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ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y1 and P2Y12 on the platelet. The clinical effectiveness of inhibiting P2Y12 has been well established, and preclinical studies indicated that the inhibition of P2Y1 could provide equivalent antithrombotic efficacy as P2Y12 antagonists and reduce bleeding risks. On the basis of the 2-phenyl-1H-imidazole scaffold of our previously reported xanthine oxidase inhibitor WSJ-557, we first achieved the transition from the xanthine oxidase inhibitors to dual-target antagonists against P2Y1 and P2Y12. We described the structure-activity relationships of the 2-phenyl-1H-imidazole compounds, which led to the identification of the most potent antiplatelet agents, 24w and 25w, both showing a rapid onset of action in pharmacokinetic study. Furthermore, the rat model suggested that 24w demonstrated a wider therapeutic window than ticagrelor, displaying equivalent and dose-dependent antithrombotic efficacy with lower blood loss compared to ticagrelor at same oral dose. These results supported that 24w and 25w could be promising drug candidates.

The impact of acoustic resonance on vortical–acoustic resonance and flow instability is studied by a combined travelling–global mode analysis about a low-speed inviscid parallel shear flow in two-dimensional symmetric duct–cavity configurations. First, in a shallow-cavity case, we show that the difference between incompressible and compressible models in describing the compact feedback loop, consisting of the Kelvin–Helmholtz (KH) instability wave and the Rayleigh–Powell–Rossiter (RPR) feedback, is small and the global mode frequency follows the Strouhal law. Using the compact case as a baseline for comparison, the influence of an acoustic resonator (AR) on the feedback loop is then examined. In this deep-cavity case, phenomena such as frequency deviation from the Strouhal law, global mode switching, global mode destabilization and stabilization, caused by a trapped or a heavily damped acoustic resonant mode, are observed. We show that those phenomena can be explained by the local–global relation of the feedback loop and the dual-feedback view: the coexistence of RPR and AR feedbacks. The Strouhal number variation is due to the phase difference of the unstable vortical wave between the upstream and downstream cavity edges being changed by the additional AR feedback. It is found that the switching is not a vortical but an acoustic effect. The destabilization and stabilization, near and far from an acoustic resonance, are respectively understood as the result of the total feedback at the upstream edge being strengthened and weakened by the AR feedback.

ADP-mediated platelet aggregation is signaled through G protein-coupled receptors P2Y

To investigate the mechanism of wave trapping, acoustic embedded trapped modes associated with two-resonant-mode interference in two-dimensional duct-cavity structures are calculated by the feedback-loop closure principle, which allows us to analyse the travelling modes that construct the trapped modes. The exact two coexisting resonant modes that underpin an embedded trapped mode in a cavity open to two semi-infinite ducts are numerically demonstrated. At the interface between the cavity segment and a duct, total reflection can occur for a particular combination of two propagative guided waves in the cavity. With a particular cavity length and a particular frequency, total reflection also happens for the two reflected waves at the opposite end of the cavity. In this way, the two coexisting standing waves underpin a trapped mode. It is found that the two standing waves are not two closed-cavity modes. Thus, this work presents a new understanding of such embedded trapped modes as a product of total reflection of two guided waves at the interface between two waveguides, rather than interference between two eigenmodes of a closed cavity. For quasi-trapped modes, the Fano scattering phenomenon owing to the effects of two acoustic channels is also shown., Comment: 15 pages, 14 figures

To explain the large-scale hydrodynamic instability along a cavity-backed perforated plate in a flow duct, a two-dimensional multimodal analysis of flow disturbances is performed. First, a hole-by-hole description of the perforated plate shows a spatially growing wave with a wavelength close to the plate length, but much larger than the period of perforation. To better understand this problem and also cavity flow oscillations, we then combine the travelling mode and global mode analyses of the flow where the plate is represented by a homogeneous impedance. The spatially growing wave is, from a homogeneous point of view, essentially a Kelvin–Helmholtz instability wave, strongly distorted by evanescent acoustic waves near the cavity downstream edge. The phase difference of the unstable hydrodynamic mode at the two edges is found to be a bit larger than , whereas the upstream-travelling evanescent waves reduce the total phase change around the feedback loop, so that the phase condition of the global mode can still be satisfied. This particular case indicates the significant effects of those evanescent waves on both the amplitude and phase of cavity flow disturbances. The criterion of the global instability is discussed: the loop gain being larger or smaller than unity determines whether the global mode is unstable or stable. A global mode in the stable regime, which has so far received little attention, is explored by investigating the system response to external forcing. It is shown that sound can be produced when a lightly damped flow–acoustic resonance is excited by a vortical wave.

