Heap analysis in the presence of collection libraries

Memory analysis techniques have become sophisticated enough to model, with a high degree of accuracy, the manipulation of simple memory structures (finite structures, single/double linked lists and trees). However, modern programming languages provide extensive library support including a wide range of generic collection objects that make use of complex internal data structures. While these data structures ensure that the collections are efficient, often these representations cannot be effectively modeled by existing methods (either due to excessive analysis runtime or due to the inability to represent the required information). This paper presents a method to represent collections using an abstraction of their semantics. The construction of the abstract semantics for the collection objects is done in a manner that allows individual elements in the collections to be identified. Our construction also supports iterators over the collections and is able to model the position of the iterators with respect to the elements in the collection. By ordering the contents of the collection based on the iterator position, the model can represent a notion of progress when iteratively manipulating the contents of a collection. These features allow strong updates to the individual elements in the collection as well as strong updates over the collections themselves.

A static heap analysis for shape and connectivity: Unified memory analysis: The base framework

Modeling the evolution of the state of program memory during program execution is critical to many parallehzation techniques. Current memory analysis techniques either provide very accurate information but run prohibitively slowly or produce very conservative results. An approach based on abstract interpretation is presented for analyzing programs at compile time, which can accurately determine many important program properties such as aliasing, logical data structures and shape. These properties are known to be critical for transforming a single threaded program into a versi��n that can be run on m��ltiple execution units in parallel. The analysis is shown to be of polynomial complexity in the size of the memory heap. Experimental results for benchmarks in the Jolden suite are given. These results show that in practice the analysis method is efflcient and is capable of accurately determining shape information in programs that cr��ate and manip��late complex data structures.

Acrobats in the rooftops of Tehran

This paper seeks to analyze the political dimension of the body, and consequently the inherently political dimension of space, through the instrumental notion of situation, understood as an spatio-temporal mesh configured by bodies, practices and discourses. The political understood as the potential for action (or non-action) underlying the individual body, implies a renewed definition of a landscape that results from the body���s doing. Landscape becomes a multiple corporeality, a field of relations in which we discover ourselves enmeshed, not just placed; a field in which the limit is not frontier but bond and common dimension. A disquieting ambiguous zone appears there where the individual spatiality is born out of the body through the actualization of its political potential and entangles with others to constitute a common spatiality, political action of the multitude. The article is organized through the description of a back-and-forth movement between the revolts of Tehran in 2009 and the Iranian revolution of 1979. Also, a detour into the works of Robert Morris and Trisha Brown is required in order to understand the link between the body and the constitution of a common spatiality.

Reconstructing the Timing and Dispersion Routes of HIV-1 Subtype B Epidemics in The Caribbean and Central America: A Phylogenetic Story.

The Caribbean and Central America are among the regions with highest HIV-1B prevalence worldwide. Despite of this high virus burden, little is known about the timing and the migration patterns of HIV-1B in these regions. Migration is one of the major processes shaping the genetic structure of virus populations. Thus, reconstruction of epidemiological network may contribute to understand HIV-1B evolution and reduce virus prevalence. We have investigated the spatio-temporal dynamics of the HIV-1B epidemic in The Caribbean and Central America using 1,610 HIV-1B partial pol sequences from 13 Caribbean and 5 Central American countries. Timing of HIV-1B introduction and virus evolutionary rates, as well as the spatial genetic structure of the HIV-1B populations and the virus migration patterns were inferred. Results revealed that in The Caribbean and Central America most of the HIV-1B variability was generated since the 80 s. At odds with previous data suggesting that Haiti was the origin of the epidemic in The Caribbean, our reconstruction indicated that the virus could have been disseminated from Puerto Rico and Antigua. These two countries connected two distinguishable migration areas corresponding to the (mainly Spanish-colonized) Easter and (mainly British-colonized) Western islands, which indicates that virus migration patterns are determined by geographical barriers and by the movement of human populations among culturally related countries. Similar factors shaped the migration of HIV-1B in Central America. The HIV-1B population was significantly structured according to the country of origin, and the genetic diversity in each country was associated with the virus prevalence in both regions, which suggests that virus populations evolve mainly through genetic drift. Thus, our work contributes to the understanding of HIV-1B evolution and dispersion pattern in the Americas, and its relationship with the geography of the area and the movements of human populations.

