Adaptive Precision Block-Jacobi for High Performance Preconditioning in the Ginkgo Linear Algebra Software

© ACM, 2021. This is the author's version of the work. It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version was published in ACM Transactions on Mathematical Software, Volume 47, Issue , June 2021, http://doi.acm.org/10.1145/3441850[EN] The use of mixed precision in numerical algorithms is a promising strategy for accelerating scientific applications. In particular, the adoption of specialized hardware and data formats for low-precision arithmetic in high-end GPUs (graphics processing units) has motivated numerous efforts aiming at carefully reducing the working precision in order to speed up the computations. For algorithms whose performance is bound by the memory bandwidth, the idea of compressing its data before (and after) memory accesses has received considerable attention. One idea is to store an approximate operator-like a preconditioner-in lower than working precision hopefully without impacting the algorithm output. We realize the first high-performance implementation of an adaptive precision block-Jacobi preconditioner which selects the precision format used to store the preconditioner data on-the-fly, taking into account the numerical properties of the individual preconditioner blocks. We implement the adaptive block-Jacobi preconditioner as production-ready functionality in the Ginkgo linear algebra library, considering not only the precision formats that are part of the IEEE standard, but also customized formats which optimize the length of the exponent and significand to the characteristics of the preconditioner blocks. Experiments run on a state-of-the-art GPU accelerator show that our implementation offers attractive runtime savings.H. Anzt and T. Cojean were supported by the "Impuls und Vernetzungsfond of the Helmholtz Association" under grant VH-NG-1241. G. Flegar and E. S. Quintana-Orti were supported by project TIN2017-82972-R of the MINECO and FEDER and the H2020 EU FETHPC Project 732631 "OPRECOMP". This research was supported by the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the U.S. Department of Energy Office of Science and the National Nuclear Security Administration. The authors want to acknowledge the access to the Piz Daint supercomputer at the Swiss National Supercomputing Centre (CSCS) granted under the project #d100 and the Summit supercomputer at the Oak Ridge National Lab (ORNL).Flegar, G.; Anzt, H.; Cojean, T.; Quintana-Ortí, ES. (2021). Adaptive Precision Block-Jacobi for High Performance Preconditioning in the Ginkgo Linear Algebra Software. ACM Transactions on Mathematical Software. 47(2):1-28. https://doi.org/10.1145/3441850S12847

Acceleration of PageRank with customized precision based on mantissa segmentation

[EN] We describe the application of a communication-reduction technique for the PageRank algorithm that dynamically adapts the precision of the data access to the numerical requirements of the algorithm as the iteration converges. Our variable-precision strategy, using a customized precision format based on mantissa segmentation (CPMS), abandons the IEEE 754 single- and double-precision number representation formats employed in the standard implementation of PageRank, and instead handles the data in memory using a customized floating-point format. The customized format enables fast data access in different accuracy, prevents overflow/underflow by preserving the IEEE 754 double-precision exponent, and efficiently avoids data duplication, since all bits of the original IEEE 754 double-precision mantissa are preserved in memory, but re-organized for efficient reduced precision access. With this approach, the truncated values (omitting significand bits), as well as the original IEEE double-precision values, can be retrieved without duplicating the data in different formats. Our numerical experiments on an NVIDIA V100 GPU (Volta architecture) and a server equipped with two Intel Xeon Platinum 8168 CPUs (48 cores in total) expose that, compared with a standard ieee double-precision implementation, the CPMS-based PageRank completes about 10% faster if high-accuracy output is needed, and about 30% faster if reduced output accuracy is acceptable.H. Anzt was supported by the "Impuls und Vernetzungsfond" of the Helmholtz Association under grant VH-NG-1241. G. Flegar and E. S. Quintana-Orti were supported by project TIN2017-82972-R of the MINECO and FEDER. This work was also supported by the EU H2020 project 732631 "OPRECOMP. Open Transprecision Computing,' and the US Department of Energy Office of Science, Office of Advanced Scientific Computing Research, Applied Mathematics program under Award Numbers DE-SC0016513 and DE-SC-0010042Gruetzmacher, T.; Cojean, T.; Flegar, G.; Anzt, H.; Quintana-Orti, ES. (2020). Acceleration of PageRank with customized precision based on mantissa segmentation. ACM Transactions on Parallel Computing. 7(1):1-19. https://doi.org/10.1145/3380934S1197

HYDROGEOBAT : Impacts géologiques et géotechniques des mouvements de nappes phréatiques sur le bâti: analyse, mesure, simulation, prévention. Rapport final