Factor XIa, as a blood coagulation enzyme, amplifies the generation of the last enzyme thrombin in the blood coagulation cascade. It was proved that direct inhibition of factor XIa could reduce pathologic thrombus formation without an enhanced risk of bleeding. WSJ-557, a nonpurine imidazole-based xanthine oxidase inhibitor in our previous reports, could delay blood coagulation during its animal experiments, which prompted us to investigate its action mechanism. Subsequently, during the exploration of the action mechanism, it was found that WSJ-557 exhibited weak in vitro factor XIa binding affinity. Under the guide of molecular modeling, we adopted molecular hybridization strategy to develop novel factor XIa inhibitors with WSJ-557 as an initial compound. This led to the identification of the most potent compound 44g with a Ki value of 0.009 μM, which was close to that of BMS-724296 (Ki = 0.0015 μM). Additionally, serine protease selectivity study indicated that compound 44g display a desired selectivity, more 400-fold than those of thrombin, factor VIIa and factor Xa in coagulation cascade. Moreover, enzyme kinetics studies suggested that the representative compound 44g acted as a competitive-type inhibitor for FXIa, and molecular modeling revealed that it could tightly bind to the S1, S1′ and S2′ pockets of factor XIa. Furthermore, in vivo efficacy in the rabbit arteriovenous shunt model suggested that compound 44g demonstrated dose-dependent antithrombotic efficacy. Therefore, these results supported that compound 44g could be a potential and efficacious agent for the treatment of thrombotic diseases.

Xanthine oxidase is the rate-limiting enzyme critical for the synthesis of uric acid, and therefore xanthine oxidase inhibitors are considered as one of the promising therapies for hyperuricemia and gout. In our previous study, series of 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids were synthesized that presented excellent in vitro xanthine oxidase inhibitory potency. Interestingly, molecular docking studies revealed that the interaction behavior of these compounds with xanthine oxidase was changed after the conversion from a hydroxy group to amine group. To further investigate the structure–activity relationships of these pyrimidine-containing xanthine oxidase inhibitors and explore the contribution of amino or hydroxy group on xanthine oxidase inhibitory potency, several 2-phenylpyrimidine derivatives with amino or hydroxy functional group were designed and synthesized. Thereafter, the structure–activity research and molecular modeling study proved that hydroxy and amino groups could be used as pharmacophore elements for the design of 2-phenylpyrimidines xanthine oxidase inhibitors. Particularly, the optimized compound, 2-(3-cyano-4-isopentoxy)phenylpyrimidine-4-ol, emerged the strongest xanthine oxidase inhibitor potency, with an IC50 value of 0.046 µM, which was approximately 120-fold more potent than that of allopurinol (IC50 = 5.462 µM). Additionally, Lineweaver-Burk plot analysis revealed that the optimized compound acted as a mixed-type inhibitor. Furthermore, the in vivo hypouricemic effect of the optimized compound was investigated in a hyperuricemia rat model induced by potassium oxonate, and the results showed that the optimized compound could effectively reduce serum uric acid levels at an oral dose of 30 mg/kg.

International audience; The long-wavelength hydrodynamic behaviour over a cavity-backed perforated plate, in a duct with a mean shear flow, is studied numerically using the multimodal method, where the acoustic and hydrodynamic disturbances are calculated from the linearized Euler equations. The flow-acoustic coupling near the perforated plate is first solved hole by hole, and results indicate a well-defined large-scale hydrodynamic wave over the plate, with a wavelength close to the plate length at the peak sound amplification frequency when a plane acoustic wave is introduced from the upstream duct. Since the hydrodynamic wavelength is one order larger than the period of the perforation, the effect of the perforated plate is then described by a homogeneous plate impedance. It is shown that the homogenized approach approximately represents the discrete approach in this problem.

