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Fe50Cr14Mo14C9B8Tm5 bulk metallic glass was prepared at a cooling rate of 6.36 × 104 K s−1. Its Young's modulus and compressive strength were modulated through controlled crystallization processing. A low cooling rate induced the formation of the Tm2Mo2C3 phase while preserving free volume. Thus, the elastic deformation limit was increased to 2.39%. After low-temperature annealing, the (Fe, Cr)23(C, B)6 phase was formed at first. As the annealing temperature increased, four types of crystalline phases appeared as dispersions in this alloy, where the hardness of the Fe3Mo3C phase reached 32.5 GPa. Even when the annealing temperature reached 1260 K, the average grain size was only 180 nm. The large volume fraction of the Fe3Mo3C phase and uniform microstructure of crystallized alloy resulted in a high strength of 4.01 GPa and a low Young's modulus of 237.11 GPa. [ABSTRACT FROM AUTHOR]

The Zr37Hf16Ni12.5Cu12.5Al11Co6Nb5 bulk metallic glass (BMG) with strong glass-forming ability (GFA) and remarkable mechanical properties was designed, and its thermophysical properties were characterized simultaneously. The glass transition temperature reached up to 726 K, while the fragility index of 43 was derived by measuring alloy viscosity. The undercooled liquid of this BMG with such a low fragility index displayed a strong liquid behavior, corresponding to its small crystallization driving force and high GFA. The thermal expansion coefficient increased from 9.76 × 10−6 K−1 of glassy state to 2.71 × 10−5 K−1 of undercooled liquid, and the close-packed structure was evidenced by the low specific energy for free volume formation of 239.4 kJ/mol. Owing to its low free volume and high glass transition temperature, this BMG exhibited remarkable tensile and compressive yield strengths up to 1660.3 and 2042.3 MPa, respectively. [ABSTRACT FROM AUTHOR]

This article studies a special rail corrugation phenomenon occurring at a braking section of Shenzhen Metro Line 3 based on friction-excited oscillation. The rail corrugation is strongly related to the braking operation: when the braking operation was canceled, the corrugation did not appear again after being ground. In this article, a new viewpoint that the corrugation originates from the unstable vibration of the wheel–rail–brake shoe braking system is put forward. To test this point of view, a finite element model composed of two wheelsets with a brake shoe braking system and two rails for complex modal analysis was established. Parameter sensitivity analysis was carried out to develop some measures to suppress rail corrugation. The results show that rail corrugation at the long downhill braking section originates from the unstable vibration at about 430 Hz of the wheel–rail–brake shoe braking system. The corrugation wavelength predicted by the finite model is about 55 mm, which shows good agreement with the on-site data. The results of parameter sensitivity analysis show that the influence of the coverage angle of the brake shoe on the rail corrugation is significant. The possibility of the rail corrugation and its progression speed increase significantly with a decrease in the coverage angle of the brake shoe. To suppress the rail corrugation, the coverage angle should not be less than 48° when designing the brake shoe structure. The influence of the installation position of the brake shoe on the rail corrugation is also obvious. The position of the brake shoe with a pressure angle of 8° can restrain rail corrugation to the greatest extent. The contact state between the brake shoe and wheel tread has little influence on rail corrugation. In practice, the brake shoe should be in full contact with the tread. [ABSTRACT FROM AUTHOR]

This paper conducts a detailed investigation into the formation mechanism of wheel polygonalization in high-speed trains and its influence factors through numerical simulation. A finite element model including two rails, one wheelset, and three disc brake units is set up to study the formation mechanism of wheel polygonalization in high-speed trains based on the point of view of frictional self-excited vibration. Using the finite element complex analysis, the dynamic stability of the wheelset-track-disc brake system is studied. In addition, the influence factors on the wheel polygonalization are investigated. Results show that when the longitudinal creep force is unsaturated, the 21-order polygonal wear of wheels occurs easily due to the self-excited vibration of the disc brake unit. When the longitudinal creep force is saturated, the 12-order polygonal wear of wheels probably occurs due to the self-excited vibration of the disc brake unit. The bigger the friction coefficient between the brake disc and pad, the greater the occurrence propensity of the polygonal wear of wheels. Vertical fastener damping that is too large or too small is disadvantageous for suppressing wheel corrugation. However, increasing the lateral fastener damping is beneficial for reducing the polygonal wear of wheels. When the vertical fastener stiffness is 25 MN/m, 7-order, 9-order, and 14-order wheel polygonalization can easily occur. A higher lateral fastener stiffness is beneficial for the suppression of wheel polygonalization. [ABSTRACT FROM AUTHOR]

