Convergent flow in a two-layer system and mountain building

With the purpose of modelling the process of mountain building, we investigate the evolution of the ridge produced by the convergent motion of a system consisting of two layers of liquids that differ in density and viscosity to simulate the crust and the upper mantle that form a lithospheric plate. We assume that the motion is driven by basal traction. Assuming isostasy, we derive a nonlinear differential equation for the evolution of the thickness of the crust. We solve this equation numerically to obtain the profile of the range. We find an approximate self-similar solution that describes reasonably well the process and predicts simple scaling laws for the height and width of the range as well as the shape of the transversal profile. We compare the theoretical results with the profiles of real mountain belts and find and excellent agreement.Comment: Accepted by Physics of Fluid

Comment on "Self segregation versus clustering in the Evolutionary Minority Game"

This is a comment on a paper by S. Hod and E. Nakar, published in Phys. Rev. Lett. 88, 238702 (2002)Comment: 1 page (PRL-like), 1 Figure. Some changes in the text. Accepted for publication in Phys.Rev. Let

Interplay of network dynamics and ties heterogeneity on spreading dynamics

The structure of a network dramatically affects the spreading phenomena unfolding upon it. The contact distribution of the nodes has long been recognized as the key ingredient in influencing the outbreak events. However, limited knowledge is currently available on the role of the weight of the edges on the persistence of a pathogen. At the same time, recent works showed a strong influence of temporal network dynamics on disease spreading. In this work we provide an analytical understanding, corroborated by numerical simulations, about the conditions for infected stable state in weighted networks. In particular, we reveal the role of heterogeneity of edge weights and of the dynamic assignment of weights on the ties in the network in driving the spread of the epidemic. In this context we show that when weights are dynamically assigned to ties in the network an heterogeneous distribution is able to hamper the diffusion of the disease, contrary to what happens when weights are fixed in time.Comment: 10 pages, 10 figure

Redistributive effects of indirect taxes: comparing arithmetical and behavioral simulations in Uruguay

In this brief paper we compare the redistributive effect of a VAT reform using an arithmetical and a behavioral microsimulation model. We analyze the effects of the elimination of the VAT for a basket of goods which is intensively consumed by the poorest population. Our microsimulations are based on data from the expenditure survey. The behavioral model uses the Quadratic Almost Ideal Demand System (QUAIDS) proposed by Banks et al (1997). Our results indicate that the change in the VAT implies a redistributive effect of small magnitude. The comparison of redistributive effects under the arithmetic and the behavioral simulation reveals that they are very similar.fiscal redistribution, income inequality, taxes

Distributive impacts of alternative tax structures. The case of Uruguay

This article considers the distributional impact of different changes in Uruguayan tax system, using a static micro-simulation framework based on the combination of data from household and expenditure surveys. On the indirect taxes side, we consider two alternatives that imply the same reduction in tax revenue: a general reduction of 2 points in the VAT basic rate, and a selective reduction in the VAT rate applied to specific goods that make up a large share of consumption of low income population. In relation to direct taxes, we consider the effects of increasing the upper limit of the tax free zone of the labor component of the dual income tax. We analyze separately the impact of each of these changes, and we also simulate a joint scenario including changes in direct and indirect taxes. Our results indicate that redistribution through the analyzed modifications in direct and indirect taxes in Uruguay is limited.Retail; fiscal redistribution, income inequality, taxes

Modeling the effects of variable feeding patterns of larval ticks on the transmission of Borrelia lusitaniae and Borrelia afzelii

Spirochetes belonging to the Borrelia burgdoferi sensu lato (sl) group cause Lyme Borreliosis (LB), which is the most commonly reported vector-borne zoonosis in Europe. B. burgdorferi sl is maintained in nature in a complex cycle involving Ixodes ricinus ticks and several species of vertebrate hosts. The transmission dynamics of B. burgdorferi sl is complicated by the varying competence of animals for different genospecies of spirochetes that, in turn, vary in their capability of causing disease. In this study, a set of difference equations simplifying the complex interaction between vectors and their hosts (competent and not for Borrelia) is built to gain insights into conditions underlying the dominance of B. lusitaniae (transmitted by lizards to susceptible ticks) and the maintenance of B. afzelii (transmitted by wild rodents) observed in a study area in Tuscany, Italy. Findings, in agreement with field observations, highlight the existence of a threshold for the fraction of larvae feeding on rodents below which the persistence of B. afzelii is not possible. Furthermore, thresholds change as nonlinear functions of the expected number of nymph bites on mice, and the transmission and recovery probabilities. In conclusion, our model provided an insight into mechanisms underlying the relative frequency of different Borrelia genospecies, as observed in field studies.Comment: 14 pages, 3 figures, to be published in Theoretical Population Biolog

