Advances in the study of KRAS in brain arteriovenous malformation.

Background：Brain arteriovenous malformation (bAVM) is an abnormal vascular mass with disordered arteriovenous connection. Endothelial KRAS mutation is common in bAVM. In vivo studies have demonstrated that mutations of KRAS in somatic cells can induce bAVM-like angiogenesis, suggesting that KRAS gene may play a key role in the development and progression of bAVM. Summary：In this article, we will provide a comprehensive review of action mechanisms of KRAS mutations in the development of bAVM and summarize potential targeting drugs for KRAS mutations in bAVM somatic cells. Key Message: KRAS mutation in human brain endothelial cells is a key driver in the pathogenesis of sporadic cerebral arteriovenous malformations. It is of great clinical importance to explore and summarize the changes in the signaling pathway induced by KRAS mutation, which may provide additional targets for the treatment of sporadic bAVM development.

Effect of Tendon-Related Variables on the Behavior of Externally CFRP Prestressed Concrete Beams.

This work assesses the flexural performance of prestressed concrete beams with external carbon fiber-reinforced polymer (CFRP) tendons, focusing on tendon-related variables. A finite element analysis (FEA) method is verified. A numerical parametric analysis of prestressed concrete beams with external CFRP tendons is carried out. Four tendon-related variables are considered, namely, the area, initial prestress, depth and elastic modulus of tendons. The analysis shows that flexural ductility decreases as the tendon area, initial prestress or elastic modulus increases but is insensitive to the tendon depth. The ultimate tendon stress increment (Δσp) is influenced by all of the four variables investigated. JGJ 92-2016 (Chinese technical specification for concrete structures prestressed with unbonded tendons) significantly underestimates Δσp and, hence, is over-conservative for the strength design of these beams. An equation is proposed for calculating Δσp, taking into account all four variables investigated. An analytical model is then developed to estimate the flexural strength (Mu) of prestressed concrete beams with external CFRP tendons. The proposed analytical model shows good agreement with FEA, i.e., the mean discrepancy for Δσp is 0.9% with a standard deviation of 11.1%; and the mean discrepancy for Mu is -1.6% with a standard deviation of 2.1%.

Prediction of Structural Behavior of Continuous Reinforced Concrete Beams with Hybrid CFRP-Steel Bars.

The present investigation aims to identify the flexural performance of two-span concrete beams reinforced with hybrid carbon fiber reinforced polymer (CFRP) and steel bars. By applying a finite element analysis, a comprehensive numerical assessment is performed. The investigated variables are Af/Ar (Af = area of CFRP bars; Ar = total area of CFRP/steel bars), load pattern (symmetrical and unsymmetrical loading) and load type (center-point, third-point and uniform loading). The results show that beams with Af/Ar of 0.25 show 16.0% and 11.3% higher ultimate load at symmetrical and unsymmetrical loading, respectively, than beams with Af/Ar of 0.0 (i.e., beams with steel bars), but the change in ultimate load is not apparent when varying Af/Ar between 0.25 and 1.0. Unsymmetrical loading causes 6.0-15.0% greater deflection capacities than the symmetrical one. When Af/Ar increases from 0.0 to 1.0, moment redistribution at symmetrical loading is decreased significantly by 62%, while the redistribution variation is marginal at unsymmetrical loading. In addition, the applicability of two equations based on the ultimate strain in tensile bars for predicting moment redistribution is evaluated. It is generally shown that these equations can account for the influence of Af/Ar and load type.

Flexural Behavior of Two-Span Continuous CFRP RC Beams.