Background: Some cancers have been shown to lack expression of argininosuccinate synthetase (ASS), an enzyme required for the synthesis of arginine and a possible biomarker of sensitivity to arginine deprivation. Arginine deiminase (ADI) is a microbial enzyme capable of efficiently depleting peripheral blood arginine.Methods: Argininosuccinate synthetase expression was assessed in human small cell lung cancer (SCLC) by immunohistochemistry (IHC), with expression also assessed in a panel of 10 human SCLC by qRT-PCR and western blot. Proliferation assays and analyses of apoptosis and autophagy assessed the effect of pegylated ADI (ADI-PEG20) in vitro. The in vivo efficacy of ADI-PEG20 was determined in mice bearing SCLC xenografts.Results: Approximately 45% of SCLC tumours and 50% of cell lines assessed were negative for ASS. Argininosuccinate synthetase-deficient SCLC cells demonstrated sensitivity to ADI-PEG20, which was associated with the induction of autophagy and caspase-independent cell death. Arginine deiminase-PEG20 treatment of ASS-negative SCLC xenografts caused significant, dose-dependent inhibition of tumour growth of both small and established tumours.Conclusion: These results suggest a role for ADI-PEG20 in the treatment of SCLC, and a clinical trial exploring this therapeutic approach in patients with ASS-negative SCLC by IHC has now been initiated. [ABSTRACT FROM AUTHOR]

The longitudinal spin Seebeck effect (LSSE) with a vertical temperature gradient is one of the most important mechanisms to generate pure spin current. Previous studies of the LSSE excited spin current focus mainly on the magnetic insulators, a little on ferromagnetic metals, and rarely on ferromagnetic half metals. In this work, we demonstrate a significant spin current injected from the highly spin polarized ferromagnetic half metal La0.7Sr0.3MnO3 by the LSSE. The sign of the thermal voltage can be reversed by using the spin current detector Cr with a large negative spin Hall angle. The ratio of the inverse spin Hall voltage to the total thermal signal in La0.7Sr0.3MnO3 is much larger than that in ferromagnetic metals, such as permalloy and CoFeB. The nontrivial temperature-dependent voltage suggests that the thermal transport in La0.7Sr0.3MnO3 is carried by magnons. This study provides insight into the mechanism of thermally excited spin current in ferromagnetic half metals and recommends the highly spin polarized La0.7Sr0.3MnO3 as a promising candidate for metal-based spin caloritronics devices. [ABSTRACT FROM AUTHOR]

The liquid state thermophysical properties and amorphous solidification kinetics of Fe_{50-x}Co_{x}Cr_{14}Mo_{14}C_{9}B_{8}Tm_{5} (x=10, 15, 20, and 25) alloys were explored by electromagnetic and electrostatic levitation techniques. It was found that the surface tension of liquid alloys with Fe contents below 30 at. % had a strong temperature dependence. The high surface tension led to a sharp increase in the interfacial free-energy penalty. A high nucleation barrier was formed inside the melt, which greatly inhibited the nucleation rate. The liquid viscosity revealed the strong liquid feature of this alloy series, which became the dominant kinetic factor determining their solidification mechanisms. The high viscosity hindered atomic diffusion and delayed nucleation. The long crystallizing incubation time of Fe_{30}Co_{20}Cr_{14}Mo_{14}C_{9}B_{8}Tm_{5} ensured a strong glass-forming ability and a low critical cooling rate of 2.11×10^{3}Ks^{-1}. As a result, a bulk metallic glass rod with an 8-mm diameter was successfully prepared by a convenient casting procedure. This rod could remain in a glassy state at a higher temperature and over a wider temperature range due to its high glass-transition temperature and large undercooled liquid region. The apparent activation energy for nucleation was derived as 463.8 kJmol^{-1} according to the nonisothermal crystallization kinetics, indicating that the bulk metallic glass had to absorb a large amount of energy to overcome the potential barriers before nucleation and thus exhibited excellent thermal stability.

