Unravelling the multiple roles of FUS in RNA processing and on ALS pathogenesis

Two genes with related functions in RNA biogenesis were recently reported in patients with familial ALS: the FUS/TLS gene at the ALS6 locus and the TARDBP/TDP-43 gene at the ALS10 locus [1, 2]. FUS has been implicated to function in several steps of gene expression, including transcription regulation [3], RNA splicing [4, 5], mRNA transport in neurons [6] and, interestingly, in microRNA (miRNA) processing [7]. The goal of this project is to identify the molecular mechanisms leading to the development of FUS mutations-associated ALS. Specifically, we want to test the hypothesis that these FUS mutations misregulate miRNA levels that in turn affect the expression of genes critical for motor neuron survival. In addition we want to test whether misregulation of the miRNA profile is a common feature in ALS. We have performed immunoprecipitations from total extracts of 293T cells expressing FLAG-tagged FUS to characterize its interactome by mass spectrometry. This proteomic study not only revealed a strong interaction of FUS with splicing factors, but shows that FUS might be involved in many, quite different pathways. To map which parts of the FUS protein contribute to the interaction with splicing factors, we have performed a set of experiments with a series of missense and deletion mutants. With this approach, we will not only gain information on the binding partners of FUS along with a map of the required domains for the interactions, but it will also help to unravel whether certain ALS-associated FUS mutations lead to a loss or gain of function due to gain or loss of interactors. Additionally, we have performed quantitative interactomics using SILAC to identify interactome differences of ALS-associated FUS mutants. To this end we have performed immunoprecipitations of total extract from 293T cells, stably transduced with constructs expressing wild-type FUS-FLAG as well as three different ALS-associated mutants (G156E, R244C, P525L). First results indicate striking differences in the interactome with certain RNA binding proteins. We are now validating these candidates in order to reveal the importance of these differential interactions in the context of ALS.

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.

Large-scale testing of proficiency in English: Back to multiple choice?

The paper analyses whether that a properly designed multiple choice test can discriminate with a high level of accuracy if a student in our context has reached a B2 level according to the CEFRL.

Multiple Hashing Integration for Real-Time Large Scale Part-to-Part Video Matching

A real-time large scale part-to-part video matching algorithm, based on the cross correlation of the intensity of motion curves, is proposed with a view to originality recognition, video database cleansing, copyright enforcement, video tagging or video result re-ranking. Moreover, it is suggested how the most representative hashes and distance functions - strada, discrete cosine transformation, Marr-Hildreth and radial - should be integrated in order for the matching algorithm to be invariant against blur, compression and rotation distortions: (R; _) 2 [1; 20]_[1; 8], from 512_512 to 32_32pixels2 and from 10 to 180_. The DCT hash is invariant against blur and compression up to 64x64 pixels2. Nevertheless, although its performance against rotation is the best, with a success up to 70%, it should be combined with the Marr-Hildreth distance function. With the latter, the image selected by the DCT hash should be at a distance lower than 1.15 times the Marr-Hildreth minimum distance.

A novel FPGA-based evolvable hardware system based on multiple processing arrays

In this paper, an architecture based on a scalable and flexible set of Evolvable Processing arrays is presented. FPGA-native Dynamic Partial Reconfiguration (DPR) is used for evolution, which is done intrinsically, letting the system to adapt autonomously to variable run-time conditions, including the presence of transient and permanent faults. The architecture supports different modes of operation, namely: independent, parallel, cascaded or bypass mode. These modes of operation can be used during evolution time or during normal operation. The evolvability of the architecture is combined with fault-tolerance techniques, to enhance the platform with self-healing features, making it suitable for applications which require both high adaptability and reliability. Experimental results show that such a system may benefit from accelerated evolution times, increased performance and improved dependability, mainly by increasing fault tolerance for transient and permanent faults, as well as providing some fault identification possibilities. The evolvable HW array shown is tailored for window-based image processing applications.