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International audience; The effect of a shear flow on an acoustic liner consisting of a perforated plate backed by cavities is studied. Two different approaches are investigated: First, the duct and the liner are considered as a periodic system while in the second approach the liner is considered as homogeneous and described by an impedance. Those two approaches coincide perfectly without flow for a small hole spacing compared to the acoustic wavelength. This work demonstrates that those two approaches are not wholly consistent when a shear flow is present and reveals some problems in the use of the local impedance with flow. The no-flow impedance cannot be used to describe the liner when a shear flow is present. An equivalent impedance with flow can be defined but it depends on the direction of the incident waves and loses its local characteristic.

Xanthine oxidase (XO) has emerged as an important target for the treatment of hyperuricemia and gout. In this study, to obtain novel nonpurine XO inhibitors, a series of 1-alkyl-5/6-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-1H-indole-3-carbonitriles (1a-1u, 2c, 2e, 2h and 2n) were designed using a bioisosteric replacement strategy and were synthesized through a five-step procedure with good yields. Thereafter, the in vitro XO inhibitory potencies of these compounds were evaluated by spectrophotometry, showing inhibitory profiles in the micromolar/submicromolar range. Particularly, compound 1h emerged as the strongest XO inhibitor, with an IC50 value of 0.36 μM, which was approximately 21-fold more potent than the positive control allopurinol. Additionally, the structure-activity relationships revealed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety linked at the 5-position of the indole scaffold was more preferable than the 6-position for the XO inhibitory potency. Enzyme kinetic studies indicated that compound 1h acted as a mixed-type XO inhibitor. Moreover, molecular modeling studies were performed on compound 1h to gain insights into its binding modes with XO. The results showed that the 5-oxo-4,5-dihydro-1,2,4-oxadiazole moiety could interact with Arg880 and Thr1010 in the innermost part of the active pocket through hydrogen bonds, while the cyano group could form hydrogen bonds with Asn768 and Lys771 in the subpocket. Furthermore, the in vivo hypouricemic effect of compound 1h was further investigated in a hyperuricemia rat model induced by potassium oxonate. The results suggested that compound 1h could effectively reduce serum uric acid levels at an oral dose of 10 mg/kg. Therefore, compound 1h could be a promising lead compound for the treatment of hyperuricemia and gout.

Xanthine oxidase (XO) is a critical target for the therapy of hyperuricemia and gout. In this study, a number of 3-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-1,2,4-oxadiazol-5(4H)-ones (3a–3w) were newly designed by a bioisosteric replacement and hybrid strategy with the hope of obtaining novel and effective nonpurine XO inhibitors. Subsequently, these compounds were synthesized through a three-step procedure, with good yields. In addition, the in vitro bovine XO inhibitions were measured by spectrophotometric determination of uric acid formation at 295 nm using allopurinol as a positive control. As a result, compound 3j was found to be the most potent XO inhibitor, with an IC50 value of 0.121 µM, which was approximately 63-fold more potent than allopurinol, and the analysis of the structure-activity relationships indicated that the hydrophobic group at 4′-position was essential for inhibitory potency. Additionally, the molecular modeling results showed that the 1,2,4-oxadiazol-5(4H)-one moiety binds to XO active site via various hydrogen bonds with Arg880 and Thr1010. Moreover, the compound 3j was demonstrated to be a mixed-type nonpurine XO inhibitor. Furthermore, the hypouricemic studies on a rat model, induced by potassium oxonate, demonstrated that serum uric acid levels could be effectually reduced by compound 3j at an oral dose of 15 mg/kg. Therefore, compound 3j could be a promising lead compound for the treatment of hyperuricemia and gout.

International audience; This paper presents a two-dimensional (2D) cavity-by-cavity description of a convective instability near a lined wall with low dissipation due to the coupling of hydrodynamic modes with resonance of the wall. For a liner consisting of an array of deep cavities periodically placed along a duct containing a mean shear flow, the acoustic and hydrodynamic disturbances are described by the linearized Euler equations. The Bloch modes and the scattering matrix of periodic cells are used to examine the instability over the liner. The unstable Bloch mode is due to the coupling of a hydrodynamic mode in the shear flow with the cavity resonance. It is demonstrated that even when all the transverse modes are stable in the duct-cavity system, i.e. when the Kelvin-Helmholtz instability of the shear flow over the cavities does not occur, such an instability over the liner can still exist. The unstable Bloch wave, excited by the incident sound wave at the upstream part of the liner, convectively grows along the liner, and regenerates sound near the downstream edge of the liner with a sound level higher than that incident sound level. It is shown that a homogenized approach, where the wall effect is described by a homogeneous impedance, can also explain the unstable behaviour above the liner. It reveals that a small wall resistance and a small and positive reactance are two necessary conditions for such an instability.