285 p.En contexte de plaine alluviale, l'hydrodynamique des nappes d'eau souterraines joue un rôle important dans le processus d'inondation. De plus, dans un environnement urbain, les conditions d'occupation du sous-sol : parkings souterrains, galeries diverses, etc. modifient considérablement les conditions d'écoulement, constituant généralement des obstacles. Le principal objectif du projet HYDROGEOBAT a été l'analyse des divers impacts géotechniques sur les constructions (fondations de bâtiments et ouvrages souterrains) qui résultent de fluctuations des niveaux piézométriques, spécialement en contexte d'inondation. Les applications réalisées concernent la ville de Paris. La méthodologie mise en oeuvre, de caractère transdisciplinaire, peut être décrite en cinq étapes. Dans une première étape, une synthèse portant sur les différents processus impliqués dans les interactions entre eaux souterraines et ouvrages a été réalisée. Les processus sont, par exemple, les impacts des fluctuations de niveaux piézométriques sur les caractéristiques physico-chimiques, hydro-mécaniques et géotechniques des sols, la modification de la stabilité interne de matériaux granulaires soumis aux forces d'écoulement, le gonflement ou le retrait de sols argileux, la réactivation de fontis, etc. Dans une deuxième étape, on a choisi un ensemble de situations types dans Paris, avec des contextes variés sur le plan géologique et hydrogéologique, et sur le type de structures souterraines, leurs positions par rapport à la Seine et leurs interactions avec les eaux souterraines. Puis, dans une troisième étape, des simulations numériques hydrogéologiques variées, prenant en compte diverses conditions hydrauliques aux limites, différents scénarios de crue, différentes positions de structures souterraines, ont été réalisées grâce à plusieurs types d'outils de modélisation. L'objectif a été d'analyser les réponses de systèmes hydrogéologiques (incluant les modifications anthropiques des aquifères, telles que des obstacles représentés par des structures linéaires : galeries et tunnels) à différentes sollicitations hydrauliques associées à des contextes de crue. Des analyses paramétriques ont permis de souligner le rôle des conditions aux limites, l'influence des aménagements souterrains, les interactions entre le contexte géologique originel et les modifications apportées par l'homme. Les résultats des approches hydrogéologiques ont été utilisés pour les simulations géomécaniques dans une quatrième étape. Ces simulations numériques ont permis d'illustrer les conséquences sur le plan mécanique des fluctuations de niveaux piézométriques dans un environnement urbain, en contexte de crue. Puis, dans une cinquième étape, les analyses et mesures d'impacts passés sur les constructions, en rapport avec des situations de crue, ont été étudiés grâce aux techniques interférométriques radar. Les faibles déplacements de surface ont été mesurés par l'interférométrie différentielle radar satellitaire DinSar et l'interférométrie PSI (Persistent Scatterer Interferometry). Pour cette application, des images SAR d'archive sélectionnées pour différentes dates depuis 1992 ont été utilisées, mais la technique PSI est apparue la plus intéressante compte tenu de la présence de nombreux réflecteurs radar en milieu urbain. Les données hydrogéologiques fournies par IGC-Ville-de-Paris ont été utilisées pour l'analyse des différents résultats obtenus soit par les simulations numériques, soit par les techniques interférométriques. Finalement, le projet HYDROGEOBAT a permis d'étudier plusieurs facettes du sujet, très ouvert, concernant les impacts des mouvements de nappes phréatiques sur le bâti. Les rôles et les limites de la modélisation ont été précisés au travers de différentes approches. Le champ d'application des techniques interférométriques (méthode PSI) pour les mesures des faibles déplacements a été cerné. Quelques difficultés qu'il convient de surmonter doivent être soulignées : 1) un réseau piézométrique de qualité, renforcé par rapport à l'actuel, est nécessaire à Paris et en banlieue ; 2) une base de données relative aux éléments naturels et artificiels constituant le sous-sol de Paris doit être élaborée sous SIG ; 3) un modèle hydrogéologique de Paris et sa banlieue, plus élaboré, est nécessaire ; 4) de nouveaux instruments satellitaires bientôt disponibles devraient permettre d'améliorer notre analyse des faibles déplacements au sol, en rapport spécialement avec les mouvements de nappe phréatique. Ainsi, le projet HYDROGEOBAT a permis d'apporter une contribution aux objectifs annoncés et d'améliorer de ce fait nos techniques de prévention concernant le risque d'inondation. L'approche pluridisciplinaire a permis de renforcer le savoir-faire des équipes concernées qui prévoient de poursuivre cette coopération

