STUDIES ON CHOLINERGIC FUNCTION AND MEMORY IN MICE (CHOLINOTOXINS, WORKING, REFERENCE MEMORY, RADIAL ARM MAZE)

Considerable evidence suggests that central cholinergic neurons participate in either acquisition, storage or retrieval of information. Experiments were designed to evaluate information processing in mice following either reversible or irreversible impairment in central cholinergic activity. The cholinergic receptor antagonists, atropine and methylatropine were used to reversibly inhibit cholinergic transmission. Irreversible impairment in central cholinergic function was achieved by central administration of the cholinergic-specific neurotoxins, N-ethyl-choline aziridinium (ECA) and N-ethyl-acetylcholine aziridinium (EACA).^ ECA and EACA appear to act by irreversible inhibition of high affinity choline uptake (proposed rate-limiting step in acetylcholine synthesis). Intraventricular administration of ECA or EACA produced persistent reduction in hippocampal choline acetyltransferase activity. Other neuronal systems and brain regions showed no evidence of toxicity.^ Mice treated with either ECA or EACA showed behavioral deficits associated with cholinergic dysfunction. Passive avoidance behavior was significantly impaired by cholinotoxin treatment. Radial arm maze performance was also significantly impaired in cholinotoxin-treated animals. Deficits in radial arm maze performance were transient, however, such that rapid and apparent complete behavioral recovery was seen during retention testing. The centrally active cholinergic receptor antagonist atropine also caused significant impairment in radial arm maze behavior, while equivalent doses of methylatropine were without effect.^ The relative effects of cholinotoxin and receptor antagonist treatment on short-term (working) memory and long-term (reference) memory in radial arm maze behavior were examined. Maze rotation studies indicated that there were at least two different response strategies which could result in accurate maze performance. One strategy involved the use of response algorithms and was considered to be a function of reference memory. Another strategy appeared to be primarily dependent on spatial working memory. However, all behavioral paradigms with multiple trails have reference memory requirements (i.e. information useful over all trials). Performance was similarly affected following either cholinotoxin or anticholinergic treatment, regardless of the response strategy utilized. In addition, rates of behavioral recovery following cholinotoxin treatment were similar between response groups. It was concluded that both cholinotoxin and anticholinergic treatment primarily resulted in impaired reference memory processes. ^

Joint effects of pulmonary function and aerobic power on survival in a cohort of healthy adults

Objective measurements of physical fitness and pulmonary function are related individually to long-term survival, both in healthy people and in those who are ill. These factors are furthermore known to be related to one another physiologically in people with pulmonary disease, because advanced pulmonary disease causes ventilatory limitation to exercise. Healthy people do not have ventilatory limitation to exercise, but rather have ventilatory reserve. The relationship between pulmonary function and exercise performance in healthy people is minimal. Exercise performance has been shown to modify the effect of pulmonary function on mortality in people with chronic obstructive pulmonary disease, but the relationship between these factors in healthy people has not been studied and is not known. The purpose of this study is to quantify the joint effects of pulmonary function and exercise performance as these bear on mortality in a cohort of healthy adults. This investigation is an historical cohort study over 20 years of follow-up of 29,624 adults who had complete preventive medicine, spirometry and treadmill stress examinations at the Cooper Clinic in Dallas, Texas.^ In 20 years of follow-up, there were 738 evaluable deaths. Forced expiratory volume in one second (FEV$\sb1$) percent of predicted, treadmill time in minutes percent of predicted, age, gender, body mass index, baseline smoking status, serum glucose and serum total cholesterol were all significant, independent predictors of mortality risk. There were no frank interactions, although age had an important increasing effect on the risk associated with smoking when other covariates were controlled for in a proportional-hazards model. There was no confounding effect of exercise performance on pulmonary function. In agreement with the pertinent literature on independent effects, each unit increase in FEV$\sb1$ percent predicted was associated with about eight tenths of a percent reduction in adjusted mortality rate. The concept of physiologic reserve is useful in interpretation of the findings. Since pulmonary function does not limit exercise tolerance in healthy adults, it is reasonable to expect that exercise tolerance would not modify the effect of pulmonary function on mortality. Epidemiologic techniques are useful for elucidating physiological correlates of mortality risk. ^

