Vanilloid receptor type 1 (TRPV1) is a ligand-gated nonselective cation channel that is considered to be an important integrator of various pain stimuli such as endogenous lipids, capsaicin, heat, ...and low pH. In addition to expression in primary afferents, TRPV1 is also expressed in the CNS. To test the hypothesis that the CNS plays a differential role in the effect of TRPV1 antagonists in various types of pain, the analgesic effects of two TRPV1 antagonists with similar in vitro potency but different CNS penetration were compared in vivo. Oral administration of either A-784168 (1-3-(trifluoromethyl)pyridin-2-yl-N-4-(trifluoromethylsulfonyl)phenyl-1,2,3,6-tetrahydropyridine-4-carboxamide) (good CNS penetration) or A-795614 (N-1H-indazol-4-yl-N'-(1R)-5-piperidin-1-yl-2,3-dihydro-1H-inden-1-ylurea) (poor CNS penetration) blocked capsaicin-induced acute pain with the same potency. In complete Freund's adjuvant (CFA)-induced chronic inflammatory pain, oral administration of either compound blocked thermal hyperalgesia with similar potency. Furthermore, intraplantar or intrathecal administration of A-784168 blocked CFA-induced thermal hyperalgesia, suggesting that both peripheral and CNS TRPV1 receptors may play a role in inflammatory thermal hyperalgesia. The effects of the two TRPV1 antagonists were further assessed in models presumably mediated by central sensitization, including CFA- and capsaicin-induced mechanical allodynia and osteoarthritic pain. In these models, the potency of the two compounds was similar after intrathecal administration. However, when administered orally, A-784168, with good CNS penetration, was much more potent than A-795614. Together, these results demonstrate that TRPV1 receptors in the CNS play an important role in pain mediated by central sensitization. In addition, these results demonstrate that significant CNS penetration is necessary for a TRPV1 antagonist to produce broad-spectrum analgesia.
Production and maintenance of virus‐free planting materials is pivotal for the control of viral diseases. The present study attempted to test exogenous application of melatonin for eradication of ...apple stem grooving virus (ASGV) from virus‐infected in vitro shoots of apple cultivar Gala. Exogenous application of 15 μm melatonin to the shoot proliferation medium significantly increased the number of shoots and shoot length. The level of endogenous indole‐3‐acetic acid (IAA) was the highest in the shoots proliferating on the shoot proliferation medium containing 15 μm melatonin. Shoot regrowth levels were significantly higher in shoot tips of the virus‐infected shoots cultured for 4 weeks on this medium than the control. In addition, culture of shoot tips of the virus‐infected in vitro shoots proliferated for 4 weeks on this medium resulted in 95% of shoots being virus‐free, while no virus‐free shoots were obtained in shoot tips of the virus‐infected shoots cultured without melatonin. Analyses by microtissue direct RT‐PCR and RT‐qPCR showed that ASGV concentration decreased in shoot tips of the virus‐infected shoots proliferating on the medium containing 15 μm melatonin for 4 weeks. Virus localization showed that exogenous application of melatonin enlarged the virus‐free area in the virus‐infected shoot tips. These data provide explanations as to why exogenous application of melatonin can efficiently eradicate ASGV. Exogenous application of melatonin provides an alternative means for plant virus eradication and has the potential to produce virus‐free plants.
In this study, the impact of stress-relief heat treatment on the microstructure and fatigue property of a laser melting deposited (LMD) 12CrNi2 low alloy steel was analyzed. Microstructural evolution ...of processed LMD 12CrNi2 steel by heat treatment was studied using electron backscatter diffraction (EBSD) and X-ray diffraction (XRD), aiming to establish a rational microstructure-fatigue property relationship. The results showed that the main phase of the samples before and after heat treatment was α-Fe phase, whereas the lattice parameter slightly decreased after annealing, as a result of stress relief and carbide formation in the heat-treated samples. Meanwhile, the increase of the hard and diffusely distributed carbides inside the matrix was the main contributor for the higher material strength. Based on the EBSD analysis, the heat treatment decreased grain boundary misorientation leading to a corresponding reduction in the dislocation density, and increased the content of high-angle grain boundaries (HAGBs) promoting the toughness of the material. Furthermore, Schmid factor results revealed that the heat-treated samples exhibited a relatively high ductility resulting from the activation for more slip systems during the cyclic deformation. The stress-relief heat treatment significantly improved the fatigue performance of samples, which was attributed to the enhanced strength and ductility owing to the related microstructure change and the relief of residual stresses.
