ESSEX: Equipping Sparse Solvers for Exascale

The ESSEX project investigates computational issues arising at exascale for large-scale sparse eigenvalue problems and develops programming concepts and numerical methods for their solution. The project pursues a coherent co-design of all software layers where a holistic performance engineering process guides code development across the classic boundaries of application, numerical method and basic kernel library. Within ESSEX the numerical methods cover both widely applicable solvers such as classic Krylov, Jacobi-Davidson or recent FEAST methods as well as domain specific iterative schemes relevant for the ESSEX quantum physics application. This report introduces the project structure and presents selected results which demonstrate the potential impact of ESSEX for efficient sparse solvers on highly scalable heterogeneous supercomputers

Pure functions in C: A small keyword for automatic parallelization

© 2017 IEEE. The need for parallel task execution has been steadily growing in recent years since manufacturers mainly improve processor performance by scaling the number of installed cores instead of the frequency of processors. To make use of this potential, an essential technique to increase the parallelism of a program is to parallelize loops. However, a main restriction of available tools for automatic loop parallelization is that the loops often have to be 'polyhedral' and that it is, e.g., not allowed to call functions from within the loops.In this paper, we present a seemingly simple extension to the C programming language which marks functions without side-effects. These functions can then basically be ignored when checking the parallelization opportunities for polyhedral loops. We extended the GCC compiler toolchain accordingly and evaluated several real-world applications showing that our extension helps to identify additional parallelization chances and, thus, to significantly enhance the performance of applications

Analysis and parallelizationstrategies for Ruge-Stüben AMGon many-core processors

The Ruge-Stuben algebraic multigrid method (AMG) is an optimal-complexity black-box approach to solve linear systems arising in discretizations of e.g. elliptic PDEs. Recently, there has been a growing interest in parallelizing this method on many-core hardware, especially graphics processing units (GPUs). This type of hardware delivers high performance for highly parallel algorithms. In this work, we analyse convergence properties of recent AMG developments for many-core processors and propose to use more classical choices of AMG components for higher robustness. Based on these choices, we introduce many-core parallelization strategies for a robust hybrid many-core AMG. The strategies can be understood and applied without deep knowledge of a given many-core architecture. We use them to propose a new hybrid GPU implementation. The implementation is tested in an in-depth performance analysis, which outlines its good convergence properties and high performance in the solve phase

Impact of the Scheduling Strategy in Heterogeneous Systems That Provide Co-Scheduling

ABSTRACT In recent years, the number of processing units per compute node has been increasing. In order to utilize all or most of the available resources of a high-performance computing cluster, at least some of its nodes will have to be shared by several applications at the same time. Yet, even if jobs are co-scheduled on a node, it can happen that high performance resources remain idle, although there are jobs that could make use of them (e. g. if the resource was temporarily blocked when the job was started). Heterogeneous schedulers, which schedule tasks for different devices, can bind jobs to resources in a way that can significantly reduce the idle time. Typically, those schedulers make their decisions based on a static strategy. In this paper, we investigate the impact if a heterogeneous scheduler allows modifications of the strategies at runtime. For a set of applications, we determine the makespan and show how it is influenced by four different scheduling strategies. A well-chosen strategy can result in a speedup of more the 2.5 in comparison to other strategies

Pure functions in C: A small keyword for automatic parallelization

© 2020, The Author(s). The need for parallel task execution has been steadily growing in recent years since manufacturers mainly improve processor performance by increasing the number of installed cores instead of scaling the processor’s frequency. To make use of this potential, an essential technique to increase the parallelism of a program is to parallelize loops. Several automatic loop nest parallelizers have been developed in the past such as PluTo. The main restriction of these tools is that the loops must be statically analyzable which, among other things, disallows function calls within the loops. In this article, we present a seemingly simple extension to the C programming language which marks functions without side-effects. These functions can then basically be ignored when the automatic parallelizer checks the parallelizability of loops. We integrated the approach into the GCC compiler toolchain and evaluated it by running several real-world applications. Our experiments show that the C extension helps to identify additional parallelization opportunities and, thus, to significantly increase the performance of applications

