Cost and performance modeling for Earth system data management and beyond

Current and anticipated storage environments confront domain scientist and data center operators with usability, performance and cost challenges. The amount of data upcoming system will be required to handle is expected to grow exponentially, mainly due to increasing resolution and affordable compute power. Unfortunately, the relationship between cost and performance is not always well understood requiring considerable effort for educated procurement. Within the Centre of Excellence in Simulation of Weather and Climate in Europe (ESiWACE) models to better understand cost and performance of current and future systems are being explored. This paper presents models and methodology focusing on, but not limited to, data centers used in the context of climate and numerical weather prediction. The paper concludes with a case study of alternative deployment strategies and outlines the challenges anticipating their impact on cost and performance. By publishing these early results, we would like to make the case to work towards standard models and methodologies collaboratively as a community to create sufficient incentives for vendors to provide specifications in formats which are compatible to these modeling tools. In addition to that, we see application for such formalized models and information in I/O re lated middleware, which are expected to make automated but reasonable decisions in increasingly heterogeneous data centers

Entwicklung eines internetbasierten Systems zur Verbreitung von therapeutischem Wissen in der dreidimensionalen Strahlentherapieplanung

In der Dissertation wird das Konzept eines internetbasierten Informationssystems für die Strahlentherapie entwickelt. Das System soll die Ausbildung, den Wissensaustausch und die Forschung auf dem Gebiet der Strahlentherapie unterstützen. Weiterhin hat es die Zielsetzung, den komplexen Prozess der dreidimensionalen Strahlentherapieplanung zu beschleunigen und zu vereinfachen. Das System bietet außerdem eine Plattform zur Diskussion von Problemen und zur gemeinsamen Erarbeitung von Behandlungsrichtlinien bzw. Bestrahlungsplänen zu speziellen Patientendaten. Mit der zusätzlichen Anbindung eines wissensbasierten Systems ist das System in der Lage, automatisch voroptimierte Behandlungspläne, passend zu vorliegenden Fällen, zu generieren. Das dazu benötigte Wissen kann mit Hilfe des Systems über das Internet in Form von Beispielplänen gesammelt und von einem Fachgremium bearbeitet werden. Es werden das erarbeitete Systemkonzept und ein Prototyp vorgestellt. Der Prototyp soll das Konzept verifizieren. Der Name des Prototyps ist IRIS (Internet Based Radiotherapy Information System). Testergebnisse des Prototyps zeigen, dass das System effektiv als Java Applet in einem Internetbrowser laufen kann, und dass ein effizientes Arbeiten mit dem System im Internet möglich ist. IRIS integriert ein Tutorial, ein Diskussionsforum, einen Isodosenatlas, ein Planungsmodul sowie ein Video- und Telekonferenzsystem zu einem Gesamtsystem. Diese Komponenten interagieren miteinander und ergänzen sich zu einem vielseitig einsetzbaren System. IRIS ist als Client-Server Applikation realisiert. Die Benutzeroberfläche, ist ein Java Applet und stellt alle Funktionalitäten des Systems zur Verfügung. Voraussetzung für die Nutzung ist lediglich die Installation eines Internetbrowsers mit einer kleinen Zusatzinstallation, die zusammen mit dem IRIS Applet heruntergeladen werden kann

How perchlorate improves excitation-contraction coupling in skeletal muscle fibers

The effect of the "chaotropic" anion, perchlorate, on the activation of contraction has been studied in voltage clamped frog skeletal muscle fibers. It was found that the voltage dependence of either the contractile force or the intramembrane charge movement was shifted towards more negative membrane potentials. The maximum values of force or charge movement attained with large depolarizing pulses did not change significantly. It is concluded that a specific perchlorate effect on the movement of charged particles can explain the potentiating effect of perchlorate anions on contractile force, strengthening the view that these charged particles serve as voltage sensors regulating Ca2+ release from the sarcoplasmic reticulum