•Laser melting deposited 12CrNi2 samples were heat treated and characterized.•Microstructure features were correlated with fatigue behaviour.•Heat treatment improved the fatigue strength from 350 MPa to 410 MPa.•The strengthening was attributed to the unique heat-treated microstructure.
Methylation-based liquid biopsies show promises in detecting cancer using circulating cell-free DNA; however, current limitations impede clinical application. Most assays necessitate substantial DNA ...inputs, posing challenges. Additionally, underrepresented tumor DNA fragments may go undetected during exponential amplification steps of traditional sequencing methods. Here, we report linear amplification-based bisulfite sequencing (LABS), enabling linear amplification of bisulfite-treated DNA fragments in a genome-wide, unbiased fashion, detecting cancer abnormalities with sub-nanogram inputs. Applying LABS to 100 patient samples revealed cancer-specific patterns, copy number alterations, and enhanced cancer detection accuracy by identifying tissue-of-origin and immune cell composition.
Recent advances in cloud technology have turned the idea of cloud gaming into a reality. Cloud gaming, in its simplest form, renders an interactive gaming application remotely in the cloud and ...streams the scenes as a video sequence back to the player over the Internet. This is an advantage for less powerful computational devices that are otherwise incapable of running high-quality games. Such industrial pioneers as Onlive and Gaikai have seen success in the market with large user bases. In this article, we conduct a systematic analysis of state-of-the-art cloud gaming platforms, and highlight the uniqueness of their framework design. We also measure their real world performance with different types of games, for both interaction latency and streaming quality, revealing critical challenges toward the widespread deployment of cloud gaming.
Endoglin, a transforming growth factor-β co-receptor, is highly expressed on angiogenic endothelial cells in solid tumors. Therefore, targeting endoglin is currently being explored in clinical trials ...for anti-angiogenic therapy. In this project, the redundancy between endoglin and vascular endothelial growth factor (VEGF) signaling in angiogenesis and the effects of targeting both pathways on breast cancer metastasis were explored. In patient samples, increased endoglin signaling after VEGF inhibition was observed. In vitro TRC105, an endoglin-neutralizing antibody, increased VEGF signaling in endothelial cells. Moreover, combined targeting of the endoglin and VEGF pathway, with the VEGF receptor kinase inhibitor SU5416, increased antiangiogenic effects in vitro and in a zebrafish angiogenesis model. Next, in a mouse model for invasive lobular breast cancer, the effects of TRC105 and SU5416 on tumor growth and metastasis were explored. Although TRC105 and SU5416 decreased tumor vascular density, tumor volume was unaffected. Strikingly, in mice treated with TRC105, or TRC105 and SU5416 combined, a strong inhibition in the number of metastases was seen. Moreover, upon resection of the primary tumor, strong inhibition of metastatic spread by TRC105 was observed in an adjuvant setting. To confirm these data, we assessed the effects of endoglin-Fc (an endoglin ligand trap) on metastasis formation. Similar to treatment with TRC105 in the resection model, endoglin-Fc-expressing tumors showed strong inhibition of distant metastases. These results show, for the first time, that targeting endoglin, either with neutralizing antibodies or a ligand trap, strongly inhibits metastatic spread of breast cancer in vivo.
► A model for the coupling phase change heat transfer process in dish collector is established. ► The heat flux distribution on the receiver surface presents non-uniform characteristics. ► ...Non-uniform heat flux boundary will result in non-uniform temperature distribution in PCM. ► Enhancing PCM thermal conductivity is an efficient way to achieve more uniform temperature distribution.
