Lack of tumor recognition by hTERT peptide 540-548-specific CD8(+) T cells from melanoma patients reveals inefficient antigen processing.

Telomerase is a ribonucleoprotein complex responsible for the maintenance of the length of the telomeres during cell division, which is active in germ-line cells as well as in the vast majority of tumors but not in most normal tissues. The wide expression of the human telomerase catalytic subunit (hTERT) in tumors makes it an interesting candidate vaccine for cancer. hTERT-derived peptide 540-548 (hTERT(540)) has been recently shown to be recognized in an HLA-A*0201-restricted fashion by T cell lines derived from peptide-stimulated peripheral blood mononuclear cells (PBMC) from healthy donors. As a first step to the inclusion of this peptide in immunotherapy clinical trials, it is crucial to assess hTERT(540)-specific T cell reactivity in cancer patients as well as the ability of hTERT-specific CD8(+) T lymphocytes to recognize and lyse hTERT-expressing target cells. Here, we have analyzed the CD8(+) T cell response to peptide hTERT(540) in HLA-A*0201 melanoma patients by using fluorescent HLA-A*0201/hTERT(540) peptide tetramers. HLA-A*0201/hTERT(540) tetramer(+) CD8(+) T cells were readily detected in peptide-stimulated PBMC from a significant proportion of patients and could be isolated by tetramer-guided cell sorting. hTERT(540)-specific CD8(+) T cells were able to specifically recognize HLA-A*0201 cells either pulsed with peptide or transiently transfected with a minigene encoding the minimal epitope. In contrast, they failed to recognize hTERT-expressing HLA-A*0201(+) target cells. Furthermore, in vitro proteasome digestion studies revealed inadequate hTERT processing. Altogether, these results raise questions on the use of hTERT(540) peptide for cancer immunotherapy.

Characterization of NALP2 and NALP3 IL-1β processing inflammasomes

Résumé II y a cinq ans, la découverte d'un nouveau domaine, le PYD domaine, lié aux domaines de la mort, a permis la description de la nouvelle famille des NALP protéines. L'analyse structurelle de cette famille de protéines révéla la présence de deux autres domaines, impliqués dans l'oligomerisation, NACHT, et la détection des ligands, Leucine rich repeats ou LRR. Cette architecture protéique est homologue à celle qui est décrite pour les NODs, les Tol1 récepteurs et tes protéines de résistance chez les plantes. Cette homologie suggère une possible implication des NALPs dans la régulation de l'immunité innée. Premièrement, nous avons décrit les composants minimaux qui permettent à l'inflammasomeNALP3 d'activer la caspase pro-inflammatoire, caspase-1. En comparaison à NALP1, NALP3 ne contient pas de FIIND domaine, ni de CARD domaine en C-terminus et n'interagit pas avec caspase-5. Nous avons découvert une protéine très homologue au C-terminus de NALP1, Cardinal, qui se lie au NACHT domaine de NALP2 et NALP3 par l'intermédiaire de son FIIND domaine. Cardinal possède la capacité d'interagir avec caspase-l, mais seul ASC semble être nécessaire à la maturation de la prointerleukine-1β suite à la stimulation de NALP3. Deuxièmement, notre étude s'est concentrée sur la nature du stimulus capable d'induire la formation et l'activation de l'inflammasome-NALP3. Nous avons démontré que l'ajout de muramyl dipeptide (MDP), produit à partir de la digestion enzymatique de peptidoglycaris bactériens, induit à la fois l'expression de la proIL-1β par la voie NOD2 et sa maturation en IL-1β active par la voie NALP3. Bien que le MDP active l'inflammasome-NALP3, il est incapable d'induire la sécrétion de l'IL-1β mature dans la lignée cellulaire THP1, comparé aux monocytes primaires humains. Cette différence pourrait être liée à l'absence, dans les THP1, de la protéine Filamin, qui est proposée d'interagir avec Cardinal. L'implication de NALP3 dans la maturation de l'IL-lb est confirmée suite à la découverte de mutations sur le gène CIAS1/NALP3/cryopyrin associées à trois maladies auto-inflammatoires : le syndrome de Muckle-Wells (MWS), l'urticaire familial au froid (FCU) et le syndrome CINCA/NOMID. Une élévation constitutive de la maturation et de la sécrétion de la proIL-1β en absence de stimulation MDP est détectée dans les macrophages des patients Muckle-Wells. En conclusion, nos études ont démontré que l'inflammasome-NALP3 doit être finement régulé pour éviter une activité incontrôlée qui représente la base moléculaire des symptômes associés aux syndromes auto-inflammatoires liés à NALP3. Summary Five years ago, the description of the NALP family originated from the discovery of a new death-domain fold family, the PYD domain. NALP contains aprotein-protein interaction domain (PYD), an oligomerization domain (NACHT) and a ligand-sensing domain, leucine rich repeats or LRR. This protein architecture shares similarity with receptors involved in immunity, such as NODS, Toll receptors (TLRs) and related plant resistance proteins, and points to an important role of NALPs in defense mechanisms. We first described the minimal complex involved in the pro-inflammatory Interleukin-1beta (IL-1β) cytokine maturation, called the inflammasome, which contains NALP3. In contrast to NALP1, NALP3, like other members of the NALP family, is devoid of C-terminal FIIND and CARD domains and does not interact with the pro-inflammatory caspase-5. Interestingly, a homolog of the C-terminal portion of NALP1 was found in the human genome and was named Cardinal. We found that NALP2 and NALP3 interact with the CARD-containing proteins Cardinal. Cardinal is able to bind to caspase-1 but is not required for IL-1β maturation through NALP3 activation, as demonstrated for the adaptor ASC. Secondly, our study focused on the stimuli involved in the activation of the NALP3 inflammasome. MDP was shown to induce the expression of proIL1β through NOD2 and then the maturation into active IL-1β by activation of the NALP3 inflammasome. However, in the monocytic THP1 cell line, secretion of IL-1β upon MDP stimulation seems to be independent of the inflammasome activation compared to human primary monocytes. This difference might be linked to a Cardinal-interacting protein, filamin. Until now, the role of Cardinal and filamin is still unknown and remains to be elucidated. Finally, mutations in the NALP3/cryopyrin/CIAS1 gene are associated with three autoinflammatory diseases: Muckle-Wells syndrome, familial cold autoinflammatory syndrome, and CINCA. Constitutive, elevated IL-1β maturation and secretion, even in the absence of MDP stimulation, was observed in macrophages from Muckle-Wells patients and confirmed a key role for the NALP3 inflammasome in innate immunity In conclusion, our studies describes the formation of the NALP3 inflammasome and suggests that this complex has to be tightly regulated to avoid an increased deregulated inflammasome activity that is the molecular basis for the symptoms associated with NALP3-dependent autoinflammatory disorders.

