Gravitational actions upon a tether in a non-uniform gravity field with arbitrary number of zonal harmonics

We develop general closed-form expressions for the mutual gravitational potential, resultant and torque acting upon a rigid tethered system moving in a non-uniform gravity field produced by an attracting body with revolution symmetry, such that an arbitrary number of zonal harmonics is considered. The final expressions are series expansion in two small parameters related to the reference radius of the primary and the length of the tether, respectively, each of which are scaled by the mutual distance between their centers of mass. A few numerical experiments are performed to study the convergence behavior of the final expressions, and conclude that for high precision applications it might be necessary to take into account additional perturbation terms, which come from the mutual Two-Body interaction.

Fashion in Actions on Social Media – Spanish SME Fashion Brands Case Studies

Fashion is one of the most vibrant sectors in Europe and important contributors to the European Union (EU) economy. In particular, Small and Medium Enterprises (SMEs) play a major part in European fashion industry (EU 2012). Just like fashion, where people¿s style has inherently meant to be shared as it is foremost a representation of one¿s self-image, social media allow the reflection of ones' personality and emotions. Although fashion practitioners have embraced social media in their marketing activities, it is still relatively few known at an academic level about the specificities of fashion industry when approaching social media marketing (SMM) strategies. This study sets out to explore fashion companies' SMM strategy and its activities. From an exploratory approach, we present case studies of two Spanish SME fashion companies, anonymously named hereafter as Company A and Company B, to deepen our understanding on how fashion brands implement their SMM strategy. Company A offers high-end fashion products while Company B produces medium fashion products. We analyzed the case studies using qualitative (interviews to companies' executives) and a mix of qualitative and quantitative (content analysis of companies' social media platform) methods. Public posts data of both companies' Facebook brand pages were used to perform the content analysis. Our findings through case studies of the two companies reveal that branding-oriented strategic objectives are the main drivers of their SMM implementations. There are significant differences between both companies. The main strategic action employed by Company A is engaging customers to participate into brand's offline social gathering events by inviting them through social media platform, while Company B focuses its effort on posting product promotion related contents and engaging influencers such as fashion bloggers. Our results are expected to serve as a basis of further investigations on how SMM strategy and strategic actions implemented by fashion brands may influence marketing outcomes.

Re-Ocupación y/o Re-Construcción de estructuras urbanas en desuso y su conexión con el espacio público y el paisaje

