) in patients with age-related macular degeneration (AMD). CLINICAL RELEVANCE Nonexudative MNV is now known to be more prevalent in patients with AMD than initially thought and is bringing new insights into both the natural history and management of this very prevalent disease. METHODS We conducted a literature search on PubMed, Scopus, and Web of Science, along with a manual search, from January 2014 to June 2019. We included studies that used optical coherence tomography angiography (OCTA) as a primary diagnostic tool to evaluate subclinical (treatment-naïve), nonexudative, neovascular AMD. RESULTS Of the 258 screened articles, 12 were included. The prevalence of subclinical nonexudative neovascular AMD in the fellow eyes of patients with unilateral exudative AMD ranged from 6.25% to 27%. Although these lesions wtudies included in this review agree that nonexudative lesions should not be treated until symptomatic exudation develops. Moreover, the existence of a nonexudative form of neovascular AMD would suggest that the term “neovascular AMD” should be preceded by either “exudative” or “nonexudative” when describing this neovascular stage of AMD. Bioethics can help address the challenges of translating research into clinical practice in the twenty-first century. The cerebroplacental ratio in obstetrical ultrasound provides a case study of how bioethical principles can help advance practical approaches when evidence is limited. This can help clinicians use cerebroplacental ratio when additional risk factors are present in critical cases that warrant increased surveillance; disclose limited information appropriately; allocate resources; and weigh benefits against risks. Balancing the key ethical principles of respect for autonomy, beneficence, non-maleficence, and justice within this context illuminates how bioethics can assist health care providers as well as help set a research agenda. Such analyses are essential to improving clinical care, given the rapid pace at which medicine is evolving. Tobacco harm reduction remains a controversial topic in tobacco control. Tobacco harm reduction involves providing tobacco users who are unwilling or unable to quit using nicotine products with less harmful nicotine-containing products for continued use. The skepticism towards harm reduction is based in part on the experience with low-yield tar/nicotine cigarettes, which were presumed to be associated with lower health risks than higher yield cigarettes and marketed as such by cigarette manufacturers. Only later did the field learn that these cigarettes were a deceptive way for cigarette manufacturers to allay the health concerns over cigarette smoking. Since this experience, there has been a proliferation of tobacco products that might potentially serve as a means to reduce tobacco harm. Some members of the tobacco control community believe that these products have great potential to reduce mortality and morbidity among smokers who completely switch to them. Others believe that we will be addicting another generation to tobacco products.