Is HIV short-sighted? Insights from a multistrain nested model

An important component of pathogen evolution at the population level is evolution within hosts. Unless evolution within hosts is very slow compared to the duration of infection, the composition of pathogen genotypes within a host is likely to change during the course of an infection, thus altering the composition of genotypes available for transmission as infection progresses. We develop a nested modeling approach that allows us to follow the evolution of pathogens at the epidemiological level by explicitly considering within-host evolutionary dynamics of multiple competing strains and the timing of transmission. We use the framework to investigate the impact of short-sighted within-host evolution on the evolution of virulence of human immunodeficiency virus (HIV), and find that the topology of the within-host adaptive landscape determines how virulence evolves at the epidemiological level. If viral reproduction rates increase significantly during the course of infection, the viral population will evolve a high level of virulence even though this will reduce the transmission potential of the virus. However, if reproduction rates increase more modestly, as data suggest, our model predicts that HIV virulence will be only marginally higher than the level that maximizes the transmission potential of the virus

Demand for rail travel to and from airports

Rail access to airports is becoming increasingly important for both train operators and the airports themselves. This paper reports analysis of inter-urban rail demand to and from Manchester and Stansted Airports and the sensitivity of this market segment to growth in air traffic and the cost and service quality of rail services. The estimated demand parameters vary in an expected manner between outward and inward air travellers as well as between airport users and general rail travellers. These parameters can be entered into the demand forecasting framework widely used in the rail industry in Great Britain to provide an appropriate means of forecasting for this otherwise neglected market segment. The novel features of this research, at least in the British context, are that it provides the first detailed analysis of aggregate rail flows to and from airports, it has disaggregated the traditional generalised time measure of rail service quality in order to estimate separate elasticities to journey time, service headway and interchange, and it has successfully explored departures from the conventional constant elasticity position

Modos de ser y temporalidad en la analítica existenciaria

En una primera instancia se analiza la función de la propiedad, la impropiedad y la originalidad dentro de la analítica existenciaria. Con respecto a la impropiedad, se descarta que sólo se contraponga a la propiedad y se determina su rol. El análisis de la propiedad lleva a destacar su carácter instantáneo y su constante posibilidad de degradación. Por último, se rechaza la identificación de la originalidad con lo ontológico, y se muestra que ella es el producto de la fusión entre la totalidad, a nivel ontológico, y la propiedad, a nivel óntico. Este nexo entre propiedad y originalidad nos llevará a descartar la posibilidad de que ésta última sirva de nexo en el pasaje de la impropiedad a la propiedad. Se destaca el rol del habla en dicho pasaje, su importancia en la historicidad, intratemporalidad y el tiempo intramundano y se esbozan las implicaciones de esta conclusión.The analysis of Dasein’s modes of being (authentic, inauthentic and original) shows us that originality has a close relation with authenticity. Originality is not an ontological dimension in opposition to authenticity and inauthenticity which are ontical dimensions, but the ontological beingtowards- death and the authentic and ontic resoluteness composes it. If that is the fact, then temporality cannot be conceived as an original and indifferent phenomenon that explains the movement from inathenticity to authenticity and the other way round. Our hypothesis is that this movement can only be explained by speech, i.e. vocation and ‘temptation’, but that Heidegger despised this fact, due to his methodological goal of having only one phenomenon, time, as sense of being

El lugar del testimonio dentro de la operación histórica

Pese a las falencias de los testimonios observadas en primer lugar y las limitaciones en la representación planteadas en segundo lugar, sigue habiendo quienes, rechazan restringir el testimonio· al ámbito de lo puramente psicológico o literario y señalan que más allá de sus inexactitudes, cumplen una labor histórica central. En lo que sigue, comenzaremos determinando cuál ha sido el rol que se le ha asignado tradicionalmente. Lo que observaremos es que el lugar asignado se supone un concepto evidencia! del testimonio. Nuestra hipótesis es que ésta no logra dar cuenta de la declaración de un sobreviviente, pues existe un elemento performativo que es dejado de lado . Teniendo en cuenta este último aspecto, concluiremos reevaluando el lugar que tiene el testimonio en la labor del historiador

