Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the d...Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/b-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.展开更多
Objective:To observe the tolerance and the dependence of endomorphin-1 (EM-1) in rats and the possible mechanisms. Methods:Sixty Sprague-Dawley rats were randomly allocated into saline, acute EM-1-treated and chro...Objective:To observe the tolerance and the dependence of endomorphin-1 (EM-1) in rats and the possible mechanisms. Methods:Sixty Sprague-Dawley rats were randomly allocated into saline, acute EM-1-treated and chronic EM-1-treated groups. The rats were intracerebroventricularly injected with saline, acute EM-1 10 μg/kg 30 rain prior to sacrifice,and chronic EM-1 by daily administration at 8:00 A.M. and 15:00 P.M. from 10 μg/kg on the 1^st day to 50 μg/kg on the 94 day, respectively. In chronic EM-1-treated group, the median antinociceptive dose (AD50) and the catatonic median effective dose (ED50) were determined by the improved Dixon's method. Natural withdrawl test was used to assess the dependence of EM-1. Maximal binding capacity (Bmax) and dissociation constant (Kd) of 3H-DAMGO, binding to mu-opioid receptor (MOR) in brain tissue, was measured by Scatchard analysis. Gene expression of MOR was measured by reverse transcription-polymerase chain reaction(RT-PCR). Results :Tolerance of the antinociceptic and catatonic effects on the 3rd day (3.1-fold and 1.9-fold ) and the 9th day (28.4-fold and 8.5-fold) were observed in chronic EM-1-treated group (P 〈 0.05). Jumping times and withdrawal scores of rats were significantly higher in the chronic EM-1-treated group than those in saline group on the 94 day (P 〈 0.05). Bmax and mRNA expression of MOR in cortex, midbrain and striatum were lower in chronic EM-1-treated group on the 94 day than the other two groups(P 〈 0.05), but Kd had no significant difference (P 〉 0.05). AD50,ED50,Bmax ,Kd and gene expression of MOR were recorded. Conclusion: EM-1 possesses the tolerance and the dependence. After a long-term treatment, EM-1 down regulates the binding capacity and mRNA of MOR, which somewhat accounts for the dependence.展开更多
Prediction of seismic attenuation and dispersion that are inherently sensitive to hydraulic and elastic properties of the medium of interest in the presence of mesoscopic fractures and pores,is of great interest in th...Prediction of seismic attenuation and dispersion that are inherently sensitive to hydraulic and elastic properties of the medium of interest in the presence of mesoscopic fractures and pores,is of great interest in the characterization of fractured formations.This has been very difficult,however,considering that stress interactions between fractures and pores,related to their spatial distributions,tend to play a crucial role on affecting overall dynamic elastic properties that are largely unexplored.We thus choose to quantitatively investigate frequency-dependent P-wave characteristics in fractured porous rocks at the scale of a representative sample using a numerical scale-up procedure via performing finite element modelling.Based on 2-D numerical quasi-static experiments,effects of fracture and fluid properties on energy dissipation in response to wave-induced fluid flow at the mesoscopic scale are quantified via solving Biot's equations of consolidation.We show that numerical results are sensitive to some key characteristics of probed synthetic rocks containing unconnected and connected fractures,demonstrating that connectivity,aperture and inclination of fractures as well as fracture infills exhibit strong impacts on the two manifestations of WIFF mechanisms in the connected scenario,and on resulting total wave attenuation and phase velocity.This,in turn,illustrates the importance of these two WIFF mechanisms in fractured rocks and thus,a deeper understanding of them may eventually allow for a better characterization of fracture systems using seismic methods.Moreover,this presented work combines rock physics predictions with seismic numerical simulations in frequency domain to illustrate the sensitivity of seismic signatures on the monitoring of an idealized geologic CO_(2) sequestration in fractured reservoirs.The simulation demonstrates that these two WIFF mechanisms can strongly modify seismic records and hence,indicating that incorporating the two energy dissipation mechanisms in the geophysical interpretation can potentially improving the monitoring and surveying of fluid variations in fractured formations.展开更多
A hyperbolic function is introduced to reflect the attenuation effect of one firm's default to its partner. If two firms are competitors (copartners), the default intensity of one firm will decrease (increase) ab...A hyperbolic function is introduced to reflect the attenuation effect of one firm's default to its partner. If two firms are competitors (copartners), the default intensity of one firm will decrease (increase) abruptly when the other firm defaults. As time goes on, the impact will decrease gradually until extinct. In this model, the joint distribution and marginal distributions of default times are derived by employing the change of measure, and the fair swap premium of a credit default swap (CDS) can be valued.展开更多
The problem of robust active vibration control for a class of electro-hydraulic actuated structural systems with time-delay in the control input channel and parameter uncertainties appearing in all the mass, damping a...The problem of robust active vibration control for a class of electro-hydraulic actuated structural systems with time-delay in the control input channel and parameter uncertainties appearing in all the mass, damping and stiffness matrices is investigated in this paper. First, by introducing a linear varying parameter, the nonlinear system is described as a linear parameter varying (LPV) model. Second, based on this LPV model, an LMI-based condition for the system to be asymptotically stabilized is deduced. By solving these LMIs, a parameter-dependent controller is established for the closed- loop system to be stable with a prescribed level of disturbance attenuation. The condition is also extended to the uncertain case. Finally, some numerical simulations demonstrate the satisfying performance of the proposed controller.展开更多
