Trade policy in a dynamic Heckscher-Ohlin model

The Import Substitution Process in Latin Amer ica was an attempt to enhance GDP growth and productivity by rising trade barriers upon capital-intensive products. Our main goal is to analyze how an increase in import tariff on a particular type of good affects the production choices and trade pattern of an economy. We develop an extension of the dynamic Heckscher-Ohlin model – a combination of a static two goods, two-factor Heckscher-Ohlin model and a two-sector growth model – allowing for import tariff. We then calibrate the closed economy model to the US. The results show that the economy will produce less of both consumption and investment goods under autarky for low and high levels of capital stock per worker. We also find that total GDP may be lower under free trade in comparison to autarky.

Essays on the Effects of Corporate Taxation

Cette thèse est une collection de trois articles en macroéconomie et finances publiques. Elle développe des modèles d'Equilibre Général Dynamique et Stochastique pour analyser les implications macroéconomiques des politiques d'imposition des entreprises en présence de marchés financiers imparfaits. Le premier chapitre analyse les mécanismes de transmission à l'économie, des effets d'un ré-échelonnement de l'impôt sur le profit des entreprises. Dans une économie constituée d'un gouvernement, d'une firme représentative et d'un ménage représentatif, j'élabore un théorème de l'équivalence ricardienne avec l'impôt sur le profit des entreprises. Plus particulièrement, j'établis que si les marchés financiers sont parfaits, un ré-échelonnement de l'impôt sur le profit des entreprises qui ne change pas la valeur présente de l'impôt total auquel l'entreprise est assujettie sur toute sa durée de vie n'a aucun effet réel sur l'économie si l'état utilise un impôt forfaitaire. Ensuite, en présence de marchés financiers imparfaits, je montre qu'une une baisse temporaire de l'impôt forfaitaire sur le profit des entreprises stimule l'investissement parce qu'il réduit temporairement le coût marginal de l'investissement. Enfin, mes résultats indiquent que si l'impôt est proportionnel au profit des entreprises, l'anticipation de taxes élevées dans le futur réduit le rendement espéré de l'investissement et atténue la stimulation de l'investissement engendrée par la réduction d'impôt. Le deuxième chapitre est écrit en collaboration avec Rui Castro. Dans cet article, nous avons quantifié les effets sur les décisions individuelles d'investis-sement et de production des entreprises ainsi que sur les agrégats macroéconomiques, d'une baisse temporaire de l'impôt sur le profit des entreprises en présence de marchés financiers imparfaits. Dans un modèle où les entreprises sont sujettes à des chocs de productivité idiosyncratiques, nous avons d'abord établi que le rationnement de crédit affecte plus les petites (jeunes) entreprises que les grandes entreprises. Pour des entreprises de même taille, les entreprises les plus productives sont celles qui souffrent le plus du manque de liquidité résultant des imperfections du marché financier. Ensuite, nous montré que pour une baisse de 1 dollar du revenu de l'impôt, l'investissement et la production augmentent respectivement de 26 et 3,5 centimes. L'effet cumulatif indique une augmentation de l'investissement et de la production agrégés respectivement de 4,6 et 7,2 centimes. Au niveau individuel, nos résultats indiquent que la politique stimule l'investissement des petites entreprises, initialement en manque de liquidité, alors qu'elle réduit l'investissement des grandes entreprises, initialement non contraintes. Le troisième chapitre est consacré à l'analyse des effets de la réforme de l'imposition des revenus d'entreprise proposée par le Trésor américain en 1992. La proposition de réforme recommande l'élimination des impôts sur les dividendes et les gains en capital et l'imposition d'une seule taxe sur le revenu des entreprises. Pour ce faire, j'ai eu recours à un modèle dynamique stochastique d'équilibre général avec marchés financiers imparfaits dans lequel les entreprises sont sujettes à des chocs idiosyncratiques de productivité. Les résultats indiquent que l'abolition des impôts sur les dividendes et les gains en capital réduisent les distorsions dans les choix d'investissement des entreprises, stimule l'investissement et entraîne une meilleure allocation du capital. Mais pour être financièrement soutenable, la réforme nécessite un relèvement du taux de l'impôt sur le profit des entreprises de 34\% à 42\%. Cette hausse du taux d'imposition décourage l'accumulation du capital. En somme, la réforme engendre une baisse de l'accumulation du capital et de la production respectivement de 8\% et 1\%. Néanmoins, elle améliore l'allocation du capital de 20\%, engendrant des gains de productivité de 1.41\% et une modeste augmentation du bien être des consommateurs.