Modelling passenger demand for parkway rail stations

Interest in Parkway stations emerged in the 1980s. These act as convenient out-of-town stations for inter-urban rail journeys. There were 13 so-called Parkway stations in Great Britain in 1999 and two have subsequently been opened. This paper reports the development and application of a new Parkway forecasting model which was conducted for the Association of Train Operating Companies (ATOC), undertaken as part of an extensive update to the Passenger Demand Forecasting Handbook, which recommends demand forecasting frameworks and associated parameters that are widely used in the railway industry in Great Britain. The objective was to develop a model that had more desirable properties and was more straightforward to apply than the previously recommended procedure. The focus is entirely upon inter-urban journeys of over 80 km.The model forecasts the demand for Parkway stations based solely on rail ticket sales data and its properties are illustrated with two case study applications. The nature of Parkway stations forces consideration of competition, and it is demonstrated that the inclusion of a station choice component leads to a somewhat improved explanatory power and a more plausible generalised cost elasticity.In addition to the methodological developments, the model has provided generally reasonable elasticities and forecasts and shown that Parkway users have different preferences to rail travellers in general. In a test based around a newly opened Parkway station, its forecasts are more accurate than the procedure it replaces

Lo mismo, otro: El uso del testimonio histórico a partir del Holocausto

El testimonio ha sido un tema especialmente conflictivo para la historia. Por una parte, el conocimiento histórico es esencialmente indirecto, procede a partir de trazos y testimonios. Como oportunamente lo expresó M. Bloch, " ... no podemos hablar de las edades que nos precedieron sino a partir de los testigos. Respecto de ellas, estamos en la misma situación que el juez que intenta reconstituir el crimen al que no asistió, o el físico, que obligado a quedarse en cama por la gripe, no se entera de los resultados de sus experimentos sino por los informes del asistente del laboratorio. En breve, en contraste con el conocimiento del presente, el conocimiento del pasado es forzosamente indirecto". Sin embargo, en la medida en que se considera a la historia como ciencia, el historiador no puede tomar la actitud pasiva de aceptar de juntillas y reproducir lo dicho por el testigo, más teniendo en cuenta la falta de precisión de la memoria y los intereses creados detrás de la declaración. La historia se alineó en este sentido con el debate epistemológico general acerca de la confiabilidad y alcance de esta fuente de conocimiento, y, en general, fue reticente en apoyarse en ella, inclinándose, en su lugar, por otras fuentes

Paul Ricoeur: Thinker of historical Testimony

Este artículo propone una lectura ética de La memoria, la historia, el olvido. Se recurre al testimonio del Holocausto, en tanto acontecimiento injustificable, como instancia de reflexión ética originada en la historia. En estos términos, la respuesta de Ricoeur al Debate de los Historiadores adquiere una importancia capital. Nuestra hipótesis es que esta respuesta es el producto de una larga reflexión sobre las consideraciones de Jean Nabert con respecto a la relación entre la dimensión fáctica y la ética.This paper proposes an ethical interpretation of Memory, History and Oblivion. Testimony of the Holocaust, as an unjustifiable event, is the historical point of departure of the ethical reflection. In these terms, Ricoeur’s position in relation to the Historikerstreit acquires a great value. Our hypotheses is that this answer is the product of a long reflection on Jean Nabert’s considerations on the relation of the factical and ethical dimensions

El rol político del historiador en el último Ricoeur y el papel de la imaginación productiva en su labor

En el presente artículo quisiéramos mostrar el papel de articulador entre la memoria y la historia que hace la imaginación en La memoria, la historia, el olvido de Paul Ricoeur. Este filósofo distingue dos funciones principales de la imaginación: una poética, asociada con la interpretación y el discurso, y otra práctica, de carácter proyectivo, que aclara, orienta y dinamiza nuestro actuar. En la obra que nos convoca se encuentran presentes ambas funciones de la imaginación aunque asociadas a distintos aspectos del tratamiento de la memoria. Pondremos de manifiesto la existencia de algunas diferencias en el modo en que se articulan ambas funciones de la imaginación entre Sí mismo como otro y en La memoria, la historia, el olvido. Mientras en la primera la dialéctica entre ambos tipos de imaginación coincide en el sí acerca del cual gira la cuestión de la identidad, en la segunda obra esta dialéctica imaginativa se produce en la figura del historiador que se contrapone al de la memoria. Nuestra hipótesis será que esta diferencia no se debe a que la memoria tratada sea una memoria abusada, sino al cambio en la concepción de repre-sentación que se produce entre ambas obras.In this paper we would like to show that in Memory, History, Forgetting Paul Ricoeur articulates memory and history through imagination. This philosopher distin-guishes two main functions of imagination: a poetical one, associated with the interpreta-tion and discourse, and a practical and projective one that clarifies and guides our actions. In Memory, History, Forgetting both functions of imagination are present but associated with different aspects of memory. We will disclose the existence of some differences in how both functions of imagination function in Oneself as Another and in Memory, History, Forgetting. While in the first the dialectic between the two types of imagination coincides with the self about which turns the question of identity, in the second work this imagina-tive dialectic occurs in the figure of the historian which is opposed to memory. Our hypothesis is that this difference was not due to the memory which is studies is an abused one, but due to the change in the conception of representation that occurs be-tween this two works

