The hedgehog pathway, initially discovered by two Nobel laureates Drs E Wieschaus and C Nusslein-Volhard in Drosophila, is a major regulator for cell differentiation, tissue polarity and cell ...proliferation. Studies from many laboratories reveal activation of this pathway in a variety of human cancer, including basal cell carcinomas (BCCs), medulloblastomas, leukemia, gastrointestinal, lung, ovarian, breast and prostate cancers. It is thus believed that targeted inhibition of hedgehog signaling may be effective in treatment and prevention of human cancer. Even more exciting is the discovery and synthesis of specific signaling antagonists for the hedgehog pathway, which have significant clinical implications in novel cancer therapeutics. In this review, we will summarize major advances in the last 2 years in our understanding of hedgehog signaling activation in human cancer, interactions between hedgehog signaling and other pathways in carcinogenesis, potential antagonists for hedgehog signaling inhibition and their clinical implications for human cancer treatment.
In the present study, a consortium of two rhizobacteria Bacillus amyloliquefaciens Bk7 and Brevibacillus laterosporus B4, termed 'BB', biochemical elicitors salicylic acid and β-aminobutyric acid ...(SB) and their mixture (BBSB) were investigated for cold and drought stress tolerance in rice plants. After withholding water for 16 days, rice plants treated with BBSB showed 100% survival, improved seedling height (35.4 cm), shoot number (6.12), and showed minimum symptoms of chlorosis (19%), wilting (4%), necrosis (6%) and rolling of leaves. Similarly, BB inoculation enhanced plant growth and reduced overall symptoms in rice seedlings subjected to 0 ± 5 °C for 24 h. Our results imply several mechanisms underlying BB- and BBSB-elicited stress tolerance. In contrast to the control, both treatments significantly decreased leaf monodehydroascorbate (MDA) content and electrolyte leakage, and increased leaf proline and cholorophyll content. Moreover, activities of antioxidant enzymes, superoxide dismutase (SOD) and catalase (CAT) increased 3.0- and 3.6-fold, respectively. Moreover, expression of OsMYB3R-2, OsDIL, OsDREB1A and OsCDPK13 genes was significantly up-regulated, suggesting that these genes play important roles in abiotic stress tolerance of rice. In addition, bacterial strains Bk7 and B4 were able to produce high amounts of IAA and siderophores, and colonise the plant roots, while only strain Bk7 exhibited the capability to form biofilms and solubilise inorganic phosphate. This study indicates that the BB and BBSB bio-formulations can be used to confer induced systematic tolerance and improve the health of rice plants subject to chilling and drought stress.
The objective of this study was to assess the antifungal potential of plant crude extracts derived from cinnamon and rosemary against three isolates of Sclerotinia sclerotiorum under in vitro and in ...vivo conditions. The crude extracts were obtained using two different solvents including ethyl acetate (EA) and ethanol. The results showed that crude extracts of cinnamon are able to reduce mycelial growth of isolate 2 at volatile and contact phase by 35.4% and 78.2%, respectively. Furthermore, sclerotial myceliogenic at contact phase and carpogenic germination of isolate 2 were inhibited by 94.3% and 68.1%, respectively. In general, rosemary extracts showed less inhibitory efficacy than cinnamon. As the most effective treatment, EA extract of cinnamon was analysed using Gas Chromatography/Mass Spectrometry. The results showed the presence of 33 components and the major constituents were E‐cinnamaldehyde (66.4%) followed by Alpha‐Muurolene (4.86%), Alpha‐Copaene (4.73%) and 2H‐1‐Benzopyran‐2‐one (3.72%). The enzyme analysis showed that the activity of phenylalanine ammonia lyase, polyphenoloxidase and peroxidase decrease in the inoculated carrots after application of plant crude extracts indicating that they cannot be considered as resistance inducers against Sclerotinia carrot rot. In conclusion, cinnamon extract was found to be more effective against the pathogen. Although crude extracts of cinnamon and rosemary were able to reduce severity of carrot rot during storage, EA extract of cinnamon (2 g L⁻¹) was found to have practically significant effect against the disease.