Objective: To establish an early prediction model for bloodstream infection in patients with extremely severe burns based on the screened independent risk factors of the infection, and to analyze its predictive value. Methods: A retrospective case-control study was conducted. From January 1, 2010 to December 31, 2019, 307 patients with extremely severe burns were admitted to the Department of Burns and Plastic Surgery of Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medcine, including 251 males and 56 females, aged from 33 to 55 years. According to the occurrence of bloodstream infection, the patients were divided into non-bloodstream infection group (221 cases) and bloodstream infection group (86 cases). The gender, age, body mass index, outcome, length of hospital stay of patients were compared between the two groups, and the detection of bacteria in blood microbial culture of patients was analyzed in bloodstream infection group. The included 307 patients were divided into modeling group (219 cases) and validation group (88 cases) according to the random number table with a ratio of about 7∶3. The gender, age, body mass index, total burn area, full-thickness burn area, combination of inhalation injury, implementation of mechanical ventilation, days of mechanical ventilation, days of intensive care unit (ICU) stay, outcome, length of hospital stay, complication of bloodstream infection of patients were compared between the two groups. According to the occurrence of bloodstream infection, the patients in modeling group were divided into bloodstream infection subgroup (154 cases) and non-bloodstream infection subgroup (165 cases). The total burn area, full-thickness burn area, combination of inhalation injury, implementation of mechanical ventilation, days of mechanical ventilation, and days of ICU stay of patients were compared between the two subgroups. The above-mentioned data between two groups were statistically analyzed with one-way analysis of independent sample t test, chi-square test, and Mann-Whitney U test to screen out the factors with statistically significant differences in the subgroup univariate analysis of modeling group. The factors were used as variables, and binary multivariate logistic regression analysis was performed to screen out the independent risk factors of bloodstream infection in patients with extremely severe burns, based on which the prediction model for bloodstream infection in patients with extremely severe burns of modeling group was established. The receiver operating characteristic (ROC) curve of the prediction model predicting the risk of bloodstream infection of patients in modeling group was drawn, and the area under the ROC curve was calculated. The sensitivity, specificity, and the best prediction probability were calculated according to the Youden index. According to the occurrence of bloodstream infection, the patients in validation group were divided into bloodstream infection subgroup (21 cases) and non-bloodstream infection subgroup (67 cases). The prediction probability >the best prediction probability of model was used as the judgment standard of bloodstream infection. The prediction model was used to predict the occurrence of bloodstream infection of patients in the two subgroups of validation group, and the incidence, specificity, and sensitivity for predicting bloodstream infection were calculated. In addition, the ROC curve of the prediction model predicting the risk of bloodstream infection of patients in validation group was drawn, and the area under the ROC curve was calculated. Results: Compared with those of non-bloodstream infection group, the mortality of patients in bloodstream infection group was significantly higher ( χ 2 =8.485, P <0.01), the length of hospital stay was significantly increased ( Z =-3.003, P <0.01), but there was no significant change in gender, age, or body mass index ( P >0.05). In patients of bloodstream infection group, 110 strains of bacteria were detected in blood microbial culture, among which Klebsiella pneumoniae , Pseudomonas aeruginosa, and Acinetobacter baumannii were the top three bacteria, accounting for 35.45% (39/110), 26.36% (29/110), and 13.64% (15/110), respectively. Gender, age, body mass index, total burn area, full-thickness burn area, proportion of combination of inhalation injury, proportion of implementation of mechanical ventilation, days of mechanical ventilation, days of ICU stay, outcome, length of hospital stay, and proportion of complication of bloodstream infection of patients were similar between modeling group and validation group ( P >0.05). Compared with those of non-bloodstream infection subgroup in modeling group, the total burn area, full-thickness burn area, proportion of combination of inhalation injury, proportion of implementation of mechanical ventilation, days of mechanical ventilation, and days of ICU stay of patients in bloodstream infection subgroup were significantly increased ( Z =-4.429, t =-4.045, χ 2 =7.845, 8.845, Z =-3.904, -4.134, P <0.01). Binary multivariate logistic regression analysis showed that total burn area, days of ICU stay, and combination of inhalation injury were the independent risk factors for bloodstream infection of patients in modeling group (odds ratio=1.031, 1.018, 2.871, 95% confidence interval=1.004-1.059, 1.006-1.030, 1.345-6.128, P <0.05 or P <0.01). In modeling group, the area under the ROC curve was 0.773 (95% confidence interval=0.708-0.838); the sensitivity was 64.6%, the specificity was 77.9%, and the best prediction probability was 0.335 when the Youden index was 0.425. The bloodstream infection incidence of patients predicted by the prediction model in validation group was 27.27% (24/88), with specificity of 82.09% (55/67) and sensitivity of 57.14% (12/21). The area under the ROC curve in validation group was 0.759 (95% confidence interval=0.637-0.882). Conclusions: The total burn area, days of ICU stay, and combination of inhalation injury are the risk factors of bloodstream infection in patients with extremely severe burns. The early prediction model for bloodstream infection risk in patients with extremely severe burns based on these factors has certain predictive value for burn centers with relatively stable treatment methods and bacterial epidemiology.

