Inference of evolutionary forces acting on human biological pathways

Because natural selection is likely to act on multiple genes underlying a given phenotypic trait, we study here the potential effect of ongoing and past selection on the genetic diversity of human biological pathways. We first show that genes included in gene sets are generally under stronger selective constraints than other genes and that their evolutionary response is correlated. We then introduce a new procedure to detect selection at the pathway level based on a decomposition of the classical McDonald–Kreitman test extended to multiple genes. This new test, called 2DNS, detects outlier gene sets and takes into account past demographic effects and evolutionary constraints specific to gene sets. Selective forces acting on gene sets can be easily identified by a mere visual inspection of the position of the gene sets relative to their two-dimensional null distribution. We thus find several outlier gene sets that show signals of positive, balancing, or purifying selection but also others showing an ancient relaxation of selective constraints. The principle of the 2DNS test can also be applied to other genomic contrasts. For instance, the comparison of patterns of polymorphisms private to African and non-African populations reveals that most pathways show a higher proportion of nonsynonymous mutations in non-Africans than in Africans, potentially due to different demographic histories and selective pressures.

Burrowing in Marine Muds by Crack Propagation: Kinematics and Forces

The polychaete Nereis virens burrows through muddy sediments by exerting dorsoventral forces against the walls of its tongue-depressor- shaped burrow to extend an oblate hemispheroidal crack. Stress is concentrated at the crack tip, which extends when the stress intensity factor (K-I) exceeds the critical stress intensity factor (K-Ic). Relevant forces were measured in gelatin, an analog for elastic muds, by photoelastic stress analysis, and were 0.015 +/- 0.001 N (mean +/- s.d.;N= 5). Measured elastic moduli (E) for gelatin and sediment were used in finite element models to convert the forces in gelatin to those required in muds to maintain the same body shapes observed in gelatin. The force increases directly with increasing sediment stiffness, and is 0.16 N for measured sediment stiffness of E=2.7x10(4) Pa. This measurement of forces exerted by burrowers is the first that explicitly considers the mechanical behavior of the sediment. Calculated stress intensity factors fall within the range of critical values for gelatin and exceed those for sediment, showing that crack propagation is a mechanically feasible mechanism of burrowing. The pharynx extends anteriorly as it everts, extending the crack tip only as far as the anterior of the worm, consistent with wedge-driven fracture and drawing obvious parallels between soft-bodied burrowers and more rigid, wedge-shaped burrowers(i.e. clams). Our results raise questions about the reputed high energetic cost of burrowing and emphasize the need for better understanding of sediment mechanics to quantify external energy expenditure during burrowing.

Effects of Externally Applied, Cyclical, Low Magnitude Forces on Orthodontic Tooth Movement in Rats