Improving the efficiency of PV low-power processing circuits by selecting an optimal inductor current of the DC/DC converter

In the context of autonomous sensors powered by small-size photovoltaic (PV) panels, this work analyses how the efficiency of DC/DC-converter-based power processing circuits can be improved by an appropriate selection of the inductor current that transfers the energy from the PV panel to a storage unit. Each component of power losses (fixed, conduction and switching losses) involved in the DC/DC converter specifically depends on the average inductor current so that there is an optimal value of this current that causes minimal losses and, hence, maximum efficiency. Such an idea has been tested experimentally using two commercial DC/DC converters whose average inductor current is adjustable. Experimental results show that the efficiency can be improved up to 12% by selecting an optimal value of that current, which is around 300-350 mA for such DC/DC converters.

Mining minimal non-redundant association rules using frequent closed itemsets

The problem of the relevance and the usefulness of extracted association rules is of primary importance because, in the majority of cases, real-life databases lead to several thousands association rules with high confidence and among which are many redundancies. Using the closure of the Galois connection, we define two new bases for association rules which union is a generating set for all valid association rules with support and confidence. These bases are characterized using frequent closed itemsets and their generators; they consist of the non-redundant exact and approximate association rules having minimal antecedents and maximal consequences, i.e. the most relevant association rules. Algorithms for extracting these bases are presented and results of experiments carried out on real-life databases show that the proposed bases are useful, and that their generation is not time consuming.

Using eye-tracking to study anaphoric relations processing in European Portuguese

In this study we evaluate processing costs of different types of anaphoric expressions during reading. We consider three types of anaphoric expressions in Subject sentential position: a null pronoun (pro), and two gaps produced by syntactic movement: a WHvariable and a NP copy. Given that coreferential pro exhibits more referential weight than wh- and NP-gaps, and grounded on theories of referential processing based on relations of hierarchy and accessibility of the antecedent, we raise the hypothesis that the more dependent on its antecedent the anaphoric null constituent is, and the more minimal is the distance in terms of hierarchical structure between the anaphoric null element and its antecedent, the lower are the cognitive costs in processing. To test our hypothesis, we registered the eye movements with R6-HS ASL system of 20 Portuguese adult native speakers. Text regions including the selected anaphoric expressions were delimited and tagged. We analyzed the reading time of each region taking into account the number and duration of eye fixations per region; we used the reading time by character in milliseconds in order to compare values between regions of different length. We found a significant advantage in the reading time of the gaps arising from movement over the reading time of pro.

