Amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD) are serious neurodegenerative diseases. Although their pathogenesis is unclear, the abnormal accumulation of TAR ...DNA-binding protein of 43 kDa (TDP-43) is a pathological feature that exists in almost all patients. Thus far, there is no drug that can cure ALS/FTLD. Tetramethylpyrazine nitrone (TBN) is a derivative of tetramethylapyrazine, derived from the traditional Chinese medicine Ligusticum chuanxiong, which has been widely proven to have therapeutic effects on models of various neurodegenerative diseases. TBN is currently under clinical investigation for several indications including a Phase II trial of ALS. Here, we explored the therapeutic effect of TBN in an ALS/FTLD mouse model. We injected the TDP-43 M337V virus into the striatum of mice unilaterally and bilaterally, and then administered 30 mg/kg TBN intragastrically to observe changes in behavior and survival rate of mice. The results showed that in mice with unilateral injection of TDP-43M337V into the striatum, TBN improved motor deficits and cognitive impairment in the early stages of disease progression. In mice with bilateral injection of TDP-43M337V into the striatum, TBN not only improved motor function but also prolonged survival rate. Moreover, we show that its therapeutic effect may be through activation of the Akt/mTOR/GSK-3β and AMPK/PGC-1α/Nrf2 signaling pathways. In summary, TBN is a promising agent for the treatment of ALS/FTLD.
Aggregation of α-synuclein (α-syn) and α-syn cytotoxicity are hallmarks of sporadic and familial Parkinson’s disease (PD). Nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-dependent enhancement of ...the expression of the 20S proteasome core particles (20S CPs) and regulatory particles (RPs) increases proteasome activity, which can promote α-syn clearance in PD. Activation of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) may reduce oxidative stress by strongly inducing Nrf2 gene expression. In the present study, tetramethylpyrazine nitrone (TBN), a potent-free radical scavenger, promoted α-syn clearance by the ubiquitin–proteasome system (UPS) in cell models overexpressing the human A53T mutant α-syn. In the α-syn transgenic mice model, TBN improved motor impairment, decreased the products of oxidative damage, and down-regulated the α-syn level in the serum. TBN consistently up-regulated PGC-1α and Nrf2 expression in tested models of PD. Additionally, TBN similarly enhanced the proteasome 20S subunit beta 8 (Psmb8) expression, which is linked to chymotrypsin-like proteasome activity. Furthermore, TBN increased the mRNA levels of both the 11S RPs subunits Pa28αβ and a proteasome chaperone, known as the proteasome maturation protein (Pomp). Interestingly, specific siRNA targeting of Nrf2 blocked TBN’s effects on Psmb8, Pa28αβ, Pomp expression, and α-syn clearance. In conclusion, TBN promotes the clearance of α-syn via Nrf2-mediated UPS activation, and it may serve as a potentially disease-modifying therapeutic agent for PD.
Based on the design concept of earthquake-resilient structure, a new-type of box-shaped steel piers with embedded energy-dissipating steel plates was proposed. Quasi-static tests of 6 box-shaped ...steel pier specimens under variable axial pressure and cyclic horizontal loading were carried out. By analyzing the failure mode, load-displacement hysteretic curve, skeleton curve, displacement ductility coefficient, stiffness degradation characteristics, strength degradation coefficient, and cumulative hysteretic energy, the effects of setting energy-dissipating steel plate, axial compression ratio, and thickness of energy dissipation steel plates on the seismic performance of new-type steel piers were discussed. Finite element models of steel bridge piers were established and compared with the test results. The analysis results using FEM agree well with the test results. Results show that the setting of energy-dissipating steel plates can effectively improve the ductility, deformation capacity, and energy-dissipating capacity of box-shaped steel piers, and effectively delay buckling deformation and cracking of wall plates. The steel plate near the bolt hole of the wall plate at the root of the new-type of box-shaped steel piers is easy to crack due to stress concentration, resulting in a rapid reduction of the maximum bearing capacity of the specimens. With the increase of axial compression ratio, the bearing capacity, energy-dissipating capacity, and earthquake-resilient capacity of the specimens increase. The smaller the thickness of the replaceable energy-dissipating steel plates, the smaller the bearing capacity and faster the stiffness degradation of the specimens become, while the ductility and energy-dissipating capacity of the specimens are improved. The axial compression ratio and the thickness of the energy-dissipating steel plate have relatively little effect on the strength degradation of the specimens. In order to facilitate the popularization and application of the new-type steel piers, formulas were also established to calculate the bearing capacity and displacement ductility factor of the new-type of box-shaped steel piers.
