Return of Equity Issues in the Spanish Stock Market from the Investor’s Perspective, during the 1997-2012 Period

Is it profitable for an investor, from a risk-return perspective, to acquire a stake in a quoted company when a capital increase is announced? This paper analyses the return obtained from the investment in equity issues with cash contribution and pre-emptive rights, aimed at funding corporate activities: acquisitions, investments in new facilities and/or strengthening the balance sheet of the companies undertaking the equity issue. During the 16 years covered by the study, the results show a negative average excess risk-adjusted return of almost 5%, from the moment that the equity offer is announced until the completion of the preferential subscription period. To obtain this excess return, the difference between the nominal Internal Rate of Return (IRR) and the expected return, using the CAPM, is computed for each equity issue. The intention behind this method is to eliminate the effects of time and any other possible effect on the stock price during the period of the analysis.The results from this article are consistent with the Pecking Order theory for the Spanish Stock Market also six months after the preferential subscription period. However, there is a positive return after three months.

Improving the pass-band return loss in liquid crystal dual-mode bandpass filters by microstrip patch reshaping

In this paper, the design and experimental characterization of a tunable microstrip bandpass filter based on liquid crystal technology are presented. A reshaped microstrip dual-mode filter structure has been used in order to improve the device performance. Specifically, the aim is to increase the pass-band return loss of the filter by narrowing the filter bandwidth. Simulations confirm the improvement of using this new structure, achieving a pass-band return loss increase of 1.5 dB at least. Because of the anisotropic properties of LC molecules, a filter central frequency shift from 4.688 GHz to 5.045 GHz, which means a relative tuning range of 7.3%, is measured when an external AC voltage from 0 Vrms to 15 Vrms is applied to the device.

Forced Response of Mistuned Bladed Disks: Quantitative Validation of the Asymptotic Description

The effect of small mistuning in the forced response of a bladed disk is analyzed using a recently introduced methodology: the asymptotic mistuning model. The asymptotic mistuning model is an extremely reduced, simplified model that is derived directly from the full formulation of the mistuned bladed disk using a consistent perturbative procedure based on the relative smallness of the mistuning distortion. A detailed description of the derivation of the asymptotic mistuning model for a realistic bladed disk configuration is presented. The asymptotic mistuning model results for several different mistuning patterns and forcing conditions are compared with those from a high-resolution finite element model. The asymptotic mistuning model produces quantitatively accurate results, and, probably more relevant, it gives precise information about the factors (tuned modes and components of the mistuning pattern) that actually play a role in the vibrational forced response of mistuned bladed disks.

Evaluación de la distribución de riesgos en los distintos modelos de asociación público-privada para la provisión de infraestructura carretera en México