Processing speed, executive function, and age differences in remembering and knowing

A group of young (n=52, M=23.27 years) and old (n=52, M=68.62 years) adults studied two lists of semantically unrelated nouns. For one list a time of 2 s was allowed for encoding, and for the other, 5 s. A recognition test followed where participants classified their responses according to Gardiner’s (1988) remember–know procedure. Age differences for remembering and knowing were minimal in the faster 2-s encoding condition. However, in the longer 5-s encoding condition, younger persons produced significantly more remember responses, and older adults a greater number of know responses. This dissociation suggests that in the longer encoding condition, younger adults utilized a greater level of elaborative rehearsal governed by executive processes, whereas older persons employed maintenance rehearsal involving short-term memory. Statistical control procedures, however, found that independent measures of processing speed accounted for age differences in remembering and knowing and that independent measures of executive control had little influence. The findings are discussed in the light of contrasting theoretical accounts of recollective experience in old age.

Induction of Psychosis by Delta 9-Tetrahydrocannabinol Reflects Modulation of Prefrontal and Striatal Function During Attentional Salience Processing

Context: The aberrant processing of salience is thought to be a fundamental factor underlying psychosis. Cannabis can induce acute psychotic symptoms, and its chronic use may increase the risk of schizophrenia. We investigated whether its psychotic effects are mediated through an influence on attentional salience processing. Objective: To examine the effects of Delta 9-tetrahydrocannabinol (Delta 9-THC) and cannabidiol (CBD) on regional brain function during salience processing. Design: Volunteers were studied using event-related functional magnetic resonance imaging on 3 occasions after administration of Delta 9-THC, CBD, or placebo while performing a visual oddball detection paradigm that involved allocation of attention to infrequent (oddball) stimuli within a string of frequent (standard) stimuli. Setting: University center. Participants: Fifteen healthy men with minimal previous cannabis use. Main Outcome Measures: Symptom ratings, task performance, and regional brain activation. Results: During the processing of oddball stimuli, relative to placebo, Delta 9-THC attenuated activation in the right caudate but augmented it in the right prefrontal cortex. Delta 9-Tetrahydrocannabinol also reduced the response latency to standard relative to oddball stimuli. The effect of Delta 9-THC in the right caudate was negatively correlated with the severity of the psychotic symptoms it induced and its effect on response latency. The effects of CBD on task-related activation were in the opposite direction of those of Delta 9-THC; relative to placebo, CBD augmented left caudate and hippocampal activation but attenuated right prefrontal activation. Conclusions: Delta 9-Tetrahydrocannabinol and CBD differentially modulate prefrontal, striatal, and hippocampal function during attentional salience processing. These effects may contribute to the effects of cannabis on psychotic symptoms and on the risk of psychotic disorders.

Digital processing and data compilation approach for using remotely sensed imagery to identify geological lineaments in hard-rock terrains : an application for groundwater explorations in Nicaragua

Sustainable yields from water wells in hard-rock aquifers are achieved when the well bore intersects fracture networks. Fracture networks are often not readily discernable at the surface. Lineament analysis using remotely sensed satellite imagery has been employed to identify surface expressions of fracturing, and a variety of image-analysis techniques have been successfully applied in “ideal” settings. An ideal setting for lineament detection is where the influences of human development, vegetation, and climatic situations are minimal and hydrogeological conditions and geologic structure are known. There is not yet a well-accepted protocol for mapping lineaments nor have different approaches been compared in non-ideal settings. A new approach for image-processing/synthesis was developed to identify successful satellite imagery types for lineament analysis in non-ideal terrain. Four satellite sensors (ASTER, Landsat7 ETM+, QuickBird, RADARSAT-1) and a digital elevation model were evaluated for lineament analysis in Boaco, Nicaragua, where the landscape is subject to varied vegetative cover, a plethora of anthropogenic features, and frequent cloud cover that limit the availability of optical satellite data. A variety of digital image processing techniques were employed and lineament interpretations were performed to obtain 12 complementary image products that were evaluated subjectively to identify lineaments. The 12 lineament interpretations were synthesized to create a raster image of lineament zone coincidence that shows the level of agreement among the 12 interpretations. A composite lineament interpretation was made using the coincidence raster to restrict lineament observations to areas where multiple interpretations (at least 4) agree. Nine of the 11 previously mapped faults were identified from the coincidence raster. An additional 26 lineaments were identified from the coincidence raster, and the locations of 10 were confirmed by field observation. Four manual pumping tests suggest that well productivity is higher for wells proximal to lineament features. Interpretations from RADARSAT-1 products were superior to interpretations from other sensor products, suggesting that quality lineament interpretation in this region requires anthropogenic features to be minimized and topographic expressions to be maximized. The approach developed in this study has the potential to improve siting wells in non-ideal regions.