Targeting retroviral vectors to tumor vasculature is an important goal of cancer gene therapy. In this study, we report a novel targeting approach wherein IgG-binding peptides were inserted into the Moloney murine leukemia virus (MuLV) envelope (env) protein. The modifications on the viral env included replacement of the entire receptor binding region of the viral env with protein A (or ZZ) domains. The truncated env incorporating IgG-binding motifs (known as proteins) provided the targeting function, while the co-expressed wild-type (WT) env protein enabled viral fusion and cell entry. An anti-human VEGF receptor (Flk-1/KDR) antibody served as a molecular bridge, directing the retroviral vector to the endothelial cell. Hence, the IgG-targeted vectors bound to the Flk-1/KDR antibody which in turn bound to VEGF receptors on Kaposi sarcoma, KSY1, endothelial cells. The net effect was increased viral fusion and infectivity of IgG-bound retroviral vectors when compared to non-targeted vectors bearing WT env alone. These data provide the proof of concept that IgG-binding vector/VEGF receptor antibody complexes may be used to enhance retroviral gene delivery to activated endothelial cells.

Aim: To study the effects of Phe-Met-Arg-Phe-NH2(FMRFa) on Na+/Ca2+ exchange and its specificity for Na+/Ca2+ exchange in rat ventricular myocytes., Methods: Na+/Ca2+ exchange current and other currents of ion channels were measured using whole cell voltage clamp techniques., Results: A dose-related inhibition of tetrapeptide FMRFa on Na+/Ca2+ exchange was observed in rat ventricular myocytes. Inward and outward INa+/Ca2+ were inhibited by 60.1% and 56.5%, respectively, at highest concentration (100 mumol.L-1) and its IC50 were 20 mumol.L-1 and 34 mumol.L-1 in inward and outward INa+/Ca2+, respectively. Inward and outward INa+/Ca2+ were inhibited 38.7% and 34.9%, respectively, at FMRFa 5 mumol.L-1. FMRFa 5 mumol.L-1 and 20 mumol.L-1 did not affect L-type calcium current, sodium current, transient outward current and inward rectifier potassium current., Conclusion: These data indicate that FMRFa is a specific inhibitor of Na+/Ca2+ exchange in intact rat ventricular myocytes.

Targeting of retroviral vectors to specific cells has been attempted through engineering of the surface (SU) protein of the murine leukemia viruses (MuLVs), but in many cases this has adversely affected protein function and targeted delivery has been difficult to achieve. In this study, we have inserted a 15-mer peptide that binds specifically to the alpha(v)beta(3) integrin into the Moloney MuLV SU protein, including regions that are surface exposed in the crystal structure of the ecotropic receptor-binding domain. We have concentrated in particular on the variable regions VRA, VRB, and VRC, which are responsible for the use of distinct cellular receptors by different MuLV subtypes and therefore may be more likely to accommodate a heterologous binding moiety. Despite these considerations, only 8 of 26 insertion sites were tolerated, including two separate regions in VRA, a cluster of sites in VRC, and previously identified sites at the N-terminus of the protein and in the proline-rich region immediately downstream of the receptor-binding domain. When expressed on retroviral vector particles, all of the viable proteins retained the ability to bind to and transduce murine cells, although the VRC mutants and an insertion in VRA gave reduced binding and titer. Finally, although all of the viable chimeras could bind to alpha(v)beta(3) in a solid-phase binding assay, we were unable to demonstrate expanded tropism for alpha(v)beta(3)-expressing human cells. This study highlights the difficulty of engineering the Moloney MuLV SU protein, even when structural information is available, and provides guidelines for the insertion of peptide ligands into the SU protein., (Copyright 2000 Academic Press.)

