Application benchmark results for Big Red, an IBM e1350 BladeCenter Cluster

The purpose of this report is to present the results of benchmark tests with Big Red, an IBM e1350 BladeCenter Cluster. This report is particularly focused on providing details of system architecture and test run results in detail to allow for analysis in other reports and comparison with other systems, rather than presenting such analysis here

The Pathway to Detangle a Scrambled Gene

Programmed DNA elimination and reorganization frequently occur during cellular differentiation. Development of the somatic macronucleus in some ciliates presents an extreme case, involving excision of internal eliminated sequences (IESs) that interrupt coding DNA segments (macronuclear destined sequences, MDSs), as well as removal of transposon-like elements and extensive genome fragmentation, leading to 98% genome reduction in Stylonychia lemnae. Approximately 20-30% of the genes are estimated to be scrambled in the germline micronucleus, with coding segment order permuted and present in either orientation on micronuclear chromosomes. Massive genome rearrangements are therefore critical for development.To understand the process of DNA deletion and reorganization during macronuclear development, we examined the population of DNA molecules during assembly of different scrambled genes in two related organisms in a developmental time-course by PCR. The data suggest that removal of conventional IESs usually occurs first, accompanied by a surprising level of error at this step. The complex events of inversion and translocation seem to occur after repair and excision of all conventional IESs and via multiple pathways.This study reveals a temporal order of DNA rearrangements during the processing of a scrambled gene, with simpler events usually preceding more complex ones. The surprising observation of a hidden layer of errors, absent from the mature macronucleus but present during development, also underscores the need for repair or screening of incorrectly-assembled DNA molecules

Osteopenia Due to Enhanced Cathepsin K Release by BK Channel Ablation in Osteoclasts

BACKGROUND: The process of bone resorption by osteoclasts is regulated by Cathepsin K, the lysosomal collagenase responsible for the degradation of the organic bone matrix during bone remodeling. Recently, Cathepsin K was regarded as a potential target for therapeutic intervention of osteoporosis. However, mechanisms leading to osteopenia, which is much more common in young female population and often appears to be the clinical pre-stage of idiopathic osteoporosis, still remain to be elucidated, and molecular targets need to be identified. METHODOLOGY/PRINCIPAL FINDINGS: We found, that in juvenile bone the large conductance, voltage and Ca(2+)-activated (BK) K(+) channel, which links membrane depolarization and local increases in cytosolic calcium to hyperpolarizing K(+) outward currents, is exclusively expressed in osteoclasts. In juvenile BK-deficient (BK(-/-)) female mice, plasma Cathepsin K levels were elevated two-fold when compared to wild-type littermates. This increase was linked to an osteopenic phenotype with reduced bone mineral density in long bones and enhanced porosity of trabecular meshwork in BK(-/-) vertebrae as demonstrated by high-resolution flat-panel volume computed tomography and micro-CT. However, plasma levels of sRANKL, osteoprotegerin, estrogene, Ca(2+) and triiodthyronine as well as osteoclastogenesis were not altered in BK(-/-) females. CONCLUSION/SIGNIFICANCE: Our findings suggest that the BK channel controls resorptive osteoclast activity by regulating Cathepsin K release. Targeted deletion of BK channel in mice resulted in an osteoclast-autonomous osteopenia, becoming apparent in juvenile females. Thus, the BK(-/-) mouse-line represents a new model for juvenile osteopenia, and revealed the BK channel as putative new target for therapeutic controlling of osteoclast activity

A Novel Function of DELTA-NOTCH Signalling Mediates the Transition from Proliferation to Neurogenesis in Neural Progenitor Cells