Humanisierung von Maus-Hybridomantikörpern

Viele murine Hybridome produzieren therapeutisch interessante Antikörper. Dazu zählt auch der monoklonale Maushybridomantikörper HEA125 (IgG1), der mit hoher Affinität an EpCAM (Epithelial Cell Adhesion Molecule) bindet. Da EpCAM auf der Oberfläche fast aller humaner epithelialer Tumore stark überexprimiert ist, eignet sich HEA125 ggf. als Therapeutikum für Karzinome. Murine Antikörper sind aber nicht in der Lage, die Effektorfunktionen des menschlichen Immunsystems zu aktivieren. Außerdem werden sie im menschlichen Organismus durch die HAMA (Human Anti Mouse Antibodies) Antwort meist sehr schnell inaktiviert. (A) Deshalb wird in dieser Arbeit am Beispiel von HEA125 ein Weg aufgezeigt, durch den die konstanten Domänen von beliebigen Hybridomantikörpern chimärisiert werden können, wodurch die Wirksamkeit der Antikörper verbessert und gleichzeitig die HAMA Bildung verringert wird. Dafür wurde mittels FACS zunächst ein stabiler Subklon HEA125-1 etabliert, dessen Zellen verglichen mit HEA125 ca. 30% mehr Antikörper auf ihrer Oberfläche exprimieren. Damit können sehr einfach per FACS solche Zellen isoliert werden, die veränderte Antikörper produzieren. Der Austausch der konstanten Domänen geschieht dabei mittels homologer Rekombination. Im Fall der leichten Kette konnte 1 von 3·108 HEA-Huk Zielzellen mittels FACS isoliert werden, deren exprimierte Antikörper statt der ursprünglich murinen nur noch eine humane konstante Kappa Kette aufweisen. An der Chimärisierung der schweren Kette wird noch gearbeitet. Kennzeichen der hier entwickelten Methode ist, dass kein Selektionsmarker benötigt wird, wodurch die Antikörpergene in ihrer ursprünglichen chromosomalen Umgebung erhalten werden. Dies führt zu stabilen und hohen Expressionsraten, wodurch der bisher sehr mühselige Weg zu einem Antikörper Therapeutikum stark verkürzt wird. (B) Ausgehend von der chimärisierten Zelllinie Hu-HEA125 soll außerdem mittels Kassettenaustausch der variablen Antikörperdomänen eine Bibliothek humaner Hybridomantikörper generiert werden. Dafür ist die Einführung von spezifischen Rekombinationsstellen ins Hu-HEA125-Genom durch zwei weitere homologe Rekombinationsereignisse notwendig. Die Einführung der loxP Stellen mittels eines flankierten NPTII Gens in den aktiven IGHV Genlokus wurde bereits erfolgreich in HEA125 getestet. Die homolog rekombinierten Zielzellen konnten mittels PCR nachgewiesen werden, waren aber nicht stabil. Deshalb ist die Einführung der spezifischen Rekombinationsstellen direkt mittels veränderter, FACS-selektionierbarer variabler Domänen geplant. Damit können die murinen variablen Domänen je nach Kassettenaustauschfrequenz gegen die Vielfalt humaner variabler Domänen ausgetauscht werden. Hierbei werden an DNA humaner B-Lymphozyten PCR amplifizierte humane schwere und leichte Ketten zufällig miteinander kombiniert. Aus der resultierenden Vielfalt sollen interessante humane Antikörper nahezu beliebiger Spezifität aufgrund der oberflächenexprimierten Antikörper durch Bindung an immobilisiertes Antigen schnell und einfach isoliert werden können

Toward understanding I/O behavior in HPC workflows

Scientific discovery increasingly depends on complex workflows consisting of multiple phases and sometimes millions of parallelizable tasks or pipelines. These workflows access storage resources for a variety of purposes, including preprocessing, simulation output, and postprocessing steps. Unfortunately, most workflow models focus on the scheduling and allocation of com- putational resources for tasks while the impact on storage systems remains a secondary objective and an open research question. I/O performance is not usually accounted for in workflow telemetry reported to users. In this paper, we present an approach to augment the I/O efficiency of the individual tasks of workflows by combining workflow description frameworks with system I/O telemetry data. A conceptual architecture and a prototype implementation for HPC data center deployments are introduced. We also identify and discuss challenges that will need to be addressed by workflow management and monitoring systems for HPC in the future. We demonstrate how real-world applications and workflows could benefit from the approach, and we show how the approach helps communicate performance-tuning guidance to users

Survey of storage systems for high-performance computing

In current supercomputers, storage is typically provided by parallel distributed file systems for hot data and tape archives for cold data. These file systems are often compatible with local file systems due to their use of the POSIX interface and semantics, which eases development and debugging because applications can easily run both on workstations and supercomputers. There is a wide variety of file systems to choose from, each tuned for different use cases and implementing different optimizations. However, the overall application performance is often held back by I/O bottlenecks due to insufficient performance of file systems or I/O libraries for highly parallel workloads. Performance problems are dealt with using novel storage hardware technologies as well as alternative I/O semantics and interfaces. These approaches have to be integrated into the storage stack seamlessly to make them convenient to use. Upcoming storage systems abandon the traditional POSIX interface and semantics in favor of alternative concepts such as object and key-value storage; moreover, they heavily rely on technologies such as NVM and burst buffers to improve performance. Additional tiers of storage hardware will increase the importance of hierarchical storage management. Many of these changes will be disruptive and require application developers to rethink their approaches to data management and I/O. A thorough understanding of today's storage infrastructures, including their strengths and weaknesses, is crucially important for designing and implementing scalable storage systems suitable for demands of exascale computing