Los nuevos comportamientos urbanos nos permiten observar cada vez con más frecuencia en nuestras calles y plazas realidades que siempre habíamos considerado domésticas. Al contrario también pasa, todos los días vivimos en nuestras casas situaciones que implican relacionarnos con personas que no son de nuestro núcleo familiar. El diseño doméstico de nuestras ciudades y el urbanismo del diseño de interiores parecen herramientas oportunas en el mundo que nos ha tocado vivir. Esto nos lleva a pensar que los espacios públicos y privados son términos simplificados, definidos en base a conceptos de propiedad para organizar la ciudad. En cambio, sus usos y vivencias, su gestión y sus comportamientos se han complejizado, distorsionando la terminología convencional hasta hacerla obsoleta. En este contexto, considerado también el marco socioeconómico actual, surgen las “acciones de abajo a arriba” como nuevo paradigma o modelo de renovación urbana, que entienden la involucración del ciudadano como parte activa en el proceso de construcción de la urbe desde la misma gestación del proyecto, frente a las acciones habituales que consideran al usuario como mero receptor de las propuestas. Un ciudadano que parece estar cada vez más radicalizado y una administración que parece asustarse ante el desconcierto que el acercamiento al ciudadano puede acarrear, han ocasionado por un lado, espacios “gueto” de carácter casi anárquico y, por el otro lado, lugares tan institucionalizados que derivan en espacios asociados a la administración y ajenos al ciudadano. Por ello, se considera imprescindible la colaboración entre ambos poderes. De acuerdo con el discurso que precede, dentro de un marco comparativo, se estudian 5 supuestos seleccionados de las ciudades Madrid y Zaragoza. Madrid porque es referencia nacional e internacional en el desarrollo urbano a través de procesos ‘abajo arriba’. Zaragoza porque es una ciudad ‘media’ que históricamente no se ha definido por estrategias urbanas claras, ya sean de carácter social o institucional. Sin embargo, en el momento actual se pueden identificar planteamientos relacionados con la recuperación de construcciones y espacios vacantes que pueden ser determinantes a la hora de alcanzar equilibrios con los intensos procesos institucionales acaecidos en las dos últimas décadas. De los procesos urbanos registrados en cada lugar, desarrollados en construcciones y espacios vacantes, he seleccionado: Construcciones Vacantes Madrid |Tabacalera de Lavapiés Zaragoza | Antiguo I.E.S. Luis Buñuel y antiguo Convento de Mínimos Espacios Vacantes Madrid | Campo de Cebada [solar] Zaragoza | Patio ‘antiguo I.E.S. Luis Buñuel [espacio libre] y plaza Eduardo Ibarra [espacio libre] El proyecto de investigación ha partido de las hipótesis de partida que siguen: UNA… Las ‘acciones de abajo arriba’ o renovación desde abajo no tienen cabida como elementos urbanos aislados sino conectados entre sí, posibilitando la producción de sinergias y la construcción de la ciudad; pudiendo ser consideradas acciones de desarrollo y enlace urbano, pues su objetivo es convertirse en motores del espacio público. Cuestión que es aplicable al resto de los procesos o acciones urbanas [‘horizontales’ o ‘institucionales’] DOS… La capacidad de adaptación manifestada por las ‘acciones de abajo arriba’ implica un marco ideológico de referencia asociado a la importancia de la construcción con mínimos recursos [Re-ocupación y/o Re- Construcción de estructuras urbanas en desuso] en los procesos urbanos descritos, como vía para comprender los concepto sostenibilidad y calidad figurativa de lo construido. Cuestión que es aplicable a la recuperación de aquellos aspectos de la arquitectura que la convierten en necesaria para la sociedad. Y tiene como objetivo: Identificar modelos de sostenibilidad urbana como una estrategia que va de lo individual a lo colectivo y que se transmite fundamentalmente con la acción, mezclando la innovación y la tecnología en múltiples ámbitos, utilizando los recursos naturales e intelectuales de una manera eficiente y entendiendo la inteligencia humana y sobre todo la inteligencia colectiva, como principio y justificación. Se han analizado los siguientes aspectos: sociales [participación ciudadana e implicación de la administración pública], urbanos [conexiones con otros colectivos o espacios urbanos / transformaciones urbanas a través de los procesos de gestión utilizados], constructivos [materiales utilizados en la re-construcción de construcciones y espacios vacantes / sistemas constructivos utilizados] y los relacionados con la sostenibilidad [sostenibilidad económica / sostenibilidad de mantenimiento / sostenibilidad funcional / inteligencia colectiva] El estudio de los aspectos considerados se ha desarrollado con las herramientas metodológicas siguientes: Entrevistas abiertas a expertos: se han obtenido respuestas de 25 personas expertas [5 por cada espacio o construcción vacante] relacionadas con las acciones urbanas sostenibles, la cultura y las relaciones sociales, y que también conocen los lugares y su entorno desde los puntos de vista urbano y construido. Son ‘tipos ideales’ asociados a uno de los cinco poderes que se manifiestan en la ciudad: el poder educativo [la universidad], el poder creativo [la cultura], el poder administrativo [la política], el poder empresarial [la empresa privada] y los usuarios [un usuario activo y representativo de cada lugar elegido que haya intervenido en la gestación del proceso]. Han sido personas que conocían el tejido social y urbano de la ciudad de Zaragoza y Madrid, ya que la herramienta ‘entrevista abierta a expertos’, recoge datos y opiniones planteadas en las construcciones y espacios vacantes ubicados en Zaragoza y Madrid. Entrevistas cerradas a usuarios: como la población de usuarios que se somete a la investigación es infinita o muy grande, resulta imposible o inconveniente realizar la obtención de los datos sobre todos aquellos elementos que la forman. Por lo tanto, he decidido estudiar sólo una parte de la población que denomino ‘tipos ideales’, obteniendo respuestas de 150 usuarios [30 personas por cada espacio o construcción vacante]. La selección de grupos de personas entrevistadas, debe permitir que los resultados sean representativos de la población total de usuarios. Además, la elección de ‘tipos ideales’ se ha identificado con los vecinos de los núcleos urbanos [o barrios] en los que se ubican las construcciones o espacios vacantes analizados. Observación estructurada: recoger información a través de la observación me ha permitido conocer las actuaciones y comportamientos de los ciudadanos en el medio urbano. Esto ha facilitado el estudio del medio a nivel práctico, valorando el uso que la sociedad da a las construcciones y a los espacios vacantes analizados. Es importante posicionar la estrategia en relación con el tema de investigación propuesto. Una estrategia que dibuje un panorama plural, desarrollado a través de herramientas sociales y constructivas que permitan que la arquitectura hable de cosas parecidas a lo que interesa a la ciudadanía. Para ello, propuse un catálogo de herramientas arquitectónicas que han permitido evaluar todas las propuestas. Un contexto de estrategias comunes que han descrito con los mismos códigos las distintas actuaciones analizadas. Estas herramientas tocan diferentes campos de interés. Desde las partes más tectónicas y constructivas, hasta las más ligadas con el desarrollo urbanístico y social. Acciones de participación colectiva: Experiencias o laboratorios urbanos participados por los alumnos del grado de arquitectura de la UNIZAR y los agentes sociales. Las acciones son una herramienta propositiva. Investigar y analizar proponiendo ha permitido que el análisis del contexto pueda llegar a capas de mucha más profundidad. No se ha trabajado estableciendo jerarquías de profesores y alumnos, sino que se ha intentado posibilitar la conexión de distintos agentes que trabajan coordinadamente durante el tiempo que han durado las acciones. Por un lado esto ha permite que cada integrante haya aportado al grupo lo que mejor sabe hacer y de la misma manera, que cada uno pueda aprender aquello de lo que tenga más ganas… y reflexionar sobre determinados aspectos objeto del análisis. Una vez interpretados los resultados, obtenidos a través de las herramientas metodológicas referenciadas, se ha concluido lo que sigue: Respecto de la Hipótesis de partida UNO LAS ACCIONES ‘ABAJO ARRIBA’ han revelado que no se puede entender ningún proceso de gestión urbana fuera de la participación ciudadana. El ‘ESPACIO LIBRE’ de una ciudad necesita lugares de autogestión, espacios de cogestión, movimientos de ‘arriba abajo’ y también modelos que todavía no sabemos ni que existen. LAS ACCIONES INSTITUCIONALES ‘ARRIBA ABAJO’ han demostrado que no han presentado permeabilidad ni relación con las circulaciones de entorno. Tampoco han tenido en cuenta a otras muchas personas, ‘usuarios productores’, a las que les interesan los procesos de búsqueda y las fórmulas de conexión más interactivas. Respecto de la hipótesis de partida DOS LAS ACCIONES ‘ABAJO ARRIBA’ han revelado que el ‘derecho a la ciudad’, paradigma defendido por Lefebvre desde el cual se piensa el urbanismo ciudadano, en estos supuestos podría entenderse como el ‘derecho a la infraestructura’. El ESPACIO LIBRE es infraestructura y se quiere para infraestructurar los derechos de cada uno. Y aunque también es verdad que estas acciones son simples destellos, han hecho visible otro paradigma de gestión y propuesta urbana que puede ser predominante en un futuro próximo. LAS ACCIONES INSTITUCIONALES ‘ARRIBA ABAJO’ han revelado que las intervenciones estuvieron enfocadas únicamente a la resolución de los procesos constructivos y a la incorporación del programa como un dato ‘problema’ que era necesario resolver para evitar la afección al diseño. ABSTRACT The new urban ways of behaviour let us watch more and more frequently in our streets and squares, realities that we had always considered as domestic. This also happens the other way round. Every day we have to go through situations at home which imply relationships with people who don’t belong to our family circle. The domestic design of our cities and the urban planning of indoor design seem to be adequate tools in the world we have to live in. This leads us to think that public and private spaces are simplified terms, defined according to concepts of property in order to organise the city. On the other hand, its uses and the experiences of people, its management and ways of behaviour is now more complex, changing the conventional terminology that has become outdated. In this context, ‘bottom-up’ actions arise as a new paradigm or model of urban renewal. These actions consider the active role of social participation in the process of building up the city from the very beginning, in comparison with the former way of acting that considered the user as mere receptor of the proposals. A citizen who seems to become more and more radical, and an administration that seems to be afraid of the unknown, have created both almost anarchic ghetto spaces and, on the other hand, spaces which have been so institutionalised that derive into areas associated to the administration but alienated from the citizen. For this reason, cowork of both forces is considered as crucial. In accordance with the above mentioned ideas and within a comparative framework, five situations chosen from the cities of Madrid and Zaragoza are studied. Madrid because is a national and international reference in urban development that uses “bottom-up” processes. Zaragoza because is a “medium-size” city that, historically, has not been defined by clear social or institutional urban strategies. Nevertheless, at the present time we can identify approaches on the recovery of constructions and empty areas that may be determining for reaching a balance with the intense institutional processes that have taken place in the two last decades. From the urban processes registered in every place and developed in vacant areas and constructions, I have chosen: Vacant constructions Madrid | Lavapiés Tobacco Factory Zaragoza | Old Secondary School Luis Buñuel and old Convent of the Minimos Vacant areas Madrid | Campo de Cebada [non-built site]. Zaragoza | Old courtyard of the secondary school and Eduardo Ibarra square [free space] The research project has been issued from the following starting hypotheses: ONE… “Bottom-up actions” or renewal from below have no place as isolated urban elements but as connected parts that can produce synergies and the construction of the city, and that