Industry 5.0 Enabled Smart Logistics: Optimization of Distribution Network in Food Industry

The fourth industrial revolution, namely Industry 4.0, has substantially impacted the supply chain and logistics operations which led to the introduction of Logistics 4.0. The incorporation of novel technologies in this context developed smart logistics; however, scholars raised the concerns about socio-economic aspects of these improvements. Industry 5.0 as a value-driven paradigm, in this regard, initiated the trinary concept of sustainability, resilience, and human-centricity to put forward the technological and conceptual developments of industry according to this framework. Given the recency of this industrial revolution, not many research works have focused on the implication of Industry 5.0 for smart logistics. Therefore, this research aims at bridging this gap by investing effort into accomplishing a thorough systematic literature review to compare the topic of smart logistics in Industry 4.0 and Industry 5.0. The results define integration and intelligence among the key features, and spot simulation and digital twin among the enabling technologies of this concept. To realize these findings, a digital model of a company’s distribution network is created, and it facilitates the possibility of performing network optimization and simulation through an integrated platform. The results show that such approach has a remarkable contribution in performing the supply chain network optimization and determining the logistics performances of the redesigned network, e.g., optimal inventory level and capacity at each facility, shipping policy in individual transportation routes, etc. This approach enables the possibility of incorporating socio-economic aspects into logistics studies, e.g., CO2 emission, which are discussed as further research directions

Density-Aware Linear Algebra in a Column-Oriented In-Memory Database System

Linear algebra operations appear in nearly every application in advanced analytics, machine learning, and of various science domains. Until today, many data analysts and scientists tend to use statistics software packages or hand-crafted solutions for their analysis. In the era of data deluge, however, the external statistics packages and custom analysis programs that often run on single-workstations are incapable to keep up with the vast increase in data volume and size. In particular, there is an increasing demand of scientists for large scale data manipulation, orchestration, and advanced data management capabilities. These are among the key features of a mature relational database management system (DBMS). With the rise of main memory database systems, it now has become feasible to also consider applications that built up on linear algebra. This thesis presents a deep integration of linear algebra functionality into an in-memory column-oriented database system. In particular, this work shows that it has become feasible to execute linear algebra queries on large data sets directly in a DBMS-integrated engine (LAPEG), without the need of transferring data and being restricted by hard disc latencies. From various application examples that are cited in this work, we deduce a number of requirements that are relevant for a database system that includes linear algebra functionality. Beside the deep integration of matrices and numerical algorithms, these include optimization of expressions, transparent matrix handling, scalability and data-parallelism, and data manipulation capabilities. These requirements are addressed by our linear algebra engine. In particular, the core contributions of this thesis are: firstly, we show that the columnar storage layer of an in-memory DBMS yields an easy adoption of efficient sparse matrix data types and algorithms. Furthermore, we show that the execution of linear algebra expressions significantly benefits from different techniques that are inspired from database technology. In a novel way, we implemented several of these optimization strategies in LAPEG’s optimizer (SpMachO), which uses an advanced density estimation method (SpProdest) to predict the matrix density of intermediate results. Moreover, we present an adaptive matrix data type AT Matrix to obviate the need of scientists for selecting appropriate matrix representations. The tiled substructure of AT Matrix is exploited by our matrix multiplication to saturate the different sockets of a multicore main-memory platform, reaching up to a speed-up of 6x compared to alternative approaches. Finally, a major part of this thesis is devoted to the topic of data manipulation; where we propose a matrix manipulation API and present different mutable matrix types to enable fast insertions and deletes. We finally conclude that our linear algebra engine is well-suited to process dynamic, large matrix workloads in an optimized way. In particular, the DBMS-integrated LAPEG is filling the linear algebra gap, and makes columnar in-memory DBMS attractive as efficient, scalable ad-hoc analysis platform for scientists