Large-scale assessment of language proficiency: theoretical and pedagogical reflections on the use of multiple-choice tests

The new requirement placed on students in tertiary settings in Spain to demonstrate a B1 or a B2 proficiency level of English, in accordance with the Common European Framework of Reference for Languages (CEFRL), has led most Spanish universities to develop a program of certification or accreditation of the required level. The first part of this paper aims to provide a rationale for the type of test that has been developed at the Universidad Politécnica de Madrid for the accreditation of a B2 level, a multiple choice version, and to describe how it was constructed and validated. Then, in the second part of the paper, the results from its application to 924 students enrolled in different degree courses at a variety of schools and faculties at the university are analyzed based on a final test version item analysis. To conclude, some theoretical as well as practical conclusions about testing grammar that affect the teaching and learning process are drawn. RESUMEN. Las nuevas exigencias sobre niveles de competencia B1 y B2 en inglés según el Marco Común Europeo de Referencia para las Lenguas (MCERL) que se imponen sobre los estudiantes de grado y posgrado han llevado a la mayoría de las universidades españolas a desarrollar programas de acreditación o de certificación de estos niveles. La primera parte de este trabajo trata sobre las razones que fundamentan la elección de un tipo concreto de examen para la acreditación del nivel B2 de lengua inglesa en la Universidad Politécnica de Madrid. Se trata de un test de opción múltiple y en esta parte del trabajo se describe cómo fue diseñado y validado. En la segunda parte, se analizan los resultados de la aplicación del test a gran escala a un total de 924 estudiantes matriculados en varias escuelas y Facultades de la Universidad. Para terminar, se apuntan una serie de conclusiones teóricas y prácticas sobre la evaluación de la gramática y de qué modo influye en los procesos de enseñanza y aprendizaje.

Heterogeneous architecture for the optimization of large-scale graph processing data centres

Con el auge del Cloud Computing, las aplicaciones de proceso de datos han sufrido un incremento de demanda, y por ello ha cobrado importancia lograr m�ás eficiencia en los Centros de Proceso de datos. El objetivo de este trabajo es la obtenci�ón de herramientas que permitan analizar la viabilidad y rentabilidad de diseñar Centros de Datos especializados para procesamiento de datos, con una arquitectura, sistemas de refrigeraci�ón, etc. adaptados. Algunas aplicaciones de procesamiento de datos se benefician de las arquitecturas software, mientras que en otras puede ser m�ás eficiente un procesamiento con arquitectura hardware. Debido a que ya hay software con muy buenos resultados en el procesamiento de grafos, como el sistema XPregel, en este proyecto se realizará una arquitectura hardware en VHDL, implementando el algoritmo PageRank de Google de forma escalable. Se ha escogido este algoritmo ya que podr��á ser m�ás eficiente en arquitectura hardware, debido a sus características concretas que se indicaráan m�ás adelante. PageRank sirve para ordenar las p�áginas por su relevancia en la web, utilizando para ello la teorí��a de grafos, siendo cada página web un vértice de un grafo; y los enlaces entre páginas, las aristas del citado grafo. En este proyecto, primero se realizará un an�álisis del estado de la técnica. Se supone que la implementaci�ón en XPregel, un sistema de procesamiento de grafos, es una de las m�ás eficientes. Por ello se estudiará esta �ultima implementaci�ón. Sin embargo, debido a que Xpregel procesa, en general, algoritmos que trabajan con grafos; no tiene en cuenta ciertas caracterí��sticas del algoritmo PageRank, por lo que la implementaci�on no es �optima. Esto es debido a que en PageRank, almacenar todos los datos que manda un mismo v�értice es un gasto innecesario de memoria ya que todos los mensajes que manda un vértice son iguales entre sí e iguales a su PageRank. Se realizará el diseño en VHDL teniendo en cuenta esta caracter��ística del citado algoritmo,evitando almacenar varias veces los mensajes que son iguales. Se ha elegido implementar PageRank en VHDL porque actualmente las arquitecturas de los sistemas operativos no escalan adecuadamente. Se busca evaluar si con otra arquitectura se obtienen mejores resultados. Se realizará un diseño partiendo de cero, utilizando la memoria ROM de IPcore de Xillinx (Software de desarrollo en VHDL), generada autom�áticamente. Se considera hacer cuatro tipos de módulos para que as�� el procesamiento se pueda hacer en paralelo. Se simplificar�á la estructura de XPregel con el fin de intentar aprovechar la particularidad de PageRank mencionada, que hace que XPregel no le saque el m�aximo partido. Despu�és se escribirá el c�ódigo, realizando una estructura escalable, ya que en la computación intervienen millones de páginas web. A continuación, se sintetizar�á y se probará el código en una FPGA. El �ultimo paso será una evaluaci�ón de la implementaci�ón, y de posibles mejoras en cuanto al consumo.