In order to improve the comfort of the living environment, the thermal performance and temperature–humidity regulation of the exterior walls of two timber-framed structure buildings is theoretically ...calculated and experimentally studied in this study. Both of the two buildings are located in Nanjing, China, the hot-summer and cold-winter zone. Then WUFI is used to simulate and predict the changes of temperature, relative humidity, and water content of the two timber-framed structure buildings, to strengthen the theoretical analysis of the thermal and humidity coupling of the external walls, and to propose an optimal design scheme for the insulation and temperature and humidity regulation of the external walls. The main results show that the tested thermal conductivity is basically consistent with the predicted value, which prove that WUFI simulation can effectively predict the thermal insulation performance of the external wall. The two timber-framed structure buildings are both suitable for the cold areas, and the reasonable optimization of the design of the structure is the key to the insulation of the building wall. Timber-framed structure is proved to have good temperature–humidity regulation effect. The moisture content of the two timber-framed structure buildings is stable, and the annual temperature and winter humidity are within the appropriate humidity range, which indicates that the wall design is suitable for Nanjing hot-summer and cold-winter climate zone. Four types of wall structure indoor mold spore germinations are less likely, which is not easy to produce the mold. The above research aims to optimize the design of the energy-saving wall of the timber-framed structure and create a comfortable and healthy living environment.
A novel liquid scintillator with the mixed solvent as the matrix was prepared for obtaining a good comprehensive performance. In this ternary liquid scintillator, the combination of 20% pseudocumene ...(PC) and 80% linear-alkyl benzene (LAB) by volume was chosen as the mixed solvent, and 2,5-diphenyloxazole (PPO) and 1,4-bis(2-Methylstyryl) benzene (bis-MSB) were as the primary fluor and wavelength shifter, respectively. The optimum prescription was obtained with regard to the light yield. Some characterizations based on the optimal formulation were conducted. The fluorescence emission spectra and wavelength-dependent optical attenuation length of the sample were measured by the fluorescence spectrophotometer and an UV–Vis spectrometer, respectively. The light yield was characterized by adopting the home-made optical platform device. The decay time was tested by adopting the time-correlated single photon counting (TCSPC) technique featured in high dynamic range of several orders of magnitude in light intensity. The experimental test results showed that the sample had a fairly good comprehensive performance.
In order to research the thermal and humidity properties and thermal performance of the exterior wall materials with different thermal insulation layers of timber-framed buildings, the thermal and ...moisture parameters of exterior wall materials of two timber-framed buildings with Insulation Cork Board (ICB) and anti-corrosion pine board were studied in this paper. The heat transfer coefficients of the two timber-framed buildings outer walls were measured and analyzed. Based on the material parameters and temperature, relative humidity and water content of the two timber-framed buildings were predicted by WUFI simulation. The main results show that: Insulation Cork Board can absorb heat more than anti-corrosion pine board. Under the condition of isothermal, moisture content of Insulation layer structure material increases exponentially with the increase of relative humidity. The Insulation performance of the whole wall of building-A with Insulation Cork Board is better than that of building-B with anti-corrosion pine board. Moreover, the overall moisture content of building-A is lower than that of building-B with anti-corrosion pine board. This study is expected to provide useful reference for the optimization design of thermal performance and hygrothermal behavior of exterior wall structure of timber-framed buildings.
•Cork board was used for external insulation layer of exterior wall, and compared with anti-corrosion pine plate.•The thermal and moisture effects on the overall structure were analyzed by parametric study.•The heat transfer coefficient of different timber-framed walls was measured on site.•Thermal performance was verified and temperature-humidity regulation was predicted.•Condensation risk, indoor molds risk, and overall living comfort of timber-framed buildings in Nanjing were evaluated.