Aim: To study the effects of E-4031 on the Na+/Ca2+ exchange currents (INa/Ca)., Methods: The quasi-steady state current-voltage relationship from the isolated rat ventricular myocytes was measured using whole-cell voltage-clamp techniques with a ramp pulse protocol., Results: At potential of mV, E-4031 5, 10, and 20 mumol.L-1 increased Ni(2+)-sensitive current from (0.48 +/- 0.12), to (0.78 +/- 0.20), (0.96 +/- 0.16), and (1.15 +/- 0.13) pA/pF, respectively; tetradecanoylphorbol acetate (TPA) 50 nmol.L-1 increased Ni(2+)-sensitive current from (0.60 +/- 0.16) to (1.33 +/- 0.25) pA/pF. Tamoxifen 20 mumol.L-1 completely prevented the current changes induced by E-4031 and TPA., Conclusion: E-4031 stimulates the Na+/Ca2+ exchange via a protein kinase C-dependent pathway.

Effects of myocardial hypertrophy on the Na+/Ca2+ exchange current in isolated rat cardiac myocytes were investigated, using whole cell patch techniques. Goldblatt 2-kidney, one-clip technique was used to induce cardiomyocyte hypertrophy. The results demonstrated that the Ni(2+)-sensitive Na+/Ca2+ exchange current density was larger in hypertrophied cells than that in normal cells. At a holding potential of mV, the outward current densities were 1.53 +/- 0.31 pA/pF in normal cells and 2.62 +/- 0.53 pA/pF in hypertrophied cells (P < 0.01). At a holding potential of -100 mV, the inward current densities were 0.42 +/- 0.14 pA/pF in normal cells and 1.12 +/- 0.33 pA/pF in hypertrophied cells (P < 0.001). The results suggest that during myocardial hypertrophy the Na+/Ca2+ exchange current is significantly increased.

Aim: To study the effects of propylbutyldopamine (PBDA) on the inward rectifier potassium current (Ik1)., Methods: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular cells were measured using whole-cell patch-clamp techniques with a slow ramp depolarization (8 mV.s-1)., Results: PBDA 5, 50, and 100 mumol.L-1 concentration-dependently reduced the inward rectifier potassium current. PBDA blocked Ik1 in guinea pig ventricular cells. The effect of PBDA was not blocked by the selective dopamine D2-receptor blocker, domperidone., Conclusion: PBDA inhibited Ik1 directly, independent of the dopamine D2-receptor.

Autoantibodies to cardiac beta1-adrenoceptors and M2-muscarinic receptors have mainly been found in the sera of patients with idiopathic dilated cardiomyopathy (DCM). In order to elucidate the pathological significance of these autoantibodies in DCM, it is necessary to understand their characteristic distribution in a healthy population of different genders and ages. The peptides corresponding to the sequences of the second extracellular loops of the human beta1-adrenoceptor and M2-muscarinic receptors were therefore used as antigens to screen the sera of 408 healthy subjects of different ages (ranging from 0.5 to 85 years). Of 408 sera, 41 (10.0%) and 46 (11.3%) recognized the beta1-adrenoceptor and M2-muscarinic receptor peptides respectively. Of the positive sera for beta1-adrenoceptors and M2-muscarinic receptors, up to 63.4% and 56.5% had both anti-beta1-adrenoceptor and anti-M2-muscarinic receptor autoantibodies respectively. The antibody titres of the positive sera of healthy subjects were all of a low level, with a geometric mean titre of 1:42+/-1.9 for anti-beta1-adrenoceptor antibodies and 1:51+/-1.7 for anti-M2-muscarinic receptor antibodies. The frequency of occurrence of autoantibodies to both receptors in the sera of healthy subjects increased significantly with age. In conclusion, the autoantibodies to beta1-adrenoceptors and M2-muscarinic receptors in the sera of healthy subjects are characterized by a low frequency of occurrence and low titre, with the frequency of occurrence increasing with age.