Orthodontic tooth movement requires external orthodontic forces to be converted to cellular signals that result in the coordinated removal of bone on one side of the tooth (compression side) by osteoclasts, and the formation of new bone by osteoblasts on the other side (tension side). The length of orthodontic treatment can take several years, leading to problems of caries, periodontal disease, root resorption, and patient dissatisfaction. It appears that the velocity of tooth movement is largely dependent on the rate of alveolar bone remodeling. Pharmacological approaches to increase the rate of tooth movement are limited due to patient discomfort, severe root resorption, and drug-induced side effects. Recently, externally applied, cyclical, low magnitude forces (CLMF) have been shown to cause an increase in the bone mineral density of long bones, and in the growth of craniofacial structures in a variety of animal models. In addition, CLMF is well tolerated by the patient and produces no known adverse effects. However, its application in orthodontic tooth movement has not been specifically determined. Since factors that increase alveolar bone remodeling enhance the rate of orthodontic tooth movement, we hypothesized that externally applied, cyclical, low magnitude forces (CLMF) will increase the rate of orthodontic tooth movement. In order to test this hypothesis we used an in vivo rat orthodontic tooth movement model. Our specific aims were: Specific Aim 1: To develop an in vivo rat model for tooth movement. We developed a tooth movement model based upon two established rodent models (Ren and Yoshimatsu et al, See Figure 1.). The amount of variation of tooth movement in rats exposed to 25-60 g of mesial force activated viii from the first molar to the incisor for 4 weeks was calculated. Specific Aim 2: To determine the frequency dose response of externally applied, cyclical, low magnitude forces (CLMF) for maximal tooth movement and osteoclast numbers. Our working hypothesis for this aim was that the amount of tooth movement would be dose dependent on the frequency of application of the CLMF. In order to test this working hypothesis, we varied the frequency of the CLMF from 30, 60, 100, and 200 Hz, 0.4N, two times per week, for 10 minutes for 4 weeks, and measured the amount of tooth movement. We also looked at the number of osteoclasts for the different frequencies; we hypothesized an increase in osteoclasts for the dose respnse of different frequencies. Specific Aim 3: To determine the effects of externally applied, cyclical, low magnitude forces (CLMF) on PDL proliferation. Our working hypothesis for this aim was that PDL proliferation would increase with CLMF. In order to test this hypothesis we compared CLMF (30 Hz, 0.4N, two times per week, for 10 minutes for 4 weeks) performed on the left side (experimental side), to the non-CLMF side, on the right (control side). This was an experimental study with 24 rats in total. The experimental group contained fifteen (15) rats in total, and they all received a spring plus a different frequency of CLMF. Three (3) received a spring and CLMF at 30 Hz, 0.4N for 10 minutes. Six (6) received a spring and CLMF at 60 Hz, 0.4N for 10 minutes. Three (3) received a spring and CLMF at 100 Hz, 0.4N for 10 minutes. Three (3) received a spring and CLMF at 200 Hz, 0.4N for 10 minutes. The control group contained six (6) rats, and received only a spring. An additional ix three (3) rats received CLMF (30 Hz, 0.4N, two times per week, for 10 minutes for 4 weeks) only, with no spring, and were used only for histological purposes. Rats were subjected to the application of orthodontic force from their maxillary left first molar to their left central incisor. In addition some of the rats received externally applied, cyclical, low magnitude force (CLMF) on their maxillary left first molar. micro-CT was used to measure the amount of orthodontic tooth movement. The distance between the maxillary first and second molars, at the most mesial point of the second molar and the most distal point of the first molar (1M-2M distance) were used to evaluate the distance of tooth movement. Immunohistochemistry was performed with TRAP staining and BrdU quantification. Externally applied, cyclical, low magnitude forces (CLMF) do appear to have an effect on the rate, while not significant, of orthodontic tooth movement in rats. It appears that lower CLMF decreases the rate of tooth movement, while higher CLMF increases the rate of tooth movement. Future studies with larger sample sizes are needed to clarify this issue. CLMF does not appear to affect the proliferation in PDL cells, and has no effect on the number of osteoclasts.

"An attentive Ear, a watchful Eye, and a Calm judicious Pen": William Samuel Johnson, the Colonial Agents, and the Transformation of the British Atlantic World

By looking at Great Britain and the American colonies in conjunction with the larger British Atlantic Empire, historians can better understand the political, social, and cultural transformations that occurred when transatlantic actors met. William Samuel Johnson is an example of an "ordinary" agent who nonetheless had extensive contacts with numerous British and American thinkers. While acting on Connecticut's behalf in London between 1767 and 1771, he sent reports back to Connecticut governors Jonathan Trumbull and William Pitkin on parliamentary proceedings while corresponding with the people who traveled around the Atlantic world during this critical period-merchants, seafarers, emigrants, soldiers, missionaries, radicals and conservatives, reformers, and politicians. He is also representative of the late eighteenth-century empire writ large. Agents, who had once been a source of stability in the far-flung colonies, became a destabilizing force as confusion and conflict grew over conceptual ideas of what constituted "the empire" and who was included in it. Johnson was a sane observer in the midst of the ideological and administrative upheaval of the 1760's and 1770's. His subsequent loyalism and political obscurity during the war years was in many ways a result of his attempts to reconcile various factional interests during his tenure as an agent. Although he did his best to resolve these divisions and provide an accurate account of the powerful nationalistic forces gathering on both sides of the Atlantic on the eve of the American Revolution, the agents' collective failures as transatlantic mediators helped bring about the collapse of an imperial community. This disintegration had dramatic effects on the whole of the Atlantic world.

Naishtat, F. Action et Langage: Desniveaux linguistiques de l'action aux forces illocutionnaires de la protestation. París: L'Hartmattan. 2010. 260 páginas

Fil: Parra, Fabiana. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Naishtat, F. Action et Langage: Desniveaux linguistiques de l'action aux forces illocutionnaires de la protestation. París: L'Hartmattan. 2010. 260 páginas

Fil: Parra, Fabiana. Universidad Nacional de La Plata. Facultad de Humanidades y Ciencias de la Educación; Argentina.

