Muscle and Heart Function Restoration in a Limb Girdle Muscular Dystrophy 2I (LGMD2I) Mouse Model by Systemic FKRP Gene Delivery

Mutations in fukutin-related protein (FKRP) gene cause a wide spectrum of disease phenotypes including the mild limb-girdle muscular dystrophy 2I (LGMD2I), the severe Walker-Warburg syndrome, and muscle-eye-brain disease. FKRP deficiency results in α-dystroglycan (α-DG) hypoglycosylation in the muscle and heart, which is a biochemical hallmark of dystroglycanopathies. To study gene replacement therapy, we generated and characterized a new mouse model of LGMD2I harboring the human mutation leucine 276 to isoleucine (L276I) in the mouse alleles. The homozygous knock-in mice (L276IKI) mimic the classic late onset phenotype of LGMD2I in both skeletal and cardiac muscles. Systemic delivery of human FKRP gene by AAV9 vector in the L276IKI mice, at either neonatal age or at the age of 9 months, rendered body wide FKRP expression and restored glycosylation of α-DG in both skeletal and cardiac muscles. FKRP gene therapy ameliorated dystrophic pathology and cardiomyopathy such as muscle degeneration, fibrosis, and myofiber membrane leakage, resulting in restoration of muscle and heart contractile functions. Thus, these results demonstrated that the treatment based on FKRP gene replacement was effective

Tyrosine Nitration of PA700 Links Proteasome Activation to Endothelial Dysfunction in Mouse Models with Cardiovascular Risk Factors

Oxidative stress is believed to cause endothelial dysfunction, an early event and a hallmark in cardiovascular diseases (CVD) including hypertension, diabetes, and dyslipidemia. However, the targets for oxidative stress-mediated endothelial dysfunction in CVD have not been completely elucidated. Here we report that 26S proteasome activation by peroxynitrite (ONOO−) is a common pathway for endothelial dysfunction in mouse models of diabetes, hypertension, and dyslipidemia. Endothelial function, assayed by acetylcholine-induced vasorelaxation, was impaired in parallel with significantly increased 26S proteasome activity in aortic homogenates from streptozotocin (STZ)-induced type I diabetic mice, angiotensin-infused hypertensive mice, and high fat-diets -fed LDL receptor knockout (LDLr−/−) mice. The elevated 26S proteasome activities were accompanied by ONOO−-mediated PA700/S10B nitration and increased 26S proteasome assembly and caused accelerated degradation of molecules (such as GTPCH I and thioredoxin) essential to endothelial homeostasis. Pharmacological (administration of MG132) or genetic inhibition (siRNA knockdown of PA700/S10B) of the 26S proteasome blocked the degradation of the vascular protective molecules and ablated endothelial dysfunction induced by diabetes, hypertension, and western diet feeding. Taken together, these results suggest that 26S proteasome activation by ONOO−-induced PA700/S10B tyrosine nitration is a common route for endothelial dysfunction seen in mouse models of hypertension, diabetes, and dyslipidemia

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Non-Data Aided Rician Parameters Estimation in Temporal Fading Channel With 3 DoFs Gaussian Mixture Model

Rician distribution has been widely utilized to describe wireless fading channel. In the non-stationary temporal fading channel like industrial scenarios, both the specular and scattered components of the multi-path fading channel will be time varying. As a result, the online estimation of Rician parameters is necessary to provide stable wireless service. The traditional estimation approaches of Rician parameters are designed for channel measurement usage and therefore have to work in the data-aided mode for online estimation with modulated I/Q samples. To solve this problem, some non-data-aided algorithms have been proposed in recent years, but only valid in specific scenarios. In this paper, we formulate the estimation of Rician parameters from modulated I/Q samples as a two-dimensional Gaussian mixture model to provide a general non-data-aided Rician parameter estimation method. By involving a priori information of modulation scheme and the motivation of optimized gradient searching, the independent parameters in the maximum likelihood estimation can be significantly decreased to three, which leads to fast convergence of the modified expectation-maximization algorithm with high accuracy. The combination of these modifications has been finally formulated as a Rician mixture model. The numerical results and field measurements illustrate the feasibility of this methodology

Performance of Poly(Styrene—Divinylbenzene) Magnetic Porous Microspheres Prepared by Suspension Polymerization for the Adsorption of 2, 4-Dichlorophenol and 2, 6-Dichlorophenol from Aqueous Solutions

Poly(styrene–divinylbenzene)/Fe 3 O 4 (Fe 3 O 4 @St–DVB) magnetic porous polymer microspheres based on suspension polymerization were prepared for adsorption of 2, 4-dichlorophenol (2, 4-DCP) and 2, 6-dichlorophenol (2, 6-DCP) from aqueous solution. The as-prepared product was characterized by Fourier transform infrared spectroscopy, Raman, X-ray diffraction, scanning electron microscopy, thermogravimetric analysis, differential thermal analysis and elemental analysis. The results showed that the composite material has both porous and magnetic characteristics, which aid in faster separation and increase in adsorption capacity. The adsorption performance of the Fe 3 O 4 @(St–DVB) magnetic porous microspheres was manifested by batch mode adsorption experiments with respect to pH, initial concentration, contact time and temperature. The adsorbent was found to be sensitive to changes in pH, and the adsorption capacity of 2, 4-DCP is higher than that of 2, 6-DCP. The kinetics experimental data fitted well with the pseudo-second-order model, as three steps belonged to the pseudo-second-order adsorption process. The adsorption isotherms were also described by the Langmuir and Freundlich isotherm models, respectively. It was found that the Langmuir isotherm model fitted the equilibrium data superior to the Freundlich model. Thermodynamic parameters were calculated by the Gibbs free energy function, confirming that adsorption process was spontaneous and endothermic. In addition, the reusability performance of the Fe 3 O 4 @(St–DVB) magnetic porous microspheres was demonstrated by four repeated cycles

Towards Sustainable Development Goals: Coupling Coordination Analysis and Spatial Heterogeneity between Urbanization, the Environment, and Food Security in China

The interconnection between urbanization, the environment, and food security necessitates an exploration of their coupling coordination to advance the attainment of Sustainable Development Goals. However, limited research directly addresses the feasibility and strategies required to achieve such coordination. This study investigates the coupling coordination and spatial heterogeneity between urbanization, the environment, and food security in China from 2004 to 2020, employing the coupling coordination degree model, the spatial correlation model, the Dagum Gini coefficient, and the obstacle degree model. The results show that: (1) the level of coordinated development between urbanization, the environment, and food security in China has significantly increased, as evidenced by a remarkable rise in the coupling coordination degree; (2) a robust positive spatial correlation is observed in the coupling coordination degree, with “Low-Low” clusters predominantly concentrated in northwest China and “High-High” clusters primarily located in southeast China; (3) inter-regional differences are identified as the primary cause of this spatial heterogeneity; (4) food security has emerged as the foremost obstacle to coordinated development between urbanization, the environment, and food security in China. Optimizing the rational allocation of natural resources across different sectors, enhancing resource use efficiency, and strengthening environmental pollution control and management have been proven to be crucial measures and key strategies for promoting their coordinated development. This study provides a novel perspective on balancing the intricate relationship between urbanization, environmental protection, and food security, which is conducive to the achievement of Sustainable Development Goals in developing countries