Dopamine receptor 4 promoter polymorphism modulates memory and neuronal responses to salience

Animal models and human functional imaging data implicate the dopamine system in mediating enhanced encoding of novel stimuli into human memory. A separate line of investigation suggests an association between a functional polymorphism in the promoter region for the human dopamine 4 receptor gene (DRD4) and sensitivity to novelty. We demonstrate, in two independent samples, that the -521Cmayor queT DRD4 promoter polymorphism determines the magnitude of human memory enhancement for contextually novel, perceptual oddball stimuli in an allele dose-dependent manner. The genotype-dependent memory enhancement conferred by the C allele is associated with increased neuronal responses during successful encoding of perceptual oddballs in the ventral striatum, an effect which is again allele dose-dependent. Furthermore, with repeated presentations of oddball stimuli, this memory advantage decreases, an effect mirrored by adaptation of activation in the hippocampus and substantia nigra/ventral tegmental area in C carriers only. Thus, a dynamic modulation of human memory enhancement for perceptually salient stimuli is associated with activation of a dopaminergic-hippocampal system, which is critically dependent on a functional polymorphism in the DRD4 promoter region.

Formal Verification of Temporal Properties for Parametrized Concurrent Programs and Concurrent Data Structures

Los tipos de datos concurrentes son implementaciones concurrentes de las abstracciones de datos cl��sicas, con la diferencia de que han sido espec��ficamente dise��ados para aprovechar el gran paralelismo disponible en las modernas arquitecturas multiprocesador y multin��cleo. La correcta manipulaci��n de los tipos de datos concurrentes resulta esencial para demostrar la completa correcci��n de los sistemas de software que los utilizan. Una de las mayores dificultades a la hora de dise��ar y verificar tipos de datos concurrentes surge de la necesidad de tener que razonar acerca de un n��mero arbitrario de procesos que invocan estos tipos de datos de manera concurrente. Esto requiere considerar sistemas parametrizados. En este trabajo estudiamos la verificaci��n formal de propiedades temporales de sistemas concurrentes parametrizados, poniendo especial ��nfasis en programas que manipulan estructuras de datos concurrentes. La principal dificultad a la hora de razonar acerca de sistemas concurrentes parametrizados proviene de la interacci��n entre el gran nivel de concurrencia que ��stos poseen y la necesidad de razonar al mismo tiempo acerca de la memoria din��mica. La verificaci��n de sistemas parametrizados resulta en s�� un problema desafiante debido a que requiere razonar acerca de estructuras de datos complejas que son accedidas y modificadas por un numero ilimitado de procesos que manipulan de manera simult��nea el contenido de la memoria din��mica empleando m��todos de sincronizaci��n poco estructurados. En este trabajo, presentamos un marco formal basado en m��todos deductivos capaz de ocuparse de la verificaci��n de propiedades de safety y liveness de sistemas concurrentes parametrizados que manejan estructuras de datos complejas. Nuestro marco formal incluye reglas de prueba y t��cnicas especialmente adaptadas para sistemas parametrizados, las cuales trabajan en colaboraci��n con procedimientos de decisi��n especialmente dise��ados para analizar complejas estructuras de datos concurrentes. Un aspecto novedoso de nuestro marco formal es que efect��a una clara diferenciaci��n entre el an��lisis del flujo de control del programa y el an��lisis de los datos que se manejan. El flujo de control del programa se analiza utilizando reglas de prueba y t��cnicas de verificaci��n deductivas especialmente dise��adas para lidiar con sistemas parametrizados. Comenzando a partir de un programa concurrente y la especificaci��n de una propiedad temporal, nuestras t��cnicas deductivas son capaces de generar un conjunto finito de condiciones de verificaci��n cuya validez implican la satisfacci��n de dicha especificaci��n temporal por parte de cualquier sistema, sin importar el n��mero de procesos que formen parte del sistema. Las condiciones de verificaci��n generadas se corresponden con los datos manipulados. Estudiamos