Mean-field theory of an asset exchange model with economic growth and wealth distribution.

We develop a mean-field theory of the growth, exchange, and distribution (GED) model introduced by Liu et al. [K. K. L. Liu et al., preceding paper, Phys. Rev. E 104, 014150 (2021)10.1103/PhysRevE.104.014150] that accurately describes the phase transition in the limit that the number of agents N approaches infinity. The GED model is a generalization of the yard-sale model in which the additional wealth added by economic growth is nonuniformly distributed to the agents according to their wealth in a way determined by the parameter λ. The model is shown numerically to have a phase transition at λ=1 and be characterized by critical exponents and critical slowing down. Our mean-field treatment of the GED model correctly predicts the existence of the phase transition, a critical slowing down, and the values of the critical exponents and introduces an energy whose probability satisfies the Boltzmann distribution for λ<1, implying that the system is in thermodynamic equilibrium in the limit that N→∞. We show that the values of the critical exponents obtained by varying λ for a fixed value of N do not satisfy the usual scaling laws, but do satisfy scaling if a combination of parameters, which we refer to as the Ginzburg parameter, is much greater than one and is held constant. We discuss possible implications of our results for understanding economic systems and the subtle nature of the mean-field limit in systems with both additive and multiplicative noise.

Simulation of a generalized asset exchange model with economic growth and wealth distribution.

The agent-based yard-sale model of wealth inequality is generalized to incorporate exponential economic growth and its distribution. The distribution of economic growth is nonuniform and is determined by the wealth of each agent and a parameter λ. Our numerical results indicate that the model has a critical point at λ=1 between a phase for λ<1 with economic mobility and exponentially growing wealth of all agents and a nonstationary phase for λ≥1 with wealth condensation and no mobility. We define the energy of the system and show that the system can be considered to be in thermodynamic equilibrium for λ<1. Our estimates of various critical exponents are consistent with a mean-field theory [see W. Klein et al., following paper, Phys. Rev. E 104, 014151 (2021)10.1103/PhysRevE.104.014151]. The exponents do not obey the usual scaling laws unless a combination of parameters that we refer to as the Ginzburg parameter is held fixed as the phase transition is approached. The model illustrates that both poorer and richer agents benefit from economic growth if its distribution does not favor the richer agents too strongly. This work and the following theoretical paper contribute to our understanding of whether the methods of equilibrium statistical mechanics can be applied to economic systems.

Multiscale simulation of plasma flows using active learning.

Plasma flows encountered in high-energy-density experiments display features that differ from those of equilibrium systems. Nonequilibrium approaches such as kinetic theory (KT) capture many, if not all, of these phenomena. However, KT requires closure information, which can be computed from microscale simulations and communicated to KT. We present a concurrent heterogeneous multiscale approach that couples molecular dynamics (MD) with KT in the limit of near-equilibrium flows. To reduce the cost of gathering information from MD, we use active learning to train neural networks on MD data obtained by randomly sampling a small subset of the parameter space. We apply this method to a plasma interfacial mixing problem relevant to warm dense matter, showing considerable computational gains when compared with the full kinetic-MD approach. We find that our approach enables the probing of Coulomb coupling physics across a broad range of temperatures and densities that are inaccessible with current theoretical models.

Discovery of potent antagonists of leukocyte function-associated antigen-1/intercellular adhesion molecule-1 interaction. 3. Amide (C-ring) structure-activity relationship and improvement of overall properties of arylthio cinnamides.

The interaction of LFA-1 and ICAM-1 plays an important role in the cell adhesion process. On the basis of previously reported SAR and structural information on the binding of our p-arylthiocinnamide series to LFA-1, we have identified the cyclic amide (C-ring) as a site for modification. Improvement in potency and, more importantly, in the physical properties and pharmacokinetic profiles of the leading compounds resulted from this modification. One of the best compounds (11f) is also shown to reduce myocardial infarct size in rat.

Evidence for vasoconstriction mediated by the endothelin-B receptor in domestic swine.