Understanding and Drugging the Bcl-2 Transmembrane Interactome for Tumor Treatment

[ES] La familia de proteínas Bcl-2 regula la apoptosis a través de una compleja red de interacciones. Las células tumorales suelen presentar mutaciones que afectan a su expresión o sus interacciones para mejorar la progresión tumoral. Además, alteraciones en su regulación también promueven la migración de células cancerígenas, la invasión y la metástasis. Para llevar a cabo sus funciones, las proteínas Bcl 2 interaccionan entre sí tanto en el citoplasma como en las membranas intracelulares. Los equilibrios de interacción de los dominios Bcl citosólicos se han investigado ampliamente y recientemente, se han propuesto como dianas terapéuticas. Sin embargo, el interactoma de los dominios transmembrana (TMD, del inglés transmembrane domains) sigue siendo poco conocido. Por ello, un conocimiento profundo de la biología de las proteínas Bcl-2 es necesario para explotar eficientemente sus superficies de unión en el tratamiento del cáncer. Para llevar a cabo este objetivo, nos hemos centrado en tres áreas: 1. La comprensión detallada de la contribución del TMD de Mcl-1 a su interactoma en membrana y su función. 2. El descubrimiento de nuevos inhibidores de Mcl-1 que actúen sobre su TMD y que permitan desarrollar una clase de drogas anticancerígenas aún por explorar. 3. La caracterización molecular de mutaciones relacionadas con el cáncer descritas en los TMD de Bcl-2 y Bcl-xL y sus implicaciones en la supervivencia de las células tumorales. La proteína antiapoptótica Mcl-1 inhibe a los miembros proapoptóticos Bak, Bax, Bok, Noxa, etc. Aunque se ha estudiado en detalle su actividad promoviendo la supervivencia celular, el mecanismo molecular por el cuál previene la apoptosis mediada por Bok aún no está claro. Además, el conocimiento de las actividades de Mcl-1, descritas hasta ahora, se basa exclusivamente en las estructuras resueltas de las regiones solubles en agua y en estudios centrados en los dominios citosólicos. Por primera vez, hemos demostrado la relevancia del TMD de Mcl-1 en su equilibrio de interacción. En este trabajo describimos su capacidad específica para homo- y hetero-oligomerizar con el TMD de Bok. También ponemos de manifiesto la influencia de estas interacciones en la modulación de apoptosis y resaltamos la relevancia clínica de los mutantes del TMD de Mcl-1 identificados en pacientes con cáncer. Muchos tumores hematológicos y sólidos sobre-expresan Mcl-1 como mecanismo para adquirir quimiorresistencia. Se han desarrollado miméticos de BH3 específicos para modular su actividad antiapoptótica en células cancerosas. Sin embargo, aún no disponemos de datos científicos que informen sobre su toxicidad y eficacia en humanos. En este trabajo, proponemos la novedosa interacción de los TMDs de Mcl-1 y Bok como un nuevo sitio de acción de fármacos quimioterapéuticos. Hemos identificado tres inhibidores de esta interacción con características que los hacen prometedores candidatos para el desarrollo farmacéutico, así como buenas herramientas moleculares para estudiar la interacción de los TMDs de Mcl-1 y Bok. Para modular la apoptosis, las células tumorales también presentan versiones mutadas de las proteínas antiapoptóticas Bcl-2 y Bcl-xL. En nuestro conocimiento, este es el primer estudio que analiza mutaciones somáticas de sus TMDs. Nuestro trabajo demuestra cómo estas mutaciones alteran el equilibrio en membrana de las proteínas. Además, nuestros resultados explican la influencia que algunos mutantes somáticos ejercen en la regulación de la apoptosis. En general, los resultados científicos que aparecen en esta tesis resaltan el papel de los Bcl TMDs en el interactoma de las proteínas Bcl-2. Estos hallazgos corroboran que las interacciones laterales entre los TMDs son específicas y contribuyen activamente a la funcionalidad de la proteína. Por lo tanto, comprender los Bcl TMDs puede proporcionar nuevos conocimientos sobre la biología de las proteínas Bcl.