el dise��o de procedimientos de decisi��n especializados capaces de lidiar con estas condiciones de verificaci��n de manera completamente autom��tica. Investigamos teor��as decidibles capaces de describir propiedades de tipos de datos complejos que manipulan punteros, tales como implementaciones imperativas de pilas, colas, listas y skiplists. Para cada una de estas teor��as presentamos un procedimiento de decisi��n y una implementaci��n pr��ctica construida sobre SMT solvers. Estos procedimientos de decisi��n son finalmente utilizados para verificar de manera autom��tica las condiciones de verificaci��n generadas por nuestras t��cnicas de verificaci��n parametrizada. Para concluir, demostramos como utilizando nuestro marco formal es posible probar no solo propiedades de safety sino adem��s de liveness en algunas versiones de protocolos de exclusi��n mutua y programas que manipulan estructuras de datos concurrentes. El enfoque que presentamos en este trabajo resulta ser muy general y puede ser aplicado para verificar un amplio rango de tipos de datos concurrentes similares. Abstract Concurrent data types are concurrent implementations of classical data abstractions, specifically designed to exploit the great deal of parallelism available in modern multiprocessor and multi-core architectures. The correct manipulation of concurrent data types is essential for the overall correctness of the software system built using them. A major difficulty in designing and verifying concurrent data types arises by the need to reason about any number of threads invoking the data type simultaneously, which requires considering parametrized systems. In this work we study the formal verification of temporal properties of parametrized concurrent systems, with a special focus on programs that manipulate concurrent data structures. The main difficulty to reason about concurrent parametrized systems comes from the combination of their inherently high concurrency and the manipulation of dynamic memory. This parametrized verification problem is very challenging, because it requires to reason about complex concurrent data structures being accessed and modified by threads which simultaneously manipulate the heap using unstructured synchronization methods. In this work, we present a formal framework based on deductive methods which is capable of dealing with the verification of safety and liveness properties of concurrent parametrized systems that manipulate complex data structures. Our framework includes special proof rules and techniques adapted for parametrized systems which work in collaboration with specialized decision procedures for complex data structures. A novel aspect of our framework is that it cleanly differentiates the analysis of the program control flow from the analysis of the data being manipulated. The program control flow is analyzed using deductive proof rules and verification techniques specifically designed for coping with parametrized systems. Starting from a concurrent program and a temporal specification, our techniques generate a finite collection of verification conditions whose validity entails the satisfaction of the temporal specification by any client system, in spite of the number of threads. The verification conditions correspond to the data manipulation. We study the design of specialized decision procedures to deal with these verification conditions fully automatically. We investigate decidable theories capable of describing rich properties of complex pointer based data types such as stacks, queues, lists and skiplists. For each of these theories we present a decision procedure, and its practical implementation on top of existing SMT solvers. These decision procedures are ultimately used for automatically verifying the verification conditions generated by our specialized parametrized verification techniques. Finally, we show how using our framework it is possible to prove not only safety but also liveness properties of concurrent versions of some mutual exclusion protocols and programs that manipulate concurrent data structures. The approach we present in this work is very general, and can be applied to verify a wide range of similar concurrent data types.

El Prado, de territorio a escenario : la construcci��n del espacio en un lugar tangible y su significado