Analysis of p53 function and regulation

p53 is a tumor suppressor gene that is the most frequent target inactivated in cancers. Overexpression of wild-type p53 in rat embryo fibroblasts suppresses foci formation by other cooperating oncogenes. Introduction of wild-type p53 into cells that lack p53 arrests them at the G1/S boundary and reverses the transformed phenotype of some cells. The function of p53 in normal cells is illustrated by the ability of p53 to arrest cells at G1 phase of the cell cycle upon exposure to DNA-damaging agents including UV-irradiation and biosynthesis inhibitors.^ Since the amino acid sequence of p53 suggested that it may function as a transcription factor, we used GAL4 fusion assays to test that possibility. We found that wild-type p53 could specifically activate transcription when anchored by the GAL4 DNA binding domain. Mutant p53s, which have lost the ability to suppress foci formation by other oncogenes, were not able to activate transcription in this assay. Thus, we established a direct correlation between the tumor suppression and transactivation functions of p53.^ Having learned that p53 was a transcriptional activator, we next sought targets of p53 activation. Because many transcription factors regulate their own expression, we tested whether p53 had this autoregulatory property. Transient expression of wild-type p53 in cells increased the levels of endogenous p53 mRNA. Cotransfection of p53 together with a reporter bearing the p53 promoter confirmed that wild-type p53 specifically activates its own promoter. Deletion analysis from both the 5$\sp\prime$ and 3$\sp\prime$ ends of the promoter minimized the region responsible for p53 autoregulation to 45 bp. Methylation interference identified nucleotides involved in protein-DNA interaction. Mutations within this protected site specifically eliminated the response of the promoter to p53. In addition, multiple copies of this element confer responsiveness to wild-type p53 expression. Thus, we identified a F53 responsive element within the p53 promoter.^ The presence of a consensus NF-$\kappa$B site in the p53 promoter suggested that NF-KB may regulate p53 expression. Gel-shift experiments showed that both the p50 homodimer and the p50/p65 heterodimer bind to the p53 promoter. In addition, the p65 subunit of NF-$\kappa$B activates the p53 promoter in transient transfection experiments. TNF $\alpha$, a natural NF-$\kappa$B inducer, also activates the p53 promoter. Both p65 activation and TNF $\alpha$ induction require an intact NF-$\kappa$B site in the p53 promoter. Since NF-$\kappa$B activation occurs as a response to stress and p53 arrests cells in G1/S, where DNA repair occurs, activation of p53 by NF-$\kappa$B could be a mechanism by which cells recover from stress.^ In conclusion, we provided the first data that wild-type p53 functions as a transcriptional activator, whereas mutant p53 cannot. The correlation between growth suppression and transcriptional activation by p53 implies a pathway of tumor suppression. We have analyzed upstream components of the pathway by the identification of both p53 and NF-$\kappa$B as regulators of the p53 promoter. ^

Origin and evolution of Cycladophora davisiana (Radiolaria) in DSDP Hole 19-192, Northwest Pacific

This paper documents the evolutionary history of Cycladophora davisiana Ehrenberg from an uppermost Miocene to Pleistocene sedimentary record in the high-latitude Northwest Pacific. It apparently evolved from C. sakaii Motoyama through a series of intermediates. C. sakaii has a relatively large shell with an external spongy layer. The evolutionary transition is characterized by a relatively rapid decrease in thorax size with a reduction of the spongy appendage. This change occurred during about 0.4 m.y. from 2.8 to 2.4 Ma without cladogenesis. Following this interval, a decrease in thorax size continued gradually up to the Recent, resulting in a very small morphology. Although the population of C. davisiana first appeared at about 2.5 Ma, some morphotypic specimens may occur in earlier periods as indistinguishable very small endmembers in the C. sakaii populations. Timing of the first appearance events both of morphotypic specimens and of a population of C. davisiana in Site 192 and previously reported cores does not disprove the idea that C. davisiana evolved first in the Northwest Pacific region, and later migrated into other regions of the world ocean. Biometrics clearly indicate no direct phylogenetic relationships between C. davisiana and C. cornutoides Kling in the studied core. Thus, the latter species, which was originally described as a variation and later elevated to a subspecies of the former species, is separated from the former species and raised to the species rank.

Backward-bending of labor supply function and free riders

It seems like that backward- bending of labor supply function can be observed in Central Asian Countries such as Uzbekistan and Kazakhstan. People’s basic needs of life are satisfied and they do not increase labor supplies even if wage increases. It is possible to find some cases in which slowdowns increase, when a manager in a firm enforces penalties for workers have slowdowns. This phenomenon occurs because a worker prefers the position of equilibrium on the labor supply function always in the upper direction. This article explains the increase of free-riders by penalties and how to avoid them.