Xanthine oxidase is an important target for the treatment of hyperuricemia, gout and other related diseases. Analysis of the high-resolution structure of xanthine oxidase with febuxostat identified the existence of a subpocket formed by the residues Leu648, Asn768, Lys771, Leu1014 and Pro1076. In this study, we designed and synthesized a series of 2-[4-alkoxy-3-(1H-tetrazol-1-yl) phenyl]-6-oxo-1,6-dihydropyrimidine-5-carboxylic acid derivatives (8a-8z) with a tetrazole group targeting this subpocket of the xanthine oxidase active site, and they were further evaluated for their inhibitory potency against xanthine oxidase in vitro. The results showed that all the tested compounds (8a-8z) exhibited an apparent xanthine oxidase inhibitory potency, with IC50 values ranging from 0.0288 μM to 0.629 μM. Among them, compound 8u emerged as the most potent xanthine oxidase inhibitor, with an IC50 value of 0.0288 μM, which was comparable to febuxostat (IC50 = 0.0236 μM). The structure-activity relationship results revealed that the hydrophobic group at the 4′-position was indispensable for the inhibitory potency in vitro against xanthine oxidase. A Lineweaver-Burk plot revealed that the representative compound 8u acted as a mixed-type inhibitor for xanthine oxidase. Furthermore, molecular modeling studies were performed to gain insights into the binding mode of 8u with xanthine oxidase and suggested that the tetrazole group of the phenyl unit was accommodated in the subpocket, as expected. Moreover, a potassium oxonate-induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 8u, and the result demonstrated that compound 8u could effectively reduce serum uric acid levels at an oral dose of 5 mg/kg. In addition, acute oral toxicity study in mice indicated that compound 8u was nontoxic and tolerated at a dose up to 2000 mg/kg. Thus, compound 8u could be a potential and efficacious agent in treatment of hyperuricemia with low toxicity.

In our previous study, we reported a series of 1-hydroxy-2-phenyl-1H-imidazole-5-carboxylic acid derivatives that presented excellent in vitro xanthine oxidase (XO) inhibitory potency. To further investigate the structure-activity relationships of these compounds, the imidazole ring was transformed to a pyrimidine ring to design 2-(4-alkoxy-3-cyano)phenyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (8a-8j), 2-(4-alkoxy-3-cyano)phenyl-4-methyl-6-oxo-1,6-dihydropyrimidine-5-carboxylic acids (9c, 9e, 9j, 9l) and 2-(4-alkoxy-3-cyano)phenyl-6-imino-1,6-dihydropyrimidine-5-carboxylic acids (10c, 10e, 10j, 10l). These compounds exhibited remarkable in vitro XO inhibitory potency with IC50 values ranging from 0.0181 μM to 0.5677 μM. Specifically, compounds 10c and 10e, with IC50 values of 0.0240 μM and 0.0181 μM, respectively, emerged as the most potent XO inhibitors, and their potencies were comparable to that of febuxostat. Structure-activity relationship analysis revealed that the methyl group at 4-position of pyrimidine ring could damage the potency, and the XO inhibitory potency was maintained when carbonyl group was changed to an imino group. Lineweaver-Burk plot analysis revealed that the representative compound 10c acted as a mixed-type inhibitor. A potassium oxonate induced hyperuricemia model in rats was chosen to further confirm the hypouricemic effect of compound 10c, and the results showed that compound 10c (5 mg/kg) was able to significantly lower the serum uric acid level. Furthermore, in acute oral toxicity study, no sign of toxicity was observed when the mice were administered with a single 2000 mg/kg oral dose of compound 10c. These results suggested that compound 10c was a potent and promising uric acid-lowing agent for the treatment of hyperuricemia.