Dynamic Management of Loyalty Program Strategies

Thesis (Ph.D.)--University of Washington, 2016-06

Influences on doctors' prescribing: Is geographical remoteness a factor?

Objective: To identify factors influencing the prescribing of medicines by general practitioners in rural and remote Australia. Design: A qualitative study using a questionnaire to determine attitudes about prescribing, specific prescribing habits and comments on prescribing in ‘rural practice’. Setting: General practice in rural and remote Queensland. Subjects: General practitioners practising in rural and remote settings in Queensland (n = 258). Main outcome measures: The factors perceived to influence the prescribing of medicines by medical practitioners in rural environments. Results: A 58% response rate (n = 142) was achieved. Most respondents agreed that they prescribe differently in rural compared with city practice. The majority of respondents agreed that their prescribing was influenced by practice location, isolation of patient home location, limited diagnostic testing and increased drug monitoring. Location issues and other issues were more likely to be identified as ‘influential’ by the more isolated practitioners. Factors such as access to continuing medical education and specialists were confirmed as having an influence on prescribing. The prescribing of recently marketed drugs was more likely by doctors practising in less remote rural areas. Conclusion: Practising in rural and remote locations is perceived to have an effect on prescribing. These influences need to be considered when developing quality use of medicines policies and initiatives for these locations. What is already known: Anecdotal and audit based studies have shown that rural general practice differs to urban-based practice in Australia, including some limited data showing some variations in prescribing patterns. No substantiated explanations for these variations have been offered. It is known that interventions to change prescribing behaviour are more likely to be effective if they are perceived as relevant and hence increasing our knowledge of rural doctors’ perceptions of differences in rural practice prescribing is required. What this study adds: Rural doctors believed that they prescribe differently in rural compared with city practice and they described a range of influences. The more remotely located doctors were more likely to report the ‘rural’ influences on prescribing, however, most results failed to reach statistical significance when compared to the less remotely located doctors. These perceptions should be considered when developing medicines policy and education for rural medical practitioners to ensure it is perceived rurally relevant.

Increased potency of a novel complement factor 5a receptor antagonist in a rat model of inflammatory bowel disease

We have previously shown that complement factor 5a(C5a) plays a role in the pathogenesis of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis in rats by using the selective, orally active C5a antagonist AcF-[OP(D-Cha) WR]. This study tested the efficacy and potency of a new C5a antagonist, hydrocinnamate (HC)-[OP(D-Cha) WR], which has limited intestinal lumenal metabolism, in this model of colitis. Analogs of AcF-[OP(D-Cha) WR] were examined for their susceptibility to alimentary metabolism in the rat using intestinal mucosal washings. One metabolically stable analog, HC-[OP(D-Cha)WR], was then evaluated pharmacokinetically and investigated at a range of doses (0.03 - 10 mg/kg/ day p.o.) in the 8-day rat TNBS- colitis model, against the comparator drug AcF-[OP(D-Cha) WR]. Using various amino acid substitutions, it was determined that the AcF moiety of AcF-[OP(D-Cha) WR] was responsible for the metabolic instability of the compound in intestinal mucosal washings. The analog HC-[OP( D-Cha) WR], equiactive in vitro to AcF-[OP(D-Cha) WR], was resistant to intestinal metabolism, but it displayed similar oral bioavailability to AcF-[OP(D-Cha) WR]. However, in the rat TNBS- colitis model, HC-[OP(D-Cha) WR] was effective at reducing mortality, colon edema, colon macroscopic scores, and increasing food consumption and body weights, at 10- to 30- fold lower oral doses than AcF-[OP( D-Cha) WR]. These studies suggest that resistance to intestinal metabolism by HC-[OP(D-Cha) WR] may result in increased local concentrations of the drug in the colon, thus affording efficacy with markedly lower oral doses than AcF-[OP(D-Cha) WR] against TNBS-colitis. This large increase in potency and high efficacy of this compound makes it a potential candidate for clinical development against intestinal diseases such as inflammatory bowel disease.