Peak ground acceleration(PGA) estimation is an important task in earthquake engineering practice.One of the most well-known models is the Boore-Joyner-Fumal formula,which estimates the PGA using the moment magnitude,t...Peak ground acceleration(PGA) estimation is an important task in earthquake engineering practice.One of the most well-known models is the Boore-Joyner-Fumal formula,which estimates the PGA using the moment magnitude,the site-to-fault distance and the site foundation properties.In the present study,the complexity for this formula and the homogeneity assumption for the prediction-error variance are investigated and an effi ciency-robustness balanced formula is proposed.For this purpose,a reduced-order Monte Carlo simulation algorithm for Bayesian model class selection is presented to obtain the most suitable predictive formula and prediction-error model for the seismic attenuation relationship.In this approach,each model class(a predictive formula with a prediction-error model) is evaluated according to its plausibility given the data.The one with the highest plausibility is robust since it possesses the optimal balance between the data fi tting capability and the sensitivity to noise.A database of strong ground motion records in the Tangshan region of China is obtained from the China Earthquake Data Center for the analysis.The optimal predictive formula is proposed based on this database.It is shown that the proposed formula with heterogeneous prediction-error variance is much simpler than the attenuation model suggested by Boore,Joyner and Fumal(1993).展开更多
To investigate the impact of microstructure interdependency of a counterparty explicitly, a geometric function is introduced in one firm's default intensity to reflect the attenuation behavior of the impact of its...To investigate the impact of microstructure interdependency of a counterparty explicitly, a geometric function is introduced in one firm's default intensity to reflect the attenuation behavior of the impact of its counterparty firm's default. The general joint distribution and marginal distributions of default times are derived by employing the change of measure. The fair premium of a vanilla CDS (credit default swap) is obtained in continuous and discrete contexts, respectively. The swap premium in a discrete context is similar to the accumulated interest during the period between two payment days, and the short rate is the swap rate in a continuous context.展开更多
BACKGROUND: Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions: the ventral tegmental area, the nuc...BACKGROUND: Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions: the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE: To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 (Gi2) in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING: A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA (Shanghai, China) between September 2002 and March 2004. MATERIALS: Thirty-six, healthy, male, Sprague-Dawley (SD) rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory (China); naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory (China); and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc (USA). METHODS: Thirty-six SD rats were randomly divided into six groups (n = 6): (1) acute morphine-dependent group, (2) acute abstinent group, (3) acute control group, (4) chronic morphine-dependent group, (5) chronic abstinent group, and (6) chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine (5 mg/kg), one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone (5 mg/kg). Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20:00, which increased by 5 mg/kg at 8:00, 12:00, and 20:00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone (5 mg/kg) at 8:00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES: The concentration of Gi2 protein in the five brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus) was detected by immunohistochemistry. RESULTS: In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group (P 〈 0.01), while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus (P 〈 0.01 ) compared to the chronic control group. CONCLUSION: Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.展开更多
The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitator...The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” evoked in naive rodents shortly after acute systemic injection of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors. These symptoms result from excessive excitatory opioid receptor signaling and increased endorphin release. Pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) signaling functions of opioid receptors have utilized microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse sensory ganglia and hot-water tail-flick assays in mice. These studies led to development of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. Critical combinations of cAMP-PDE inhibitors that release endorphins plus specific agents that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled signaling were shown to attenuate hyperalgesia and distress evoked by diverse chemical stressors in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naive rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may be manifestations of a common Endorphinergic Distress Syndrome (EDS). We suggest that many distress symptoms are caused by EDS, a dysfunctional imbalance in the endogenous opioid system, consisting of abnormal endorphin levels, together with opioid receptors predominately in their excitatory mode. Therefore, concomitantly enhancing endogenous opioid release and switching excessive excitatory opioid receptor signaling to inhibitory signaling can attenuate these distress symptoms. Trials of a critically formulated oral preparation, containing both endorphin enhancers and opioid receptor switchers, have resulted in long-term anxiolytic efficacy and enhanced calm and mental clarity in large numbers of individuals with distress symptoms. These endorphinergic formulations may provide treatment for the emotional and physical distress associated with many psychiatric, neurologic, and neurodevelopmental disorders.展开更多