International audience; The scattering of sound by a membrane-covered cavity in a duct with shear flow is calculated with a linear model based on the multimodal method. The model is verified by comparison against the previous experiments focused on sound suppression of a stable system with high-tension membranes and a low-speed flow. It is shown in this paper that such a situation is drastically changed when the flow velocity is larger than the in vacuo flexural wave speed of the membrane. One of the neutral hydrodynamic modes can be destabilized under certain conditions, and this flexural instability can lead to sound amplification. For a given flow profile, the axial growth rate of the instability increases with the mean flow velocity but saturates at high velocities. For a given mean flow velocity, there is an optimum boundary layer thickness for the instability. Increasing the structural damping tends to stabilize the instability and thus inhibit the sound amplification.

A finite element acoustic model was proposed for investigating the characteristic of a novel non-locally reacting acoustic liner. This non-locally reacting acoustic liner was based on the so-called multiple cavity resonance mechanism which could broaden the absorption bandwidth. The basic idea of it was that when the back cavity of the liner was partitioned into sub-volumes of different size, multiple resonances relating to different length were produced so that the attenuation peaks came closer and worked jointly to provide high attenuation over a broad frequency band. There were strong coupling effects of the resonances inside the back cavities and in the duct when the sound propagated in the duct installed this non-locally acoustic liner. The proposed finite element acoustic model could simulate the entire sound field both in the duct and inside the back non-uniform cavities of the liner including the strong coupling effects. The comparison between the numerical and the experimental results demonstrated that, the finite element acoustic model was an accurate, stable and rapid method for investigating the acoustic characteristic of this novel non-locally reacting acoustic liner. The numerical study was also targeted for developing an optimal non-locally acoustic liner for engineering applications.

When a Helmholtz resonator is exposed to grazing flow, an unstable shear layer at the opening can cause the occurrence of acoustic resonance under appropriate conditions. In this paper, in order to suppress the flow-induced resonance, the effects of inside acoustic liners placed on the side wall or the bottom of a Helmholtz resonator are investigated. Based on the one-dimensional sound propagation theory, the time domain impedance model of a Helmholtz resonator with inside acoustic liner is derived, and then combined with a discrete vortex model the resonant behavior of the resonator under grazing flow is simulated. Besides, an experiment is conducted to validate the present model, showing significant reduction of the peak sound pressure level achieved by the use of the side-wall liners. And the simulation results match reasonably well with the experimental data. The present results reveal that the inside acoustic liner can not only absorb the resonant sound pressure, but also suppress the fluctuation motion of the shear layer over the opening of the resonator. In all, the impact of the acoustic liners is to dampen the instability of the flow-acoustic coupled system. This demonstrates that it is a convenient and effective method for suppressing Helmholtz resonance by using inside acoustic liner.

The acoustical response of a slit with a mean bias flow is numerically studied. By means of a potential flow model based on the discrete vortex method and a spanwise-averaged three-dimensional Green׳s function, both unsteady vortical flow and slit impedance are obtained in a unified theoretical framework. The numerical simulation focuses on the acoustic-excited vortex structures of the slit flow while neglecting the viscous damping effect. Three representative flow features are demonstrated, which are the destabilized jet flow, the rolling up of vortex sheets and formation of vortex pairs, and the reversal flow with alternating vortex shedding on both sides of the slit. These features are corresponding to low, moderate, and high sound amplitude, respectively. The acoustic behavior of the slit can be divided into linear, transition, and nonlinear regimes. During its evolution through the three regimes, the resistance exhibits a constant value, a slight decrease, and a significant increase with the increasing sound amplitude. Correspondingly, the reactance first remains constant and then shows a modest decrease as the sound amplitude increases. The nonlinear effect also causes the gradual decrease of the mean bias velocity in company with the marked increase of the amplitude of the fluctuating velocity in the slit. The mean bias velocity decreases to about 80 percent of its linear value at the transition point where reversal flow begins to occur, and further decreases to only 10 percent in the highly nonlinear region. The slit impedance is also presented as a function of frequency and for different aspect ratios. And the effects of frequency and slit geometry are discussed.

