Characterization of Fabry mice treated with recombinant adeno-associated virus 2/8-mediated gene transfer

<p>Abstract</p> <p>Background</p> <p>Enzyme replacement therapy (ERT) with α-galactosidase A (α-Gal A) is currently the most effective therapeutic strategy for patients with Fabry disease, a lysosomal storage disease. However, ERT has limitations of a short half-life, requirement for frequent administration, and limited efficacy for patients with renal failure. Therefore, we investigated the efficacy of recombinant adeno-associated virus (rAAV) vector-mediated gene therapy for a Fabry disease mouse model and compared it with that of ERT.</p> <p>Methods</p> <p>A pseudotyped rAAV2/8 vector encoding α-Gal A cDNA (rAAV2/8-hAGA) was prepared and injected into 18-week-old male Fabry mice through the tail vein. The α-Gal A expression level and globotriaosylceramide (Gb3) levels in the Fabry mice were examined and compared with Fabry mice with ERT. Immunohistochemical and ultrastructural studies were conducted.</p> <p>Results</p> <p>Treatment of Fabry mice with rAAV2/8-hAGA resulted in the clearance of accumulated Gb3 in tissues such as liver, spleen, kidney, heart, and brain with concomitant elevation of α-Gal A enzyme activity. Enzyme activity was elevated for up to 60 weeks. In addition, expression of the α-Gal A protein was identified in the presence of rAAV2/8-hAGA at 6, 12, and 24 weeks after treatment. α-Gal A activity was significantly higher in the mice treated with rAAV2/8-hAGA than in Fabry mice that received ERT. Along with higher α-Gal A activity in the kidney of the Fabry mice treated with gene therapy, immunohistochemical studies showed more α-Gal A expression in the proximal tubules and glomerulus, and less Gb3 deposition in Fabry mice treated with this gene therapy than in mice given ERT. The α-gal A gene transfer significantly reduced the accumulation of Gb3 in the tubules and podocytes of the kidney. Electron microscopic analysis of the kidneys of Fabry mice also showed that gene therapy was more effective than ERT.</p> <p>Conclusions</p> <p>The rAAV2/8-hAGA mediated α-Gal A gene therapy provided improved efficiency over ERT in the Fabry disease mouse model. Furthermore, rAAV2/8-hAGA-mediated expression showed a greater effect in the kidney than ERT.</p

Nearly Massless Electrons in the Silicon Interface with a Metal Film

We demonstrate the realization of nearly massless electrons in the most widely used device material, silicon, at the interface with a metal film. Using angle-resolved photoemission, we found that the surface band of a monolayer lead film drives a hole band of the Si inversion layer formed at the interface with the film to have nearly linear dispersion with an effective mass about 20 times lighter than bulk Si and comparable to graphene. The reduction of mass can be accounted for by repulsive interaction between neighboring bands of the metal film and Si substrate. Our result suggests a promising way to take advantage of massless carriers in silicon-based thin-film devices, which can also be applied for various other semiconductor devices.Comment: 4 pages, 4 figures, accepted for publication in Physical Review Letter

Structure stability evaluation of offshore heave compensator using multi-body dynamics analysis method

Heave compensator attenuate vessel heave motion during drilling operation of drillship. Heave compensator functions as damping form motion of drillship, such as principle spring of suspension system. The load transfers on the parts of heave compensator. Stress and deformation of all parts is evaluated to diagnose the stability of the compensator. This study makes a decision on the safety of structure. Results of analysis confirm the structure stability of heave compensator for simulation. This result can be used as data for structural analysis to determine safety of a structure

Association of serum adipocytokine levels with cardiac autonomic neuropathy in type 2 diabetic patients