The friction and wear behavior of carbon nanotube reinforced polyamide 6 (PA6/CNT) composites under dry sliding and water lubricated condition was comparatively investigated using a pin-on-disc wear ...tester at different normal loads. The morphologies of the worn surfaces and counterfaces of the composites were also observed with scanning electron microscopy (SEM). The results showed that CNTs could improve the wear resistance and reduce the friction coefficient of PA6 considerably under both sliding conditions, due to the effective reinforcing and self-lubricating effects of CNTs on the PA6 matrix. The composites exhibited lower friction coefficient and higher wear rate under water lubricated condition than under dry sliding. Although the cooling and boundary lubrication effect of the water contributed to reduce the friction coefficient of the composites, the adsorbed water lowered the strength of the composites and also inhibited the formation of transfer layers on the counterfaces resulting in less wear resistance. With the increasing normal loads, the friction coefficient of the composites increased under the dry sliding and decreased under the water lubricated condition, owing to inconsistent influences of shear strength and real contact areas. The specific wear rate of the composites increased under both sliding conditions.
In this study a plate–fin type Compact Heat Exchanger (CHE) is considered for optimization. The optimization method uses a Genetic Algorithm (GA) to search, combine and optimize structure sizes of ...the CHE. The minimum total volume or/and total annual cost of the CHE are taken as objective functions in the GA, respectively. The geometries of the fins are fixed while three shape parameters are varied for the optimization objectives with or without pressure drop constraints, respectively. Performance of the CHE is evaluated according to the conditions of the structure sizes that the GA generated, and the corresponding volume and cost are calculated. It is shown that with pressure drop constraints the optimized CHE provides about 30% lower volume or about 15% lower annual cost, while without pressure drop constraints the optimized CHE provides about 49% lower volume or about 16% lower annual cost than those presented in the literature.
The presence of gas hydrates (GHs) increases the stiffness and strength of marine sediments. In elasto‐plastic constitutive models, it is common to consider GH saturation (Sh) as key internal ...variable for defining the contribution of GHs to composite soil mechanical behavior. However, the stress‐strain behavior of GH‐bearing sediments (GHBS) also depends on the microscale distribution of GH and on GH‐sediment fabrics. A thorough analysis of GHBS is difficult, because there is no unique relation between Sh and GH morphology. To improve the understanding of stress‐strain behavior of GHBS in terms of established soil models, this study summarizes results from triaxial compression tests with different Sh, pore fluids, effective confining stresses, and strain histories. Our data indicate that the mechanical behavior of GHBS strongly depends on Sh and GH morphology, and also on the strain‐induced alteration of GH‐sediment fabrics. Hardening‐softening characteristics of GHBS are strain rate‐dependent, which suggests that GH‐sediment fabrics dynamically rearrange during plastic yielding events. We hypothesize that rearrangement of GH‐sediment fabrics, through viscous deformation or transient dissociation and reformation of GHs, results in kinematic hardening, suppressed softening, and secondary strength recovery, which could potentially mitigate or counteract large‐strain failure events. For constitutive modeling approaches, we suggest that strain rate‐dependent micromechanical effects from alterations of the GH‐sediment fabrics can be lumped into a nonconstant residual friction parameter. We propose simple empirical evolution functions for the mechanical properties and calibrate the model parameters against the experimental data.
Plain Language Summary
Gas hydrates (GHs) are crystalline‐like solids, which are formed from natural gas molecules and water at high pressure and low temperature. GHs, and particularly methane hydrates, are naturally abundant in marine sediments. It is known that the presence of GH increases the mechanical stiffness and strength of sediments, and there is strong effort in analyzing and quantifying these effects in order to understand potential risks of sediment destabilization or slope failure. Based on our experimental results from high‐pressure geotechnical studies, we show that not only the initial amount and distribution of GH are important for the increased strength of GH‐bearing sediments but also the dynamic rearrangement of GH‐sediment fabrics during deformation characterizes the stress‐strain response and enables strength recovery after failure. We propose that different microstructural mechanisms contribute to this rearrangement and strength recovery of GH sediment. However, we consider these complicated processes in a simplified manner in an improved numerical model, which can be applied for geotechnical risk assessment on larger scales.