"Si el hombre es el cuidador de las palabras y s��lo de ellas emerge el sentido de las cosas, la arquitectura tiene un cometido preciso: hacer de las condiciones ya dadas de cada lugar palabras que signifiquen las cualidades de la existencia, y que desvelen la riqueza y contenidos que en ellas se contienen potencialmente" Ignasi Sol�� Morales. Lugar: permanencia o producci��n, 1992. Esta tesis surge tanto del af��n por comprender la identidad de uno de los espacios m��s representativos de mi ciudad, asumido familiarmente pero que plantea muchas dudas respecto a su caracterizaci��n, como de la preocupaci��n personal respecto a la aparente hegemon��a del modelo urbano de la "ciudad gen��rica", crudamente expuesto por Rem Koolhaas a finales del siglo XX, que pone en crisis la ciudad hist��rica. El territorio, espacio f��sico concreto, y la memoria asociada a este, obliterados, son considerados como punto de partida para confrontarlos con la proclamaci��n del nuevo modelo de "ciudad gen��rica", de ra��z eminentemente econ��mica y tecnol��gica. La realidad tangible de un espacio, aparentemente forjado en base a los valores denostados por el nuevo modelo propuesto, se estudia desde las premisas opuestas. La idea del no-lugar, teorizado por Marc Aug�� y tomado como modelo por Koolhaas, supone ��ste emancipado tanto de las preexistencias hist��ricas como de su ubicaci��n f��sica concreta, planteando un tipo de espacio de representaci��n al margen del territorio y la memoria. Sin pretender adoptar una postura resistente u opuesta, sino antit��tica y complementaria, se toman aqu�� las premisas de Koolhaas para contrastarlas con una porci��n del territorio a medio camino entre la arquitectura y la ciudad, a fin de desarrollar una reflexi��n que sirva de complemento y contrapeso al paradigma espacial que la ���ciudad gen��rica��� implica y cuya inmediatez y supuesta anomia parecen anular cualquier intenci��n interpretativa al neutralizar los centros hist��ricos y proclamar el agotamiento de la historia. El planteamiento de una teor��a dicot��mica frente al espacio y las teor��as arquitect��nicas asociadas a este ya fue formulado por Colin Rowe y Fred Koetter a finales de los a��os setenta del siglo pasado. Se plantea aqu�� la idea de una ���ciudad tangible��� como opuesta a la idea de la "ciudad gen��rica" enunciada por Koolhaas. Tomando el territorio y la memoria como referencia principal en un lugar concreto y huyendo de la premisa de la inmediatez del instante y el "presente perpetuo" proclamado por Koolhaas, del que seg��n ��l ser��amos prisioneros, se establece una distancia respecto al objeto de an��lisis que desarrolla el estudio en la direcci��n opuesta al supuesto origen del mismo, planteando la posibilidad de reactivar una reflexi��n en torno al territorio y la memoria en el seno del proceso global de habitaci��n para poner de manifiesto determinados mecanismos de configuraci��n de un espacio de representaci��n al margen de la urgencia del presente, reactivando la memoria y su relaci��n con el territorio como punto de partida. Desde de la reconstrucci��n hipot��tica del territorio, partiendo de la propia presencia f��sica del mismo, su orograf��a, la paleo-biolog��a, las analog��as etol��gicas, los restos arqueol��gicos, la antropolog��a o la historia, se reivindica la reflexi��n arquitect��nica como disciplina diversa y privilegiada en cuanto al an��lisis espacial, tratando de discernir el proceso mediante el cual el Prado pas�� de territorio a escenario. La organizaci��n cronol��gica del estudio y la incorporaci��n de muy diversas fuentes, en su mayor��a directas, pretende poner de manifiesto la condici��n transitiva del espacio de representaci��n y contrastar el pasado remoto del lugar y su construcci��n con el momento actual, inevitablemente encarnado por el punto de vista desde el cual se desarrolla la tesis. El Prado parece albergar, agazapado en su nombre, la ra��z de un origen remoto y olvidado. Si como enunciaba Ignasi Sol��-Morales la funci��n de la arquitectura es hacer aflorar los significados inherentes al lugar, esta tesis se plantea como una recuperaci��n de la idea del v��nculo entre el territorio y la memoria como fuente fundamental en la definici��n de un espacio de representaci��n espec��fico. El escrutinio del pasado constituye un acto eminentemente contempor��neo, pues el punto de vista y la distancia, inevitablemente condicionados por el presente, determinan la mirada. El culto contempor��neo a la inmediatez y la proclamaci��n de la superaci��n de los procesos hist��ricos han relegado el pasado, en cierto grado, a dep��sito de restos o referente a superar, obviando su ineluctable condici��n de origen o momento anterior condicionante. Partiendo de la reconstrucci��n del lugar sobre el cual se halla el Prado ubicado y reconsiderando, seg��n las premisas desarrolladas por la moderna