The frequency-dependent characteristics of P- and S-wave attenuation in the upper crust of NW Himalayas have been estimated using local earthquakes for a frequency range of 1.5 to 18 Hz. A total of 43 local events of ...The frequency-dependent characteristics of P- and S-wave attenuation in the upper crust of NW Himalayas have been estimated using local earthquakes for a frequency range of 1.5 to 18 Hz. A total of 43 local events of magnitude 2.1 - 4.8, mostly from the vicinity of Main Boundary Thrust (MBT) and Main Central Thrust (MCT) have been used in the analysis. The extended coda normalization methods were applied to estimate the quality factors for P- waves (QP) and S-waves (QS) and the single back-scattering model has been used earlier (Kumar et al. [1]) to determine the quality factor for coda waves (QC). The observed quality factors QP and QS is strongly frequency dependent and the estimated average frequency dependent relation is given by QP = (97 ± 3)f (1.06 ± 0.06) and QS = (127 ± 6)f (0.96±0.06) respectively for P- and S-waves. A comparison of QS estimated in this study and QC previously reported shows that QC > QS for entire frequency range. This indicates the enrichment of coda waves and the importance of scattering attenuation to the attenuation of S-waves in the study region infested with faults and fractures. The ratio QS/QP is found to be greater than unity for the entire frequency range indicating that the body waves from source to station paths crossed a crustal volume with dry and rigid rocks. The frequency dependent relations developed in this study can be very useful to ground motion modeling which in turn is required in the seismic hazard assessment of the region.展开更多
Acoustic Emission Testing (AT) is one of the major non-destructive testing methods used for severity evaluation of structures. Amplitude distributions of AE signals are characterized by b-value and the value is mainly...Acoustic Emission Testing (AT) is one of the major non-destructive testing methods used for severity evaluation of structures. Amplitude distributions of AE signals are characterized by b-value and the value is mainly used for the severity evaluation of concrete structures until now. The value is assumed to be independent with propagation distance between acoustic emission sources to AE sensors. We evaluate the influence of the wide frequency band encountered in the fracture behavior of glass fiber reinforced plastic (GFRP) on the b-value analysis. In tensile tests, the b-value was determined from an acoustic emission (AE) source generated near a centered hole in a specimen of GFRP. At 15 mm from the hole, the b-value analysis indicated a decreasing trend with increasing tensile stress. At a propagation length of 45 mm, farthest from the hole, a?small number of AE signals were received. The attenuation is more rapid for high-frequency AE signals. Thus, the amplitude distribution bandwidth is wide and the b-value changes. This change in b-value for GFRPs is investigated by analyzing the spectral components of the AE signals. For a single-frequency AE source, the b-value is unchanged with propagation length. In contrast, multiple-frequency AE sources produce changes in b-value proportional to the fraction of each spectral component in the received signal. This is due to the frequency dependence of the attenuation with propagation length.?From these results, the b-value analysis cannot be applied to considering frequency dependence of AE attenuation.展开更多
A nonlinear finite-element program was developed to simulate the dynamic evolution of coagulation in tissue considering temperature and thermal-dose dependence of the ultrasound attenuation and blood perfusion rate. T...A nonlinear finite-element program was developed to simulate the dynamic evolution of coagulation in tissue considering temperature and thermal-dose dependence of the ultrasound attenuation and blood perfusion rate. The effects of these dynamic parameters on the lesion formation were investigated in the particular case of ultrasound hepatic ablation with bi-focus intensity pattern. The results of simulations were compared that incorporate dynamic changes of ultrasound attenuation and perfusion and results that neglect these effects. The result shows that thermal-dose-dependent ultrasound attenuation is the dominating factor in the full dynamic model. If the dynamic ultrasound attenuation is ignored, a relatively significant underestimation of the temperature rise appears in the focal plane and the region next to the focal plane, resulting in an underestimation in predicting diameter of coagulation. Higher heating intensity leads to greater underestimation.展开更多
In a fractured porous hydrocarbon reservoir,wave velocities and refections depend on frequency and incident angle.A proper description of the frequency dependence of amplitude variations with ofset(AVO)signatures shou...In a fractured porous hydrocarbon reservoir,wave velocities and refections depend on frequency and incident angle.A proper description of the frequency dependence of amplitude variations with ofset(AVO)signatures should allow efects of fracture inflls and attenuation and dispersion of fractured media.The novelty of this study lies in the introduction of an improved approach for the investigation of incident-angle and frequency variations-associated refection responses.The improved AVO modeling method,using a frequency-domain propagator matrix method,is feasible to accurately consider velocity dispersion predicted from frequency-dependent elasticities from a rock physics modeling.And hence,the method is suitable for use in the case of an anisotropic medium with aligned fractures.Additionally,the proposed modeling approach allows the combined contributions of layer thickness,interbedded structure,impedance contrast and interferences to frequency-dependent refection coefcients and,hence,yielding seismograms of a layered model with a dispersive and attenuative reservoir.Our numerical results show bulk modulus of fracture fuid signifcantly afects anisotropic attenuation,hence causing frequencydependent refection abnormalities.These implications indicate the study of amplitude versus angle and frequency(AVAF)variations provides insights for better interpretation of refection anomalies and hydrocarbon identifcation in a layered reservoir with vertical transverse isotropy(VTI)dispersive media.展开更多