Syntaxin 6 and Vti1b form a novel SNARE complex, which is up-regulated in activated macrophages to facilitate exocytosis of tumor necrosis factor-alpha

A key function of activated macrophages is to secrete proinflammatory cytokines such as TNF alpha; however, the intracellular pathway and machinery responsible for cytokine trafficking and secretion is largely undefined. Here we show that individual SNARE proteins involved in vesicle docking and fusion are regulated at both gene and protein expression upon stimulation with the bacterial cell wall component lipopolysaccharide. Focusing on two intracellular SNARE proteins, Vti1b and syntaxin 6 (Stx6), we show that they are up-regulated in conjunction with increasing cytokine secretion in activated macrophages and that their levels are selectively titrated to accommodate the volume and timing of post-Golgi cytokine trafficking. In macrophages, Vti1b and syntaxin 6 are localized on intracellular membranes and are present on isolated Golgi membranes and on Golgi-derived TNF alpha vesicles budded in vitro. By immunoprecipitation, we find that Vti1b and syntaxin 6 interact to form a novel intracellular Q-SNARE complex. Functional studies using overexpression of full-length and truncated proteins show that both Vti1b and syntaxin 6 function and have rate-limiting roles in TNF alpha trafficking and secretion. This study shows how macrophages have uniquely adapted a novel Golgi-associated SNARE complex to accommodate their requirement for increased cytokine secretion.

Integrated actions of transforming growth factor-beta(1) and connective tissue growth factor in renal fibrosis

Matrix accumulation in the renal tubulointerstitium is predictive of a progressive decline in renal function. Transforming growth factor-beta(1) (TGF-beta(1)) and, more recently, connective tissue growth factor (CTGF) are recognized to play key roles in mediating the fibrogenic response, independently of the primary renal insult. Further definition of the independent and interrelated effects of CTGF and TGF-beta(1) is critical for the development of effective antifibrotic strategies. CTGF (20 ng/ml) induced fibronectin and collagen IV secretion in primary cultures of human proximal tubule cells (PTC) and cortical fibroblasts (CF) compared with control values (P < 0.005 in all cases). This effect was inhibited by neutralizing antibodies to either TGF-beta or to the TGF-beta type II receptor (TbetaRII). TGF-beta(1) induced a greater increase in fibronectin and collagen IV secretion in both PTC (P < 0.01) and CF (P < 0.01) compared with that observed with CTGF alone. The combination of TGF-beta(1) and CTGF was additive in their effects on both PTC and CF fibronectin and collagen IV secretion. TGF-beta(1) (2 ng/ml) stimulated CTGF mRNA expression within 30 min, which was sustained for up to 24 h, with a consequent increase in CTGF protein (P < 0.05), whereas CTGF had no effect on TGF-beta(1) mRNA or protein expression. TGF-beta(1) (2 ng/ml) induced phosphorylated (p)Smad-2 within 15 min, which was sustained for up to 24 h. CTGF had a delayed effect on increasing pSmad-2 expression, which was evident at 24 h. In conclusion, this study has demonstrated the key dependence of the fibrogenic actions of CTGF on TGF-beta. It has further uniquely demonstrated that CTGF requires TGF-beta, signaling through the TbetaRII in both PTCs and CFs, to exert its fibrogenic response in this in vitro model.