México es de los pocos países en el mundo que ha realizado dos grandes programas para la construcción de autopistas en colaboración con el sector privado. El primero, fue realizado entre 1989 y 1994, con resultados adversos por el mal diseño del esquema de concesiones; y, el segundo con mejores resultados, en operación desde 2003 mediante nuevos modelos de asociación público-privada (APP). El objetivo de la presente investigación es estudiar los modelos de asociación público-privada empleados en México para la provisión de infraestructura carretera, realizando el análisis y la evaluación de la distribución de riesgos entre el sector público y privado en cada uno de los modelos con el propósito de establecer una propuesta de reasignación de riesgos para disminuir el costo global y la incertidumbre de los proyectos. En la primera parte se describe el estado actual del conocimiento de las asociaciones público-privadas para desarrollar proyectos de infraestructura, incluyendo los antecedentes, la definición y las tipologías de los esquemas APP, así como la práctica internacional de programas como el modelo británico Private Finance Initiative (PFI), resultados de proyectos en la Unión Europea y programas APP en otros países. También, se destaca la participación del sector privado en el financiamiento de la infraestructura del transporte de México en la década de 1990. En los capítulos centrales se aborda el estudio de los modelos APP que se han utilizado en el país en la construcción de la red de carreteras de alta capacidad. Se presentan las características y los resultados del programa de autopistas 1989-94, así como el rescate financiero y las medidas de reestructuración de los proyectos concesionados, aspectos que obligaron a las autoridades mexicanas a cambiar la normatividad para la aprobación de los proyectos según su rentabilidad, modificar la legislación de caminos y diseñar nuevos esquemas de colaboración entre el gobierno y el sector privado. Los nuevos modelos APP vigentes desde 2003 son: nuevo modelo de concesiones para desarrollar autopistas de peaje, modelo de proyectos de prestación de servicios (peaje sombra) para modernizar carreteras existentes y modelo de aprovechamiento de activos para concesionar autopistas de peaje en operación a cambio de un pago. De estos modelos se realizaron estudios de caso en los que se determinan medidas de desempeño operativo (niveles de tráfico, costos y plazos de construcción) y rentabilidad financiera (tasa interna de retorno y valor presente neto). En la última parte se efectúa la identificación, análisis y evaluación de los riesgos que afectaron los costos, el tiempo de ejecución y la rentabilidad de los proyectos de ambos programas. Entre los factores de riesgo analizados se encontró que los más importantes fueron: las condiciones macroeconómicas del país (inflación, producto interno bruto, tipo de cambio y tasa de interés), deficiencias en la planificación de los proyectos (diseño, derecho de vía, tarifas, permisos y estimación del tránsito) y aportaciones públicas en forma de obra. Mexico is one of the few countries in the world that has developed two major programs for highway construction in collaboration with the private sector. The first one was carried out between 1989 and 1994 with adverse outcomes due to the wrong design of concession schemes; and, the second one, in operation since 2003, through new public-private partnership models (PPPs). The objective of this research is to study public-private partnership models used in Mexico for road infrastructure provision, performing the analysis and evaluation of risk’s distribution between the public and the private sector in each model in order to draw up a proposal for risk’s allocation to reduce the total cost and the uncertainty of projects. The first part describes the current state of knowledge in public-private partnership to develop infrastructure projects, including the history, definition and types of PPP models, as well as international practice of programs such as the British Private Finance Initiative (PFI) model, results in the European Union and PPP programs in other countries. Also, it stands out the private sector participation in financing of Mexico’s transport infrastructure in 1990s. The next chapters present the study of public-private partnerships models that have been used in the country in the construction of the high capacity road network. Characteristics and outcomes of the highway program 1989-94 are presented, as well as the financial bailout and restructuring measures of the concession projects, aspects that forced the Mexican authorities to change projects regulations, improve road’s legislation and design new schemes of cooperation between the Government and the private sector. The new PPP models since 2003 are: concession model to develop toll highways, private service contracts model (shadow toll) to modernize existing roads and highway assets model for the concession of toll roads in operation in exchange for a payment. These models were analyzed using case studies in which measures of operational performance (levels of traffic, costs and construction schedules) and financial profitability (internal rate of return and net present value) are determined. In the last part, the analysis and assessment of risks that affect costs, execution time and profitability of the projects are carried out, for both programs. Among the risk factors analyzed, the following ones were found to be the most important: country macroeconomic conditions (inflation, gross domestic product, exchange rate and interest rate), deficiencies in projects planning (design, right of way, tolls, permits and traffic estimation) and public contributions in the form of construction works.

The forced oscillations of submerged bodies

The increasing use of very light structures in aerospace applications are given rise to the need of taking into account the effects of the surrounding media in the motion of a structure (as for instance, in modal testing of solar panels or antennae) as it is usually performed in the motion of bodies submerged in water in marine applications. New methods are in development aiming at to determine rigid-body properties (the center of mass position and inertia properties) from the results of oscillations tests (at low frequencies during modal testing, by exciting the rigid-body modes only) by using the equations of the rigid-body dynamics. As it is shown in this paper, the effect of the surrounding media significantly modifies the oscillation dynamics in the case of light structures and therefore this effect should be taken into account in the development of the above-mentioned methods. The aim of the paper is to show that, if a central point exists for the aerodynamic forces acting on the body, the motion equations for the small amplitude rotational and translational oscillations can be expressed in a form which is a generalization of the motion equations for a body in vacuum, thus allowing to obtain a physical idea of the motion and aerodynamic effects and also significantly simplifying the calculation of the solutions and the interpretation of the results. In the formulation developed here the translational oscillations and the rotational motion around the center of mass are decoupled, as is the case for the rigid-body motion in vacuum, whereas in the classical added mass formulation the six motion equations are coupled. Also in this paper the nonsteady motion of small amplitude of a rigid body submerged in an ideal, incompressible fluid is considered in order to define the conditions for the existence of the central point in the case of a three-dimensional body. The results here presented are also of interest in marine applications.