Acerca de las fronteras del lenguaje: las dificultades de la analítica existenciaria en el desarrollo proposicional del ser

La analítica existenciaria toma como manifestación lingüística de partida a la proposición. Sin embargo, en la medida en que Heidegger intentaba establecer los fundamentos ontológicos de la lógica, no permaneció dentro de esta esfera. El presente escrito analiza de qué manera la elección de este punto de partida influyó en el derrotero de este filósofo. En primer lugar describiremos el proceso de ontologización que establece de qué manera toda articulación lingüística se funda en una referencialidad pre-lingüística. En segundo paso nos estudiaremos en el problema de las fronteras del lenguaje, esto es, el modo en que Heidegger describe aquello que como condición de posibilidad de todo lenguaje proposicional no puede ser descrito proposicionalmente. Nos adentraremos a la indicación formal como posible metodología para llevar a cabo una ontología que evite la ontificación y la objetivación. Para concluir nos detendremos en los obstáculos metalógicos que presenta esta propuesta, y evaluaremos las consecuencias que supone para el desarrollo de una ontología.The existential analysis’ linguistical point of departure is proposition. However, Heidegger did not stay in the logical sphere, because he wanted to establish its ontological foundation. This paper studies how the election of this point of departure affected in his philosophy. In first place, we will describe the ontologization process which shows how every linguistical articulation is prelinguistical founded. In second place, we will study the problem of the limits of language, that is, the way in which Heidegger describes that that as condition of possibility of every propositional language cannot be described propositionally. We will consider the formal indication as a possible ontological methodology, which does not fail in ontification or objetivation. We will finish showing the metalogical obstacles of this proposal, and evaluate its consequences for an ontological development

Hyperthermia treatment of tumors by mesenchymal stem cell-delivered superparamagnetic iron oxide nanoparticles.

Magnetic hyperthermia - a potential cancer treatment in which superparamagnetic iron oxide nanoparticles (SPIONs) are made to resonantly respond to an alternating magnetic field (AMF) and thereby produce heat - is of significant current interest. We have previously shown that mesenchymal stem cells (MSCs) can be labeled with SPIONs with no effect on cell proliferation or survival and that within an hour of systemic administration, they migrate to and integrate into tumors in vivo. Here, we report on some longer term (up to 3 weeks) post-integration characteristics of magnetically labeled human MSCs in an immunocompromized mouse model. We initially assessed how the size and coating of SPIONs dictated the loading capacity and cellular heating of MSCs. Ferucarbotran(®) was the best of those tested, having the best like-for-like heating capability and being the only one to retain that capability after cell internalization. A mouse model was created by subcutaneous flank injection of a combination of 0.5 million Ferucarbotran-loaded MSCs and 1.0 million OVCAR-3 ovarian tumor cells. After 2 weeks, the tumors reached ~100 µL in volume and then entered a rapid growth phase over the third week to reach ~300 µL. In the control mice that received no AMF treatment, magnetic resonance imaging (MRI) data showed that the labeled MSCs were both incorporated into and retained within the tumors over the entire 3-week period. In the AMF-treated mice, heat increases of ~4°C were observed during the first application, after which MRI indicated a loss of negative contrast, suggesting that the MSCs had died and been cleared from the tumor. This post-AMF removal of cells was confirmed by histological examination and also by a reduced level of subsequent magnetic heating effect. Despite this evidence for an AMF-elicited response in the SPION-loaded MSCs, and in contrast to previous reports on tumor remission in immunocompetent mouse models, in this case, no significant differences were measured regarding the overall tumor size or growth characteristics. We discuss the implications of these results on the clinical delivery of hyperthermia therapy to tumors and on the possibility that a preferred therapeutic route may involve AMF as an adjuvant to an autologous immune response