Kyotorphin and its derivatives : unveiling routes and targets

Tese de doutoramento, Ciências Biomédicas (Bioquímica Médica), Universidade de Lisboa, Faculdade de Medicina, 2018The endogenous neuropeptide kyotorphin (L-Tyr-L-Arg, KTP) has remarkable analgesic activity, up to 4.2 fold more potent than endogenous opioids when administered directly into the brain, but is inefficient after systemic administration. Our group has designed and studied several KTP analogues, among them KTP-amide (LTyr L-Arg-NH2, KTP-NH2), which is analgesic, anti-inflammatory and neuroprotective after systemic administration. Despite this interesting set of biological properties, what makes of KTP-NH2 an interesting candidate for pharmacological development, the lack of knowledge on its mechanism of action is limiting. We need to improve our knowledge on the molecular basis of action of the peptide so then we can execute an industrial development plan for the drug. Understanding the relationships between the structure of the drug and its function, efficacy and pharmacokinetics as well as the identification and characterization of molecular targets will contribute to progress in that area. The aim of this thesis is contribute to understand the mechanism of action of KTP-NH2 and to identify molecular targets of this peptide. To achieve such aim, we have designed and studied KTP-NH2 derivatives to elucidate new aspects of the structure-activity relationship; and we looked for specific targets that could explain KTP-NH2 biological activities. First, we introduced selective changes in the chemical structure of KTP-NH2 by introducing D-amino acids residues and/or N-terminal methylation, in order to improve lipophilicity and resistance to enzymatic degradation. We found that D-Tyr-L-Arg-NH2 (KTP-NH2-DL) has a pronounced anti-inflammatory effect, but insignificant analgesic action probably due to its low permeation through lipid membranes. KTP-NH2 has a similar behavior, except for its potent analgesic action in several pain models. The results support the hypothesis that KTP-NH2 uses a specific transporter to cross the blood brain barrier (BBB), which is not efficient to transport KTP-NH2 analogues. Methylated KTP-NH2 isomers, LL and LD, are very permeable through lipid membranes and probably diffuse passively across the BBB. They are also more resistant to enzymatic degradation. Therefore, they have a prolonged analgesic effect in comparison with KTP NH2, but the pro-inflammatory activity jeopardizes their pharmacological potential. In a second phase, to elucidate the mechanism of action of KTP-NH2 at the molecular level, we used an approach based on intravital microscopy (IVM) and pharmacological inhibitors. We have demonstrated that KTP-NH2 is able to decrease, within 10 minutes, the number of rolling leukocytes induced either by lipopolysaccharide (LPS) or CXCL-1, suggesting a nongenomic mechanism of action. In the inflammation model induced by LPS, KTP-NH2 failed to decrease the number of rolling leukocytes in mice pre-treated either with metyrapone, an inhibitor of glucocorticoid (GC) synthesis, or with an inhibitor of interleukin-1 receptor (IL-1R). In addition, KTP-NH2 was not as effective reducing the number of rolling leukocytes of LPS-stimulated mice pre-treated with an inhibitor of heme-oxygenase-1 (HO-1) or with an inhibitor of interleukin-10 (IL-10), but pre-treatment of the LPS-stimulated animals with an inhibitor of MyD88 did not affect the action of KTP-NH2. In the inflammation model induced with CXCL-1, pre-treatment with metyrapone did not affect the anti-inflammatory action of KTP-NH2. Thus, we concluded that KTP-NH2 has dual action: a GC-mediated action, which is dominant in full-fledged inflammation models, and a GC-independent mechanism, which is predominant in models in which leukocyte rolling is stimulated but inflammation is not totally developed. We also tested the hypothesis that KTP-NH2 could act as an inhibitor of enkephalinases. Unlike the endogenous dipeptide KTP, KTP-NH2 did not inhibit angiotensin-converting enzyme (ACE) neither dipeptidyl-peptidase III (DPP3). However, we do not rule out the possibility that KTP-NH2 can inhibit other untested enkephalinases. The work in this thesis suggests that KTP-NH2 is a multifunctional peptide that has both central and peripheral actions. KTP-NH2 presents a very fast (10 minutes) anti inflammatory mechanism that blocks the expression/activation of adhesion molecules on the endothelium and we propose that GCs might be the molecular link to explain the analgesics, anti-inflammatory and neuroprotective effects of the peptide.O neuropéptido endógeno denominado quiotorfina (L-Tyr-L-Arg, KTP) tem demonstrado uma notável atividade analgésica, podendo ser até 4.2 vezes mais potente do que opióides endógenos quando administrados diretamente no cérebro, mas é ineficiente quando administrado sistemicamente. O nosso grupo tem desenvolvido e estudado vários análogos da quiotorfina, entre eles a quiotorfina-amida (L-Tyr-L-Arg-NH2, KTP-NH2), que é analgésica, anti-inflamatória e neuroprotetora após administração sistémica. Apesar deste conjunto interessante de propriedades biológicas, que tornam a KTP-NH2 um candidato interessante para desenvolvimento farmacológico, o desconhecimento do seu mecanismo de ação torna-se muito limitativo. É necessário progredir no avanço do entendimento das suas bases moleculares de ação para conseguir depois executar um plano de desenvolvimento industrial do fármaco. Este avanço passa por conseguir uma melhor compreensão da relação estrutura-função, estrutura-eficácia e estrutura-farmacocinética do fármaco, bem como revelar e caracterizar os seus alvos. O objetivo desta tese é contribuir para compreender os alvos e mecanismos de ação da KTP-NH2. Para alcançar esse objetivo, desenvolveram-se derivados da KTP-NH2 que contribuíram para elucidar novos aspetos da relação estrutura-atividade; e procuraram-se alvos específicos que pudessem explicar as atividades biológicas da KTP-NH2. Primeiro, introduziram-se pequenas alterações seletivas na estrutura química da KTP-NH2 através da introdução de D-aminoácidos e/ou metilação N-terminal, de modo a aumentar a lipofilicidade e resistência à degradação enzimática. Observou-se que o péptido D-Tyr-L-Arg-NH2 (KTP-NH2-DL) tem um efeito anti-inflamatório pronunciado mas apresenta uma baixa atividade analgésica, provavelmente devido à baixa permeabilidade em membranas lipídicas. A KTP-NH2 apresenta um comportamento semelhante, exceto pela sua potente ação analgésica em vários modelos de dor. Estes resultados suportam a hipótese de que a KTP-NH2 utiliza transportadores específicos para atravessar a barreira hematoencefálica, transportadores esses que não são capazes de transportar os seus análogos, como a KTP-NH2-DL. Os isómeros metilados, quer seja em conformação LL ou LD, são bastante permeáveis em membranas lipídicas e provavelmente atravessam passivamente a barreira hematoencefálica. Este resultado, provavelmente associado a uma maior resistência à digestão enzimática, contribui para explicar o efeito analgésico prolongado desses derivados em comparação a KTP-NH2. No entanto, os isómeros metilados (LL e LD) têm atividade pró-inflamatória, o que lhes retira potencial farmacológico. Numa segunda fase, na tentativa de elucidar os mecanismos moleculares por detrás da ação da KTP-NH2, utilizou-se uma abordagem baseada em microscopia intravital e inibidores farmacológicos. Demonstrou-se que o KTP-NH2 é capaz de diminuir, em apenas 10 minutos, o número de leucócitos rolantes induzidos por lipopolissacáridos (LPS) ou CXCL-1, sugerindo um mecanismo de ação não genómico. No modelo de inflamação induzido por LPS, a KTP-NH2 não conseguiu diminuir o número de leucócitos rolantes em ratinhos pré-tratados com metirapone, um inibidor da síntese de glucocorticóides (GCs), ou com um inibidor do receptor de interleucina-1. Além disso, o mesmo dipéptido não foi tão eficaz na redução do número de leucócitos rolantes em ratinhos estimulados com LPS e pré-tratados com um inibidor de heme-oxigenase-1 ou com um inibidor de interleucina-10. O pré-tratamento dos animais estimulados com LPS com um inibidor de MyD88 não afectou a ação da KTP-NH2. No modelo de inflamação induzido com CXCL-1, o pré-tratamento com metirapone não afectou a ação anti-inflamatória da KTP-NH2. Assim, concluiu-se que a KTP NH2 tem dupla ação: uma ação mediada por GCs, que é dominante em modelos de inflamação completos, e um mecanismo independente de GCs, que é predominante em modelos em que o rolamento de leucócitos é estimulado, mas a inflamação não está totalmente desenvolvida. Testou-se também a hipótese da KTP-NH2 ser um inibidor de encefalinases. Ao contrário do dipeptídeo endógeno KTP, a KTP-NH2 não inibiu a enzima conversora da angiotensina (ECA) nem a dipeptidil-peptidase III (DPP3). Contudo, não descartamos a possibilidade da KTP-NH2 poder inibir outras encefalinases não testadas. O trabalho nesta tese sugere que KTP-NH2 é um péptido multifuncional que tem ações tanto a nível central como periférico. A KTP-NH2 apresenta um mecanismo anti-inflamatório muito rápido (10 minutos) que bloqueia a expressão/ativação de moléculas de adesão no endotélio e propõe-se que os GCs sejam o elo molecular que explica as propriedades analgésicas, anti inflamatórias e neuroprotetoras deste péptido