La arquitectura religiosa en Santiago de Chile 1850-1950: razones de las reminiscencias góticas

Históricamente la estrategia de localización de la infraestructura religiosa católica en Chile ha estado condicionada por intenciones destinadas a la captación y tutela de feligreses, proceso desarrollado a través de intervenciones que han generado externalidades difíciles de anticipar y posibles de visualizar en un marco temporal mayor. En este contexto la producción e instalación de los templos católicos en distintos lugares de la ciudad condicionaron los territorios y marcaron presencia en su afán por colonizar y mantener el dominio, mecanismo propio de la institución religiosa que se adaptó al medio y a las circunstancias político social para cumplir su misión y mantener el poder. En esta investigación se buscó identificar desde las edificaciones destinadas al culto, la relación escalar entre localización, modo de instalación y morfología que incluye la forma y técnica de construcción, reconociendo la manera cómo modifican los entornos, el efecto que provocan y las expectativas que abren a nuevas intervenciones. El escenario escogido para realizar el estudio correspondió a un período de la historia de la ciudad de Santiago de Chile no documentado en que las circunstancias políticas, económicas, sociales y culturales contribuyeron a que el modo de disposición de las edificaciones de culto condicionaron el desarrollo urbano y orientaron el crecimiento de la ciudad. El período en que se desarrolló el estudio correspondió a la época de mayor riqueza material y cultural de la historia del país y estuvo modelada por las intenciones y planes de desarrollo tendientes a consolidar lo que se ha denominado el modelo Republicano. Escenario en que el espacio público cobró interés y se transformó en el motor de los cambios e indicador de la escala de la ciudad, estableciendo las condiciones para que las distintas corrientes europeas se manifestaran en el hacer arquitectónico cambiando la imagen original de la ciudad colonial. Este proceso que ocurrió sobre la estructura existente, densificó la manzana a través de la subdivisión predial, que complementado con los avances tecnológicos permitieron mayores alturas de edificación, situación que dio origen a nuevas concepciones espaciales, posibles de desarrollar con los recursos materiales, intelectuales y técnicos disponibles. El estudio se centró en la centuria 1850-1950 analizando la forma como la infraestructura religiosa Católica se localizó en el tejido urbano adoptando distintas tipologías edilicias, en una época caracterizada por el eclecticismo arquitectónico. Específicamente se estudiaron las edificaciones que utilizaron reminiscencias góticas, identificando los casos más significativos, estableciendo el contexto en que se originaron e indagando en la significación que tuvieron por la función que cumplieron, considerando emplazamiento y conexión con el entorno construido, conformación, dimensiones, destino y patrocinios. El área de estudio se fundamentó por la concentración de construcciones con la tendencia historicista, producciones que en el corto y mediano plazo orientaron las transformaciones de la ciudad y por la presencia que conservan hasta estos días. Se observó la incidencia de la acción de la Iglesia Católica en las políticas de Estado, orientando las decisiones de planificación y ocupación del territorio, condicionando la localización de los templos a fin de conseguir las mayores coberturas de la población y el mayor rendimiento de las inversiones. En el contexto latinoamericano la construcción de iglesias, templos y catedrales con reminiscencias góticas fue una constante que caracterizó al último cuarto del siglo XIX y las tres primeras décadas del siglo XX. El estudio permitió conocer en términos cuantitativos y cualitativos la producción, destacando la morfología y materialidad caracterizada por la adopción de estrategias contemporáneas estructuralmente exigentes. Se observó la utilización de la arquitectura como un medio de acercamiento a la población, capaz de transformar a los edificios en símbolos barriales, que facilitaron la generación de identidad, al convertirse en los referentes materiales que se destacan, que se recuerdan y que asumen la representatividad de barrios, permaneciendo en el tiempo y convirtiéndose en íconos asociados a la cultura local. En síntesis, la instalación de las infraestructuras religiosas en la ciudad de Santiago fue consecuencia de un modo de producción, que entregó lugares de encuentro y símbolos para la ciudad, a través de la localización de los edificios que buscaron ocupar áreas visibles, relevantes y convocantes, lo que consiguieron mediante la instalación geográfica, central y equidistante de conglomerados residenciales consolidados o en vías de desarrollo, como también a través de edificaciones monumentales y siempre destacadas respecto de su entorno, lo que marcó exclusividad y dominio. La elección de tipos arquitectónicos fue coyuntural a los tiempos e inspirada en intelectuales y profesionales mayoritariamente foráneos que aportaron conocimientos y experiencia para auspiciar edificaciones que fueron reconocidas como señeras y precursoras de la época. La intensidad en el uso de los recursos que demandaron las exigentes estructuras obligó a la iglesia católica a establecer estrategias de financiación destinadas a suplir la falta de recursos provenientes del Estado. Para lo cual convocaron a distintos actores los que participaron desde sus fronteras y en función de sus intereses cubriendo desde el altruismo hasta la rentabilización de su patrimonio. La organización iglesia católica se comporta de la misma manera que cualquier otra organización: busca