Key Points
The mechanical properties and hardening‐softening characteristics of gas hydrate‐bearing sediments are dependent on strain rates
Hardening‐softening behavior and strength evolution depend on structural alterations and dynamic rearrangement of gas hydrate‐sediment fabrics
The effects of strain rate‐dependent structural alterations can be conceptualized as a nonconstant residual friction term in soil mechanical modeling
Background: A large number of clinical studies have documented that a loss‐of‐function variant CYP2C19*2 affects clinical profiles of clopidogrel (efficacy and safety). However, data on the impact of ...a gain‐of‐function variant CYP2C19*17 on the response to that drug seem to be less consistent. Objectives: To systematically summarize all available clinical data assessing the role of the CYP2C19*17 variant in patients taking clopidogrel. Methods: A literature search was conducted and a meta‐analysis was performed for 11 eligible studies. The endpoints included the major adverse cardiovascular events (MACE, representing non‐fatal myocardial infarction, stroke, revascularization, or death), bleeding events, mortality, stent thrombosis and high platelet reactivity (HPR). Results: Data from six clinical studies demonstrated that carriers of the CYP2C19*17 variant had a marked protection against recurrent cardiovascular events in patients with coronary artery disease compared with non‐carriers, as measured by a 16% decrease in the incidence of MACE (10.0% vs. 11.9%; OR, 0.82; 95% CI, 0.72–0.94; P = 0.005). On the other hand, carriers had an increased risk of developing bleeding as expected (8.0% vs. 6.5%; OR, 1.25; 95% CI, 1.07–1.47; P = 0.006; four studies). Moreover, the presence of the CYP2C19*17 variant might lead to increased response to clopidogrel, as shown by a marked lower prevalence of HPR in carriers than in non‐carriers (37.9% vs. 50.8%; OR, 0.60; 95% CI, 0.45–0.79; P = 0.0003; three studies). Conclusions: Carriers of the CYP2C19*17 variant have greater therapeutic responsiveness to clopidogrel than non‐carriers, but they have an increased risk of developing bleeding as well.
Metallic glass-reinforced metal matrix composites are an emerging class of composite materials. The metallic nature and the high mechanical strength of the reinforcing phase offers unique ...possibilities for improving the engineering performance of composites. Understanding the structure at the amorphous/crystalline interfaces and the deformation behavior of these composites is of vital importance for their further development and potential application. In the present work, Zr-based metallic glass fibers have been introduced in Al7075 alloy (Al-Zn-Mg-Cu) matrices using spark plasma sintering (SPS) producing composites with low porosity. The addition of metallic glass reinforcements in the Al-based matrix significantly improves the mechanical behavior of the composites in compression. High-resolution TEM observations at the interface reveal the formation of a thin interdiffusion layer able to provide good bonding between the reinforcing phase and the Al-based matrix. The deformation behavior of the composites was studied, indicating that local plastic deformation occurred in the matrix near the glassy reinforcements followed by the initiation and propagation of cracks mainly through the matrix. The reinforcing phase is seen to inhibit the plastic deformation and retard the crack propagation. The findings offer new insights into the mechanical behavior of metal matrix composites reinforced with metallic glasses.
Currently no drugs are employed clinically to reverse the unconsciousness induced by general anesthetics. Our previous studies showed that caffeine, when given near the end of an anesthesia session, ...accelerated emergence from isoflurane anesthesia, likely caused by caffeine's ability to elevate intracellular cAMP levels and to block adenosine receptors. These earlier studies showed that caffeine did not rouse either rats or humans from deep anesthesia (≥ 1 minimum alveolar concentration, MAC). In this current crossover study, we examined whether caffeine reversed the unconsciousness produced by light anesthesia (< 1 MAC) in the continued presence of isoflurane. The primary endpoint of this study was to measure isoflurane levels at the time of recovery of righting reflex, which was a proxy for consciousness. Rats were deeply anesthetized with 2% isoflurane (~1.5 MAC) for 20 minutes. Subsequently, isoflurane was reduced to 1.2% for 10 minutes, then by 0.2% every 10 min; animals were monitored until the recovery of righting reflex occurred, in the continued presence of isoflurane. Respiration rate, heart rate and electroencephalogram (EEG) were monitored. Our results show that caffeine-treated rats recovered their righting reflex at a significantly higher inspired isoflurane concentration, corresponding to light anesthesia, than the same rats treated with saline (control). Respiration rate and heart rate increased initially after caffeine injection but were then unchanged for the rest of the anesthesia session. Deep anesthesia is correlated with burst suppression in EEG recordings. Our data showed that caffeine transiently reduced the burst suppression time produced by deep anesthesia, suggesting that caffeine altered neuronal circuit function but not to a point where it caused arousal. In contrast, under light anesthesia, caffeine shifted the EEG power to high frequency beta and gamma bands. These data suggest that caffeine may represent a clinically viable drug to reverse the unconsciousness produced by light anesthesia.
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