A complete account of the whole developmental process of neurogenesis involves understanding a number of complex underlying molecular processes. Among them, those that govern the crucial transition from proliferative (self-replicating) to neurogenic neural progenitor (NP) cells remain largely unknown. Due to its sequential rostro-caudal gradients of proliferation and neurogenesis, the prospective spinal cord of the chick embryo is a good experimental system to study this issue. We report that the NOTCH ligand DELTA-1 is expressed in scattered cycling NP cells in the prospective chick spinal cord preceding the onset of neurogenesis. These Delta-1-expressing progenitors are placed in between the proliferating caudal neural plate (stem zone) and the rostral neurogenic zone (NZ) where neurons are born. Thus, these Delta-1-expressing progenitors define a proliferation to neurogenesis transition zone (PNTZ). Gain and loss of function experiments carried by electroporation demonstrate that the expression of Delta-1 in individual progenitors of the PNTZ is necessary and sufficient to induce neuronal generation. The activation of NOTCH signalling by DELTA-1 in the adjacent progenitors inhibits neurogenesis and is required to maintain proliferation. However, rather than inducing cell cycle exit and neuronal differentiation by a typical lateral inhibition mechanism as in the NZ, DELTA-1/NOTCH signalling functions in a distinct manner in the PNTZ. Thus, the inhibition of NOTCH signalling arrests proliferation but it is not sufficient to elicit neuronal differentiation. Moreover, after the expression of Delta-1 PNTZ NP continue cycling and induce the expression of Tis21, a gene that is upregulated in neurogenic progenitors, before generating neurons. Together, these experiments unravel a novel function of DELTA–NOTCH signalling that regulates the transition from proliferation to neurogenesis in NP cells. We hypothesize that this novel function is evolutionary conserved

The Orchestration Stack: The Impossible Task of Designing Software for Unknown Future Post-CMOS Hardware

Future systems based on post-CMOS technologies will be wildly heterogeneous, with properties largely unknown today. This paper presents our design of a new hardware/software stack to address the challenge of preparing software development for such systems. It combines well-understood technologies from different areas, e.g., network-on-chips, capability operating systems, flexible programming models and model checking. We describe our approach and provide details on key technologies

The Changing Landscape for Stroke\ua0Prevention in AF: Findings From the GLORIA-AF Registry Phase 2

Background GLORIA-AF (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients with Atrial Fibrillation) is a prospective, global registry program describing antithrombotic treatment patterns in patients with newly diagnosed nonvalvular atrial fibrillation at risk of stroke. Phase 2 began when dabigatran, the first non\u2013vitamin K antagonist oral anticoagulant (NOAC), became available. Objectives This study sought to describe phase 2 baseline data and compare these with the pre-NOAC era collected during phase 1. Methods During phase 2, 15,641 consenting patients were enrolled (November 2011 to December 2014); 15,092 were eligible. This pre-specified cross-sectional analysis describes eligible patients\u2019 baseline characteristics. Atrial fibrillation disease characteristics, medical outcomes, and concomitant diseases and medications were collected. Data were analyzed using descriptive statistics. Results Of the total patients, 45.5% were female; median age was 71 (interquartile range: 64, 78) years. Patients were from Europe (47.1%), North America (22.5%), Asia (20.3%), Latin America (6.0%), and the Middle East/Africa (4.0%). Most had high stroke risk (CHA2DS2-VASc [Congestive heart failure, Hypertension, Age  6575 years, Diabetes mellitus, previous Stroke, Vascular disease, Age 65 to 74 years, Sex category] score  652; 86.1%); 13.9% had moderate risk (CHA2DS2-VASc = 1). Overall, 79.9% received oral anticoagulants, of whom 47.6% received NOAC and 32.3% vitamin K antagonists (VKA); 12.1% received antiplatelet agents; 7.8% received no antithrombotic treatment. For comparison, the proportion of phase 1 patients (of N = 1,063 all eligible) prescribed VKA was 32.8%, acetylsalicylic acid 41.7%, and no therapy 20.2%. In Europe in phase 2, treatment with NOAC was more common than VKA (52.3% and 37.8%, respectively); 6.0% of patients received antiplatelet treatment; and 3.8% received no antithrombotic treatment. In North America, 52.1%, 26.2%, and 14.0% of patients received NOAC, VKA, and antiplatelet drugs, respectively; 7.5% received no antithrombotic treatment. NOAC use was less common in Asia (27.7%), where 27.5% of patients received VKA, 25.0% antiplatelet drugs, and 19.8% no antithrombotic treatment. Conclusions The baseline data from GLORIA-AF phase 2 demonstrate that in newly diagnosed nonvalvular atrial fibrillation patients, NOAC have been highly adopted into practice, becoming more frequently prescribed than VKA in Europe and North America. Worldwide, however, a large proportion of patients remain undertreated, particularly in Asia and North America. (Global Registry on Long-Term Oral Antithrombotic Treatment in Patients With Atrial Fibrillation [GLORIA-AF]; NCT01468701