International audience; Vorticity convection as well as its excitation to a Helmholtz resonator is studied numerically. Convection velocities of both the concentrated vortical structure and the total distributed vorticity in the orifice region are calculated. Results indicate that the vortex convection velocity is the more useful one in controlling the oscillation frequency. The excitation pressure from the vortical flow is found almost in phase with the fluctuation of the total circulation in the orifice region. This helps us to deduce that vorticity accumulation in the opening region and its relatively simultaneous efflux, due to the shear layer rolling-up into a vortex, are responsible for the pressure fluctuation that excites the acoustic mode of the cavity. It is found that the frequency characteristics can be significantly varied by the system damping. Increasing the damping leads to a reduction in the range of the Strouhal number of oscillation, which is associated with the disappearing lock-in effect in frequency. The dependence of the vortex convection velocity and the critical Strouhal number for the maximum oscillation on damping is also shown.

This paper presents a theoretical study of the nonlinear acoustic properties of a slit in a thin plate subjected to highintensity sound excitation. In the present model, the conventional discrete vortexmethod is employed to simulate the near-field two-dimensional unsteady flow in order to capture the mechanism of the sound–vortex interaction, which is in combination with a spanwise-averaged three-dimensional Green’s function method used to connect the nearfield flow quantities with the far-field sound pressure. This model is compared with an existing particle image velocimetry flow visualization and a direct numerical simulation model, showing good qualitative agreement. It is revealed that the oscillatory slitflow is dominated by a pair of spiral-like counter-rotating vorticesmoving away from the slit and eventually colliding into each other. Because of the vortical flow effect, increases in the sound pressure level result in significant increases in acoustic resistance and modest decreases in acoustic reactance. For the parametric range in this study, increases in the aspect ratio of the slit result in slight increases in acoustic resistance but unnegligible reductions in acoustic reactance. However, the influence of the aspect ratio on acoustic impedance tends to be less important when the sound pressure level exceeds a certain high value.

Hydrodynamic journal bearings under large perturbations go beyond the serviceable range of the linear theory and thus should be treated as nonlinear systems. Three kinds of nonlinear oil-film force models (24-co., 28-co. and 36-co. models) are proposed to denote the oil-film forces by retaining certain terms of Taylor series expansion of the oil-film force. A least-mean squares method in time domain is proposed to identify the oil-film coefficients. The study shows that these three nonlinear models are feasible to describe the oil-film forces and reliable linear oil-film coefficients can be identified from these models.

Linear sound propagation in an axisymmetric corrugated pipe with shear flow is studied numerically and experimentally. The acoustic and hydrodynamic perturbations are described by the linearized Euler equations (LEEs) in a parallel shear flow. Wave propagation and scattering are computed by means of a multimodal method where the disturbances are expressed as a linear combination of acoustic modes and hydrodynamic modes. The Floquet-Bloch approach is used to calculate the wavenumber in the periodic system. Both sound amplification and absorption, depending on the Strouhal number, are well predicted compared to experiments, which means that the flow-acoustic coupling in the system is effectively described by the present model. It is also shown that the corrugated pipe can amplify the sound even if the shear layer over the cavities is stable everywhere.

In this paper, sound generated by large-scale votices in a two-dimensional low-Mach number turbulent shear layer is investigated. A hybrid DVM/APE (Discrete-Vortex Model and Acoustic Perturbation Equations) approach is proposed to study this vortex sound phenomenon. A discrete-vortex model is used to simulate unsteady fluid motions of the trailing edge shear layer. A conformal mapping is applied to solve the 2D inviscid flow near the half plane, which is originally used for the problem of a slit geometry. At the trailing edge of the plane, the effect of fluid’s viscosity is imposed by a vortex shedding model and Kutta condition. The unsteady flow field is obtained after DVM simulation. The background mean flow field is acquired by a time-average algorithm. Then, acoustic perturbation equations are solved to obtain the acoustic field by CAA approaches with both acoustic sources and the background mean flow field determined from the results of DVM. Results demonstrate that this hybrid DVM/APE method is a feasible approach to simulate sound generated by the motions of vortices.

