Tuberous sclerosis complex (TSC) is caused by mutations of either the
or
tumor suppressor gene. TSC causes tumors of the brain, heart, kidney, skin and lymphangioleiomyomatosis (LAM). Here we report ...that the TSC2 protein physically binds to high-density lipoprotein binding protein (HDLBP), also called vigilin, a core stress granule (SG) protein, and that TSC2 localizes to SGs. SGs contain mRNAs and translation initiation complexes, and regulate gene expression by sequestering specific transcripts, thereby serving a cytoprotective role. TSC2 has never before been shown to localize to SGs and knocking down vigilin impacts SG translocation of TSC2. TSC2-deficient cells showed a striking increase in the number of SGs after thermal shock and arsenite treatment relative to Tsc2-expressing cells. Our findings also show that murine kidney lysates from a model of TSC have increased levels of SG components including G3BP1 and Caprin1. G3BP1 and Caprin are elevated in renal angiomyolipomas (a renal tumor common in patients with TSC) compared with control normal kidney. G3BP1 is also elevated in TSC-associated subependymal giant cell astrocytomas. We found that genetic inhibition of G3BP1 inhibits the proliferation of TSC2-deficient cells
. Finally, in a mouse model of TSC, genetic inhibition of SGs suppresses cell growth, suggesting that targeting SGs may have efficacy in the therapy of TSC. IMPLICATIONS: This study demonstrates that TSC2 physically interacts with HDLBP/vigilin, a component of SGs, that TSC2 localizes to SG and that TSC2-deficient cells have more SGs, suggesting that SGs represent a novel therapeutic target in TSC.
We demonstrate hierarchical multiscale PAM-4 transmission combining 500 Mbps data transfer with optical-layer cryptographic key distribution at rates 24.14 Mbps and 8.38 Mbps secure against passive ...eavesdropper advantage 0 dB and 6 dB respectively.
Abstract Objective To establish the association between prior knee-pain consultations and early diagnosis of knee osteoarthritis (OA) by weighted cumulative exposure (WCE) models. Study Design and ...Setting Data were from an electronic health care record (EHR) database (Consultations in Primary Care Archive). WCE functions for modeling the cumulative effect of time-varying knee-pain consultations weighted by recency were derived as a predictive tool in a population-based case-control sample and validated in a prospective cohort sample. Two WCE functions (i weighting of the importance of past consultations determined a priori; ii flexible spline-based estimation) were comprehensively compared with two simpler models (iii time since most recent consultation; total number of past consultations) on model goodness of fit, discrimination, and calibration both in derivation and validation phases. Results People with the most recent and most frequent knee-pain consultations were more likely to have high WCE scores that were associated with increased risk of knee OA diagnosis both in derivation and validation phases. Better model goodness of fit, discrimination, and calibration were observed for flexible spline-based WCE models. Conclusion WCE functions can be used to model prediagnostic symptoms within routine EHR data and provide novel low-cost predictive tools contributing to early diagnosis.
The multi core fibre can be successfully applied not only the long-haul ultra-high capacity transmission but also in data interconnects and integrated distribution networks. In this paper, the ...proposed application areas are reviewed.
Aims To compare the effect of trimetazidine (TMZ) versus placebo administered during the acute phase of myocardial infarction on long- and short-term mortality. Methods and Results EMIP–FR (European ...Myocardial Infarction Project–Free Radicals) was a prospective, double-blind, European multicentre trial in which 19725 patients, presenting symptoms of acute myocardial infarction within the previous 24h were randomized. Stratification was according to thrombolytic therapy (56%) or not (44%). An intravenous bolus injection of trimetazidine (40mg) was given just before or simultaneously with thrombolysis, followed by continuous infusion (60mg.24h−1) for 48h. Overall, no difference was found between trimetazidine and placebo for the main end-point, short-term (35-day) mortality, (P=0·98) in an intention-to-treat analysis. This was the result of opposing trends in the two strata. Thrombolysed patients showed a tendency towards more short-term deaths with trimetazidine, compared to placebo (trimetazidine: 11·3%, placebo: 10·5%, P=0·15) and non-thrombolysed patients the converse (trimetazidine: 14·0%, placebo: 15·1%, P=0·14). In a per-protocol analysis the beneficial effect of trimetazidine for non-thrombolysed patients became statistically significant (trimetazidine: 13·3%, placebo: 15·1%,P =0·027). Conclusion Trimetazidine does not reduce mortality in patients undergoing thrombolytic therapy; however, it might have some beneficial effect for non-thrombolysed patients.
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