historiograf��a, fundamentalmente desarrolladas por la Escuela francesa de los Annales, la cotidianeidad y lo an��nimo como fuente de la que dimanan muchos de los actuales significados de nuestros espacios de representaci��n, tomando como punto de partida un lugar remoto y olvidado, se estudia como se fue consolidando el Prado hasta devenir un lugar insigne de referencia asociado a los poderes f��cticos y el espacio ��ulico de la capital de las Espa��as en el siglo XVII. El proceso mediante el cual el Prado pas�� de territorio a escenario implica la recuperaci��n de la memoria de un espacio agropecuario an��nimo y el an��lisis de c��mo, poco a poco, se fue depositando sobre el mismo el acervo de los diversos pobladores de la regi��n que con sus particularidades culturales y sociales fueron condicionando, en mayor o menor grado, un lugar cuyo origen se extiende retrospectivamente hasta hace m��s de dos mil a��os, cuando se considera que pudo darse la primera habitaci��n a partir de la cual, de manera ininterrumpida, el Prado ha venido siendo parte de lo que devino, m��s tarde, Madrid. La llegada de nuevos agentes, vinculados con estructuras de poder y territoriales que trascend��an la inmediatez del territorio sobre el que se comenz�� a erigir dicho lugar, sirven para repasar los diferentes dep��sitos ideol��gicos y culturales que han ido conformando el mismo, reivindicando la diversidad y lo heterog��neo del espacio de representaci��n frente a la idea homogeneizadora que el modelo gen��rico implica. La constituci��n del Prado como un espacio de referencia asociado al paganismo arcaico a partir de la praxis espacial cotidiana, su relaci��n con las estructuras defensivas de Al-Andalus y la atalaya Omeya, la apropiaci��n del los primitivos santuarios por parte la iglesia, su relaci��n con un determinado tipo de espiritualidad y las ��rdenes religiosas m��s poderosas de la ��poca, la preferencia de Carlos V por Madrid y sus v��nculos con la cultura europea del momento, o la definitiva metamorfosis del lugar a partir del siglo XVI y el advenimiento de un nuevo paganismo emblem��tico y estetizado, culminan con el advenimiento de lo econ��mico como representaci��n del poder en el seno de la corte y la erecci��n del Palacio del Buen Retiro como manifestaci��n tangible de la definitiva exaltaci��n del Prado a espacio de representaci��n ��ulico. Dec��a T.S. Elliot que la pugna por el espacio de la memoria constituye el principal rasgo del clasicismo, y el Prado, ciertamente, participa de ese car��cter al que est�� profundamente asociado en la conciencia espacial de los madrile��os como lugar de referencia. Acaso la obliteraci��n del territorio y la memoria, propuestas en la ���ciudad gen��rica��� tambi��n tengan algo que ver con ello. ABSTRACT "If man is the caretaker of words and only they provide the sense of things, the architecture has a precise mission: to make out from the given conditions of each place words that mean the qualities of existence, and which unveil the wealth and content they potentially contain " Ignasi Sol�� Morales. Place: permanence or production, 1992. This thesis arises from both the desire to understand the identity of one of the most representative spaces of my city, assumed in a familiar way but that raises many doubts about its characterization, and from a personal concern about the apparent hegemony of the urban model of the "generic city " so crudely exposed by Rem Koolhaas in the late twentieth century that puts a strain on the historic city. The obliteration of the territory, specific physical space, and its associated memory, are considered as a starting point to confront them with the proclamation of the new model of "generic city" raised from eminently economic and technological roots. The tangible reality of a space, apparently forged based on the values reviled by the proposed new model, is studied from opposite premises. The idea of non-place, theorized by Marc Aug�� and modeled by Koolhaas, implies the emancipation from both historical preexistences and physical location, posing a type of space representation outside the territory and memory. Without wishing to establish a confrontational or opposite position, but an antithetical and complementary stance, the premises of Koolhaas are here taken to contrast them with a portion of territory halfway between architecture and the city, to develop a study that will complement and counterbalance the spatial paradigm that the "generic city" means and whose alleged immediacy and anomie appear to nullify any interpretative intention by neutralizing the historic centers and proclaiming the exhaustion of history. The approach of a dichotomous theory versus space and architectural theories associated with this were already formulated by Colin Rowe and Fred Koetter during the late seventies of last century. The idea of a "tangible city" as