Background and Purpose
Cerebral vasospasm and neuronal apoptosis after subarachnoid haemorrhage (SAH) is the major cause of morbidity and mortality in SAH patients. So far, single‐target agents have ...not prevented its occurrence. Memantine, a non‐competitive NMDA re3ceptor antagonist, is known to alleviate brain injury and vasospasm in experimental models of SAH. Impairment of NO availability also contributes to vasospasm. Recently, we designed and synthesized a memantine nitrate MN‐08, which has potent dual functions: neuroprotection and vasodilation. Here, we have tested the therapeutic effects of MN‐08 in animal models of SAH.
Experimental Approach
Binding to NMDA receptors (expressed in HEK293 cells), NO release and vasodilator effects of MN‐08 were assessed in vitro. Therapeutic effects of MN‐08 were investigated in vivo, using rat and rabbit SAH models.
Key Results
MN‐08 bound to the NMDA receptor, slowly releasing NO in vitro and in vivo. Consequently, MN‐08 relaxed the pre‐contracted middle cerebral artery ex vivo and increased blood flow velocity in small vessels of the mouse cerebral cortex. It did not, however, lower systemic blood pressure. In an endovascular perforation rat model of SAH, MN‐08 improved the neurological scores and ameliorated cerebral vasospasm. Moreover, MN‐08 also alleviated cerebral vasospasm in a cisterna magna single‐injection model in rabbits. MN‐08 attenuated neural cell apoptosis in both rat and rabbit models of SAH. Importantly, the therapeutic benefit of MN‐08 was greater than that of memantine.
Conclusion and Implications
MN‐08 has neuroprotective potential and can ameliorate vasospasm in experimental SAH models.
An improved chemical reaction protocol with short time and easy work-up was described here for 2-phenylbenzofuran derivatives. The final purified products, 2-phenylbenzofuran derivatives 5a-g and the ...intermediate diols 4a-g, were evaluated for their estrogen receptor (ER) binding affinity and selective activity in vitro. Among these fourteen tested compounds, 4g and 5g showed higher binding affinity on ER subtypes, ERα and ERβ. Compound 4g exhibited preferable ERα binding, while 5g was more estrogen selective for ERβ. The molecular docking was also performed to explore the detailed interactive interface between ER and the compounds.
Erection dysfunction has been associated with hypertension in several epidemiological and observational studies. But the causal association between hypertension and erectile dysfunction requires ...further investigation.
A two-sample Mendelian randomization (MR) was conducted to analyze the causal effect of hypertension on risk of erection dysfunction. Large-scale publicly available genome-wide association study data were used to estimate the putative causality between hypertension and risk of erectile dysfunction. A total of 67 independent single nucleotide polymorphisms were selected as instrumental variables. Inverse-variant weighted, maximum likelihood, weighted median, penalized weighted median, and MR-PRESSO approaches were utilized in MR analyses. Heterogeneity test, horizontal pleiotropy test, and leave-one-out method were used to prove the stability of the results.
In total, all
values were less than 0.05, demonstrating a positive causal link between hypertension and risk of erectile dysfunction in multiple MR methods, such as inverse-variant weighted (random and fixed effect) (OR 3.8315, 95% CI 2.3004-6.3817,
= 0.0085), maximum likelihood (OR 3.8877, 95% CI 2.3224-6.5081,
= 0.0085), weighted median (OR 4.9720, 95% CI 2.3645-10.4550,
= 0.0309), penalized weighted median (OR 4.9760, 95% CI 2.3201-10.6721,
= 0.0355), and MR-PRESSO (OR 3.6185, 95% CI 2.2387-5.8488,
= 0.0092). Sensitivity analysis detected no evidence of heterogeneity, pleiotropy, or outlier single nucleotide polymorphisms.
The study revealed a positive causal link between the presence of hypertension and the risk of erectile dysfunction. More attention should be paid during the management of hypertension with the purpose of preventing erectile dysfunction or improving erectile function.
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