The SIOX architecture – coupling automatic monitoring and optimization of parallel I/O

Performance analysis and optimization of high-performance I/O systems is a daunting task. Mainly, this is due to the overwhelmingly complex interplay of the involved hardware and software layers. The Scalable I/O for Extreme Performance (SIOX) project provides a versatile environment for monitoring I/O activities and learning from this information. The goal of SIOX is to automatically suggest and apply performance optimizations, and to assist in locating and diagnosing performance problems. In this paper, we present the current status of SIOX. Our modular architecture covers instrumentation of POSIX, MPI and other high-level I/O libraries; the monitoring data is recorded asynchronously into a global database, and recorded traces can be visualized. Furthermore, we offer a set of primitive plug-ins with additional features to demonstrate the flexibility of our architecture: A surveyor plug-in to keep track of the observed spatial access patterns; an fadvise plug-in for injecting hints to achieve read-ahead for strided access patterns; and an optimizer plug-in which monitors the performance achieved with different MPI-IO hints, automatically supplying the best known hint-set when no hints were explicitly set. The presentation of the technical status is accompanied by a demonstration of some of these features on our 20 node cluster. In additional experiments, we analyze the overhead for concurrent access, for MPI-IO’s 4-levels of access, and for an instrumented climate application. While our prototype is not yet full-featured, it demonstrates the potential and feasibility of our approach

A malignant hyperthermia–inducing mutation in RYR1 (R163C): alterations in Ca2+ entry, release, and retrograde signaling to the DHPR

Bidirectional signaling between the sarcolemmal L-type Ca2+ channel (1,4-dihydropyridine receptor [DHPR]) and the sarcoplasmic reticulum (SR) Ca2+ release channel (type 1 ryanodine receptor [RYR1]) of skeletal muscle is essential for excitation–contraction coupling (ECC) and is a well-understood prototype of conformational coupling. Mutations in either channel alter coupling fidelity and with an added pharmacologic stimulus or stress can trigger malignant hyperthermia (MH). In this study, we measured the response of wild-type (WT), heterozygous (Het), or homozygous (Hom) RYR1-R163C knock-in mouse myotubes to maintained K+ depolarization. The new findings are: (a) For all three genotypes, Ca2+ transients decay during prolonged depolarization, and this decay is not a consequence of SR depletion or RYR1 inactivation. (b) The R163C mutation retards the decay rate with a rank order WT > Het > Hom. (c) The removal of external Ca2+ or the addition of Ca2+ entry blockers (nifedipine, SKF96365, and Ni2+) enhanced the rate of decay in all genotypes. (d) When Ca2+ entry is blocked, the decay rates are slower for Hom and Het than WT, indicating that the rate of inactivation of ECC is affected by the R163C mutation and is genotype dependent (WT > Het > Hom). (e) Reduced ECC inactivation in Het and Hom myotubes was shown directly using two identical K+ depolarizations separated by varying time intervals. These data suggest that conformational changes induced by the R163C MH mutation alter the retrograde signal that is sent from RYR1 to the DHPR, delaying the inactivation of the DHPR voltage sensor

The acute effects of plyometric and sled towing stimuli with and without caffeine ingestion on vertical jump performance in professional soccer players

Abstract Background Post-activation potentiation (PAP) is the phenomenon by which muscular performance is enhanced in response to a conditioning stimulus. PAP has typically been evidenced via improved counter movement jump (CMJ) performance. This study examined the effects of PAP, with and without prior caffeine ingestion, on CMJ performance. Methods Twelve male professional soccer players (23 ± 5 years) performed two trials of plyometric exercises and sled towing 60 min after placebo or caffeine ingestion (5 mg.kg− 1) in a randomized, counterbalanced and double-blinded design. CMJ performance was assessed at baseline and 1, 3 and 5 min after the conditioning stimulus (T1, T3 and T5, respectively). Results Two way ANOVA main effects indicated a significant difference in jump height after the PAP protocol (F[3, 11] = 14.99, P  0.05) compared to placebo. Conclusions The results of this study suggest that acute plyometric and sled towing stimuli enhances jump performance and that this potentiation is augmented by caffeine ingestion in male soccer players