In solar dish collector system, the heat transfer process is a typical coupling heat transfer problem, where the heat conduction, radiation heat transfer, convection heat transfer and phase change heat transfer are coexisting. In the present paper, a coupling model for Monte Carlo Ray Trace Method (MCRTM) and Finite Volume Method (FVM) was established to study the coupling heat transfer problem. Firstly, based on MCRTM, the non-uniform 3D heat flux distributions on the solar dish receiver inner surface were obtained. Then the non-uniform heat flux distribution is used as the boundary condition to simulate the phase change and convection heat transfer process inside the heat transfer tube. The effects of the non-uniform heat flux distribution on temperature field in phase change material (PCM) were examined. The results show that the non-uniform heat flux on the tube surface will result in seriously non-uniform temperature distribution in PCM. Then the optimization analyses for the temperature distribution were performed according to the convection heat transfer process and heat conduction process respectively. The results show that in the studied conditions, when heat transfer fluid (HTF) velocity increases from 10m/s to 25m/s, the maximum temperature difference in PCM will decrease from 781.2K to 497.8K, which reduces about 36.3%. However, it will cause the heat storage capacity and HTF outlet temperature decrease. When the thermal conductivity increases from 3.8Wm−1K−1 to 19.0Wm−1K−1, the maximum temperature difference will decrease from 781.2K to 409.5K, which reduces about 47.6%. And it will not result in HTF outlet temperature and heat storage capacity decreasing. So, enhancing the PCM thermal conductivity is an efficient method to achieve more uniform temperature distribution in PCM.
In this research, 12CrNi2 low alloy steel was successfully prepared by laser melting deposition (LMD). The mechanisms driving high cycle fatigue fracture of the as-built LMD 12CrNi2 low alloy steel ...were investigated and a concurrent process-microstructure-property relationship was established through microstructural analysis. The results showed that the crystal structures of the as-built LMD 12CrNi2 steel mainly consisted of the ferrite and a small amount of Cr23C6 carbides. No preferred texture was observed as a result of the complicated heat flux direction during fabrication. Based on the examination of the fracture surface, fatigue cracks of the as-built LMD 12CrNi2 steel initiated from subsurface defects for all the cases. Crack propagation zones showed a mixed mode of transgranular and intergranular fracture in a brittle manner, whereas the final fracture zones displayed dimples typical of ductile fracture. The kernel average misorientation (KAM) map indicated that the strain localization predominantly occurred at the grain boundaries and slightly appeared at the interior of the ferrite grains. Schmid factor distribution results implied that fatigue cracks originated from grains with {123} slip system due to the prior activation of {123} slip system.
SFTS virus (SFTSV) is a novel bunyavirus that causes severe fever with thrombocytopenia syndrome (SFTS), an emerging infectious disease that occurred in China in recent years, with an average case ...fatality rate of 10–12%. Intervention in the early clinical stage is the most effective measure to reduce the mortality rate of disease. To elucidate the natural course of and immune mechanisms associated with the pathogenesis of SFTSV, 59 laboratory-confirmed SFTS patients in the acute phase, who were hospitalized between October 2010 and September 2011, were enrolled in this study, and the patients sera were dynamically collected and tested for SFTSV viral RNA load, 34 cytokines or chemokines and other related laboratory parameters. All clinical diagnostic factors in the acute phase of SFTS were evaluated and assessed. The study showed that the severity of the disease in 11 (18.6%) patients was associated with abdominal pain (p 0.007; OR = 21.95; 95% CI, 2.32–208.11) and gingival bleeding (p 0.001; OR = 122.11; 95% CI, 6.41–2328). The IP-10, TNF-α, IL-6, IL-10, granzyme B and HSP70 levels were higher over the 7–8 days in severe cases, accompanied by altered AST, CK and LDH levels. HSP70 (p 0.012; OR = 8.29; 95% CI, 1.58–43.40) was independently correlated with the severity of the early acute phase of SFTSV infection. The severity of SFTS can be predicted based on the presence of symptoms such as abdominal pain and gingival bleeding and on the level of HSP70 in the acute phase of the disease.
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