Endothelin-1 (ET-1), a potent vasoactive and mitogenic peptide, has been implicated in a number of cardiovascular diseases, including congestive heart failure, neointimal hyperplasia associated with restenosis, and hypertension. The vasoconstriction induced by ET-1 is thought to be mediated mainly by its action on ET(A) receptors on vascular smooth muscle cells. Recent studies have indicated that vasoconstriction also may be mediated by stimulation of an ET(B)-receptor subtype. Increased use of the pig as a cardiovascular model prompted us to examine the receptor profile in this species using ABT-627, a potent, nonpeptide antagonist of the ET(A) receptor. The precursor to ET-1, big ET-1 (0.02 nmol/kg/min), was infused intravenously in domestic swine, resulting in a sustained increase in mean blood pressure of 38 +/- 3 mm Hg. After stabilization of the pressor response, ABT-627 (0.1-10 microg/kg/min) or vehicle was infused for 30 min. Whereas vehicle infusion had no appreciable effect, a dose-related reversal of the pressor response to big ET-1 (11-100%) was observed by the end of the ABT-627 infusion. Blood samples were assayed for plasma concentrations of ABT-627; peak levels ranged from 9 +/- 2 to 937 +/- 168 ng/ml. In a separate group of pigs, the highest dose of ABT-627 produced only a modest reversal of the hypertensive response to an infusion of angiotensin II (300 ng/kg/min). Additional results indicate that the vasoconstrictor effects produced by sarafotoxin 6C (0.03 and 0.3 nmol/kg), an agonist of the ET(B) receptor, are not blocked by treatment with ABT-627 (10 microg/kg/min). However, complete blockade of the S6C response could be achieved using the ET(B) antagonist, A-192621 (0.33 mg/kg/min). Our results define the dose-response relation for the ET(A)-receptor antagonist ABT-627 in the vasculature of the domestic pig and suggest the presence of an ET(B)-receptor subtype that mediates vasoconstriction in this species.

Neointimal formation after balloon-induced vascular injury in Yucatan minipigs is reduced by oral rapamycin.

Rapamycin, a macrolide antibiotic known to prevent allograft rejection, is a potent inhibitor of cell proliferation. Therefore we studied the effects of orally administered rapamycin in a pig model of balloon injury in an attempt to reduce the cellular proliferation and neointimal formation thought to play a role in restenosis. Twenty Yucatan minipigs, divided into groups of 10 animals each, were subjected to balloon inflation of the carotid arteries. One group received the methylcellulose vehicle for rapamycin, whereas the second group was treated for a total of 31 days with 2.0 mg/kg of rapamycin administered daily by oral gavage. This dose and treatment regimen produced significant (p < 0.05) reductions in neointimal area (59%) and in the maximal thickness of the neointima (59%) when comparisons were made with vehicle-treated animals. These effects were accompanied by a significant increase in the lumen area in animals that received rapamycin (33%). Medial area was decreased by 18% in these animals. Blood samples from rapamycin-treated pigs indicated peak concentrations of 1.87 +/- 0.45 and 1.70 +/- 0.24 ng/ml at 2 and 4 weeks after balloon angioplasty, respectively. Significant increases in blood pressure of 21 mm Hg and decreases in heart rate of 25 beats/min also were observed in rapamycin-treated animals relative to those that received vehicle. These results indicate that the antiproliferative effect of rapamycin can be demonstrated after oral dosing in a pig vascular injury model, suggesting a possible therapeutic utility for rapamycin or its analogs in patients undergoing balloon angioplasty.

Profile of recombinant pro-urokinase given by intraarterial versus intravenous routes of administration in a canine thrombosis model.

Catheter-directed thrombolysis has gained increasing acceptance for the treatment of patients who present with vascular occlusion; however, intravenous injection may be preferable in selected patients. Recombinant prourokinase (r-proUK) is a recently-developed fibrin-selective thrombolytic agent with specificity for clot-bound plasminogen. To compare the effects of r-proUK on clot lysis and restoration of blood flow when injected by either intraarterial or intravenous routes of administration, we utilized a dog model of arterial thrombosis in which a radiolabelled clot is formed in the femoral artery. The r-proUK was given by intravenous infusion to one group of 18 animals in doses ranging from 10,000 IU/kg to 100,000 IU/kg; a second group of 27 dogs was treated with r-proUK administered by the intra-arterial route in a dose range from 300 IU to 10,000 IU. Clot lysis was measured by monitoring the loss of counts from the radiolabelled clot over time; blood flow was also monitored throughout the experimental period. Animals which received intravenous treatment showed dose-related clot lysis ranging from 14% to 70% at 2 h, while those which received intra-arterial infusions showed lysis ranging from 22% to 79% over the same period. For similar degrees of clot lysis attained at the highest dose levels of 100,000 IU/kg and 10,000 IU, blood flow was restored to 77% and 35% of control levels in dogs which received intravenous and intraarterial treatment, respectively. The hemostatic protein fibrinogen was not reduced in any of the treatment groups. The results indicate that 100 times more intravenous than intra-arterial r-proUK is required to produce similar clot lysis in this canine model, and that the agent can be administered at this level without induction of a systemic lytic state.