opposed to the idea of the "generic city" enunciated by Koolhaas arises here. Taking the territory and memory as the main reference in a particular place and trying to avoid the premise of the immediacy of the moment and the "perpetual present" proclaimed by Koolhaas, of which he pleas we would be prisoners, a distance is established from the object of analysis developing the study in the opposite direction to the alleged origin of it, raising the possibility of reactivating a reflection on the territory and memory within the overall process of inhabiting to reveal certain representational space configuration mechanisms outside the urgency of the present, reviving the memory and its relationship with the territory as a starting point. From the hypothetical reconstruction of the territory, starting from its physical presence, geography, paleo-biology, ethological analogies, archaeological remains, anthropology or history, architecture is claimed as a diverse as privileged discipline for spatial analysis, trying to discern the process by which the Prado moved from territory to stage. The chronological organization of the study and incorporating a variety of sources, most direct, aims to highlight the transitive condition of representational space and contrast the remote past of the place and its construction with the current moment, inevitably played by the view point from which the thesis develops. The Prado seems to harbor, in its name, the root of a remote and forgotten origin. If, as Ignasi Sola-Morales said, the aim of architecture is to bring out the meanings inherent in the site, this thesis is presented as a recovery of the idea of the link between the territory and memory as a key source in defining a specific space of representation. The scrutiny of the past is an eminently contemporary act, for the view and distance inevitably conditioned by the present, determine the way we look. The contemporary cult of immediacy and the proclamation of overcoming historical processes have relegated the past, to some extent, to remains deposit or a reference to overcome, ignoring its ineluctable condition as origin or previous constraint. From rebuilding the site on which the Prado is located and reconsidering everyday life and the anonymous as a source of many arising current meanings of our space of representation, according to the premises developed by modern historiography mainly developed by the French school of Annales, trying to recover the remote and forgotten is attempted, the thesis studies how el Prado was consolidated to become the most significant place of Madrid, deeply associated with the power in the capital of Spain during the XVII century. The process by which the Prado evolved from territory to stage involves the recovery of the memory of an anonymous agricultural space and the analysis of how, little by little, the influence of the various inhabitants of the region with their own and how their cultural and social peculiarities was deposited through time on the common ground and how that determined, to a greater or lesser degree, a place whose origin retrospectively extends over more than two thousand years ago, when we can consider the first inhabiting from which, without interruption, the Prado has come to be part of what became, later, Madrid. The arrival of new players, linked to power structures and territorial issues which transcended the immediacy of the territory on which the place begun to be a characteristic space, serve to review the different ideological and cultural deposits that have shaped the place, claiming diversity and heterogeneous space of representation before the homogenizing idea which the generic model implies. The constitution of the Prado as a benchmark associated with the archaic paganism developed from the ancient everyday spatial praxis, its relationship with the defensive structures of Al-Andalus and the Umayyad watchtower, the appropriation of the early sanctuaries by the roman church, its relationship with a certain type of spirituality and the most powerful religious orders of the time, the preference of Carlos V towards Madrid and its links with the European culture of the moment and the final metamorphosis of the place during the sixteenth century, end at the moment on which the advent of the economic as a representation of power within the court and the erection of the Palacio del Buen Retiro, as a tangible manifestation of the ultimate exaltation of courtly Prado space representation, happened in the mid XVII century. T. S. Elliot said that the struggle for memory space is the main feature of classicism, and the Prado certainly shares part of that character deeply associated in the mental spatial structure of the locals as a landmark. Perhaps the obliteration of territory and memory proposed in the "generic city" might also have something to do with that.