Cuba's social policy after the disintegration of the Soviet Union -- social development as legitimacy of regime and its economy effectiveness

Since the disintegration of the Soviet Union, Cuba has experienced a severe economic crisis, and the country's social policy has played an important role in showing the people a raison-d'etre for the revolution. This role has become even stronger in recent years, as internal and external actors demand political reforms and economic liberalization. This article first examines the Cuban government's use of social development to counter the demands for changes. It then looks at the extent that government social policy contributes economically to improving the Cuban living standard. The article demonstrates empirically how the leadership emphasizes their social accomplishments whenever demands for change come, and then shows that after the suspension of Soviet aid, Cuban social policy has been able to provide services mainly by relying on human capital and reducing quality materially because of the shortage of foreign reserves. This has limited the economic effectiveness of the services.

Desintegración vertical en la industria del automóvil en España: un caso de estudio = Vertical disintegration in the automotive industry in Spain: a case study

En los años recientes se ha producido un rápido crecimiento del comercio internacional en productos semielaborados que son diseñados, producidos y ensamblados en diferentes localizaciones a lo largo de diferentes países, debido principalmente a los siguientes motivos: el desarrollo de las tecnologías de la información, la reducción de los costes de transporte, la liberalización de los mercados de capitales, la armonización de factores institucionales, la integración económica regional que implica la reducción y la eliminación de las barreras al comercio, el desarrollo económico de los países emergentes, el uso de economías de escala, así como una desregulación del comercio internacional. Todo ello ha incrementado la competencia a nivel mundial en los mercados y ha posibilitado a las compañías tener más facilidad de acceso a potenciales mercados, así como a la adquisición de capacidades y conocimientos en otros países y a la realización de alianzas estratégicas internacionales con terceros, creando un entorno con mayor incertidumbre y más exigente para las compañías que componen una industria, y que tiene consecuencias directas en las operaciones de las compañías y en la organización de su producción. Las compañías, para adaptarse, ser competitivas y beneficiarse de este nuevo escenario globalizado y más competitivo, han externalizado partes del proceso productivo hacia proveedores especializados, creando un nuevo mercado intermedio que divide el proceso productivo, anteriormente integrado en las compañías que conforman una industria, entre dos conjuntos de empresas especializadas en esa industria. Dicho proceso suele ocurrir conservando la industria en que tiene lugar, los mismos servicios y productos, la tecnología empleada y las compañías originales que la conformaban previamente a la desintegración vertical. Todo ello es así debido a que es beneficioso tanto para las compañías originales de la industria como para las nuevas compañías de este mercado intermedio por diversos motivos. La desintegración vertical en una industria tiene unas consecuencias que la transforman completamente, así como la forma de operar de las compañías que la integran, incluso para aquellas que permanecen verticalmente integradas. Una de las características más importantes de esta desintegración vertical en una industria es la posibilidad que tiene una compañía de adquirir a una tercera la primera parte del proceso productivo o un bien semielaborado, que posteriormente será finalizado por la compañía adquiriente con la práctica del outsourcing; así mismo, una compañía puede realizar la primera parte del proceso productivo o un bien semielaborado, que posteriormente será finalizado por una tercera compañía con la práctica de la fragmentación. El principal objetivo de la presente investigación es el estudio de los motivos, los facilitadores, los efectos, las consecuencias y los principales factores significativos, microeconómicos y macroeconómicos, que desencadenan o incrementan la práctica de la desintegración vertical en una industria; para ello, la investigación se divide en dos líneas completamente diferenciadas: el estudio de la práctica del outsourcing y, por otro lado, el estudio de la fragmentación por parte de las compañías que componen la industria del automóvil en España, puesto que se trata de una de las industrias más desintegradas verticalmente y fragmentadas, y este sector posee una gran importancia en la economía del país. En primer lugar, se hace una revisión de la literatura existente relativa a los siguientes aspectos: desintegración vertical, outsourcing, fragmentación, teoría del comercio internacional, historia de la industria del automóvil en España y el uso de las aglomeraciones geográficas y las tecnologías de la información en el sector del automóvil. La metodología empleada en cada uno de ellos ha sido diferente en función de la disponibilidad de los datos y del enfoque de investigación: los factores microeconómicos, utilizando el outsourcing, y los factores macroeconómicos, empleando la fragmentación. En el estudio del outsourcing, se usa un índice basado en las compras externas sobre el valor total de la producción. Así mismo, se estudia su correlación y significación con las variables económicas más importantes que definen a una compañía del sector del automóvil, utilizando la técnica estadística de regresión lineal. Aquellas variables relacionadas con la competencia en el mercado, la externalización de las actividades de menor valor añadido y el incremento de la modularización de las actividades de la cadena de valor, han resultado significativas con la práctica del outsourcing. En el estudio de la fragmentación se seleccionan un conjunto de factores macroeconómicos, comúnmente usados en este tipo de investigaciones, relacionados con las principales magnitudes económicas de un país, y un conjunto de factores macroeconómicos, no comúnmente usados en este tipo de investigaciones, relacionados con la libertad económica y el comercio internacional de un país. Se emplea un modelo de regresión logística para identificar qué factores son significativos en la práctica de la fragmentación. De entre todos los factores usados en el modelo, los relacionados con las economías de escala y los costes de servicio han resultado significativos. Los resultados obtenidos de los test estadísticos realizados en el modelo de regresión logística han resultado satisfactorios; por ello, el modelo propuesto de regresión logística puede ser considerado sólido, fiable y versátil; además, acorde con la realidad. De los resultados obtenidos en el estudio del outsourcing y de la fragmentación, combinados conjuntamente con el estado del arte, se concluye que el principal factor que desencadena la desintegración vertical en la industria del automóvil es la competencia en el mercado de vehículos. Cuanto mayor es la demanda de vehículos, más se reducen los beneficios y la rentabilidad para sus fabricantes. Estos, para ser competitivos, diferencian sus productos de la competencia centrándose en las actividades que mayor valor añadido aportan al producto final, externalizando las actividades de menor valor añadido a proveedores especializados, e incrementando la modularidad de las actividades de la cadena de valor. Las compañías de la industria del automóvil se especializan en alguna o varias de estas actividades modularizadas que, combinadas con el uso de factores facilitadores como las economías de escala, las tecnologías de la información, las ventajas de la globalización económica y la aglomeración geográfica de una industria, incrementan y motivan la desintegración vertical en la industria del automóvil, desencadenando la coespecialización en dos sectores claramente diferenciados: el sector de fabricantes de vehículos y el sector de proveedores especializados. Cada uno de ellos se especializa en unas actividades y en unos productos o servicios específicos de la cadena de valor, lo cual genera las siguientes consecuencias en la industria del automóvil: se reducen los costes de transacción en los productos o servicios intercambiados; se incrementan la relación de dependencia entre fabricantes de vehículos y proveedores especializados, provocando un aumento en la cooperación y la coordinación, acelerando el proceso de aprendizaje, posibilitando a ambos adquirir nuevas capacidades, conocimientos y recursos, y creando nuevas ventajas competitivas para ambos; por último, las barreras de entrada a la industria del automóvil y el número de compañías se ven alteradas cambiando su estructura. Como futura línea de investigación, los fabricantes de vehículos tenderán a centrarse en investigar, diseñar y comercializar el producto o servicio, delegando el ensamblaje en manos de nuevos especialistas en la materia, el contract manufacturer; por ello, sería conveniente investigar qué factores motivantes o facilitadores existen y qué consecuencias tendría la implantación de los contract manufacturer en la industria del automóvil. 