Selective antagonism of the ET(A) receptor reduces neointimal hyperplasia after balloon-induced vascular injury in pigs.

Balloon angioplasty has become an important intervention in clinical cardiology; however, the technique is associated with a high incidence of restenosis, requiring repeated procedures. Endothelin-1 (ET-1), specifically through its action on ET(A) receptors, has been implicated in the cell proliferation and subsequent neointimal formation that leads to restenosis. Therefore we examined a potent antagonist of the ET(A) receptor, A127722.5, in a pig model of balloon angioplasty in iliac and carotid arteries. Ten pigs received A-127722.5 (7.5 mg/kg b.i.d.) orally, starting 3 days before angioplasty and continuing for 4 weeks; 10 additional pigs were treated with the same dosing regimen of the angiotensin-converting enzyme (ACE) inhibitor captopril (3.0 mg/kg b.i.d.), while a third group of 10 animals received placebo. At 2 and 4 weeks after the start of treatment, these doses of the ET(A) receptor antagonist and ACE inhibitor blocked the presser responses induced by big ET-1 and angiotensin I, respectively. In the iliac arteries, neointimal formation, neointimal/medial ratio, and maximal neointimal thickness were all significantly reduced, and the residual lumen area was significantly increased in pigs treated with the ET(A) receptor antagonist compared with placebo and captopril-treated groups. Medial collagen content, collagen deposition, and medial growth also were significantly reduced relative to the placebo group. Beneficial effects also were observed in the carotid arteries, although the results were less striking. Captopril was ineffective in protecting against the effects of balloon angioplasty in both vessels. Our results indicate that an orally active and potent antagonist of the ET(A) receptor inhibits cell proliferation and synthesis of extracellular matrix in pigs and may provide an important therapeutic approach to the prevention of restenosis.

Comparison of dose regimens for the administration of recombinant pro-urokinase in a canine thrombosis model.

Pro-urokinase represents an important addition to the array of thrombolytic drugs currently available for clinical use because of its high clot specificity but distinctly different mechanism compared with that of t-PA. Recombinant pro-urokinase (r-proUK) is a single-chain precursor of high molecular weight urokinase which has been expressed in a mouse myeloma cell line. The present study was conducted to determine the dosing regimen which would produce optimal clot lysis and restoration of blood flow 2 h after treatment with r-proUK, using a dog model of arterial thrombosis. Efficacy was indicated by lysis of a radio-labelled clot which was formed in the heat-damaged femoral arteries of 39 male beagle dogs. The animals were divided into six heparinized treatment groups, each receiving one of five dosing regimens or the vehicle for r-proUK. The total dose (80,000 U/kg) was divided into an initial loading bolus, followed by either a second bolus or by infusions for various time periods, as shown below: Group Treatment Regimen % Lysis 1 r-proUK Bolus/bolus, 50%/50% at 0 and 15 min 52 +/- 7 2 r-proUK Bolus/bolus, 50%/50% at 0 and 30 min 62 +/- 7 3 r-proUK Bolus/infusion, 20%/80% infused to 30 min 41 +/- 8 4 r-proUK Bolus/infusion, 20%/80% infused to 60 min 66 +/- 5 5 r-proUK Bolus/infusion, 50%/50% infused to 30 min 73 +/- 4 6 Vehicle Bolus/infusion, 50%/50% infused to 30 min 12 +/- 6 It was concluded that optimal clot lysis and restoration of femoral flow was accomplished using a regimen in which 50% of the dose was given as a bolus, followed immediately by the remaining 50% given as a 30 min intravenous infusion (Group 5). At the dose used in this study, r-proUK did not produce degradation of fibrinolytic or hemostatic plasma proteins.

Differential effects of Lys- and mini-plasminogen on clot lysis induced by recombinant urokinase and recombinant pro-urokinase in a canine thrombosis model.