31st Annual Meeting and Associated Programs of the Society for Immunotherapy of Cancer (SITC 2016) : part two

Background The immunological escape of tumors represents one of the main ob- stacles to the treatment of malignancies. The blockade of PD-1 or CTLA-4 receptors represented a milestone in the history of immunotherapy. However, immune checkpoint inhibitors seem to be effective in specific cohorts of patients. It has been proposed that their efficacy relies on the presence of an immunological response. Thus, we hypothesized that disruption of the PD-L1/PD-1 axis would synergize with our oncolytic vaccine platform PeptiCRAd. Methods We used murine B16OVA in vivo tumor models and flow cytometry analysis to investigate the immunological background. Results First, we found that high-burden B16OVA tumors were refractory to combination immunotherapy. However, with a more aggressive schedule, tumors with a lower burden were more susceptible to the combination of PeptiCRAd and PD-L1 blockade. The therapy signifi- cantly increased the median survival of mice (Fig. 7). Interestingly, the reduced growth of contralaterally injected B16F10 cells sug- gested the presence of a long lasting immunological memory also against non-targeted antigens. Concerning the functional state of tumor infiltrating lymphocytes (TILs), we found that all the immune therapies would enhance the percentage of activated (PD-1pos TIM- 3neg) T lymphocytes and reduce the amount of exhausted (PD-1pos TIM-3pos) cells compared to placebo. As expected, we found that PeptiCRAd monotherapy could increase the number of antigen spe- cific CD8+ T cells compared to other treatments. However, only the combination with PD-L1 blockade could significantly increase the ra- tio between activated and exhausted pentamer positive cells (p= 0.0058), suggesting that by disrupting the PD-1/PD-L1 axis we could decrease the amount of dysfunctional antigen specific T cells. We ob- served that the anatomical location deeply influenced the state of CD4+ and CD8+ T lymphocytes. In fact, TIM-3 expression was in- creased by 2 fold on TILs compared to splenic and lymphoid T cells. In the CD8+ compartment, the expression of PD-1 on the surface seemed to be restricted to the tumor micro-environment, while CD4 + T cells had a high expression of PD-1 also in lymphoid organs. Interestingly, we found that the levels of PD-1 were significantly higher on CD8+ T cells than on CD4+ T cells into the tumor micro- environment (p < 0.0001). Conclusions In conclusion, we demonstrated that the efficacy of immune check- point inhibitors might be strongly enhanced by their combination with cancer vaccines. PeptiCRAd was able to increase the number of antigen-specific T cells and PD-L1 blockade prevented their exhaus- tion, resulting in long-lasting immunological memory and increased median survival

Dynamische Lastbalancierung und Modellkopplung zur hochskalierbaren Simulation von Wolkenprozessen