expandirse, concentrar, controlar y administrar. Busca codificar todo su entorno (Raffestin, 2011), busca trascender y materialmente lo logra desde sus construcciones. ABSTRACT Historically the location strategies of the catholic religious infrastructure in Chile has been conditioned by intentions aimed at attracting and guardianship of parishioners, process developed through interventions that have generated externalities difficult to anticipate and possible to visualize in a in a major temporary frame. In this context, the production and installation of the catholic churches in different places in the city determined the territories and marked presence in their quest to colonize and maintain domain, mechanism of the religious institution that was adapted to the environment and in the political and social circumstances to fulfill its mission and maintain power. This research sought to identify from the buildings intended for worship in a multi-scale relationship between location, the placement mode, morphology and shape and construction technique and the effect caused by them, the way how they alter the environments and the expectations that are open to new interventions. The chosen scenario for the study corresponded to a not documented period in the history of the city of Santiago de Chile in which political, economic, social and cultural circumstances contributed to the form of disposition of the buildings of worship that determined the urban development and guided the growth of the city. The study period was the epoch of largest material and cultural wealth of Chile history and it was modeled by the intentions and development plans tending to consolidate what has been named the Republican ideal. Scenario in which public space gained interest and became the engine of change and indicator of the scale of the city, establishing the conditions for the various European trends manifested themselves in transforming the original image of the colonial city. This process that took place on the existing structure, produced a higher density of the original blocks through the predial compartimentation, which supplemented with technological advances enabled greater building heights, a situation that gave rise to new spatial conceptions, possible of developing with the material resources, intellectuals and technicians available at the moment. The study focused on the century 1850-1950 by analyzing how the Catholic religious infrastructure was located in the urban fabric by adopting different typologies locality, in an epoch characterised by architectural eclecticism. Specifica lly, it is studied the buildings that used gothic reminiscences, identifying the most significant cases, establishing the context in which they originated and inquiring about the significance that they had for the role it played, considering location and connection to the built environment, shaping, dimensions, destination, and sponsorships. The study area was established by the concentration of buildings with this historicist trend, productions that in the short and medium term guided the transformation of the city and the presence that keeps up to these days. It was noted the incidence of the of the Catholic Church actions in guiding State policies, planning decisions and occupation of the territory, as well as conditioning the location of the temples in order to achieve greater coverage of the population and the greatest return on investment. In the context of Latin America the construction of churches, temples and cathedrals with reminiscences gothic was a constant that characterized the last quarter of the nineteenth century and the first three decades of the twentieth century. The study allowed to know in quantitative and qualitative terms the production of the period, highlighting the morphology and materiality characterized by contemporary and structurally challenging strategies. It was noted the use of architecture as a means of approaching to the population, able to transform buildings into neighborhood symbols, which facilitated the production of identity, to become the reference materials that stand out, that will be remembered and that assume the representativeness of neighborhoods, remaining in the time and becoming icons associated with the local culture. In synthesis, the installation of religious infrastructure in the city of Santiago was result of a mode of production, that provided meeting places and symbols for the city, through the location of buildings that sought to occupy visible, relevant and summoning areas, what they obtained by means of the geographical, central and equidistant installation of consolidated residential conglomerates cluster or about to development, as also through always outstanding and monumental buildings with respect to its surroundings, which marked uniqueness and domain. The choice of architectural types was related to the time and inspired by intellectuals and professionals mostly outsiders who contributed with expertise and experience to sponsor buildings were recognized as outstanding and precursor of the time. The intensity of use of the resources that requested the demanding structures forced to the Catholic church to establish funding strategies designed to compensate for the lack of funds from the State. For which convened to different actors who participated from their borders and depending on their interests covering from the altruism up to the rentabilización of its patrimony. The Catholic Church organization behaves the same way as any other organization: seeks to expand, focus, control and manage. Looking for coding the entire environment (Raffestin, 2011), seeks to transcend and succeeds materially from its building.