Multiple-complete-digest restriction fragment mapping: Generating sequence-ready maps for large-scale DNA sequencing

Multiple-complete-digest mapping is a DNA mapping technique based on complete-restriction-digest fingerprints of a set of clones that provides highly redundant coverage of the mapping target. The maps assembled from these fingerprints order both the clones and the restriction fragments. Maps are coordinated across three enzymes in the examples presented. Starting with yeast artificial chromosome contigs from the 7q31.3 and 7p14 regions of the human genome, we have produced cosmid-based maps spanning more than one million base pairs. Each yeast artificial chromosome is first subcloned into cosmids at a redundancy of ×15–30. Complete-digest fragments are electrophoresed on agarose gels, poststained, and imaged on a fluorescent scanner. Aberrant clones that are not representative of the underlying genome are rejected in the map construction process. Almost every restriction fragment is ordered, allowing selection of minimal tiling paths with clone-to-clone overlaps of only a few thousand base pairs. These maps demonstrate the practicality of applying the experimental and software-based steps in multiple-complete-digest mapping to a target of significant size and complexity. We present evidence that the maps are sufficiently accurate to validate both the clones selected for sequencing and the sequence assemblies obtained once these clones have been sequenced by a “shotgun” method.

The silver gene of Drosophila melanogaster encodes multiple carboxypeptidases similar to mammalian prohormone-processing enzymes.

The silver (svr) gene of Drosophila melanogaster is required for viability, and severe mutant alleles result in death prior to eclosion. Adult flies homozygous or hemizygous for weaker alleles display several visible phenotypes, including cuticular structures that are pale and silvery in color due to reduced melanization. We have identified and cloned the DNA encoding the svr gene and determined the sequence of several partially overlapping cDNAs derived from svr mRNAs. The predicted amino acid sequence of the polypeptides encoded by these cDNAs indicates that the silver proteins are members of the family of preprotein-processing carboxypeptidases that includes the human carboxypeptidases E, M, and N. One class of svr mRNAs is alternatively spliced to encode at least two polyproteins, each of which is composed of two carboxypeptidase domains.

Contribuição para a validação da escala "children's auditory processing performance scale" para a população portuguesa

A perturbação do processamento auditivo pode afectar negativamente o comportamento auditivo da criança, levando, entre outros, a um baixo rendimento escolar e a alterações do comportamento. Por este motivo é importante a identificação precoce desta perturbação. No entanto em Portugal não se encontra nenhum instrumento de medida disponível para o efeito, o que motivou este estudo. Assim sendo, este estudo tem como objectivos a tradução, adaptação cultural e validação da escala Children's Auditory Processing Performance Scale (CHAPPS) (Smoski, Brunt, & Tannahill, 1992) para o Português Europeu. Depois de traduzida e adaptada culturalmente a escala foi validada. Esta foi administrada a 154 indivíduos, dos quais 125 eram pais/encarregados de educação e 29 eram professores de crianças em idade escolar, do 1º ciclo. A versão portuguesa da escala (P-CHAPPS) apresentou uma excelente consistência interna (=0,950), estabilidade temporal e uma correlação entre as subescalas e o total com valores entre 0,581 e 0,857. As características psicométricas da P-CHAPPS revelam que esta pode ser utilizada na população portuguesa, ficando assim disponível, em Portugal um instrumento de medida a ser utilizado na identificação precoce das perturbações do processamento auditivo.

Tests on a quarter scale model of a multiple-panel reinforced concrete flat plate floor /

Mode of access: Internet.

Submodular Optimization and Data Processing

Thesis (Ph.D.)--University of Washington, 2016-06

Indexing and integrating multiple features for WWW images

In this paper, we present a novel indexing technique called Multi-scale Similarity Indexing (MSI) to index image's multi-features into a single one-dimensional structure. Both for text and visual feature spaces, the similarity between a point and a local partition's center in individual space is used as the indexing key, where similarity values in different features are distinguished by different scale. Then a single indexing tree can be built on these keys. Based on the property that relevant images have similar similarity values from the center of the same local partition in any feature space, certain number of irrelevant images can be fast pruned based on the triangle inequity on indexing keys. To remove the dimensionality curse existing in high dimensional structure, we propose a new technique called Local Bit Stream (LBS). LBS transforms image's text and visual feature representations into simple, uniform and effective bit stream (BS) representations based on local partition's center. Such BS representations are small in size and fast for comparison since only bit operation are involved. By comparing common bits existing in two BSs, most of irrelevant images can be immediately filtered. To effectively integrate multi-features, we also investigated the following evidence combination techniques-Certainty Factor, Dempster Shafer Theory, Compound Probability, and Linear Combination. Our extensive experiment showed that single one-dimensional index on multi-features improves multi-indices on multi-features greatly. Our LBS method outperforms sequential scan on high dimensional space by an order of magnitude. And Certainty Factor and Dempster Shafer Theory perform best in combining multiple similarities from corresponding multiple features.