<p>Abstract</p> <p>Background</p> <p>Cardiac autonomic neuropathy (CAN) is a common complication of diabetes associated with poor prognosis. In addition, the autonomic imbalance is associated with cardiovascular disease (CVD) in diabetes. It is thought that adipocytokines contribute to the increased risk of vascular complications in patients with type 2 diabetes mellitus (T2DM). However, literature data on the association between CAN with adipocytokines such as leptin, tumor necrosis factor-alpha (TNF-alpha), adiponectin in subjects with T2DM is limited.</p> <p>Therefore, in the present study, we examined the relationship between fasting serum leptin, TNF- alpha and adiponectin and CAN in Korean T2DM patients.</p> <p>Methods</p> <p>A total of 142 T2DM patients (94 males, 48 females) were recruited. CAN was assessed by the five tests according to the Ewing's protocol and the time and frequency domain of the heart rate variability (HRV) was evaluated. Serum TNF-alpha and adiponectin levels were measured using enzyme-linked immunosorbent assay and serum leptin levels were measured using radioimmunoassay.</p> <p>Results</p> <p>Although, the mean levels of leptin, TNF-alpha and adiponectin were not significantly different between the groups with and without CAN, the levels of leptin and adiponectin had a tendency to increase as the score of CAN increased (p = 0.05, p = 0.036). Serum leptin levels demonstrated a negative correlation with low frequency (LF) in the upright position (p = 0.037). Regarding TNF-alpha, a significant negative correlation was observed with SDNN and RMSSD in the upright position (p = 0.023, p = 0.019). Adiponectin levels were not related to any HRV parameters. Multivariate logistic regression analysis demonstrated that the odds of CAN increased with a longer duration of diabetes (1.25, [1.07-1.47]) and higher homeostatic model of assessment-insulin resistance (HOMA-IR) (5.47, [1.8-16.5]). The relative risks for the presence of CAN were 14.1 and 51.6 for the adiponectin 2^nd, 3^rdtertiles when compared with first tertile (p-value for trend = 0.022).</p> <p>Conclusions</p> <p>In the present study, the higher serum adiponectin levels and HOMA-IR were associated with an increased risk for the presence of CAN. Also, the CAN score correlated with the serum adiponectin. Serum adipocytokines such as leptin and TNF-alpha were significantly correlated with parameters of HRV, representative markers of CAN. Future prospective studies with larger number of patients are required to establish a direct relationship between plasma adipocytokine concentrations and the development or severity of CAN.</p

Vitamin D3 Supplementation Reduces the Symptoms of Upper Respiratory Tract Infection during Winter Training in Vitamin D-Insufficient Taekwondo Athletes: A Randomized Controlled Trial

Vitamin D insufficiency may be associated with increased risk of upper respiratory tract infection (URTI) in athletes. This study examined the effects of vitamin D3 supplementation on salivary immune functions and symptoms of URTI in vitamin D-insufficient taekwondo athletes. Twenty-five male taekwondo athletes, aged 19–22 years with vitamin D insufficiency [serum 25-hydroxyvitamin-D concentrations (25(OH)D, 31.3 ± 1.39 nmol/L)], participated in this study. They were randomized to receive 5000 IU/day of vitamin D3 (n = 13) or placebo capsule (n = 12) during 4 weeks of winter training. Blood samples were collected two times (pre- and post-tests) for analyzing serum 25(OH)D concentration while salivary samples were obtained three times (pre-, mid-, and post-tests) for secretory immunoglobulin A (SIgA) and lactoferrin analyses. The symptoms of URTI were reported daily during the intervention. Serum 25(OH)D concentration significantly increased by 255.6% in the vitamin D group, whereas in the placebo group it did not change (p \u3c 0.001). While the significant increase in SIgA was observed in both groups (p \u3c 0.001), elevated salivary lactoferrin level in response to winter training was found only in the placebo group (p = 0.011). The change in serum 25(OH)D concentration was negatively associated with total URTI symptoms (r = −0.435, p = 0.015). Vitamin D3 supplementation may be effective in reducing the symptoms of URTI during winter training in vitamin D-insufficient taekwondo athletes

Dihydrotestosterone-Inducible IL-6 Inhibits Elongation of Human Hair Shafts by Suppressing Matrix Cell Proliferation and Promotes Regression of Hair Follicles in Mice

Autocrine and paracrine factors are produced by balding dermal papilla (DP) cells following dihydrotestosterone (DHT)-driven alterations and are believed to be key factors involved in male pattern baldness. Herein we report that the IL-6 is upregulated in balding DP cells compared with non-balding DP cells. IL-6 was upregulated 3hours after 10–100nM DHT treatment, and ELISA showed that IL-6 was secreted from balding DP cells in response to DHT. IL-6 receptor (IL-6R) and glycoprotein 130 (gp130) were expressed in follicular keratinocytes, including matrix cells. Recombinant human IL-6 (rhIL-6) inhibited hair shaft elongation and suppressed proliferation of matrix cells in cultured human hair follicles. Moreover, rhIL-6 injection into the hypodermis of mice during anagen caused premature onset of catagen. Taken together, our data strongly suggest that DHT-inducible IL-6 inhibits hair growth as a paracrine mediator from the DP