To handle the effects of single event upsets(SEU),which are common to computers in space radiation environment,a new fault-tolerant system with dual-module redundancy is proposed using dynamic reconfigurable techniq...To handle the effects of single event upsets(SEU),which are common to computers in space radiation environment,a new fault-tolerant system with dual-module redundancy is proposed using dynamic reconfigurable technique of field programmable gate array(FPGA). This system contains detection and backup alternative functions,that is,the self-detection and self-healing functions can be completed,and consequently a system design with low hardware redundancy and high resource utilization can be achieved successfully. So it can not only detect fault but also repair the fault effectively after failure. Hence,this method is especially practical to the dynamically reconfigurable computers based on FPGAs. Design methodology has been verified by Virtex-4 FPGA on Xilinx Ml403 development platform.展开更多
Objective:To evaluate the effects of Zhumeria majdae essential oil(ZMEO)on morphine dependence and tolerance in mice.Methods:ZMEO(10,20,and 40 mg/kg)and clonidine(0.1 mg/kg)as the positive control were injected intrap...Objective:To evaluate the effects of Zhumeria majdae essential oil(ZMEO)on morphine dependence and tolerance in mice.Methods:ZMEO(10,20,and 40 mg/kg)and clonidine(0.1 mg/kg)as the positive control were injected intraperitoneally(i.p.).The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone(5 mg/kg)while the tolerance was evaluated by the tail-flick test.Results:ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance(P<0.01),while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg.ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity(P<0.01),and significantly reduced the withdrawal signs(number of jumps)of mice(P<0.01).Conclusions:ZMEO had significant effects on morphine tolerance and dependence.The linalool rich essential oil of Zmajdae plays a major role in the reduction of tolerance and dependence induced by morphine.展开更多
This paper introduces an architecture of distributed systems that facilitates the implementation of a substantial range of dependable system properties, i.e., properties that span an entire system, or a set of compone...This paper introduces an architecture of distributed systems that facilitates the implementation of a substantial range of dependable system properties, i.e., properties that span an entire system, or a set of components dispersed throughout it. This architecture, called GDS, for governed distributed system, governs the system by controlling the flow of messages between its actors, independently of the internals of the interacting actors. This governance is done via an enforced collection of interaction laws organized into a modular and conflict free hierarchical ensemble. This ensemble of laws is sensitive to the history of interaction;and it is enforced in a decentralized manner, and is thus scalable. The dependable system properties that can be implemented under GDS can have the following beneficial consequences, among others: a) the ability to establish regularities over the system, rendering it more coherent, and easier to reason about;b) the ability to provide a degree of trust among the disparate actor of the system;and c) the ability to ensure compliance with interaction protocols that are essential for distributed computing. Consequently, the GDS architecture can have a significant impact on the following important system qualities: security, fault tolerance, auditability, and manageability.展开更多
基金supported by the National Basic Research Program of China(Grant No.:2015CB553701)the National Science and Technology Major Project,China(Grant No.:2019ZX09732001).
文摘Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/b-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knockdown.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/b-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alleviated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/b-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.
文摘Objective:To observe the tolerance and the dependence of endomorphin-1 (EM-1) in rats and the possible mechanisms. Methods:Sixty Sprague-Dawley rats were randomly allocated into saline, acute EM-1-treated and chronic EM-1-treated groups. The rats were intracerebroventricularly injected with saline, acute EM-1 10 μg/kg 30 rain prior to sacrifice,and chronic EM-1 by daily administration at 8:00 A.M. and 15:00 P.M. from 10 μg/kg on the 1^st day to 50 μg/kg on the 94 day, respectively. In chronic EM-1-treated group, the median antinociceptive dose (AD50) and the catatonic median effective dose (ED50) were determined by the improved Dixon's method. Natural withdrawl test was used to assess the dependence of EM-1. Maximal binding capacity (Bmax) and dissociation constant (Kd) of 3H-DAMGO, binding to mu-opioid receptor (MOR) in brain tissue, was measured by Scatchard analysis. Gene expression of MOR was measured by reverse transcription-polymerase chain reaction(RT-PCR). Results :Tolerance of the antinociceptic and catatonic effects on the 3rd day (3.1-fold and 1.9-fold ) and the 9th day (28.4-fold and 8.5-fold) were observed in chronic EM-1-treated group (P 〈 0.05). Jumping times and withdrawal scores of rats were significantly higher in the chronic EM-1-treated group than those in saline group on the 94 day (P 〈 0.05). Bmax and mRNA expression of MOR in cortex, midbrain and striatum were lower in chronic EM-1-treated group on the 94 day than the other two groups(P 〈 0.05), but Kd had no significant difference (P 〉 0.05). AD50,ED50,Bmax ,Kd and gene expression of MOR were recorded. Conclusion: EM-1 possesses the tolerance and the dependence. After a long-term treatment, EM-1 down regulates the binding capacity and mRNA of MOR, which somewhat accounts for the dependence.