1.1. ABSTRACT In recent years there has been a rapid growth of international trade in semi-finished products designed, produced and assembled in different locations across different countries, mainly due to the following reasons: development of information technologies, reduction of transportation costs, liberalisation of capital markets, harmonisation of institutional factors, regional economic integration, which involves the reduction and elimination of trade barriers, economic development of emerging countries, use of economies of scale and deregulation of international trade. All these factors have increased competition in markets at a global level and have allowed companies to gain easier access to potential markets and to the acquisition of skills and knowledge in other countries, as well as to the completion of international strategic alliances with third parties, thus creating a more demanding and uncertain environment for these companies constituting an industry, which has a direct impact on the companies' operations and the organization of their production. In order to adapt, be competitive and benefit from this new and more competitive global scenario, companies have outsourced some parts of their production process to specialist suppliers, generating a new intermediate market which divides the production process, previously integrated in the companies that made up the industry, into two sets of companies specialized in that industry. This process often occurs while preserving the industry where it takes place, its same services and products, the technology used and the original companies that formed it prior to vertical disintegration. This is because it is beneficial for both the industry's original companies and the companies belonging to this new intermediate market, for various reasons. Vertical disintegration has consequences which completely transform the industry where it takes place as well as the modus operandi of the companies that are part of it, even of those who remain vertically integrated. One of the most important features of vertical disintegration of an industry is the possibility for a company to acquire from a third one the first part of the production process or a semi-finished product, which will then be finished by the acquiring company through the practice of outsourcing; also, a company can perform the first part of the production process or a semi-finish product, which will then be completed by a third company through the practice of fragmentation. The main objective of this research is to study the motives, facilitators, effects, consequences and major significant microeconomic and macroeconomic factors that trigger or increase the practice of vertical disintegration in a certain industry; in order to do so, research is divided into two completely differentiated lines: on the one hand, the study of the practise of outsourcing and, on the other, the study of fragmentation by companies constituting the automotive industry in Spain, since this is one of the most vertically disintegrated and fragmented industries and this particular sector is of major significance in this country's economy. First, a review is made of the existing literature, on the following aspects: vertical disintegration, outsourcing, fragmentation, international trade theory, history of the automobile industry in Spain and the use of geographical agglomeration and information technologies in the automotive sector. The methodology used for each of these aspects has been different depending on the availability of data and the research approach: the microeconomic factors, using outsourcing, and the macroeconomic factors, using fragmentation. In the study on outsourcing, an index is used based on external purchases in relation to the total value of production. Likewise, their significance and correlation with the major economic variables that define an automotive company are studied, using the statistical technique of linear regression. Variables related to market competition, outsourcing of lowest value-added activities and increased modularisation of the activities of the value chain have turned out to be significant with the practice of outsourcing. In the study of fragmentation, a set of macroeconomic factors commonly used for this type of research, is selected, related to the main economic indicators of a country, as well as a set of macroeconomic factors, not commonly used for this type of research, which are related to economic freedom and the international trade of a certain country. A logistic regression model is used to identify which factors are significant in the practice of fragmentation. Amongst all factors used in the model, those related to economies of scale and service costs have turned out to be significant. The results obtained from the statistical tests performed on the logistic regression model have been successful; hence, the suggested logistic regression model can be considered to be solid, reliable and versatile; likewise, it is in line with reality. From the results obtained in the study of outsourcing and fragmentation, combined with the state of the art, it is concluded that the main factor that triggers vertical disintegration in the automotive industry is competition within the vehicle market. The greater the vehicle demand, the lower the earnings and profitability for manufacturers. These, in order to be competitive, differentiate their products from the competition by focusing on those activities that contribute with the highest added value to the final product, outsourcing the lower valueadded activities to specialist suppliers, and increasing the modularity of the activities of the value chain. Companies in the automotive industry specialize in one or more of these modularised activities which, combined with the use of enabling factors such as economies of scale, information technologies, the advantages of economic globalisation and the geographical agglomeration of an industry, increase and encourage vertical disintegration in the automotive industry, triggering co-specialization in two clearly distinct sectors: the sector of vehicle manufacturers and the specialist suppliers sector. Each of them specializes in certain activities and specific products or services of the value chain, generating the following consequences in the automotive industry: reduction of transaction costs of the goods or services exchanged; growth of the relationship of dependency between vehicle manufacturers and specialist suppliers, which causes an increase in cooperation and coordination, accelerates the learning process, enables both to acquire new skills, knowledge and resources, and creates new competitive advantages for both; finally, barriers to entry the automotive industry and the number of companies are altered, changing their structure. As a future line of research, vehicle manufacturers will tend to focus on researching, designing and marketing the product or service, delegating the assembly in the hands of new specialists in the field, the contract manufacturer; for this reason, it would be useful to investigate what motivating or facilitating factors exist in this respect and what consequences would the implementation of contract manufacturers have in the automotive industry.