can also be considered as actions producing urban development and links. This can also be applied to the rest of urban processes or actions [‘horizontal’ or ‘institutional’]. TWO… The capacity of adaptation shown by “bottom-up actions” implies an ideological framework of reference which is related to the importance of construction with minimal resources (re-occupation and/or reconstruction of urban structures in disuse) in the above mentioned urban processes, as a way for understanding the concepts of sustainability and the representational quality of what has been constructed. This can also be applied to the recovery of those architectural aspects that make architecture necessary for society. And its objective is: Identify models of urban sustainability as a strategy going from the individual to the collective, which are mainly transferred by action and that mix innovation and technology in many fields. Models that use natural and intellectual resources in an efficient way, and understand human intelligence and, above all, collective intelligence, as principle and justification. The following aspects have been analysed: social [civic participation and involvement of the public Administration], urban [connections with other collectives or urban spaces / urban transformation by the processes of administration used], constructive [materials used for the re-construction of empty spaces / construction systems used] and those focusing on sustainability [economic sustainability /maintenance sustainability /functional sustainability / collective intelligence]. For researching into the above mentioned aspects, the following methodological tools have been developed: Open interviews with experts: answers from 25 experts have been obtained [five for every vacant space or empty construction] on sustainable urban actions, culture and social relations, who also know the places and their environment from an urban and constructive point of view. These are “ideal types” linked to one of the five powers acting in the city: the educational power [University], the creative power [culture], the administration power [politics], the corporate power [private companies] and the users [an active and representative user for every place selected during the establishment of the process]. They were people who knew the social and urban fabric of Zaragoza and Madrid, since the “open interview for experts” tool collects data and points of view set out in vacant constructions and spaces of Zaragoza and Madrid. Close interviews with users: as the number of users targeted for the research is very big or infinite, it is impossible or inconvenient to get data from all its constituent parts. Therefore, I have decided to research into the part of the population that I call “ideal types”, obtaining answers from 150 users [30 people for every empty space or construction]. The selection of the groups of people interviewed must produce results which are representative of the total population of users. Furthermore, the election of “ideal types” has been identified with the inhabitants of urban areas [or city districts] in which the vacant spaces or constructions analysed are located. A structured observation: I have known the actions and ways of behaving of the citizens in the urban environment by means of collecting information after observation. Therefore, the practical research into the target environment has been easier by valuing the use that society gives to the empty constructions and spaces analysed. It is important to position the strategy with respect to the research subject proposed. It involves a strategy able to get an overview of a plural landscape, developed by social and constructive tools, allowing architecture to talk about topics which are interesting for city dwellers. Therefore, I proposed a set of architectural tools to evaluate all the proposals. A context of common strategies describing the different actions analysed by using the same codes. These tools focus on different fields of interests, from the most tectonic and constructive parts, to the most related to urban and social development. Actions on collective participation: experiences or urban laboratories shared by the students of architecture of the University of Zaragoza and social agents. The actions are a proactive tool. Researching and analysing by means of proposing, has allowed me to analyse the context and much deeper layers. This work has not been done by establishing ranks of professors and student, but trying to get an interaction between the different agents who work in close coordination during the implementation of the actions. This has allowed every agent to contribute the group what they do the best, and also every individual has had the possibility to learn what s/he prefers…, thinking about the different aspects targeted by the analysis. Once the different methodological tools have been interpreted, this is the conclusion: With regard to the initial hypothesis ONE “BOTTOM-UP” ACTIONS have proven that no process of urban management can be understood outside civic participation. The “FREE SPACE” of a city needs self-managed places, co-managed spaces, “up-bottom” movements, and also models whose existence is still ignored. “UP-BOTTOM” INSTITUTIONAL ACTIONS have proven that they have not presented neither permeability nor relation with local ideas. They have also disregarded many other people, the “usersproducers”, who are interested in the most interactive means of searching and connecting processes. With regard to the initial hypothesis TWO Under these premises, “BOTTOM-UP” ACTIONS have shown that the “right to the city”, a paradigm defended by Lefebvre and from which citizen-focused urbanism is conceived, could be considered as a “right to the infrastructures”. A FREE SPACE is an infrastructure and must be used to “infrastructure” the rights of every citizen. And, even though it is true that these actions are mere flashes, they have made visible another paradigm of management and urban proposal that can be prevailing in a near future. “UP-BOTTOM” INSTITUTIONAL ACTIONS have revealed that the interventions have only focused on resolving construction processes and the incorporation of the program as a “problem” data that was necessary to resolve in order to avoid its influence on the design.

