With the Internet of Things (IoT) becoming part of our daily life and our environment, we expect rapid growth in the number of connected devices. IoT is expected to connect billions of devices and humans to bring promising advantages for us. With this growth, fog computing, along with its related edge computing paradigms, such as multi-access edge computing (MEC) and cloudlet, are seen as promising solutions for handling the large volume of securitycritical and time-sensitive data that is being produced by the IoT. In this paper, we first provide a tutorial on fog computing and its related computing paradigms, including their similarities and differences. Next, we provide a taxonomy of research topics in fog computing, and through a comprehensive survey, we summarize and categorize the efforts on fog computing and its related computing paradigms. Finally, we provide challenges and future directions for research in fog computing.

CONTEXT Telemedicine is a promising but largely unproven technology for providing case management services to patients with chronic conditions and lower access to care. OBJECTIVES To examine the effectiveness of a telemedicine intervention to achieve clinical management goals in older, ethnically diverse, medically underserved patients with diabetes. DESIGN, Setting, and Patients A randomized controlled trial was conducted, comparing telemedicine case management to usual care, with blinded outcome evaluation, in 1,665 Medicare recipients with diabetes, aged >/= 55 years, residing in federally designated medically underserved areas of New York State. Interventions Home telemedicine unit with nurse case management versus usual care. Main Outcome Measures The primary endpoints assessed over 5 years of follow-up were hemoglobin A1c (HgbA1c), low density lipoprotein (LDL) cholesterol, and blood pressure levels. RESULTS Intention-to-treat mixed models showed that telemedicine achieved net overall reductions over five years of follow-up in the primary endpoints (HgbA1c, p = 0.001; LDL, p < 0.001; systolic and diastolic blood pressure, p = 0.024; p < 0.001). Estimated differences (95% CI) in year 5 were 0.29 (0.12, 0.46)% for HgbA1c, 3.84 (-0.08, 7.77) mg/dL for LDL cholesterol, and 4.32 (1.93, 6.72) mm Hg for systolic and 2.64 (1.53, 3.74) mm Hg for diastolic blood pressure. There were 176 deaths in the intervention group and 169 in the usual care group (hazard ratio 1.01 [0.82, 1.24]). CONCLUSIONS Telemedicine case management resulted in net improvements in HgbA1c, LDL-cholesterol and blood pressure levels over 5 years in medically underserved Medicare beneficiaries. Mortality was not different between the groups, although power was limited. Trial Registration http://clinicaltrials.gov Identifier: NCT00271739.

Growing evidence indicates that translational control of specific mRNAs contributes importantly to genetic regulation across the breadth of cellular and developmental processes. Synthesis of protein from a specific mRNA can be controlled by RNA-binding proteins at the level of translational initiation and elongation, and translational control is also sometimes coupled to mRNA localization mechanisms. Recent discoveries from invertebrate and vertebrate systems have uncovered novel modes of translational regulation, have provided new insights into how specific regulators target the general translational machinery and have identified several new links between translational control and human disease.

There is a growing body of evidence that the nondegradable fluorophores that accumulate as the lipofuscin of retinal pigment epithelium (RPE) are involved in mechanisms leading to the degeneration of RPE in macular degeneration. Most of the constituents of RPE lipofuscin are inadvertent products of the retinoid visual cycle, the enzymatic pathway by which the 11-cis-retinal chromophore of rhodopsin is generated. Indeed, a major constituent of RPE lipofuscin, the pyridinium bisretinoid A2E, is a diretinal conjugate that forms in photoreceptor cells and is deposited in RPE cells as a consequence of the phagocytosis of the outer segment membrane by RPE cells. Given the adverse effects of A2E, there is considerable interest in combating its deposition so as to protect against vision loss. These efforts, however, necessitate an understanding of factors that modulate its formation. Here we show that an amino acid variant in murine Rpe65, a visual-cycle protein required for the regeneration of 11-cis-retinal, is associated with reduced A2E accumulation. The visual cycle employs a panel of proteins whose roles in enzymatic processing and trafficking enable regeneration of the 11-cis chromophore of rhodopsin (1) (Fig. 1). One of these proteins, retinal pigment epithelium (RPE) 65 (2), has been known for some time to be essential for the regeneration of rhodopsin. Recent studies have shown that RPE65 serves as a binding protein for retinyl esters (3-5), thereby delivering these hydrophobic compounds to the isomerohydrolase, which converts them to 11-cis-retinol (6). Mutations in RPE65, including missense-or nonsense-point mutations, insertions, deletions, and splice site defects, lead to severe, childhood-onset retinal degeneration (7-9), including Ϸ5-10% of cases of Lebers congenital amaurosis (10). A null mutation of Rpe65 in mice results in a complete absence of 11-cis-retinaldehyde with the visual cycle arrest producing a severely depressed electroretinographic response (11). Retinal dystrophy with functional deficits similar to that observed in Rpe65 Ϫ/Ϫ mice is also present in the Swedish Briard dog, a strain carrying a 4-bp deletion in RPE65. Transfer of the RPE65 gene has restored vision in both the Briard dog (12, 13) and Rpe65 Ϫ/Ϫ mice (14).Work in the Rpe65-null mutant mouse has also shown that nearly all of the lipofuscin that accumulates in RPE cells with age is derived as a byproduct of the visual cycle. This conclusion is based on the observation that in Rpe65 Ϫ/Ϫ mice, wherein the 11-cis and all-trans-retinal chromophores are absent, RPE lipofuscin is decreased Ͼ90% (15). Thus, it is not surprising that all of the RPE lipofuscin fluorophores isolated to date, including A2E, the photoisomer iso-A2E, minor cis-isomers of A2E, and ATR dimer (5,(16)(17)(18)(19), are generated by reactions between phosphatidylethanolamine and first one and then a second molecule of all-trans-retinal (Fig. 1). The all-trans-retinal that enters the A2E biosynthetic pathway is generated upon photoisomerization of 11-cis-retinal. A...