These studies were conducted to examine the lytic efficacy of recombinant urokinase (r-UK) and pro-urokinase (r-proUK) in the presence and absence of truncated forms of plasminogen. Due to differences in their structures, these modified proteins are more readily activated to plasmin than the circulating form of plasminogen. Use of such modified substrates for plasminogen activators may improve the clinical outcome in patients treated for a variety of thrombotic diseases. Lys-plasminogen (46 units) or mini-plasminogen (in units of equivalent chromogenic activity), in conjunction with r-UK (7,500 units), were administered in the absence of heparin to dogs (9-11 kg) in which a radiolabelled thrombus was formed in a femoral artery. Fibrinolysis was measured as a loss of radioactivity from the clot. After intra-arterial administration of the agents, clot lysis was 48 +/- 8%, 50 +/- 9% and 75 +/- 2% in the presence of r-UK + vehicle, r-UK + lys-plasminogen, and r-UK + mini-plasminogen, respectively. When these treatment groups were examined in the presence of heparin (500 units + 350 units/hour) in a second study, r-UK (2,000 units) produced clot lysis of 54 +/- 3%; addition of lys- or mini-plasminogen to the regimen resulted in lysis of 62 +/- 9% and 46 +/- 10%, respectively. A third phase of the study examined r-proUK (1,000 units) with heparin; in this case, lysis was 51 +/- 9% in the presence of vehicle, but 55 +/- 17% and 10 +/- 5% when lys- and mini-plasminogen were administered, respectively. Flow restoration, measured in the femoral artery in each experiment, generally paralleled the lytic profile. The results indicate that supplementation with mini-plasminogen is only useful when added to a lytic regimen in the absence of heparin, and that lys-plasminogen, in conjunction with either of the lytic agents, does not improve clot lysis in this canine model.

Recombinant pro-urokinase requires heparin for optimal clot lysis and restoration of blood flow in a canine femoral artery thrombosis model.

Heparin is often used as an adjunct to thrombolytic therapy in order to prevent reocclusion of the patent vessels in patients with thrombotic disease. Controversy exists as to whether heparin is required for effective clot lysis with tissue-type plasminogen activator, while in vitro data and small scale clinical trials have suggested an enhancement of pro-urokinase efficacy by heparin. The present study was conducted to determine whether heparin pre-treatment is required to produce optimal clot lysis and blood flow restoration in response to recombinant pro-urokinase (r-proUK). In four groups of dogs, blood clots labelled with 125Iodine were formed in the femoral artery and were monitored continuously for loss of counts as an indicator of clot lysis. Femoral artery blood flow was measured simultaneously. Group 1 received vehicle (n = 5), while group 2 was given vehicle + heparin (n = 6; 500 U bolus + 350 U/h). This dose of heparin increased the activated partial thromboplastin time (APTT) by at least 1.5 times the control level for the 4 h observation period. Group 3 received r-proUK alone at a dose of 100,000 U/kg (50% given as a 1-min bolus injection, 50% as a 30 min infusion) (n = 8), while group 4 was treated with the same dose of r-proUK in the presence of heparin as described (n = 8).2

Mechanisms mediating the positive inotropic and chronotropic changes induced by dopexamine in the anesthetized dog.

Mechanisms contributing to the increments in heart rate (HR) and cardiac contractile force (CCF) produced by dopexamine (DPX) were studied in anesthetized dogs. Intravenous infusions of DPX (4.0 micrograms/kg/min) produced increments in HR, CCF and renal blood flow and decrements in mean arterial pressure (MAP). The sequential administration of atenolol (0.5 mg/kg i.v.) administered at a dose selective for beta-1 adrenoceptors, propranolol (2.5 mg/kg i.v.) and the DA1 dopamine receptor antagonist, SCH 23390 (10 micrograms/kg i.v.) blocked the DPX-induced changes in HR, CCF, MAP and renal blood flow, respectively. After ganglionic blockade, the increments in HR and CCF produced by DPX (4.0 and 16.0 micrograms/kg i.v.) were reduced 90 and 76%, respectively, with little or no change in its hypotensive effect. In separate dogs, administration of the beta-2 adrenoceptor agonist salbutamol (0.55 microgram/kg i.v.) produced a comparable decrement in MAP but smaller increments in HR and CCF than produced by DPX (16.0 micrograms/kg i.v.). DPX (64 micrograms/kg i.v.) also produced greater increments in HR during cardioaccelerator nerve stimulation (1 Hz, 0.5 msec, supramaximal voltage) than before nerve stimulation. Therefore, we tested the effect of DPX (1.0, 4.0 and 8.0 micrograms/kg/min i.v.) on the increments in HR, CCF and MAP produced by norepinephrine (0.25 microgram/kg i.v.) and the indirect acting sympathomimetic amine, tyramine (60 micrograms/kg i.v.). DPX potentiated the increments in HR, CCF and MAP produced by norepinephrine and suppressed those produced by tyramine. Thus, the positive inotropic and chronotropic effects of DPX in the intact dog are due primarily to baroreceptor-mediated stimulation and inhibition of neuronal uptake of norepinephrine.