On the actions that one nerve cell can have on another: Distinguishing “drivers” from “modulators”

When one nerve cell acts on another, its postsynaptic effect can vary greatly. In sensory systems, inputs from “drivers” can be differentiated from those of “modulators.” The driver can be identified as the transmitter of receptive field properties; the modulator can be identified as altering the probability of certain aspects of that transmission. Where receptive fields are not available, the distinction is more difficult and currently is undefined. We use the visual pathways, particularly the thalamic geniculate relay for which much relevant evidence is available, to explore ways in which drivers can be distinguished from modulators. The extent to which the distinction may apply first to other parts of the thalamus and then, possibly, to other parts of the brain is considered. We suggest the following distinctions: Cross-correlograms from driver inputs have sharper peaks than those from modulators; there are likely to be few drivers but many modulators for any one cell; and drivers are likely to act only through ionotropic receptors having a fast postsynaptic effect whereas modulators also are likely to activate metabotropic receptors having a slow and prolonged postsynaptic effect.

Distinct Actions and Cooperative Roles of ROCK and mDia in Rho Small G Protein-induced Reorganization of the Actin Cytoskeleton in Madin–Darby Canine Kidney Cells

Rho, a member of the Rho small G protein family, regulates the formation of stress fibers and focal adhesions in various types of cultured cells. We investigated here the actions of ROCK and mDia, both of which have been identified to be putative downstream target molecules of Rho, in Madin–Darby canine kidney cells. The dominant active mutant of RhoA induced the formation of parallel stress fibers and focal adhesions, whereas the dominant active mutant of ROCK induced the formation of stellate stress fibers and focal adhesions, and the dominant active mutant of mDia induced the weak formation of parallel stress fibers without affecting the formation of focal adhesions. In the presence of C3 ADP-ribosyltransferase for Rho, the dominant active mutant of ROCK induced the formation of stellate stress fibers and focal adhesions, whereas the dominant active mutant of mDia induced only the diffuse localization of actin filaments. These results indicate that ROCK and mDia show distinct actions in reorganization of the actin cytoskeleton. The dominant negative mutant of either ROCK or mDia inhibited the formation of stress fibers and focal adhesions, indicating that both ROCK and mDia are necessary for the formation of stress fibers and focal adhesions. Moreover, inactivation and reactivation of both ROCK and mDia were necessary for the 12-O-tetradecanoylphorbol-13-acetate–induced disassembly and reassembly, respectively, of stress fibers and focal adhesions. The morphologies of stress fibers and focal adhesions in the cells expressing both the dominant active mutants of ROCK and mDia were not identical to those induced by the dominant active mutant of Rho. These results indicate that at least ROCK and mDia cooperatively act as downstream target molecules of Rho in the Rho-induced reorganization of the actin cytoskeleton.