文摘Prediction of seismic attenuation and dispersion that are inherently sensitive to hydraulic and elastic properties of the medium of interest in the presence of mesoscopic fractures and pores,is of great interest in the characterization of fractured formations.This has been very difficult,however,considering that stress interactions between fractures and pores,related to their spatial distributions,tend to play a crucial role on affecting overall dynamic elastic properties that are largely unexplored.We thus choose to quantitatively investigate frequency-dependent P-wave characteristics in fractured porous rocks at the scale of a representative sample using a numerical scale-up procedure via performing finite element modelling.Based on 2-D numerical quasi-static experiments,effects of fracture and fluid properties on energy dissipation in response to wave-induced fluid flow at the mesoscopic scale are quantified via solving Biot's equations of consolidation.We show that numerical results are sensitive to some key characteristics of probed synthetic rocks containing unconnected and connected fractures,demonstrating that connectivity,aperture and inclination of fractures as well as fracture infills exhibit strong impacts on the two manifestations of WIFF mechanisms in the connected scenario,and on resulting total wave attenuation and phase velocity.This,in turn,illustrates the importance of these two WIFF mechanisms in fractured rocks and thus,a deeper understanding of them may eventually allow for a better characterization of fracture systems using seismic methods.Moreover,this presented work combines rock physics predictions with seismic numerical simulations in frequency domain to illustrate the sensitivity of seismic signatures on the monitoring of an idealized geologic CO_(2) sequestration in fractured reservoirs.The simulation demonstrates that these two WIFF mechanisms can strongly modify seismic records and hence,indicating that incorporating the two energy dissipation mechanisms in the geophysical interpretation can potentially improving the monitoring and surveying of fluid variations in fractured formations.
基金the National Basic Research Program of China(973 Program)(No.2007CB814903)the National Natural Science Foundation of China(No.70671069)
文摘A hyperbolic function is introduced to reflect the attenuation effect of one firm's default to its partner. If two firms are competitors (copartners), the default intensity of one firm will decrease (increase) abruptly when the other firm defaults. As time goes on, the impact will decrease gradually until extinct. In this model, the joint distribution and marginal distributions of default times are derived by employing the change of measure, and the fair swap premium of a credit default swap (CDS) can be valued.
基金National Natural Science Foundation Under Grant No.61074045,60721062the 973 Program 2006CB705400 of China
文摘The problem of robust active vibration control for a class of electro-hydraulic actuated structural systems with time-delay in the control input channel and parameter uncertainties appearing in all the mass, damping and stiffness matrices is investigated in this paper. First, by introducing a linear varying parameter, the nonlinear system is described as a linear parameter varying (LPV) model. Second, based on this LPV model, an LMI-based condition for the system to be asymptotically stabilized is deduced. By solving these LMIs, a parameter-dependent controller is established for the closed- loop system to be stable with a prescribed level of disturbance attenuation. The condition is also extended to the uncertain case. Finally, some numerical simulations demonstrate the satisfying performance of the proposed controller.
基金Research Committee of University of Macao under Research Grant No.MYRG081(Y1-L2)-FST13-YKVthe Science and Technology Development Fund of the Macao SAR government under Grant No.012/2013/A1
文摘Peak ground acceleration(PGA) estimation is an important task in earthquake engineering practice.One of the most well-known models is the Boore-Joyner-Fumal formula,which estimates the PGA using the moment magnitude,the site-to-fault distance and the site foundation properties.In the present study,the complexity for this formula and the homogeneity assumption for the prediction-error variance are investigated and an effi ciency-robustness balanced formula is proposed.For this purpose,a reduced-order Monte Carlo simulation algorithm for Bayesian model class selection is presented to obtain the most suitable predictive formula and prediction-error model for the seismic attenuation relationship.In this approach,each model class(a predictive formula with a prediction-error model) is evaluated according to its plausibility given the data.The one with the highest plausibility is robust since it possesses the optimal balance between the data fi tting capability and the sensitivity to noise.A database of strong ground motion records in the Tangshan region of China is obtained from the China Earthquake Data Center for the analysis.The optimal predictive formula is proposed based on this database.It is shown that the proposed formula with heterogeneous prediction-error variance is much simpler than the attenuation model suggested by Boore,Joyner and Fumal(1993).