Aim: To study the effects of norepinephrine (NE) and isopentenyladenosine (Iso) on Na+/Ca2+ exchange currents and the receptor mechanism., Methods: The quasi-steady state current-voltage relationship from the isolated guinea pig ventricular myocytes was measured using whole-cell voltage-clamp techniques with a ramp pulse protocol., Results: At potential of +50 mV, NE 0.005, 0.05, and 5 mumol.L-1 increased the Ni(2+)-sensitive current by 29% +/- 9%, 72% +/- 11%, and 124% +/- 31.4%, respectively; Iso 1.5, 150, and 1500 nmol.L-1 caused increases in the Ni(2+)-sensitive current by 2.8% +/- 2.8%, 56% +/- 13%, and 102% +/- 12%, respectively. Propranolol 10 mumol.L-1 completely inhibited the current changes induced by NE and Iso while phentolamine 50 mumol.L-1 showed no effects., Conclusion: NE and Iso increased the Na+/Ca2+ exchange currents via stimulation of cardiac beta-adrenoceptor.

Aim: To study the effect of phentolamine on L-type calcium currents (ICa) and ATP-sensitive K+ currents (IK,ATP) in ventricular myocytes., Methods: ICa and IK,ATP were observed using patch clamp techniques in whole-cell recording configuration., Results: Phentolamine reduced ICa of ventricular myocytes in concentration-dependent and voltage-independent manners. Phentolamine 5, 25, and 100 mumol.L-1 decreased ICa from 370 +/- 99 nA to 310 +/- 95 nA (17% block, n = 6, P < 0.01), from 230 +/- 98 nA to 180 +/- 73 nA (23% block, n = 5, P < 0.05), and from 293 +/- 66 nA to 206 +/- 44 nA (30% block, n = 5, P < 0.01), respectively, without affecting the current-voltage relationship. Prazosin 100 mumol.L-1 and yohimbine 100 mumol.L-1, which were specific blockers of alpha 1 and alpha 2 adrenoceptors respectively, did not show the inhibitory effect on ICa. Phentolamine 100 mumol.L-1 also inhibited the IK,ATP induced by 2, 4-dinitrophenol (DNP) at 0 mV from 3.2 +/- 0.6 nA to 0.8 +/- 0.5 nA (75% block, n = 4, P < 0.01)., Conclusion: Phentolamine directly inhibits ICa and IK,ATP in guinea pig ventricular myocytes.

Current pharmacological agents for human immunodeficiency virus (HIV) infection include drugs targeted against HIV reverse transcriptase and HIV protease. An understudied therapeutic target is HIV integrase, an essential enzyme that mediates integration of the HIV genome into the host chromosome. The dicaffeoylquinic acids (DCQAs) and the dicaffeoyltartaric acids (DCTAs) have potent activity against HIV integrase in vitro and prevent HIV replication in tissue culture. However, their specificity against HIV integrase in cell culture has been questioned. Thus, the ability of the DCQAs and DCTAs to inhibit binding of HIV type 1 (HIV-1) gp120 to CD4 and their activities against HIV-1 reverse transcriptase and HIV RNase H were studied. The DCQAs and DCTAs inhibited HIV-1 integrase at concentrations between 150 and 840 nM. They inhibited HIV replication at concentrations between 2 and 12 microM. Their activity against reverse transcriptase ranged from 7 microM to greater than 100 microM. Concentrations that inhibited gp120 binding to CD4 exceeded 80 microM. None of the compounds blocked HIV-1 RNase H by 50% at concentrations exceeding 80 microM. Furthermore, when the effects of the DCTAs on reverse transcription in acutely infected cells were measured, they were found to have no activity. Therefore, the DCQAs and DCTAs exhibit > 10- to > 100-fold specificity for HIV integrase, and their activity against integrase in biochemical assays is consistent with their observed anti-HIV activity in tissue culture. Thus, the DCQAs and DCTAs are a potentially important class of HIV inhibitors that act at a site distinct from that of current HIV therapeutic agents.

The mechanisms responsible for the cardiac positive inotropic effects of dopexamine hydrochloride, a combined dopamine receptor agonist at both D1-receptors and beta 2-adrenoceptors, were studied. The calcium channel currents were recorded using whole-cell patch clamp technique in isolated guinea pig ventricular myocytes. At a holding potential of -40 mV, cells were depolarized to 0 mV for 400 ms at a frequency of 0.2 Hz. Dopexamine hydrochloride at doses of 5, 50 and 100 microM increased the verapamil-sensitive Ca2+ inward current by 109, 147 and 194%, respectively. The effects of dopexamine hydrochloride on Ca2+ current reached its maximum at 5 min and partially recovered after washout of the drugs. The increased Ca2+ current induced by dopexamine hydrochloride was completely inhibited by 20 microM propranolol, a beta-adrenoceptor antagonist, and was not antagonized by 20 microM of SCH23390, a highly selective D1-receptor antagonist. These results suggest that the cardiac positive inotropic effects of dopexamine hydrochloride are brought about by the increase of Ca2+ current via stimulation of beta 2-adrenoceptors.