Regulation of mitochondrial ATP synthesis by calcium: Evidence for a long-term metabolic priming

In recent years, mitochondria have emerged as important targets of agonist-dependent increases in cytosolic Ca2+ concentration. Here, we analyzed the significance of Ca2+ signals for the modulation of organelle function by directly measuring mitochondrial and cytosolic ATP levels ([ATP]m and [ATP]c, respectively) with specifically targeted chimeras of the ATP-dependent photoprotein luciferase. In both HeLa cells and primary cultures of skeletal myotubes, stimulation with agonists evoking cytosolic and mitochondrial Ca2+ signals caused increases in [ATP]m and [ATP]c that depended on two parameters: (i) the amplitude of the Ca2+ rise in the mitochondrial matrix, and (ii) the availability of mitochondrial substrates. Moreover, the Ca2+ elevation induced a long-lasting priming that persisted long after agonist washout and caused a major increase in [ATP]m upon addition of oxidative substrates. These results demonstrate a direct role of mitochondrial Ca2+ in driving ATP production and unravel a form of cellular memory that allows a prolonged metabolic activation in stimulated cells.

Specific therapy regimes could lead to long-term immunological control of HIV

We use mathematical models to study the relationship between HIV and the immune system during the natural course of infection and in the context of different antiviral treatment regimes. The models suggest that an efficient cytotoxic T lymphocyte (CTL) memory response is required to control the virus. We define CTL memory as long-term persistence of CTL precursors in the absence of antigen. Infection and depletion of CD4+ T helper cells interfere with CTL memory generation, resulting in persistent viral replication and disease progression. We find that antiviral drug therapy during primary infection can enable the development of CTL memory. In chronically infected patients, specific treatment schedules, either including deliberate drug holidays or antigenic boosts of the immune system, can lead to a re-establishment of CTL memory. Whether such treatment regimes would lead to long-term immunologic control deserves investigation under carefully controlled conditions.

CTACK, a skin-associated chemokine that preferentially attracts skin-homing memory T cells

In contrast to naive lymphocytes, memory/effector lymphocytes can access nonlymphoid effector sites and display restricted, often tissue-selective, migration behavior. The cutaneous lymphocyte-associated antigen (CLA) defines a subset of circulating memory T cells that selectively localize in cutaneous sites mediated in part by the interaction of CLA with its vascular ligand E-selectin. Here, we report the identification and characterization of a CC chemokine, cutaneous T cell-attracting chemokine (CTACK). Both human and mouse CTACK are detected only in skin by Southern and Northern blot analyses. Specifically, CTACK message is found in the mouse epidermis and in human keratinocytes, and anti-CTACK mAbs predominantly stain the epithelium. Finally, CTACK selectively attracts CLA+ memory T cells. Taken together, these results suggest an important role for CTACK in recruitment of CLA+ T cells to cutaneous sites. CTACK is predominantly expressed in the skin and selectively attracts a tissue-specific subpopulation of memory lymphocytes.

Progressive entorhinal cortex lesions accelerate hippocampal sprouting and spare spatial memory in���rats

Accelerating hippocampal sprouting by making unilateral progressive lesions of the entorhinal cortex spared the spatial memory of rats tested for retention of a learned alternation task. Subsequent transection of the sprouted crossed temporodentate pathway (CTD), as well as a simultaneous CTD transection and progressive entorhinal lesion, produced a persistent deficit on the memory task. These results suggest that CTD sprouting, which is homologous to the original perforant path input to the dentate gyrus of the hippocampus, is behaviorally significant and can ameliorate at least some of the memory deficits associated with hippocampal deafferentation.