基金The National Basic Research Program of China (973 Program)(No.2007CB814903)the National Natural Science Foundationof China (No.70671069)
文摘To investigate the impact of microstructure interdependency of a counterparty explicitly, a geometric function is introduced in one firm's default intensity to reflect the attenuation behavior of the impact of its counterparty firm's default. The general joint distribution and marginal distributions of default times are derived by employing the change of measure. The fair premium of a vanilla CDS (credit default swap) is obtained in continuous and discrete contexts, respectively. The swap premium in a discrete context is similar to the accumulated interest during the period between two payment days, and the short rate is the swap rate in a continuous context.
文摘BACKGROUND: Drug addiction involves two main central nervous systems, namely the dopamine and noradrenaline systems. These systems are primarily distributed in five brain regions: the ventral tegmental area, the nucleus accumbens, the prefrontal cortex, the hippocampus, and the locus coeruleus. OBJECTIVE: To investigate regional changes of guanine nucleotide binding protein-inhabitant 2 (Gi2) in dopaminergic and noradrenergic neurons in brains of morphine-tolerant and -dependent rats. DESIGN, TIME, AND SETTING: A randomized control study was performed at the Department of Neurobiology in the Second Military Medical University of Chinese PLA (Shanghai, China) between September 2002 and March 2004. MATERIALS: Thirty-six, healthy, male, Sprague-Dawley (SD) rats were used to establish morphine-dependent models. Morphine hydrochloride was a product of Shenyang First Pharmaceutical Factory (China); naloxone hydrochloride was a product of Beijing Four-Ring Pharmaceutical Factory (China); and α subunit of Gi2 antibody was offered by Santa Cruz Biotechnology, lnc (USA). METHODS: Thirty-six SD rats were randomly divided into six groups (n = 6): (1) acute morphine-dependent group, (2) acute abstinent group, (3) acute control group, (4) chronic morphine-dependent group, (5) chronic abstinent group, and (6) chronic control group. Rats in the acute morphine-dependent and the acute groups were injected with morphine (5 mg/kg), one injection every two hours, for a total of eight injections. In the acute and chronic morphine-dependent rat models, morphine withdrawal syndrome was precipitated by an injection of naloxone (5 mg/kg). Rats in the acute control group were given a peritoneal injection of physiological saline at the same administration time as the above two groups. Rats in the chronic morphine-dependent and chronic abstinent groups were injected with morphine three times per day. The administration dose on day 1 was initially 5 mg/kg at 20:00, which increased by 5 mg/kg at 8:00, 12:00, and 20:00 until day 7. On day 13, the dose continuously increased by 10 mg/kg until a chronic morphine-dependent rat model was successfully induced. Afterwards, the rats presented with withdrawal syndromes on naloxone (5 mg/kg) at 8:00 on the same day. Rats in the chronic control group were injected with physiological saline at the same time of the two chronic groups. MAIN OUTCOME MEASURES: The concentration of Gi2 protein in the five brain regions (ventral tegmental area, nucleus accumbens, prefrontal cortex, locus coeruleus, and hippocampus) was detected by immunohistochemistry. RESULTS: In the acute morphine-dependent and acute abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, compared to the acute control group (P 〈 0.01), while no obvious changes were detected in other brain regions. In the chronic morphine-dependent and chronic abstinent groups, Gi2 protein concentration was significantly decreased in the nucleus accumbens, but significantly increased in the locus coeruleus (P 〈 0.01 ) compared to the chronic control group. CONCLUSION: Morphine dependence and tolerance may induce obvious reductions of Gi2 protein levels in the nucleus accumbens of rats. Chronic morphine dependence desensitizes the homologous neurons.