Die komplexen Interaktionen von Aerosolen, Wolken und Niederschlag werden in aktuellen Vorhersagemodellen nur ungenügend dargestellt. Simulationen mit spektraler Beschreibung von Wolkenprozessen können zu verbesserten Vorhersagen beitragen, sind jedoch weitaus rechenintensiver. Die Beschleunigung dieser Simulationen erfordert eine hochparallele Ausführung. In dieser Arbeit wird ein Konzept zur Kopplung spektraler Wolkenmikrophysikmodelle mit atmosphärischen Modellen entwickelt, das eine effiziente Nutzung der heute verfügbaren Parallelität der Größenordnung von 100.000 Prozessorkernen ermöglicht. Aufgrund des stark variierenden Rechenaufwands ist dafür eine hochskalierbare dynamische Lastbalancierung des Wolkenmikrophysikmodells unumgänglich. Dies wird durch ein hierarchisches Partitionierungsverfahren erreicht, das auf raumfüllenden Kurven basiert. Darüber hinaus wird eine hochskalierbare Verknüpfung von dynamischer Lastbalancierung und Modellkopplung durch ein effizientes Verfahren für die regelmäßige Bestimmung der Überschneidungen zwischen unterschiedlichen Partitionierungen ermöglicht. Durch die effiziente Nutzung von Hochleistungsrechnern ermöglichen die Ergebnisse der Arbeit die Anwendung spektraler Wolkenmikrophysikmodelle zur Simulation realistischer Szenarien auf hochaufgelösten Gittern.Current forecast models insufficiently represent the complex interactions of aerosols, clouds and precipitation. Simulations with spectral description of cloud processes allow more detailed forecasts. However, they are much more computationally expensive. Reducing the runtime of such simulations requires a highly parallel execution. This thesis presents a concept for coupling spectral cloud microphysics models with atmospheric models that allows for efficient utilization of today\'s available parallelism in the order of 100.000 processor cores. Due to the strong workload variations, highly scalable dynamic load balancing of the cloud microphysics model is essential in order to reach this goal. This is achieved through a hierarchical partitioning method based on space-filling curves. Furthermore, a highly scalable connection of dynamic load balancing and model coupling is facilitated by an efficient method to regularly determine the intersections between different partitionings. The results of this thesis enable the application of spectral cloud microphysics models for the simulation of realistic scenarios with high resolution grids by efficient use of high performance computers

Dynamische Lastbalancierung und Modellkopplung zur hochskalierbaren Simulation von Wolkenprozessen

Die komplexen Interaktionen von Aerosolen, Wolken und Niederschlag werden in aktuellen Vorhersagemodellen nur ungenügend dargestellt. Simulationen mit spektraler Beschreibung von Wolkenprozessen können zu verbesserten Vorhersagen beitragen, sind jedoch weitaus rechenintensiver. Die Beschleunigung dieser Simulationen erfordert eine hochparallele Ausführung. In dieser Arbeit wird ein Konzept zur Kopplung spektraler Wolkenmikrophysikmodelle mit atmosphärischen Modellen entwickelt, das eine effiziente Nutzung der heute verfügbaren Parallelität der Größenordnung von 100.000 Prozessorkernen ermöglicht. Aufgrund des stark variierenden Rechenaufwands ist dafür eine hochskalierbare dynamische Lastbalancierung des Wolkenmikrophysikmodells unumgänglich. Dies wird durch ein hierarchisches Partitionierungsverfahren erreicht, das auf raumfüllenden Kurven basiert. Darüber hinaus wird eine hochskalierbare Verknüpfung von dynamischer Lastbalancierung und Modellkopplung durch ein effizientes Verfahren für die regelmäßige Bestimmung der Überschneidungen zwischen unterschiedlichen Partitionierungen ermöglicht. Durch die effiziente Nutzung von Hochleistungsrechnern ermöglichen die Ergebnisse der Arbeit die Anwendung spektraler Wolkenmikrophysikmodelle zur Simulation realistischer Szenarien auf hochaufgelösten Gittern.Current forecast models insufficiently represent the complex interactions of aerosols, clouds and precipitation. Simulations with spectral description of cloud processes allow more detailed forecasts. However, they are much more computationally expensive. Reducing the runtime of such simulations requires a highly parallel execution. This thesis presents a concept for coupling spectral cloud microphysics models with atmospheric models that allows for efficient utilization of today\'s available parallelism in the order of 100.000 processor cores. Due to the strong workload variations, highly scalable dynamic load balancing of the cloud microphysics model is essential in order to reach this goal. This is achieved through a hierarchical partitioning method based on space-filling curves. Furthermore, a highly scalable connection of dynamic load balancing and model coupling is facilitated by an efficient method to regularly determine the intersections between different partitionings. The results of this thesis enable the application of spectral cloud microphysics models for the simulation of realistic scenarios with high resolution grids by efficient use of high performance computers