Globin mRNAs accumulate to 95% of total cellular mRNA during terminal erythroid differentiation, reflecting their extraordinary stability. The stability of human alpha-globin mRNA is paralleled by formation of a sequence-specific RNA-protein (RNP) complex at a pyrimidine-rich site within its 3' untranslated region (3'UTR), the alpha-complex. The proteins of the alpha-complex are widely expressed. The alpha-complex or a closely related complex also assembles at pyrimidine-rich 3'UTR segments of other stable mRNAs. These data suggest that the alpha-complex may constitute a general determinant of mRNA stability. One or more alphaCPs, members of a family of hnRNP K-homology domain poly(C) binding proteins, are essential constituents of the alpha-complex. The ability of alphaCPs to homodimerize and their reported association with additional RNA binding proteins such as AU-rich binding factor 1 (AUF1) and hnRNP K have suggested that the alpha-complex is a multisubunit structure. In the present study, we have addressed the composition of the alpha-complex. An RNA titration recruitment assay revealed that alphaCPs were quantitatively incorporated into the alpha-complex in the absence of associated AUF1 and hnRNP K. A high-affinity direct interaction between each of the three major alphaCP isoforms and the alpha-globin 3'UTR was detected, suggesting that each of these proteins might be sufficient for alpha-complex assembly. This sufficiency was further supported by the sequence-specific binding of recombinant alphaCPs to a spectrum of RNA targets. Finally, density sedimentation analysis demonstrated that the alpha-complex could accommodate only a single alphaCP. These data established that a single alphaCP molecule binds directly to the alpha-globin 3'UTR, resulting in a simple binary structure for the alpha-complex.

PURPOSE. Excessive accumulation of lipofuscin is associated with pathogenesis of atrophic age-related macular degeneration (AMD) and Stargardt disease. Pharmacologic inhibition of the retinol-induced interaction of retinol-binding protein 4 (RBP4) with transthyretin (TTR) in the serum may decrease the uptake of serum retinol to the retina and reduce formation of lipofuscin bisretinoids. We evaluated in vitro and in vivo properties of the new nonretinoid RBP4 antagonist, A1120.METHODS. RBP4 binding potency, ability to antagonize RBP4-TTR interaction, and compound specificity were analyzed for A1120 and for the prototypic RBP4 antagonist fenretinide. A1120 ability to inhibit RPE65-mediated isomerohydrolase activity was assessed in the RPE microsomes. The in vivo effect of A1120 administration on serum RBP4, visual cycle retinoids, lipofuscin bisretinoids, and retinal visual function was evaluated using a combination of biochemical and electrophysiologic techniques.RESULTS. In comparison to fenretinide, A1120 did not act as a RARa agonist, while exhibiting superior in vitro potency in RBP4 binding and RBP4-TTR interaction assays. A1120 did not inhibit isomerohydrolase activity in the RPE microsomes. A1120 dosing in mice induced 75% reduction in serum RBP4, which correlated with reduction in visual cycle retinoids and ocular levels of lipofuscin fluorophores. A1120 dosing did not induce changes in kinetics of dark adaptation. CONCLUSIONS. A1120 significantly reduces accumulation of lipofuscin bisretinoids in the Abca4À/À animal model. This activity correlates with reduction in serum RBP4 and visual cycle retinoids confirming the mechanism of action for A1120.In contrast to fenretinide, A1120 does not act as a RARa agonist indicating a more favorable safety profile for this nonretinoid compound. (Invest Ophthalmol Vis Sci. 2013; 54:85-95)

National Institute on Aging.

Background Elder abuse in long term care has received considerable attention; however, resident-to-resident elder mistreatment (R-REM) has not been well researched. Preliminary findings from studies of R-REM suggest that it is sufficiently widespread to merit concern, and is likely to have serious detrimental outcomes for residents. However, no evidence-based training, intervention and implementation strategies exist that address this issue. Objectives The objective was to evaluate the impact of a newly developed R-REM training intervention for nursing staff on knowledge, recognition and reporting of R-REM. Design The design was a prospective cluster randomized trial with randomization at the unit level. Methods A sample of 1405 residents (685 in the control and 720 in the intervention group) from 47 New York City nursing home units (23 experimental and 24 control) in 5 nursing homes was assessed. Data were collected at three waves: baseline, 6 and 12 months. Staff on the experimental units received the training and implementation protocols, while those on the comparison units did not. Evaluation of outcomes was conducted on an intent-to-treat basis using mixed (random and fixed effects) models for continuous knowledge variables and Poisson regressions for longitudinal count data measuring recognition and reporting. Results There was a significant increase in knowledge post-training, controlling for pre-training levels for the intervention group (p<0.001), significantly increased recognition of R-REM (p<0.001), and longitudinal reporting in the intervention as contrasted with the control group (p=0.0058). Conclusions A longitudinal evaluation demonstrated that the training intervention was effective in enhancing knowledge, recognition and reporting of R-REM. It is recommended that this training program be implemented in long term care facilities.