Influence of carbon enrichment on electrical conductivity and processing of polycarbosilane derived ceramic for MEMS applications

An analysis about the effect of carbon enrichment of allylhydridopolycarbosilane SMP10® with divinylbenzene (DVB) as a promising material for electrical conductive micro-electrical mechanical systems (MEMS) is presented. The liquid precursors can be micropipetted and cured in polytetrafluoroethylene (PTFE) molds to produce 14 mm diameter disc shaped samples. The effect of pyrolysis temperature and carbon content on the electrical conductivity is discussed. The addition of 28.7 wt.% of DVB was found to be the optimum amount. Carbon was preserved in the microstructure during pyrolysis and the ceramic yield increased from 77.5 to 80.5 wt.%. The electrical conductivity increased from 10−6 to 1 S/cm depending on the annealing temperature. Furthermore, the ceramic samples obtained with this composition were found to be in many cases crack free or with minimal cracks in contrast with the behavior of pure SMP10. Using the same process we demonstrate that also microsized ceramic samples can be produced.

BIOMEDICAL LANGUAGE UNDERSTANDING AND EXTRACTION (BLUE-TEXT): A MINIMAL SYNTACTIC, SEMANTIC METHOD

Clinical text understanding (CTU) is of interest to health informatics because critical clinical information frequently represented as unconstrained text in electronic health records are extensively used by human experts to guide clinical practice, decision making, and to document delivery of care, but are largely unusable by information systems for queries and computations. Recent initiatives advocating for translational research call for generation of technologies that can integrate structured clinical data with unstructured data, provide a unified interface to all data, and contextualize clinical information for reuse in multidisciplinary and collaborative environment envisioned by CTSA program. This implies that technologies for the processing and interpretation of clinical text should be evaluated not only in terms of their validity and reliability in their intended environment, but also in light of their interoperability, and ability to support information integration and contextualization in a distributed and dynamic environment. This vision adds a new layer of information representation requirements that needs to be accounted for when conceptualizing implementation or acquisition of clinical text processing tools and technologies for multidisciplinary research. On the other hand, electronic health records frequently contain unconstrained clinical text with high variability in use of terms and documentation practices, and without commitmentto grammatical or syntactic structure of the language (e.g. Triage notes, physician and nurse notes, chief complaints, etc). This hinders performance of natural language processing technologies which typically rely heavily on the syntax of language and grammatical structure of the text. This document introduces our method to transform unconstrained clinical text found in electronic health information systems to a formal (computationally understandable) representation that is suitable for querying, integration, contextualization and reuse, and is resilient to the grammatical and syntactic irregularities of the clinical text. We present our design rationale, method, and results of evaluation in processing chief complaints and triage notes from 8 different emergency departments in Houston Texas. At the end, we will discuss significance of our contribution in enabling use of clinical text in a practical bio-surveillance setting.

A big data platform for large scale event processing

To date, big data applications have focused on the store-and-process paradigm. In this paper we describe an initiative to deal with big data applications for continuous streams of events. In many emerging applications, the volume of data being streamed is so large that the traditional ‘store-then-process’ paradigm is either not suitable or too inefficient. Moreover, soft-real time requirements might severely limit the engineering solutions. Many scenarios fit this description. In network security for cloud data centres, for instance, very high volumes of IP packets and events from sensors at firewalls, network switches and routers and servers need to be analyzed and should detect attacks in minimal time, in order to limit the effect of the malicious activity over the IT infrastructure. Similarly, in the fraud department of a credit card company, payment requests should be processed online and need to be processed as quickly as possible in order to provide meaningful results in real-time. An ideal system would detect fraud during the authorization process that lasts hundreds of milliseconds and deny the payment authorization, minimizing the damage to the user and the credit card company.