Sequential Actions of Phospholipase D and Phosphatidic Acid Phosphohydrolase 2b Generate Diglyceride in Mammalian Cells

Phosphatidylcholine (PC) is a major source of lipid-derived second messenger molecules that function as both intracellular and extracellular signals. PC-specific phospholipase D (PLD) and phosphatidic acid phosphohydrolase (PAP) are two pivotal enzymes in this signaling system, and they act in series to generate the biologically active lipids phosphatidic acid (PA) and diglyceride. The identity of the PAP enzyme involved in PLD-mediated signal transduction is unclear. We provide the first evidence for a functional role of a type 2 PAP, PAP2b, in the metabolism of PLD-generated PA. Our data indicate that PAP2b localizes to regions of the cell in which PC hydrolysis by PLD is taking place. Using a newly developed PAP2b-specific antibody, we have characterized the expression, posttranslational modification, and localization of endogenous PAP2b. Glycosylation and localization of PAP2b appear to be cell type and tissue specific. Biochemical fractionation and immunoprecipitation analyses revealed that PAP2b and PLD2 activities are present in caveolin-1–enriched detergent-resistant membrane microdomains. We found that PLD2 and PAP2b act sequentially to generate diglyceride within this specialized membrane compartment. The unique lipid composition of these membranes may provide a selective environment for the regulation and actions of enzymes involved in signaling through PC hydrolysis.

Cortical cell death induced by IL-1 is mediated via actions in the hypothalamus of the rat

The cytokine IL-1 mediates diverse forms of neurodegeneration, but its mechanism of action is unknown. We have demonstrated previously that exogenous and endogenous IL-1 acts specifically in the rat striatum to dramatically enhance ischemic and excitotoxic brain damage and cause extensive cortical injury. Here we tested the hypothesis that this distant effect of IL-1 is mediated through polysynaptic striatal outputs to the cortex via the hypothalamus. We show that IL-1β injected into the rat striatum with the excitotoxin α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (S-AMPA) caused increased expression of IL-1β (mRNA and protein) mainly in the cortex where maximum injury occurs. Marked increases in IL-1β mRNA and protein were also observed in the hypothalamus. S-AMPA, injected alone into the striatum, caused only localized damage, but administration of IL-1β into either the striatum or the lateral hypothalamus immediately after striatal S-AMPA resulted in widespread cell loss throughout the ipsilateral cortex. Finally we showed that the cortical cell death produced by striatal coinjection of S-AMPA and IL-1β was significantly reduced by administration of the IL-1 receptor antagonist into the lateral hypothalamus. These data suggest that IL-1β can act in the hypothalamus to modify cell viability in the cortex. We conclude that IL-1-dependent pathways project from the striatum to the cortex via the hypothalamus and lead to cortical injury, and that these may contribute to a number of human neurological conditions including stroke and head trauma.

The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

Progesterone (P) powerfully inhibits gonadotropin-releasing hormone (GnRH) secretion in ewes, as in other species, but the neural mechanisms underlying this effect remain poorly understood. Using an estrogen (E)-free ovine model, we investigated the immediate GnRH and luteinizing hormone (LH) response to acute manipulations of circulating P concentrations and whether this response was mediated by the nuclear P receptor. Simultaneous hypophyseal portal and jugular blood samples were collected over 36 hr: 0–12 hr, in the presence of exogenous P (P treatment begun 8 days earlier); 12–24 hr, P implant removed; 24–36 hr, P implant reinserted. P removal caused a significant rapid increase in the GnRH pulse frequency, which was detectable within two pulses (175 min). P insertion suppressed the GnRH pulse frequency even faster: the effect detectable within one pulse (49 min). LH pulsatility was modulated identically. The next two experiments demonstrated that these effects of P are mediated by the nuclear P receptor since intracerebroventricularly infused P suppressed LH release but 3α-hydroxy-5α-pregnan-20-one, which operates through the type A γ-aminobutyric acid receptor, was without effect and pretreatment with the P-receptor antagonist RU486 blocked the ability of P to inhibit LH. Our final study showed that P exerts its acute suppression of GnRH through an E-dependent system because the effects of P on LH secretion, lost after long-term E deprivation, are restored after 2 weeks of E treatment. Thus we demonstrate that P acutely inhibits GnRH through an E-dependent nuclear P-receptor system.