In this paper, a theoretical model is developed to study the acoustical response of a Helmholtz resonator as a duct-branched acoustic absorber subjected to both high-intensity sound and grazing flow. The present model is comprised of a discrete vortex model in combination with a one-dimensional duct sound propagation model. The present work is to study the overall effect of incident sound interacting with grazing flow but putting emphasis on the nonlinear or intermediate regime where the sound intensity has a marked or non-negligible influence on the acoustic behavior of the Helmholtz resonator. The numerical results reveal that the flow field around the orifice is dominated by the evolution of the vortex sheet and the flow pattern is influenced by the ratio of the orifice flow velocity to the grazing flow velocity. When the incident sound pressure is high or the resonance occurs, the resonator shows nonlinearity, i.e., the acoustic impedance and absorption coefficient vary not only with duct flow Mach number buy also with incident frequency and incident sound pressure level.

This paper presents a theoretical study of the acoustic properties of a small rectangular orifice in a plate of finite thickness, in the presence of both grazing flow and high-intensity sound wave. The present investigation has three basic objectives. The first is to study the plate thickness effect on acoustic properties of the orifice. The second is to study the interaction of high-intensity sound with grazing flow. The third objective is to present flow details around the orifice. On the assumption of large aspect ratio, a 2D discrete vortex method is employed to provide the near field unsteady flow simulation results that are then substituted into a spanwise-averaged 3D Green function integral formula to develop a quasi3D model. Depending on this strategy, the nonlinear acoustic impedance of the orifice is calculated from the average flow velocity through the orifice. The reactance of the orifice increases markedly with the increase of the plate thickness, and the reactance results of the finite-thickness plate are apparently larger than the one of the zero-thickness plate. The calculated resistance reveals that the acoustic property of the orifice undergoes a transition from linear to nonlinear, as the sound pressure amplitude increases; the grazing flow velocity has influence on the transition SPL, resulting from the interaction. More detailed analyses of the effects of the grazing flow and the incident sound wave on the acoustic properties of the orifice are carried out. The vortex shedding process at the orifice edge and the evolution of the shed vortex sheet are simulated, the simulation results exhibit the major features of the vortex sheet, such as the rolling up nature and the “flapping” motion of the shear layer over the orifice.

The acoustic resonance in a Helmholtz resonator excited by a low Mach number grazing flow is studied theoretically. The nonlinear numerical model is established by coupling the vortical motion at the cavity opening with the cavity acoustic mode through an explicit force balancing relation between the two sides of the opening. The vortical motion is modeled in the potential flow framework, in which the oscillating motion of the thin shear layer is described by an array of convected point vortices, and the unsteady vortex shedding is determined by the Kutta condition. The cavity acoustic mode is obtained from the one-dimensional acoustic propagation model, the time-domain equivalent of which is given by means of a broadband time-domain impedance model. The acoustic resistances due to radiation and viscous loss at the opening are also taken into account. The physical processes of the self-excited oscillations, at both resonance and off-resonance states, are simulated directly in the time domain. Results show that the shear layer exhibits a weak flapping motion at the off-resonance state, whereas it rolls up into large-scale vortex cores when resonances occur. Single and dual-vortex patterns are observed corresponding to the first and second hydrodynamic modes. The simulation also reveals different trajectories of the two vortices across the opening when the first and second hydrodynamic modes co-exist. The strong modulation of the shed vorticity by the acoustic feedback at the resonance state is demonstrated. The model overestimates the pressure pulsation amplitude by a factor 2, which is expected to be due to the turbulence of the flow which is not taken into account. The model neglects vortex shedding at the downstream and side edges of the cavity. This will also result in an overestimation of the pulsation amplitude.

Objective: To investigate the effect of Yishen Huanshuai recipe (YSHSR) on the progression of chronic renal failure (CRF).Methods: Forty-six patients with CRF were divided into two groups: group A (self-controlled group, n= 18), whose treatment plan was subdivided into two phases. During the first phase, the patients treated with low protein diet and controlling blood pressure, while in the second phase, YSHSR was given. Group B (n = 28), whose treatment plan was similar with that of group A in the second phase. The rate of progression of CRF was estimated by slope of the creatinine reciprocal (dl/mg) with time (month).Results: Mean slope of the creatinine reciprocal with time from the group A during the first phase was - 0. 0104 ± 0. 0021, while during the second phase, it was - 0. 0034 ± 0. 0018. There was significant difference between them (P