A simulation method to estimate closing forces in car-sealing rubber elements

The door-closing process can reinforce the impression of a solid, rock-proof, car body or of a rather cheap, flimsy vehicle. As there are no real prototypes during rubber profile bidding-out stages, engineers need to carry out non-linear numerical simulations that involve complex phenomena as well as static and dynamic loads for several profile candidates. This paper presents a structured virtual design tool based on FEM, including constitutive laws and incompressibility constraints allowing to predict more realistically the final closing forces and even to estimate sealing overpressure as an additional guarantee of noise insulation. Comparisons with results of physical tests are performed.

Asymptotic Description of Flutter Amplitude Saturation by Nonlinear Friction Forces

The computation of the non-linear vibration dynamics of an aerodynamically unstable bladed-disk is a formidable numerical task, even for the simplified case of aerodynamic forces assumed to be linear. The nonlinear friction forces effectively couple dif- ferent travelling waves modes and, in order to properly elucidate the dynamics of the system, large time simulations are typically required to reach a final, saturated state. Despite of all the above complications, the output of the system (in the friction microslip regime) is basically a superposition of the linear aeroelastic un- stable travelling waves, which exhibit a slow time modulation that is much longer than the elastic oscillation period. This slow time modulation is due to both, the small aerodynamic effects and the small nonlinear friction forces, and it is crucial to deter- mine the final amplitude of the flutter vibration. In this presenta- tion we apply asymptotic techniques to obtain a new simplified model that captures the slow time dynamics of the amplitudes of the travelling waves. The resulting asymptotic model is very re- duced and extremely cheap to simulate, and it has the advantage that it gives precise information about the characteristics of the nonlinear friction models that actually play a role in the satura- tion of the vibration amplitude.