Opposing mitogenic and anti-mitogenic actions of parathyroid hormone-related protein in vascular smooth muscle cells: A critical role for nuclear targeting

Parathyroid hormone-related protein (PTHrP) is a prohormone that is posttranslationally processed to a family of mature secretory forms, each of which has its own cognate receptor(s) on the cell surface that mediate the actions of PTHrP. In addition to being secreted via the classical secretory pathway and interacting with cell surface receptors in a paracrine/autocrine fashion, PTHrP appears to be able to enter the nucleus directly following translation and influence cellular events in an “intracrine” fashion. In this report, we demonstrate that PTHrP can be targeted to the nucleus in vascular smooth muscle cells, that this nuclear targeting is associated with a striking increase in mitogenesis, that this nuclear effect on proliferation is the diametric opposite of the effects of PTHrP resulting from interaction with cell surface receptors on vascular smooth muscle cells, and that the regions of the PTHrP sequence responsible for this nuclear targeting represent a classical bipartite nuclear localization signal. This report describes the activation of the cell cycle in association with nuclear localization of PTHrP in any cell type. These findings have important implications for the normal physiology of PTHrP in the many tissues which produce it, and suggest that gene delivery of PTHrP or modified variants may be useful in the management of atherosclerotic vascular disease.

Nontropic actions of neurotrophins: Subcortical nerve growth factor gene delivery reverses age-related degeneration of primate cortical cholinergic innervation

Normal aging is associated with a significant reduction in cognitive function across primate species. However, the structural and molecular basis for this age-related decline in neural function has yet to be defined clearly. Extensive cell loss does not occur as a consequence of normal aging in human and nonhuman primate species. More recent studies have demonstrated significant reductions in functional neuronal markers in subcortical brain regions in primates as a consequence of aging, including dopaminergic and cholinergic systems, although corresponding losses in cortical innervation from these neurons have not been investigated. In the present study, we report that aging is associated with a significant 25% reduction in cortical innervation by cholinergic systems in rhesus monkeys (P < 0.001). Further, these age-related reductions are ameliorated by cellular delivery of human nerve growth factor to cholinergic somata in the basal forebrain, restoring levels of cholinergic innervation in the cortex to those of young monkeys (P = 0.89). Thus, (i) aging is associated with a significant reduction in cortical cholinergic innervation; (ii) this reduction is reversible by growth-factor delivery; and (iii) growth factors can remodel axonal terminal fields at a distance, representing a nontropic action of growth factors in modulating adult neuronal structure and function (i.e., administration of growth factors to cholinergic somata significantly increases axon density in terminal fields). These findings are relevant to potential clinical uses of growth factors to treat neurological disorders.

Intervening in evolution: Ethics and actions

Biologists should help to guide a process of cultural evolution in which society determines how much effort, if any, is ethically required to preserve options in biological evolution. Evolutionists, conservation biologists, and ecologists should be doing more research to determine actions that would best help to avoid foreclosing evolutionary options.

Opposite actions of nitric oxide on cholinergic synapses: which pathways?