Prediction of protein B-factor profiles

The polypeptide backbones and side chains of proteins are constantly moving due to thermal motion and the kinetic energy of the atoms. The B-factors of protein crystal structures reflect the fluctuation of atoms about their average positions and provide important information about protein dynamics. Computational approaches to predict thermal motion are useful for analyzing the dynamic properties of proteins with unknown structures. In this article, we utilize a novel support vector regression (SVR) approach to predict the B-factor distribution (B-factor profile) of a protein from its sequence. We explore schemes for encoding sequences and various settings for the parameters used in SVR. Based on a large dataset of high-resolution proteins, our method predicts the B-factor distribution with a Pearson correlation coefficient (CC) of 0.53. In addition, our method predicts the B-factor profile with a CC of at least 0.56 for more than half of the proteins. Our method also performs well for classifying residues (rigid vs. flexible). For almost all predicted B-factor thresholds, prediction accuracies (percent of correctly predicted residues) are greater than 70%. These results exceed the best results of other sequence-based prediction methods. (C) 2005 Wiley-Liss, Inc.

An adaptive and dynamic dimensionality reduction method for high-dimensional indexing

The notorious "dimensionality curse" is a well-known phenomenon for any multi-dimensional indexes attempting to scale up to high dimensions. One well-known approach to overcome degradation in performance with respect to increasing dimensions is to reduce the dimensionality of the original dataset before constructing the index. However, identifying the correlation among the dimensions and effectively reducing them are challenging tasks. In this paper, we present an adaptive Multi-level Mahalanobis-based Dimensionality Reduction (MMDR) technique for high-dimensional indexing. Our MMDR technique has four notable features compared to existing methods. First, it discovers elliptical clusters for more effective dimensionality reduction by using only the low-dimensional subspaces. Second, data points in the different axis systems are indexed using a single B+-tree. Third, our technique is highly scalable in terms of data size and dimension. Finally, it is also dynamic and adaptive to insertions. An extensive performance study was conducted using both real and synthetic datasets, and the results show that our technique not only achieves higher precision, but also enables queries to be processed efficiently. Copyright Springer-Verlag 2005

Patterns of neuronal activation in the rat brain and spinal cord in response to increasing durations of restraint stress

By most accounts the psychological stressor restraint produces a distinct pattern of neuronal activation in the brain. However, some evidence is incongruous with this pattern, leading us to propose that the restraint- induced pattern in the central nervous system might depend on the duration of restraint used. We therefore determined the pattern of neuronal activation ( as indicated by the presence of Fos protein) seen in the paraventricular nucleus (PVN), bed nucleus of the stria terminalis, amygdala, locus coeruleus, nucleus tractus solitarius (NTS), ventrolateral medulla (VLM) and thoracic spinal cord of the rat in response to 0, 15, 30 or 60 min periods of restraint. We found that although a number of cell groups displayed a linear increase in activity with increasing durations of restraint ( e. g. hypothalamic corticotrophin-releasing factor (CRF) cells, medial amygdala neurons and sympathetic preganglionic neurons of the thoracic spinal cord), a number of cell groups did not. For example, in the central amygdala restraint produced both a decrease in CRF cell activity and an increase in non-CRF cell activity. In the locus coeruleus, noradrenergic neurons did not display Fos in response to 15 min of restraint, but were significantly activated by 30 or 60 min restraint. After 30 or 60 min restraint a greater degree of activation of more rostral A1 noradrenergic neurons was observed compared with the pattern of A1 noradrenergic neurons in response to 15 min restraint. The results of this study demonstrate that restraint stress duration determines the amount and the pattern of neuronal activation seen in response to this psychological stressor.

Regulation of albumin endocytosis by PSD95/Dlg/ZO-1 (PDZ) scaffolds - Interaction of Na+-H+ exchange regulatory factor-2 with ClC-5