[CA] La família de proteïnes Bcl-2 regula l'apoptosi a través d'una complexa xarxa d'interaccions. Les cèl·lules tumorals solen presentar mutacions que afecten la seua expressió o les seues interaccions per a millorar la progressió tumoral. A més, alteracions en la seua regulació també promouen la migració de cèl·lules cancerígenes, la invasió i la metàstasi. Per a dur a terme les seues funcions, les proteïnes Bcl-2 interaccionen entre si tant en el citoplasma com en les membranes intracel·lulars. Els equilibris d'interacció dels dominis Bcl citosòlics s'han investigat àmpliament i recentment, s'han proposat com a dianes terapèutiques. No obstant això, l'interactoma dels dominis transmembrana (TMD, de l'anglés transmembrane domains) continua sent poc conegut. Per això, un coneixement profund de la biologia de les proteïnes Bcl-2 és necessari per a explotar eficientment les seues superfícies d'unió en el tractament del càncer. Per a dur a terme aquest objectiu, ens hem centrat en tres àrees: 1. La comprensió detallada de la contribució del TMD de Mcl-1 al seu interactoma en membrana i la seua funció. 2. El descobriment de nous inhibidors de Mcl-1 que actuen sobre el seu TMD i que permeten desenvolupar una classe de drogues anticanceroses encara per explorar. 3. La caracterització molecular de mutacions relacionades amb el càncer descrites en els TMD de Bcl-2 i Bcl-xL i les seues implicacions en la supervivència de les cèl·lules tumorals. La proteïna anti apoptòtica Mcl-1 inhibeix als membres pro apoptòtics Bak, Bax, Bok, Noxa, etc. Encara que s'ha estudiat detalladament la seua activitat promovent la supervivència cel·lular, el mecanisme molecular pel qual prevé l'apoptosi mediada per Bok encara no és clar. A més, el coneixement de les activitats de Mcl-1, descrites fins ara, es basa exclusivament en les estructures resoltes solubles en aigua i en estudis centrats en els dominis externs a la membrana. Per primera vegada, hem demostrat la rellevància del TMD de Mcl-1 el seu equilibri d'interacció. En aquest treball descrivim la seua capacitat específica per a unir-se amb si mateix i per a hetero-oligomeritzar amb el TMD de Bok. També expliquem la influència d'aquestes interaccions en l'apoptosi i ressaltem la rellevància clínica dels mutants del TMD de Mcl-1 identificats en pacients amb càncer. Molts tumors hematològics i sòlids sobre-expressen Mcl-1 com un mecanisme per a adquirir quimioresistència. S'han desenvolupat mimètics de BH3 específics per a modular la seua activitat anti apoptòtica en cèl·lules canceroses. No obstant això, encara no disposem de dades científiques que informen sobre la seua toxicitat i eficàcia en humans. Per això, proposem la nova interacció dels TMDs de Mcl-1 i Bok com un lloc d'actuació de fàrmacs quimioterapèutiques. Hem identificat tres inhibidors d'aquesta interacció amb característiques que els fan prometedors candidats per al desenvolupament farmacèutic, així com bones eines moleculars per a estudiar la interacció dels TMDs de Mcl-1 i Bok. Per a modular l'apoptosi, les cèl·lules tumorals també presenten versions mutades de les proteïnes anti apoptòtiques Bcl-2 i Bcl-xL. En el nostre coneixement, aquest és el primer estudi que analitza mutacions somàtiques de les seues TMDs. El nostre treball demostra com aquestes mutacions alteren l'equilibri en membrana de les proteïnes. A més, els nostres resultats expliquen la influència que alguns mutants somàtics exerceixen en la regulació de l'apoptosi. En general, els resultats científics que apareixen en aquesta tesi ressalten el paper dels Bcl TMDs en l'interactoma de les proteïnes Bcl-2. Aquestes troballes corroboren que les interaccions laterals entre els TMDs són específiques de la seqüència i contribueixen activament a la funcionalitat de la proteïna. Per tant, comprendre els Bcl TMDs pot proporcionar nous coneixements sobre la biologia de les proteïnes Bcl[EN] The family of the Bcl-2 proteins modulates the apoptotic pathway by a complex network of interactions. Tumor cells frequently