Prefrontal cortex and episodic memory retrieval mode

A multistudy analysis of positron emission tomography data identified three right prefrontal and two left prefrontal cortical sites, as well as a region in the anterior cingulate gyrus, where neuronal activity is correlated with the maintenance of episodic memory retrieval mode (REMO), a basic and necessary condition of remembering past experiences. The right prefrontal sites were near the frontal pole [Brodmann's area (BA) 10], frontal operculum (BA 47/45), and lateral dorsal area (BA 8/9). The two left prefrontal sites were homotopical with the right frontal pole and opercular sites. The same kinds of REMO sites were not observed in any other cerebral region. Many previous functional neuroimaging studies of episodic memory retrieval have reported activations near the frontal REMO sites identified here, although their function has not been clear. Many of these, too, probably have signaled their involvement in REMO. We propose that REMO activations largely if not entirely account for the frontal hemispheric asymmetry of retrieval as described by the original hemispheric encoding retrieval asymmetry model.

Verb generation in patients with focal frontal lesions: A neuropsychological test of neuroimaging findings

What are the neural bases of semantic memory? Traditional beliefs that the temporal lobes subserve the retrieval of semantic knowledge, arising from lesion studies, have been recently called into question by functional neuroimaging studies finding correlations between semantic retrieval and activity in left prefrontal cortex. Has neuroimaging taught us something new about the neural bases of cognition that older methods could not reveal or has it merely identified brain activity that is correlated with but not causally related to the process of semantic retrieval? We examined the ability of patients with focal frontal lesions to perform a task commonly used in neuroimaging experiments, the generation of semantically appropriate action words for concrete nouns, and found evidence of the necessity of the left inferior frontal gyrus for certain components of the verb generation task. Notably, these components did not include semantic retrieval per se.

Tracking memory's trace

There is strong converging evidence that the intermediate and medial part of the hyperstriatum ventrale of the chick brain is a memory store for information acquired through the learning process of imprinting. Neurons in this memory system come, through imprinting, to respond selectively to the imprinting stimulus (IS) neurons and so possess the properties of a memory trace. Therefore, the responses of the intermediate and medial part of the hyperstriatum ventrale neurons to a visual imprinting stimulus were determined before, during, and after training. Of the total recorded population, the proportions of IS neurons shortly after each of two 1-h training sessions were significantly higher (approximately 2 times) than the pretraining proportion. However, ���4.5 h later this proportion had fallen significantly and did not differ significantly from the pretraining proportion. Nevertheless, ���21.5 h after the end of training, the proportion of IS neurons was at its highest (approximately 3 times the pretraining level). No significant fluctuations occurred in the proportions of neurons responding to the alternative stimulus. In addition, nonmonotonic changes were found commonly in the activity of 230 of the neurons tracked individually from before training to shortly after the end of training. Thus the pattern of change in responsiveness both at the population level and at the level of individual neurons was highly nonmonotonic. Such a pattern of change is not consistent with simple models of memory based on synaptic strengthening to asymptote. A model is proposed that accounts for the changes in the population responses to the imprinting stimulus in terms of changes in the responses of individual neurons.

Germ line deletion of the CD1 locus exacerbates diabetes in the NOD mouse

Quantitative and qualitative defects in CD1-restricted natural killer T cells have been reported in several autoimmune-prone strains of mice, including the nonobese diabetic (NOD) mouse. These defects are believed to be associated with the emergence of spontaneous autoimmunity. Here we demonstrate that both CD1d-null NOD and CD1d-null NOD/BDC2.5 T cell receptor transgenic mice have an accelerated onset and increased incidence of diabetes when compared with CD1d+/��� and CD1d+/+ littermates. The acceleration of disease did not seem to result from changes in the T helper (Th)1/Th2 balance because lymphocytes purified from lymphoid organs and pancreatic islets of wild-type and CD1d-null mice secreted equivalent amounts of IFN-�� and IL-4 after stimulation. In contrast, the pancreata of CD1d-null mice harbored significantly higher numbers of activated memory T cells expressing the chemokine receptor CCR4. Notably, the presence of these T cells was associated with immunohistochemical evidence of increased destructive insulitis. Thus, CD1d-restricted T cells are critically important for regulation of the spontaneous disease process in NOD mice.