This paper investigates the feasibility of replacing steel bars with carbon-fiber-reinforced polymer (CFRP) bars in continuous reinforced concrete (RC) beams. A numerical model is introduced. Model predictions are compared with the experimental results that are available in the literature. A comprehensive numerical investigation is then performed on two-span CFRP/steel RC beams with ρb2 = 0.61-3.03% and ρb1/ρb2 = 1.5, where ρb1 and ρb2 are tensile bar ratios (ratios of tensile bar area to effective cross-sectional area of beams) over positive and negative moment regions, respectively. The study shows that replacing steel bars with CFRP bars greatly improves the crack mode at a low bar ratio. The ultimate load of CFRP RC beams is 89% higher at ρb2 = 0.61% but 7.2% lower at ρb2 = 3.03% than that of steel RC beams. In addition, CFRP RC beams exhibit around 13% greater ultimate deflection compared to steel RC beams. The difference of moment redistribution between CFRP and steel RC beams diminishes as ρb2 increases. ACI 318-19 appears to be conservative, and it leads to more accurate predictions of moment redistribution in CFRP RC beams than that in steel RC beams.

Moment Redistribution in Continuous Externally CFRP Prestressed Beams with Steel and FRP Rebars.

This paper assesses the impact of adopting carbon- or glass-fiber-reinforced polymer (CFRP or GFRP) instead of steel rebars on the redistribution of moments in prestressed concrete beams (PCBs) with external CFRP tendons. A numerical program is introduced, and numerical simulations are performed on two-span continuous beams with steel, CFRP or GFRP rebars of various areas, i.e., Ar2 = 360-3560 mm2, and Ar1/Ar2 = 1.5, where Ar1 and Ar2 are areas of tensile rebars over the positive and negative moment zones, respectively. The results show the moment redistribution is contributed by concrete cracking only for the beams with fiber-reinforced polymer (FRP) rebars, and by concrete cracking and steel yielding for the beams with steel rebars. As a result, the use of FRP rebars leads to a substantially lower moment redistribution than in steel rebars. It is also demonstrated that Eurocode 2, CSA A23.3-04 and ACI 318-19 fail to reflect the rebar influence on moment redistribution in PCBs with external tendons. A simplified equation for the quantification of moment redistribution in externally PCBs with steel and FRP rebars is recommended, which yields accurate and conservative predictions.

Numerical Study of Using FRP and Steel Rebars in Simply Supported Prestressed Concrete Beams with External FRP Tendons.

This study aimed at examining the feasibility of using fiber-reinforced polymer (FRP) rebars instead of steel ones in prestressed concrete beams (PCBs) with external FRP tendons. By applying an experimentally validated program, numerical tests were performed on simply supported PCBs, with investigated variables including rebars' type and area. Three types of rebars were considered, i.e., carbon, glass FRPs (CFRP, GFRP), and reinforcing steel. The ratio of tensile rebars ranged from 0.22% to 2.16%. The results indicated that the beams with CFRP rebars exhibited better crack mode and higher ultimate load than the beams with GFRP or steel rebars. GFRP rebars led to considerably higher ultimate deflection and tendon stress increment than steel rebars. In addition, several models for calculating the ultimate stress in unbonded tendons were assessed. An analytical model was also proposed to predict the tendon stress at ultimate and flexural strength in externally PCBs with steel and FRP rebars. The model predictions agreed well with the numerical results.

The neuroprotection of liraglutide on diabetic cognitive deficits is associated with improved hippocampal synapses and inhibited neuronal apoptosis.