The constitutive reuptake of albumin from the glomerular filtrate by receptor-mediated endocytosis is a key function of the renal proximal tubules. Both the Cl- channel ClC-5 and the Na+-H+ exchanger isoform 3 are critical components of the macromolecular endocytic complex that is required for albumin uptake, and therefore the cell-surface levels of these proteins may limit albumin endocytosis. This study was undertaken to investigate the potential roles of the epithelial PDZ scaffolds, Na+-H+ exchange regulatory factors, NHERF1 and NHERF2, in albumin uptake by opossum kidney ( OK) cells. We found that ClC-5 co-immunoprecipitates with NHERF2 but not NHERF1 from OK cell lysate. Experiments using fusion proteins demonstrated that this was a direct interaction between an internal binding site in the C terminus of ClC-5 and the PDZ2 module of NHERF2. In OK cells, NHERF2 is restricted to the intravillar region while NHERF1 is located in the microvilli. Silencing NHERF2 reduced both cell-surface levels of ClC-5 and albumin uptake. Conversely, silencing NHERF1 increased cell-surface levels of ClC-5 and albumin uptake, presumably by increasing the mobility of NHE3 in the membrane and its availability to the albumin uptake complex. Surface biotinylation experiments revealed that both NHERF1 and NHERF2 were associated with the plasma membrane and that NHERF2 was recruited to the membrane in the presence of albumin. The importance of the interaction between NHERF2 and the cytoskeleton was demonstrated by a significant reduction in albumin uptake in cells overexpressing an ezrin binding-deficient mutant of NHERF2. Thus NHERF1 and NHERF2 differentially regulate albumin uptake by mechanisms that ultimately alter the cell-surface levels of ClC-5.

Definition and spatial annotation of the dynamic secretome during early kidney development

The term secretome has been defined as a set of secreted proteins (Grimmond et al. [2003] Genome Res 13:1350-1359). The term secreted protein encompasses all proteins exported from the cell including growth factors, extracellular proteinases, morphogens, and extracellular matrix molecules. Defining the genes encoding secreted proteins that change in expression during organogenesis, the dynamic secretome, is likely to point to key drivers of morphogenesis. Such secreted proteins are involved in the reciprocal interactions between the ureteric bud (UB) and the metanephric mesenchyme (AM) that occur during organogenesis of the metanephros. Some key metanephric secreted proteins have been identified, but many remain to be determined. In this study, microarray expression profiling of E10.5, E11.5, and E13.5 kidney and consensus bioinformatic analysis were used to define a dynamic secretome of early metanephric development. In situ hybridisation was used to confirm microarray results and clarify spatial expression patterns for these genes. Forty-one secreted factors were dynamically expressed between the E10.5 and E13.5 timeframe profiled, and 25 of these factors had not previously been implicated in kidney development. A text-based anatomical ontology was used to spatially annotate the expression pattern of these genes in cultured metanephric explants.

The impact of supply chain performance measurement systems on dynamic behaviour in supply chains

The amplification of demand variation up a supply chain widely termed ‘the Bullwhip Effect’ is disruptive, costly and something that supply chain management generally seeks to minimise. Originally attributed to poor system design; deficiencies in policies, organisation structure and delays in material and information flow all lead to sub-optimal reorder point calculation. It has since been attributed to exogenous random factors such as: uncertainties in demand, supply and distribution lead time but these causes are not exclusive as academic and operational studies since have shown that orders and/or inventories can exhibit significant variability even if customer demand and lead time are deterministic. This increase in the range of possible causes of dynamic behaviour indicates that our understanding of the phenomenon is far from complete. One possible, yet previously unexplored, factor that may influence dynamic behaviour in supply chains is the application and operation of supply chain performance measures. Organisations monitoring and responding to their adopted key performance metrics will make operational changes and this action may influence the level of dynamics within the supply chain, possibly degrading the performance of the very system they were intended to measure. In order to explore this a plausible abstraction of the operational responses to the Supply Chain Council’s SCOR® (Supply Chain Operations Reference) model was incorporated into a classic Beer Game distribution representation, using the dynamic discrete event simulation software Simul8. During the simulation the five SCOR Supply Chain Performance Attributes: Reliability, Responsiveness, Flexibility, Cost and Utilisation were continuously monitored and compared to established targets. Operational adjustments to the; reorder point, transportation modes and production capacity (where appropriate) for three independent supply chain roles were made and the degree of dynamic behaviour in the Supply Chain measured, using the ratio of the standard deviation of upstream demand relative to the standard deviation of the downstream demand. Factors employed to build the detailed model include: variable retail demand, order transmission, transportation delays, production delays, capacity constraints demand multipliers and demand averaging periods. Five dimensions of supply chain performance were monitored independently in three autonomous supply chain roles and operational settings adjusted accordingly. Uniqueness of this research stems from the application of the five SCOR performance attributes with modelled operational responses in a dynamic discrete event simulation model. This project makes its primary contribution to knowledge by measuring the impact, on supply chain dynamics, of applying a representative performance measurement system.