Structure function and Multifractal spectrum applied to Digital Elevation Model

A Digital Elevation Model (DEM) provides the information basis used for many geographic applications such as topographic and geomorphologic studies, landscape through GIS (Geographic Information Systems) among others. The DEM capacity to represent Earth?s surface depends on the surface roughness and the resolution used. Each DEM pixel depends on the scale used characterized by two variables: resolution and extension of the area studied. DEMs can vary in resolution and accuracy by the production method, although there are statistical characteristics that keep constant or very similar in a wide range of scales. Based on this property, several techniques have been applied to characterize DEM through multiscale analysis directly related to fractal geometry: multifractal spectrum and the structure function. The comparison of the results by both methods is discussed. The study area is represented by a 1024 x 1024 data matrix obtained from a DEM with a resolution of 10 x 10 m each point, which correspond with a region known as ?Monte de El Pardo? a property of Spanish National Heritage (Patrimonio Nacional Español) of 15820 Ha located to a short distance from the center of Madrid. Manzanares River goes through this area from North to South. In the southern area a reservoir is found with a capacity of 43 hm3, with an altitude of 603.3 m till 632 m when it is at the highest capacity. In the middle of the reservoir the minimum altitude of this area is achieved.

Agile Construction and Evolution of Product-Line Architectures

Software Product Line Engineering (SPLE) has proved to have significant advantages in family-based software development, but also implies the up¬front design of a product-line architecture (PLA) from which individual product applications can be engineered. The big upfront design associated with PLAs is in conflict with the current need of "being open to change". However, the turbulence of the current business climate makes change inevitable in order to stay competitive, and requires PLAs to be open to change even late in the development. The trend of "being open to change" is manifested in the Agile Software Development (ASD) paradigm, but it is spreading to the domain of SPLE. To reduce the big upfront design of PLAs as currently practiced in SPLE, new paradigms are being created, one being Agile Product Line Engineering (APLE). APLE aims to make the development of product-lines more flexible and adaptable to changes as promoted in ASD. To put APLE into practice it is necessary to make mechanisms available to assist and guide the agile construction and evolution of PLAs while complying with the "be open to change" agile principle. This thesis defines a process for "the agile construction and evolution of product-line architectures", which we refer to as Agile Product-Line Archi-tecting (APLA). The APLA process provides agile architects with a set of models for describing, documenting and tracing PLAs, as well as an algorithm to analyze change impact. Both the models and the change impact analysis offer the following capabilities: Flexibility & adaptability at the time of defining software architectures, enabling change during the incremental and iterative design of PLAs (anticipated or planned changes) and their evolution (unanticipated or unforeseen changes). Assistance in checking architectural integrity through change impact analysis in terms of architectural concerns, such as dependencies on earlier design decisions, rationale, constraints, and risks, etc.Guidance in the change decision-making process through change im¬pact analysis in terms of architectural components and connections. Therefore, APLA provides the mechanisms required to construct and evolve PLAs that can easily be refined iteration after iteration during the APLE development process. These mechanisms are provided in a modeling frame¬work called FPLA. The contributions of this thesis have been validated through the conduction of a project regarding a metering management system in electrical power networks. This case study took place in an i-smart software factory and was in collaboration with the Technical University of Madrid and Indra Software Labs. La Ingeniería de Líneas de Producto Software (Software Product Line Engi¬neering, SPLE) ha demostrado tener ventajas significativas en el desarrollo de software basado en familias de productos. SPLE es un paradigma que se basa en la reutilización sistemática de un conjunto de características comunes que comparten los productos de un mismo dominio o familia, y la personalización masiva a través de una variabilidad bien definida que diferencia unos productos de otros. Este tipo de desarrollo requiere el diseño inicial de una arquitectura de línea de productos (Product-Line Architecture, PLA) a partir de la cual los productos individuales de la familia son diseñados e implementados. La inversión inicial que hay que realizar en el diseño de PLAs entra en conflicto con la necesidad actual de estar continuamente "abierto al cam¬bio", siendo este cambio cada vez más frecuente y radical en la industria software. Para ser competitivos es inevitable adaptarse al cambio, incluso en las últimas etapas del desarrollo de productos software. Esta tendencia se manifiesta de forma especial en el paradigma de Desarrollo Ágil de Software (Agile Software Development, ASD) y se está extendiendo también al ámbito de SPLE. Con el objetivo de reducir la inversión inicial en el diseño de PLAs en la manera en que se plantea en SPLE, en los último años han surgido nuevos enfoques como la Ingeniera de Líneas de Producto Software Ágiles (Agile Product Line Engineering, APLE). APLE propone el desarrollo de líneas de producto de forma más flexible y adaptable a los cambios, iterativa e incremental. Para ello, es necesario disponer de mecanismos que ayuden y guíen a los arquitectos de líneas de producto en el diseño y evolución ágil de PLAs, mientras se cumple con el principio ágil de estar abierto al cambio. Esta tesis define un proceso para la "construcción y evolución ágil de las arquitecturas de lineas de producto software". A este proceso se le ha denominado Agile Product-Line Architecting (APLA). El proceso APLA proporciona a los arquitectos software un conjunto de modelos para de¬scribir, documentar y trazar PLAs, así como un algoritmo para analizar vel impacto del cambio. Los modelos y el análisis del impacto del cambio ofrecen: Flexibilidad y adaptabilidad a la hora de definir las arquitecturas software, facilitando el cambio durante el diseño incremental e iterativo de PLAs (cambios esperados o previstos) y su evolución (cambios no previstos). Asistencia en la verificación de la integridad arquitectónica mediante el análisis de impacto de los cambios en términos de dependencias entre decisiones de diseño, justificación de las decisiones de diseño, limitaciones, riesgos, etc. Orientación en la toma de decisiones derivadas del cambio mediante el análisis de impacto de los cambios en términos de componentes y conexiones. De esta manera, APLA se presenta como una solución para la construcción y evolución de PLAs de forma que puedan ser fácilmente refinadas iteración tras iteración de un ciclo de vida de líneas de producto ágiles. Dicha solución se ha implementado en una herramienta llamada FPLA (Flexible Product-Line Architecture) y ha sido validada mediante su aplicación en un proyecto de desarrollo de un sistema de gestión de medición en redes de energía eléctrica. Dicho proyecto ha sido desarrollado en una fábrica de software global en colaboración con la Universidad Politécnica de Madrid e Indra Software Labs.