Estrogen alters behavior and forebrain c-fos expression in ovariectomized rats subjected to the forced swim test

Estrogen has been implicated in brain functions related to affective state, including hormone-related affective disorders in women. Although some reports suggest that estrogen appears to decrease vulnerability to affective disorders in certain cases, the mechanisms involved are unknown. We used the forced swim test (FST), a paradigm used to test the efficacy of antidepressants, and addressed the hypotheses that estrogen alters behavior of ovariectomized rats in the FST and the FST-induced expression of c-fos, a marker for neuronal activity, in the rat forebrain. The behaviors displayed included struggling, swimming, and immobility. One hour after the beginning of the test on day 2, the animals were perfused, and the brains were processed for c-fos immunocytochemistry. On day 1, the estradiol benzoate-treated animals spent significantly less time struggling and virtually no time in immobility and spent most of the time swimming. Control rats spent significantly more time struggling or being immobile during a comparable period. On day 2, similar behavioral patterns with still more pronounced differences were observed between estradiol benzoate and ovariectomized control groups in struggling, immobility, and swimming. Analysis of the mean number of c-fos immunoreactive cell nuclei showed a significant reduction in the estradiol benzoate versus control groups in areas of the forebrain relating to sensory, contextual, and integrative processing. Our results suggest that estrogen-induced neurochemical changes in forebrain neurons may translate into an altered behavioral output in the affective domain.

Forced unfolding modulated by disulfide bonds in the Ig domains of a cell adhesion molecule

Cell adhesion molecules (CAMs) mediate cell attachment and stress transfer through extracellular domains. Here we forcibly unfold the Ig domains of a prototypical Ig superfamily CAM that contains intradomain disulfide bonds. The Ig domains of all such CAMs have conformations homologous to cadherin extracellular domains, titin Ig-type domains, and fibronectin type-III (FNIII) domains. Atomic force microscopy has been used to extend the five Ig domains of Mel-CAM (melanoma CAM)—a protein that is overexpressed in metastatic melanomas—under conditions where the disulfide bonds were either left intact or disrupted through reduction. Under physiological conditions where intradomain disulfide bonds are intact, partial unfolding was observed at forces far smaller than those reported previously for either titin's Ig-type domains or tenascin's FNIII domains. This partial unfolding under low force may be an important mechanism for imparting elasticity to cell–cell contacts, as well as a regulatory mechanism for adhesive interactions. Under reducing conditions, Mel-CAM's Ig domains were found to fully unfold through a partially folded state and at slightly higher forces. The results suggest that, in divergent evolution of all such domains, stabilization imparted by disulfide bonds relaxes requirements for strong, noncovalent, folded-state interactions.