StreamCloud: An Elastic Parallel-Distributed Stream Processing Engine

In recent years, applications in domains such as telecommunications, network security or large scale sensor networks showed the limits of the traditional store-then-process paradigm. In this context, Stream Processing Engines emerged as a candidate solution for all these applications demanding for high processing capacity with low processing latency guarantees. With Stream Processing Engines, data streams are not persisted but rather processed on the fly, producing results continuously. Current Stream Processing Engines, either centralized or distributed, do not scale with the input load due to single-node bottlenecks. Moreover, they are based on static configurations that lead to either under or over-provisioning. This Ph.D. thesis discusses StreamCloud, an elastic paralleldistributed stream processing engine that enables for processing of large data stream volumes. Stream- Cloud minimizes the distribution and parallelization overhead introducing novel techniques that split queries into parallel subqueries and allocate them to independent sets of nodes. Moreover, Stream- Cloud elastic and dynamic load balancing protocols enable for effective adjustment of resources depending on the incoming load. Together with the parallelization and elasticity techniques, Stream- Cloud defines a novel fault tolerance protocol that introduces minimal overhead while providing fast recovery. StreamCloud has been fully implemented and evaluated using several real word applications such as fraud detection applications or network analysis applications. The evaluation, conducted using a cluster with more than 300 cores, demonstrates the large scalability, the elasticity and fault tolerance effectiveness of StreamCloud. Resumen En los útimos años, aplicaciones en dominios tales como telecomunicaciones, seguridad de redes y redes de sensores de gran escala se han encontrado con múltiples limitaciones en el paradigma tradicional de bases de datos. En este contexto, los sistemas de procesamiento de flujos de datos han emergido como solución a estas aplicaciones que demandan una alta capacidad de procesamiento con una baja latencia. En los sistemas de procesamiento de flujos de datos, los datos no se persisten y luego se procesan, en su lugar los datos son procesados al vuelo en memoria produciendo resultados de forma continua. Los actuales sistemas de procesamiento de flujos de datos, tanto los centralizados, como los distribuidos, no escalan respecto a la carga de entrada del sistema debido a un cuello de botella producido por la concentración de flujos de datos completos en nodos individuales. Por otra parte, éstos están basados en configuraciones estáticas lo que conducen a un sobre o bajo aprovisionamiento. Esta tesis doctoral presenta StreamCloud, un sistema elástico paralelo-distribuido para el procesamiento de flujos de datos que es capaz de procesar grandes volúmenes de datos. StreamCloud minimiza el coste de distribución y paralelización por medio de una técnica novedosa la cual particiona las queries en subqueries paralelas repartiéndolas en subconjuntos de nodos independientes. Ademas, Stream- Cloud posee protocolos de elasticidad y equilibrado de carga que permiten una optimización de los recursos dependiendo de la carga del sistema. Unidos a los protocolos de paralelización y elasticidad, StreamCloud define un protocolo de tolerancia a fallos que introduce un coste mínimo mientras que proporciona una rápida recuperación. StreamCloud ha sido implementado y evaluado mediante varias aplicaciones del mundo real tales como aplicaciones de detección de fraude o aplicaciones de análisis del tráfico de red. La evaluación ha sido realizada en un cluster con más de 300 núcleos, demostrando la alta escalabilidad y la efectividad tanto de la elasticidad, como de la tolerancia a fallos de StreamCloud.

TCAD for PV: a fast method for accurately modelling metal impurity evolution during solar cell processing

Coupled device and process silumation tools, collectively known as technology computer-aided design (TCAD), have been used in the integrated circuit industry for over 30 years. These tools allow researchers to quickly converge on optimized devide designs and manufacturing processes with minimal experimental expenditures. The PV industry has been slower to adopt these tools, but is quickly developing competency in using them. This paper introduces a predictive defect engineering paradigm and simulation tool, while demonstrating its effectiveness at increasing the performance and throughput of current industrial processes. the impurity-to-efficiency (I2E) simulator is a coupled process and device simulation tool that links wafer material purity, processing parameters and cell desigh to device performance. The tool has been validated with experimental data and used successfully with partners in industry. The simulator has also been deployed in a free web-accessible applet, which is available for use by the industrial and academic communities.