Dynamic measurement of accommodative responses while viewing stereoscopic images

Using video refraction accommodative and convergence dynamic responses were measured to stepped changes in convergence stimuli with unchanged accommodative stimuli (conflicting stereoscopic image) and compared with responses to non-conflicting target stimuli. Three targets were used that varied in their spatial frequency components. An accommodative transient overshoot was evident in four out of seven subjects for only conflicting stimuli. One showed accommodative and convergence oscillation probably due to difficulty in fusing the stereoscopic target when it had a higher spatial component, however, this oscillation diminished when the target was spatial low-pass filtered. We hypothesise that transient responses to step stimuli is initiated by convergence-driven accommodation and subsequently followed by slower fine-control of accommodation modulated by the amount of blur. Inter-subject differences in convergence-driven accommodation may also be a factor to consider. For stereoscopic stimuli, it is proposed that the increase in blur immediately after the onset of the accommodative response inhibits cessation of the response.

Tear film lipids:dynamic composition and clinical performance

Purpose: Meibomian-derived lipid secretions are well characterised but their subsequent fate in the ocular environment is less well understood. Phospholipids are thought to facilitate the interface between aqueous and lipid layers of the tear film and to be involved in ocular lubrication processes. We have extended our previous studies on phospholipid levels in the tear film to encompass the fate of polar and non-polar lipids in progressive accumulation and aging processes on both conventional and silicone-modified hydrogel lenses. This is an important aspect of the developing understanding of the role of lipids in the clinical performance of silicone hydrogels. Method: Several techniques were used to identify lipids in the tear film. Mass-spectrometric methods included Agilent 1100-based liquid chromatography coupled to mass spectrometry (LCMS) and Perkin Elmer gas chromatography mass spectrometry (GCMS). Thin layer chromatography (TLC) was used for separation of lipids on the basis of increasing solvent polarity. Routine assay of lipid extractions from patient-worn lenses was carried out using a Hewlett Packard 1090 liquid chromatograph coupled to both uv and Agilent 1100 fluorescence detection. A range of histological together with optical, and electron microscope techniques was used in deposit analysis. Results: Progressive lipid uptake was assessed in various ways, including: composition changes with wear time, differential lipid penetrate into the lens matrix and, particularly, the extent to which lipids become unextractable as a function of wear time. Solvent-based separation and HPLC gave consistent results indicating that the polarity of lipid classes decreased as follows: phospholipids/fatty acids > triglycerides > cholesterol/cholesteryl esters. Tear lipids were found to show autofluorescence—which underpinned the value of fluorescence microscopy and fluorescence detection coupled with HPLC separation. The most fluorescent lipids were found to be cholesteryl esters; histological techniques coupled with fluorescence microscopy indicated that white spots (’’jelly bumps’’) formed on silicone hydrogel lenses contain a high proportion of cholesteryl esters. Lipid profiles averaged for 30 symptomatic and 30 asymptomatic contact lens wearers were compiled. Peak classes were split into: cholesterol (C), cholesteryl esters (CE), glycerides (G), polar fatty acids/phospholipids (PL). The lipid ratio for ymptomatic/symptomatic was 0.6 ± 0.1 for all classes except one—the cholesterol ratio was 0.2 ± 0.05. Significantly the PL ratio was no different from that of any other class except cholesterol. Chromatography indicated that: lipid polarity decreased with depth of penetration and that lipid extractability decreased with wear time. Conclusions: Meibomian lipid composition differs from that in the tear film and on worn lenses. Although the same broad lipid classes were obtained by extraction from all lenses and all patients studied, quantities vary with wear and material. Lipid extractability diminishes with wear time regardless of the use of cleaning regimes. Dry eye symptoms in contact lens wear are frequently linked to lipid layer behaviour but seem to relate more to total lipid than to specific composition. Understanding the detail of lipid related processes is an important element of improving the clinical performance of materials and care solutions.