present mutations that affect Bcl-2 proteins expression or interactions to enhance cancer progression. Dysregulation of these proteins also promotes cancer cell migration, invasion, and metastasis. To execute their functions, Bcl-2 proteins interact in both the cytosol and intracellular membranes. Binding equilibria of Bcl extramembrane domains has been largely investigated and recently proposed as chemotherapeutic targets. However, the interactome of transmembrane domains (TMDs) remains poorly understood. In this scenario, a deep knowledge of the biology of Bcl-2 proteins is needed to exploit efficiently their binding surfaces for cancer treatment. To address this aim, our research focuses on three areas: 1. The detailed comprehension of the TMD contribution to both the Mcl-1 membrane interactome and protein functionality. 2. The discovery of new Mcl-1 inhibitors that target the transmembrane surface to develop a class of anticancer drugs currently unexplored. 3. The molecular characterization of cancer-related mutations within the Bcl-2 and Bcl-xL TMDs and their implications for the survival of cancer cells. Antiapoptotic Mcl-1 protein inhibits the proapoptotic members Bak, Bax, Bok, and Noxa, among others. Although its prosurvival activity has been well studied, the molecular mechanism to prevent Bok-mediated apoptosis remains unclear. Furthermore, understanding of Mcl-1 activities described to date is only based on water-soluble structures and studies focused on extramembrane domains. For the first time, we uncover the relevance of the Mcl-1 TMD in the interaction equilibria of the protein. In the present work, we describe its specific capacity to self-associate and hetero-oligomerize with the Bok TMD. We also explain the influence of these interactions in the apoptotic pathway and highlight the clinical relevance of Mcl-1 TMD mutants identified in tumor patients. Many hematological and solid malignancies overexpress Mcl-1 as an acquired chemoresistance mechanism. To modulate its antiapoptotic activity in cancer cells, specific BH3 mimetics have been developed; however, there is no scientific data yet regarding human toxicity and efficacy. In this work, we propose the novel Mcl-1 and Bok TMDs interaction interface as a drugging site in the development of chemotherapeutics. We identify three potential inhibitors of such molecular interface with promising features to become both drug candidates for pharmaceutical development and research toosl for the molecular study of the Mcl-1 and Bok TMDs interaction. To take advantage of apoptosis modulation, tumor cells also present mutated versions of the antiapoptotic members Bcl-2 and Bcl-xL. To our knowledge, this is the first study that analyzes patient-derived mutations within Bcl-2 and Bcl-xL TMDs and demonstrates how said mutations alter the membrane equilibria of these proteins. The results presented here also explain the functional influence of some somatic mutants in apoptosis regulation. Overall, the scientific results exhibited in this Thesis highlight the role of Bcl TMDs in the interactome of Bcl-2 proteins. These findings corroborate that lateral interactions between TMDs are sequence-specific and actively contribute to protein functionality. Therefore, understanding of Bcl transmembrane segments may provide new insights into the biology of Bcl 2 proteins for their pharmaceutical modulation in antitumoral therapy.The student has been granted with a PhD fellowship and a short-term fellowship from the Generalitat Valenciana (Subvenciones para la contratación de personal investigador de carácter predoctoral, 2016-2019, and Grant for predoctoral stays out of the Comunitat Valenciana, 2019). This work has been supported by the Spanish Ministry of Economy and Competitiveness (projects SAF2014-52614-R and SAF2017-84689-RLucendo Gutiérrez, E. (2020). Understanding and Drugging the Bcl-2 Transmembrane Interactome for Tumor Treatment [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/155914TESI