Comparison of the early stages of forced unfolding for fibronectin type III modules

The structural changes accompanying stretch-induced early unfolding events were investigated for the four type III fibronectin (FN-III) modules, FN-III7, FN-III8, FN-III9, and FN-III10 by using steered molecular dynamics. Simulations revealed that two main energy barriers, I and II, have to be overcome to initiate unraveling of FN-III's tertiary structure. In crossing the first barrier, the two opposing β-sheets of FN-III are rotated against each other such that the β-strands of both β-sheets align parallel to the force vector (aligned state). All further events in the unfolding pathway proceed from this intermediate state. A second energy barrier has to be overcome to break the first major cluster of hydrogen bonds between adjacent β-strands. Simulations revealed that the height of barrier I varied significantly among the four modules studied, being largest for FN-III7 and lowest for FN-III10, whereas the height of barrier II showed little variation. Key residues affecting the mechanical stability of FN-III modules were identified. These results suggest that FN-III modules can be prestretched into an intermediate state with only minor changes to their tertiary structures. FN-III10, for example, extends 12 Å from the native “twisted” to the intermediate aligned state, and an additional 10 Å from the aligned state to further unfolding where the first β-strand is peeled away. The implications of the existence of intermediate states regarding the elasticity of fibrillar fibers and the stretch-induced exposure of cryptic sites are discussed.

Forced expression of the tumor suppressor adenomatosis polyposis coli protein induces disordered cell migration in the intestinal epithelium.

Mutations of the human adenomatosis polyposis coli (APC) gene are associated with the development of familial as well as sporadic intestinal neoplasia. To examine the in vivo function of APC, 129/Sv embryonic stem (ES) cells were transfected with DNA encoding the wild-type human protein under the control of a promoter that is active in all four of the small intestine's principal epithelial lineages during their migration-associated differentiation. ES-APC cells were then introduced into C57BL/6-ROSA26 blastocysts. Analyses of adult B6-ROSA26<-->129/Sv-APC chimeric mice revealed that forced expression of APC results in markedly disordered cell migration. When compared with the effects of forced expression of E-cadherin, the data suggest that APC-catenin and E-cadherin-catenin complexes have opposing effects on intestinal epithelial cell movement/adhesiveness; augmentation of E-cadherin-beta-catenin complexes produces a highly ordered, "adhesive" migration, whereas augmentation of APC-beta-catenin complexes produces a disordered, nonadhesive migratory phenotype. We propose that APC mutations may promote tumorigenesis by increasing the relative activity of cadherin-catenin complexes, resulting in enhanced adhesiveness and functional anchorage of initiated cells within the intestinal crypt. Our studies also indicate that chimeric mice generated from B6-ROSA26 blastocysts and genetically manipulated ES cells should be useful for auditing gene function in the gastrointestinal tract and in other tissues.

Forced expression of tropomyosin 2 or 3 in v-Ki-ras-transformed fibroblasts results in distinct phenotypic effects.

Transformation of cells in tissue culture results in a variety of cellular changes including alterations in cell growth, adhesiveness, motility, morphology, and organization of the cytoskeleton. Morphological and cytoskeletal changes are perhaps the most readily apparent features of transformed cells. Although a number of studies have documented a decrease in the expression of specific tropomyosin (TM) isoforms in transformed cells, it remains to be determined if the suppression of TM synthesis is essential in the establishment and maintenance of the transformed pheno-type. To address the roles of different TM isoforms in transformed cells we have examined the effects of expressing specific TM isoforms in transformed cells using a Kirsten virus-transformed cell line (ATCC NRK1569) as a model system. In contrast to normal fibroblasts, the NRK 1569 cells contain reduced levels of TM-1 and undetectable levels of TM-2 and TM-3. These cells have a rounded morphology and are devoid of stress fibers. Employing expression plasmids for TM-2 and TM-3, stable cell lines were established from the NRK 1569 cells that express these isoforms individually. We demonstrate that expression of TM-2 or TM-3 leads to increased cell spreading accompanied by the formation of identifiable microfilament bundles, as well as significant restoration of well-defined vinculin-containing focal adhesion plaques, although expression of each isoform exhibited distinct properties. In addition, cells expressing TM-2, but not TM-3, exhibited contact-inhibited cell growth and a requirement for serum.

Surface antigen cross-linking triggers forced exit of a protozoan parasite from its host.