文摘The endogenous opioid system plays a significant role in the modulation of distress in many psychiatric, neurologic, and neurodevelopmental disorders. Many clinical distress symptoms show similarities to the excitatory autonomic withdrawal effects in chronic opioid-dependent animals and humans, as well as to the “quasi-morphine withdrawal syndrome” evoked in naive rodents shortly after acute systemic injection of cyclic AMP-phosphodiesterase (cAMP-PDE) inhibitors. These symptoms result from excessive excitatory opioid receptor signaling and increased endorphin release. Pharmacologic analyses of the remarkably plastic bimodal (excitatory/inhibitory) signaling functions of opioid receptors have utilized microelectrode recordings from opioid-sensitive neurons in tissue cultures of mouse sensory ganglia and hot-water tail-flick assays in mice. These studies led to development of specific chemical formulations that switch opioid receptor signaling from an excessively excitatory to a normal inhibitory mode. Critical combinations of cAMP-PDE inhibitors that release endorphins plus specific agents that switch opioid receptors from excitatory Gs-coupled to inhibitory Gi/Go-coupled signaling were shown to attenuate hyperalgesia and distress evoked by diverse chemical stressors in mouse tail-flick assays. Both the “quasi-morphine withdrawal syndrome” in naive rodents as well as the excitatory withdrawal effects in chronic, opioid-dependent animals and humans may be manifestations of a common Endorphinergic Distress Syndrome (EDS). We suggest that many distress symptoms are caused by EDS, a dysfunctional imbalance in the endogenous opioid system, consisting of abnormal endorphin levels, together with opioid receptors predominately in their excitatory mode. Therefore, concomitantly enhancing endogenous opioid release and switching excessive excitatory opioid receptor signaling to inhibitory signaling can attenuate these distress symptoms. Trials of a critically formulated oral preparation, containing both endorphin enhancers and opioid receptor switchers, have resulted in long-term anxiolytic efficacy and enhanced calm and mental clarity in large numbers of individuals with distress symptoms. These endorphinergic formulations may provide treatment for the emotional and physical distress associated with many psychiatric, neurologic, and neurodevelopmental disorders.
文摘The frequency-dependent characteristics of P- and S-wave attenuation in the upper crust of NW Himalayas have been estimated using local earthquakes for a frequency range of 1.5 to 18 Hz. A total of 43 local events of magnitude 2.1 - 4.8, mostly from the vicinity of Main Boundary Thrust (MBT) and Main Central Thrust (MCT) have been used in the analysis. The extended coda normalization methods were applied to estimate the quality factors for P- waves (QP) and S-waves (QS) and the single back-scattering model has been used earlier (Kumar et al. [1]) to determine the quality factor for coda waves (QC). The observed quality factors QP and QS is strongly frequency dependent and the estimated average frequency dependent relation is given by QP = (97 ± 3)f (1.06 ± 0.06) and QS = (127 ± 6)f (0.96±0.06) respectively for P- and S-waves. A comparison of QS estimated in this study and QC previously reported shows that QC > QS for entire frequency range. This indicates the enrichment of coda waves and the importance of scattering attenuation to the attenuation of S-waves in the study region infested with faults and fractures. The ratio QS/QP is found to be greater than unity for the entire frequency range indicating that the body waves from source to station paths crossed a crustal volume with dry and rigid rocks. The frequency dependent relations developed in this study can be very useful to ground motion modeling which in turn is required in the seismic hazard assessment of the region.
文摘Acoustic Emission Testing (AT) is one of the major non-destructive testing methods used for severity evaluation of structures. Amplitude distributions of AE signals are characterized by b-value and the value is mainly used for the severity evaluation of concrete structures until now. The value is assumed to be independent with propagation distance between acoustic emission sources to AE sensors. We evaluate the influence of the wide frequency band encountered in the fracture behavior of glass fiber reinforced plastic (GFRP) on the b-value analysis. In tensile tests, the b-value was determined from an acoustic emission (AE) source generated near a centered hole in a specimen of GFRP. At 15 mm from the hole, the b-value analysis indicated a decreasing trend with increasing tensile stress. At a propagation length of 45 mm, farthest from the hole, a?small number of AE signals were received. The attenuation is more rapid for high-frequency AE signals. Thus, the amplitude distribution bandwidth is wide and the b-value changes. This change in b-value for GFRPs is investigated by analyzing the spectral components of the AE signals. For a single-frequency AE source, the b-value is unchanged with propagation length. In contrast, multiple-frequency AE sources produce changes in b-value proportional to the fraction of each spectral component in the received signal. This is due to the frequency dependence of the attenuation with propagation length.?From these results, the b-value analysis cannot be applied to considering frequency dependence of AE attenuation.
基金The National Natural Science Foundation ofChina (No 30500124)Shanghai Key Tech-nologies R&D Program of China ( No05DZ19509)
文摘A nonlinear finite-element program was developed to simulate the dynamic evolution of coagulation in tissue considering temperature and thermal-dose dependence of the ultrasound attenuation and blood perfusion rate. The effects of these dynamic parameters on the lesion formation were investigated in the particular case of ultrasound hepatic ablation with bi-focus intensity pattern. The results of simulations were compared that incorporate dynamic changes of ultrasound attenuation and perfusion and results that neglect these effects. The result shows that thermal-dose-dependent ultrasound attenuation is the dominating factor in the full dynamic model. If the dynamic ultrasound attenuation is ignored, a relatively significant underestimation of the temperature rise appears in the focal plane and the region next to the focal plane, resulting in an underestimation in predicting diameter of coagulation. Higher heating intensity leads to greater underestimation.