AIMS: Diabetes mellitus can cause cognitive impairments, a state between normal aging and dementia. Effective clinical interventions are urgently needed to prevent or treat this complication. Liraglutide as a glucagon-like peptide 1 analog has been shown to exert memory-enhancing and neuroprotective effects on neurodegenerative diseases. This study aims to investigate the neuroprotective effects of liraglutide in streptozotocin (STZ)-induced diabetic mice with cognitive deficits. METHODS: Male C57BL/6J mice were intraperitoneal injected with STZ (65 mg/kg body weight daily for 5 days) to induce type 1 diabetes model. Then the mice were treated with liraglutide (250 mg/kg/day, for 6 weeks) or saline. Weekly changes of body weight and fasting blood glucose were measured. Cognitive performance was evaluated by Morris water maze test. The ultrastructure of hippocampus was observed by transmission electron microscope. The superoxide dismutase activities and malondialdehyde levels in the hippocampus were detected by biochemistry assay. Apoptosis-related proteins and phosphoinositide 3-kinase (PI3K)/protein kinase-B (Akt) signaling were detected by Western blotting. KEY FINDINGS: We found that STZ-induced diabetic mice exhibited impaired learning and memory, ultrastructure damage of hippocampal neurons and synapses, exacerbated oxidative stress and neuronal apoptosis, as compared to the control mice. These effects were attenuated by the treatment with liraglutide. Furthermore, liraglutide reversed diabetes-induced alterations in PI3K/Akt signaling pathway that plays an essential role in modulating neuronal survival, apoptosis and plasticity. SIGNIFICANCE: These data suggest that the neuroprotective effects of liraglutide on diabetes-induced cognitive impairments are associated with the improvements of hippocampal synapses and inhibition of neuronal apoptosis.

The angiotensin-converting enzyme 2/angiotensin (1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rho kinase pathway.

UNLABELLED: Reactive oxygen species (ROS) generated by NADPH oxidase-4 (NOX4) have been shown to initiate lung fibrosis. The migration of lung fibroblasts to the injured area is a crucial early step in lung fibrosis. The angiotensin-converting enzyme 2 (ACE2)/angiotensin (1-7) [Ang(1-7)]/Mas axis, which counteracts the ACE/angiotensin II (AngII)/angiotensin II type 1 receptor (AT1R) axis, has been shown to attenuate pulmonary fibrosis. Nevertheless, the exact molecular mechanism remains unclear. AIMS: To investigate the different effects of the two axes of the renin-angiotensin system (RAS) on lung fibroblast migration and extracellular matrix accumulation by regulating the NOX4-derived ROS-mediated RhoA/Rho kinase (Rock) pathway. RESULTS: In vitro, AngII significantly increased the NOX4 level and ROS production in lung fibroblasts, which stimulated cell migration and α-collagen I synthesis through the RhoA/Rock pathway. These effects were attenuated by N-acetylcysteine (NAC), diphenylene iodonium, and NOX4 RNA interference. Moreover, Ang(1-7) and lentivirus-mediated ACE2 (lentiACE2) suppressed AngII-induced migration and α-collagen I synthesis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway. However, Ang(1-7) alone exerted analogous effects on AngII. In vivo, constant infusion with Ang(1-7) or intratracheal instillation with lenti-ACE2 shifted the RAS balance toward the ACE2/Ang(1-7)/Mas axis, alleviated bleomycin-induced lung fibrosis, and inhibited the RhoA/Rock pathway by reducing NOX4-derived ROS. INNOVATION: This study suggests that the ACE2/Ang(1-7)/Mas axis may be targeted by novel pharmacological antioxidant strategies to treat lung fibrosis induced by AngII-mediated ROS. CONCLUSION: The ACE2/Ang(1-7)/Mas axis protects against lung fibroblast migration and lung fibrosis by inhibiting the NOX4-derived ROS-mediated RhoA/Rock pathway.

Array detector for high energy laser based on diffuse transmission sampling.

In order to improve the ability and accuracy of measuring the temporal-spatial distribution of the intensity of a large-size, high-energy laser beam, a novel array detecting method based on diffuse transmission sampling is proposed. The measurement principle and the design of the sampling and attenuating unit are presented. High-temperature-resistant diffuse transmission material is used to sample and attenuate a high energy laser beam. Pure copper, whose surface is first sand-blasted and then gold-plated, is applied to scatter the incident high-energy laser beam. The formula for the attenuation ratio was derived in detail. We developed two large-aperture array detectors with spatial resolution of 5 mm, spatial duty ratio of 20%, and useable angle range of ±30° without varying the responsivity, the non-uniformity in the laser profile measurement is below 1%, and the repeatability error in the laser power measurement is approximately 1%. The maximal energy density that the array detector can endure is more than 10 kJ/cm(2).