The effects of anti-peptide antibodies (Ab) against the second extracellular loop of human muscarinic receptor-2 on cardiac function in rats in vivo were studied. These effects were compared with those of the muscarinic receptor agonist, carbachol (Carb). It was shown that: (1) both Carb and Ab administered intravenously in the same doses of 0.4 nmol, 1.0 nmol, and 2.0 nmol were able to inhibit the maximal rate of rise of ventricular pressure (+dp/dt max) in a dose-dependent manner. (2) The isoproterenol (Iso)-induced increase in HR and +dp/dt max were also markedly inhibited by Carb and Ab. Administration of 1.0 nmol Carb decreased the Iso-stimulated increase of HR from 13.6 +/- 2.0 to 4.9 +/- 0.7% and decreased the increase of +dp/dt max from 27.9 +/- 3.2 to 4.8 +/- 0.6%, respectively; whereas Ab decreased the HR to 6.5 +/- 1.1% and +dp/dt max to 13.5 +/- 1.2%, respectively. (3) Both the inhibitory effects of Carb and Ab could be significantly blocked by atropine (1.4 nmol). These findings suggest that the Ab display a stimulatory muscarinic activity similar to Carb in inhibiting the cardiac function as evidenced by its negative chronotropic and inotropic effects.

The effects of dopexamine (DPX), a new dopamine receptor agonist, on transmembrane potential and effective refractory period (ERP) of isolated guinea pig ventricular muscle superfused either with hypoxia or mimic ischemia perfusates were investigated by using intracellular microelectrode technique and compared with fenoldopam (FODA) and procaterol. DPX (3 x 10(-6) mol.L-1) was found to significantly reduce both the extent of decrease of resting potential, action potential amplitude and maximal upstroke velocity and the degree of shortening of action potential duration caused by hypoxia or ischemia. These effects of DPX were significantly greater than those of FODA and procaterol albeit the latter showed effects similar to DPX. DPX could not only lengthen the abbreviated ERP resulting from hypoxia, but also shorten the prolonged ERP caused by ischemia. This action of DPX was more evident than that of FODA and procaterol. The results reveal the potential advantages of DPX over other dopaminergic agonists in the antiarrhythmic activity during myocardial ischemia.

In whole cell voltage clamp experiment with isolated guinea pig ventricular myocytes, tocainide was shown to exhibit a concentration-dependent inhibition of calcium current (ICa) and delayed rectifier potassium current (IK). Tocainide with a therapeutic concentration of 50 mumol.L-1 significantly inhibited the ICa and Itail (deactivating tail current of IK) by 16% and 3% respectively. Inhibition of ICa by tocainide was also shown to be dependent upon stimulating frequencies, with a greater blockade occurring at 2.0 Hz (57%) than at 0.2 Hz (17%). Tocainide was found to inhibit the IK,ATP by 74% at 200 mumol.L-1 but not at 50 mumol.L-1. These inhibitory effects on ICa and IK can probably explain the therapeutic effect of tocainide on supraventricular tachycardia, and the shortening of plateau phase of action potential.

The X-ray crystal-structure-based design, synthesis, computational evaluation, and activity of a novel class of HIV protease inhibitors are described. The initial lead compounds 2 and 3 were designed by modeling replacement groups for the C-terminal Val-Val-OCH3 of a known hydroxyethylene inhibitor into the active site of the reported crystal structure of HIV protease complexed with MVT-101. The lead compound 2 was found to be a modest inhibitor with a Ki = 1.67 microM. The X-ray crystal structure of compound 2 complexed with HIV protease was solved and used for subsequent design. The lead compound 3 was found to be a more potent inhibitor with Ki = 0.2 microM, and the structure of it complexed with HIV protease was also solved and used for subsequent design. Modification of both the C-terminus and N-terminus of indole 3 resulted in compounds with Ki = 30 nM. Using the crystal structure of compounds 2 and 3 with HIV protease as a starting point, the thermodynamic cycle perturbation molecular dynamics method was applied to a select group of compounds in order to test the accuracy of this type of computation within a series of closely related compounds.