基金This work was financially supported by the Science Foundation of China University of Petroleum(Beijing)(2462020YXZZ008)the National Natural Science Foundation of China(41804104,41930425,U19B6003-04-03,41774143)+2 种基金the National Key R&D Program of China(2018YFA0702504)the PetroChina Innovation Foundation(2018D-5007-0303)the Science Foundation of SINOPEC Key Laboratory of Geophysics(33550006-20-ZC0699-0001).
文摘In a fractured porous hydrocarbon reservoir,wave velocities and refections depend on frequency and incident angle.A proper description of the frequency dependence of amplitude variations with ofset(AVO)signatures should allow efects of fracture inflls and attenuation and dispersion of fractured media.The novelty of this study lies in the introduction of an improved approach for the investigation of incident-angle and frequency variations-associated refection responses.The improved AVO modeling method,using a frequency-domain propagator matrix method,is feasible to accurately consider velocity dispersion predicted from frequency-dependent elasticities from a rock physics modeling.And hence,the method is suitable for use in the case of an anisotropic medium with aligned fractures.Additionally,the proposed modeling approach allows the combined contributions of layer thickness,interbedded structure,impedance contrast and interferences to frequency-dependent refection coefcients and,hence,yielding seismograms of a layered model with a dispersive and attenuative reservoir.Our numerical results show bulk modulus of fracture fuid signifcantly afects anisotropic attenuation,hence causing frequencydependent refection abnormalities.These implications indicate the study of amplitude versus angle and frequency(AVAF)variations provides insights for better interpretation of refection anomalies and hydrocarbon identifcation in a layered reservoir with vertical transverse isotropy(VTI)dispersive media.
基金supported by the National Natural Science Foundation of China under Grant No. 60971036the National High Technology Research and Development Program of China under Grant No. 2008AA01Z104+1 种基金the Fundamental Research Funds for the Central Universities under Grant No. ZYGX2009Z004the New Century Excellent Talents in University under Grant No. NCET-08-0087
文摘To handle the effects of single event upsets(SEU),which are common to computers in space radiation environment,a new fault-tolerant system with dual-module redundancy is proposed using dynamic reconfigurable technique of field programmable gate array(FPGA). This system contains detection and backup alternative functions,that is,the self-detection and self-healing functions can be completed,and consequently a system design with low hardware redundancy and high resource utilization can be achieved successfully. So it can not only detect fault but also repair the fault effectively after failure. Hence,this method is especially practical to the dynamically reconfigurable computers based on FPGAs. Design methodology has been verified by Virtex-4 FPGA on Xilinx Ml403 development platform.
文摘Objective:To evaluate the effects of Zhumeria majdae essential oil(ZMEO)on morphine dependence and tolerance in mice.Methods:ZMEO(10,20,and 40 mg/kg)and clonidine(0.1 mg/kg)as the positive control were injected intraperitoneally(i.p.).The effect of ZMEO and clonidine on the dependence were evaluated by counting the number of jumps induced by naloxone(5 mg/kg)while the tolerance was evaluated by the tail-flick test.Results:ZMEO at the dose of 10 mg/kg during the development period led to a significant inhibition of morphine tolerance(P<0.01),while it led to reduced morphine dependence with the doses of 20 and 40 mg/kg.ZMEO at two dose levels of 20 and 40 mg/kg indicated significant antinociceptive activity(P<0.01),and significantly reduced the withdrawal signs(number of jumps)of mice(P<0.01).Conclusions:ZMEO had significant effects on morphine tolerance and dependence.The linalool rich essential oil of Zmajdae plays a major role in the reduction of tolerance and dependence induced by morphine.
文摘This paper introduces an architecture of distributed systems that facilitates the implementation of a substantial range of dependable system properties, i.e., properties that span an entire system, or a set of components dispersed throughout it. This architecture, called GDS, for governed distributed system, governs the system by controlling the flow of messages between its actors, independently of the internals of the interacting actors. This governance is done via an enforced collection of interaction laws organized into a modular and conflict free hierarchical ensemble. This ensemble of laws is sensitive to the history of interaction;and it is enforced in a decentralized manner, and is thus scalable. The dependable system properties that can be implemented under GDS can have the following beneficial consequences, among others: a) the ability to establish regularities over the system, rendering it more coherent, and easier to reason about;b) the ability to provide a degree of trust among the disparate actor of the system;and c) the ability to ensure compliance with interaction protocols that are essential for distributed computing. Consequently, the GDS architecture can have a significant impact on the following important system qualities: security, fault tolerance, auditability, and manageability.