We used the common fish pathogen Ichthyophthirius multifiliis as a model for studying interactions between parasitic ciliates and their vertebrate hosts. Although highly pathogenic, Ichthyophthirius can elicit a strong protective immune response in fish after exposure to controlled infections. To investigate the mechanisms underlying host resistance, a series of passive immunization experiments were carried out using mouse monoclonal antibodies against a class of surface membrane proteins, known as immobilization antigens (or i-antigens), thought to play a role in the protective response. Such antibodies bind to cilia and immobilize I. multifiliis in vitro. Surprisingly, we found that passive antibody transfer in vivo caused rapid exit of parasites from the host. The effect was highly specific for a given I. multifiliis serotype. F(ab)2 subfragments had the same effect as intact antibody, whereas monovalent Fab fragments failed to protect. The activity of Fab could, nevertheless, be restored after subsequent i.p. injection of bivalent goat anti-mouse IgG. Parasites that exit the host had detectable antibody on their surface and appeared viable in all respects. These findings represent a novel instance among protists in which protective immunity (and evasion of the host response) result from an effect of antibody on parasite behavior.

Forced evolution of glutathione S-transferase to create a more efficient drug detoxication enzyme.

Glutathione S-transferases (EC 2.5.1.18) in mammalian cells catalyze the conjugation, and thus, the detoxication of a structurally diverse group of electrophilic environmental carcinogens and alkylating drugs, including the antineoplastic nitrogen mustards. We proposed that structural alteration of the nonspecific electrophile-binding site would produce mutant enzymes with increased efficiency for detoxication of a single drug and that these mutants could serve as useful somatic transgenes to protect healthy human cells against single alkylating agents used in cancer chemotherapy protocols. Random mutagenesis of three regions (residues 9-14, 102-112, and 210-220), which together compose the glutathione S-transferase electrophile-binding site, followed by selection of Escherichia coli expressing the enzyme library with the nitrogen mustard mechlorethamine (20-500 microM), yielded mutant enzymes that showed significant improvement in catalytic efficiency for mechlorethamine conjugation (up to 15-fold increase in kcat and up to 6-fold increase in kcat/Km) and that confer up to 31-fold resistance, which is 9-fold greater drug resistance than that conferred by the wild-type enzyme. The results suggest a general strategy for modification of drug- and carcinogen-metabolizing enzymes to achieve desired resistance in both prokaryotic and eukaryotic plant and animal cells.

A Return to Little Things: Stories on Motherhood and Mistakes

A Return to Little Things includes three nonfiction pieces that revolve around the mistakes made by mothers and daughters. The collection investigates the idea that our lives are a sum total of the choices we have made. The essays directly address three specific situations that touch on the themes of motherhood, choices, and the human inclination to recall them with bitterness, and offer proof that time often allows us to move forward to forgiveness. Using humor and acceptance, the narrator is led through a labyrinth of emotions to come to peace with these choices. The stories serve as reminders that there are no mistakes, only lessons, and we must seek to understand them to live happy lives. This manuscript is a work in progress.

The Impact of BIM on the Distribution of Cost and Return on Investment in UK Construction Projects

It has been widely documented that when Building Information Modelling (BIM) is used, there is a shift in effort to the design phase. Little investigation into the impact of this shift in effort has been done and how it impacts on costs. It can be difficult to justify the increased expenditure on BIM in a market that is heavily driven by costs. There are currently studies attempting to quantify the return on investment (ROI) for BIM for which these returns can be seen to balance out the shift in efforts and costs to the design phase. The studies however quantify the ROI based on the individual stakeholder’s investment without consideration for the impact that the use of BIM from their project partners may have on their own profitability. In this study, a questionnaire investigated opinions and experience of construction professionals, representing clients, consultants, designers and contractors, to determine fluctuations in costs by their magnitude and when they occur. These factors were examined more closely by interviewing senior members representing each of the stakeholder categories and comparing their experience in using BIM within environments where their project partners were also using BIM and when they were not. This determined the differences in how the use and the investment in BIM impacts on others and how costs are redistributed. This redistribution is not just through time but also between stakeholders and categories of costs. Some of these cost fluctuations and how the cost of BIM is currently financed are also highlighted in several case studies. The results show that the current distribution of costs set for traditional 2D delivery is hindering the potential success of BIM. There is also evidence that stakeholders who don’t use BIM may benefit financially from the BIM use of others and that collaborative BIM is significantly different to the use of ‘lonely’ BIM in terms of benefits and profitability.