Geomorphological analysis and evolution of an altered floodplain drainage system. The case of the Partido Stream (Spain)

The Partido Stream is a small torrential course that flows into the marsh of the Doñana National Park, an area that was declared a World Heritage Site in 1994. Before 1981, floods occurred, and the stream overflowed onto a floodplain. As an old alluvial fan, the floodplain has its singular orography and functionality. Fromthe floodplain, several drainage channels, locally called caño, discharged into themarsh. The Partido Streamhad themorphology of a caño and covered approximately 8 km from the old fan to the marsh. The stream was straightened and channelised in 1981 to cultivate the old fan. This resulted in floods that were concentrated between the banks in the following years, which caused the depth of water and the shear stress to increase, thus, scouring the river bed and river banks. In this case, the eroded materials were carried towards the marsh where a new alluvial fan evolved. Control measures on the old fan were implemented in 2006 to stop the development of the new alluvial fan downstream over the marsh. Thus, the stream would partially recover its original behaviour that it had before channelisation, moving forwards in a new, balanced state. The present study describes the geomorphological evolution that channelisation has caused since 1981 and the later slow process of recovery of the original hydraulic-sedimentation regime since 2006. Additionally, it deepens the understanding of the original hydraulic behaviour of the stream, combining field data and 2D simulations.

Teaching Planning of Forestry Engineering in Spain : origins and evolution

This paper addresses the historical evolution of, from its inception, to the present day, within the changing context of EHEA and linked to professional competences. The research methodology, although it is mainly a historical document review, expert opinions on university educational planning of university education of forestry engineering in Spain are also included. The results show the evolution of centralized planning, based on technical knowledge transmission to an approach based on competences (technical, contextual and behavioral) focusing on learning for improving employability.

Clearing Up Confusions about Religion and Evolution

A number of confusions plague the debate concerning religion and evolution. Included here are the belief that religion and science must be incompatible and the thesis that evolution is evidence for atheism. Clearing up these confusions helps remove obstacles to genuine dialogue, while acknowledging that difficulties remain.

A mutation in the transmembrane/luminal domain of the ryanodine receptor is associated with abnormal Ca2+ release channel function and severe central core disease

Central core disease is a rare, nonprogressive myopathy that is characterized by hypotonia and proximal muscle weakness. In a large Mexican kindred with an unusually severe and highly penetrant form of the disorder, DNA sequencing identified an I4898T mutation in the C-terminal transmembrane/luminal region of the RyR1 protein that constitutes the skeletal muscle ryanodine receptor. All previously reported RYR1 mutations are located either in the cytoplasmic N terminus or in a central cytoplasmic region of the 5,038-aa protein. The I4898T mutation was introduced into a rabbit RYR1 cDNA and expressed in HEK-293 cells. The response of the mutant RyR1 Ca2+ channel to the agonists halothane and caffeine in a Ca2+ photometry assay was completely abolished. Coexpression of normal and mutant RYR1 cDNAs in a 1:1 ratio, however, produced RyR1 channels with normal halothane and caffeine sensitivities, but maximal levels of Ca2+ release were reduced by 67%. [3H]Ryanodine binding indicated that the heterozygous channel is activated by Ca2+ concentrations 4-fold lower than normal. Single-cell analysis of cotransfected cells showed a significantly increased resting cytoplasmic Ca2+ level and a significantly reduced luminal Ca2+ level. These data are indicative of a leaky channel, possibly caused by a reduction in the Ca2+ concentration required for channel activation. Comparison with two other coexpressed mutant/normal channels suggests that the I4898T mutation produces one of the most abnormal RyR1 channels yet investigated, and this level of abnormality is reflected in the severe and penetrant phenotype of affected central core disease individuals.