Nitric oxide (NO) produced opposite effects on acetylcholine (ACh) release in identified neuroneuronal Aplysia synapses depending on the excitatory or the inhibitory nature of the synapse. Extracellular application of the NO donor, SIN-1, depressed the inhibitory postsynaptic currents (IPSCs) and enhanced the excitatory postsynaptic currents (EPSCs) evoked by presynaptic action potentials (1/60 Hz). Application of a membrane-permeant cGMP analog mimicked the effect of SIN-1 suggesting the participation of guanylate cyclase in the NO pathway. The guanylate cyclase inhibitor, methylene blue, blocked the NO-induced enhancement of EPSCs but only reduced the inhibition of IPSCs indicating that an additional mechanism participates to the depression of synaptic transmission by NO. Using nicotinamide, an inhibitor of ADP-ribosylation, we found that the NO-induced depression of ACh release on the inhibitory synapse also involves ADP-ribosylation mechanism(s). Furthermore, application of SIN-1 paired with cGMP-dependent protein kinase (cGMP-PK) inhibitors showed that cGMP-PK could play a role in the potentiating but not in the depressing effect of NO on ACh release. Increasing the frequency of stimulation of the presynaptic neuron from 1/60 Hz to 0.25 or 1 Hz potentiated the EPSCs and reduced the IPSCs. In these conditions, the potentiating effect of NO on the excitatory synapse was reduced, whereas its depressing effect on the inhibitory synapse was unaffected. Moreover the frequency-dependent enhancement of ACh release in the excitatory synapse was greatly reduced by the inhibition of NO synthase. Our results indicate that NO may be involved in different ways of modulation of synaptic transmission depending on the type of the synapse including synaptic plasticity.

cGMP mediates the vascular and platelet actions of nitric oxide: confirmation using an inhibitor of the soluble guanylyl cyclase.

The L-arginine:nitric oxide (NO) pathway is believed to exert many of its physiological effects via stimulation of the soluble guanylyl cyclase (SGC); however, the lack of a selective inhibitor of this enzyme has prevented conclusive demonstration of this mechanism of action. We have found that the compound 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one (ODQ) inhibits the elevation of cGMP induced by the NO donor S-nitroso-DL-penicillamine in human platelets and rat vascular smooth muscle (IC50 = 10-60 nM and <10 nM, respectively) and that this is accompanied by prevention of the platelet inhibitory and vasodilator actions of NO donors. ODQ also inhibited the antiaggregatory action of NO generated by the platelets but did not affect the action of prostacyclin or that of a cGMP mimetic. In addition, ODQ inhibited the vasodilator actions of endogenously released NO and of NO generated after induction of NO synthase in vascular preparations. It did not, however, affect the increase in vascular smooth muscle cGMP or the dilatation induced by atrial natriuretic factor. ODQ had no effect on NO synthase activity, nor did it react with NO. It did, however, potently (IC50 approximately 10 nM) inhibit the activity of the SGC in cytosol obtained from crude extract of rat aortic smooth muscle. Thus ODQ prevents the actions of NO on platelets and vascular smooth muscle through its potent inhibitory effect on the SGC.

Disparate actions of hydroxyurea in potentiation of purine and pyrimidine 2',3'-dideoxynucleoside activities against replication of human immunodeficiency virus.

We and other groups have recently reported the potentiation by ribonucleotide reductase inhibitors such as hydroxyurea of the anti-human immunodeficiency virus type 1 (HIV-1) activity of purine and pyrimidine 2',3'-dideoxynucleosides in both resting and phytohemagglutinin-stimulated peripheral blood mononuclear cells. Little agreement prevails, however, as to the mechanism of the synergistic effects described. We report here that in phytohemagglutinin-stimulated peripheral blood mononuclear cells, two mechanisms exist for the potentiation of the anti-HIV-1 activity by low-dose hydroxyurea of the purine-based dideoxynucleoside 2',3'-dideoxyinosine and the pyrimidine-based dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine. For 2',3'-dideoxyinosine, the enhancement arises from a specific depletion of dATP by hydroxyurea, resulting in a favorable shift of the 2',3'-dideoxyadenosine 5'-triphosphate/dATP ratio. For the pyrimidine dideoxynucleosides 3'-azido-3'-deoxythymidine and 2',3'-dideoxycytidine, the more modest anti-HIV enhancement results from hydroxyurea-induced increases of pyrimidine kinase activities in the salvage pathway and, hence, increased 5'-phosphorylation of these drugs, while depletion of the corresponding deoxynucleoside 5'-triphosphates (dTTP and dCTP) plays no significant role.