Ginkgo: A Modern Linear Operator Algebra Framework for High Performance Computing

© ACM, YYYY. This is the author's version of the work "Anzt, H., Cojean, T., Flegar, G., Göbel, F., Grützmacher, T., Nayak, P., ... & Quintana-Ortí, E. S. (2022). Ginkgo: A modern linear operator algebra framework for high performance computing. ACM Transactions on Mathematical Software (TOMS), 48(1), 1-33". It is posted here by permission of ACM for your personal use. Not for redistribution. The definitive version was published in ACM Transactions on Mathematical Software, {VOL48, ISS 1, (MAR 2022)} http://doi.acm.org/10.1145/3480935"[EN] In this article, we present GINKGO, a modern C++ math library for scientific high performance computing. While classical linear algebra libraries act on matrix and vector objects, Gnswo's design principle abstracts all functionality as linear operators," motivating the notation of a "linear operator algebra library" GINKGO'S current focus is oriented toward providing sparse linear algebra functionality for high performance graphics processing unit (GPU) architectures, but given the library design, this focus can be easily extended to accommodate other algorithms and hardware architectures. We introduce this sophisticated software architecture that separates core algorithms from architecture-specific backends and provide details on extensibility and sustainability measures. We also demonstrate GINKGO'S usability by providing examples on how to use its functionality inside the MFEM and deal.ii finite element ecosystems. Finally, we offer a practical demonstration of GINKGO'S high performance on state-of-the-art GPU architectures.This work was supported by the "Impuls und Vernetzungsfond of the Helmholtz Association" under grant VH-NG-1241. G. Flegar and E. S. Quintana-Orti were supported by project TIN2017-82972-R of the MINECO and FEDER and the H2020 EU FETHPC Project 732631 "OPRECOMP". This researchwas also supported by the Exascale Computing Project (17-SC-20-SC), a collaborative effort of the U.S. Department of Energy Office of Science and the National Nuclear Security Administration. The experiments on the NVIDIA A100 GPU were performed on the HAICORE@KIT partition, funded by the "Impuls und Vernetzungsfond" of the Helmholtz Association. The experiments on the AMD MI100 GPU were performed on Tulip, an early-access platform hosted by HPE.Anzt, H.; Cojean, T.; Flegar, G.; Göbel, F.; Grützmacher, T.; Nayak, P.; Ribizel, T.... (2022). Ginkgo: A Modern Linear Operator Algebra Framework for High Performance Computing. ACM Transactions on Mathematical Software. 48(1):1-33. https://doi.org/10.1145/348093513348

In Silico Mining for Antimalarial Structure-Activity Knowledge and Discovery of Novel Antimalarial Curcuminoids.

Malaria is a parasitic tropical disease that kills around 600,000 patients every year. The emergence of resistant Plasmodium falciparum parasites to artemisinin-based combination therapies (ACTs) represents a significant public health threat, indicating the urgent need for new effective compounds to reverse ACT resistance and cure the disease. For this, extensive curation and homogenization of experimental anti-Plasmodium screening data from both in-house and ChEMBL sources were conducted. As a result, a coherent strategy was established that allowed compiling coherent training sets that associate compound structures to the respective antimalarial activity measurements. Seventeen of these training sets led to the successful generation of classification models discriminating whether a compound has a significant probability to be active under the specific conditions of the antimalarial test associated with each set. These models were used in consensus prediction of the most likely active from a series of curcuminoids available in-house. Positive predictions together with a few predicted as inactive were then submitted to experimental in vitro antimalarial testing. A large majority from predicted compounds showed antimalarial activity, but not those predicted as inactive, thus experimentally validating the in silico screening approach. The herein proposed consensus machine learning approach showed its potential to reduce the cost and duration of antimalarial drug discovery

A TLR9-adjuvanted vaccine formulated into dissolvable microneedle patches or cationic liposomes protects against leishmaniasis after skin or subcutaneous immunization

Re-emergence and geographic expansion of leishmaniasis is accelerating efforts to develop a safe and effective Leshmania vaccine. Vaccines using Leishmania recombinant antigens, such as LiHyp1, which is mostly present in the amastigote parasite form, are being developed as a next generation to crude killed parasite-based vaccines. The main objective of this work was to develop a LiHyp1-based vaccine and determine if it can induce protective immunity in BALB/c mice when administered using a dissolvable microneedle (DMN) patch by the skin route. The LiHyp1 antigen was incorporated into cationic liposomes (CL), with or without the TLR9 agonist, CpG. The LiHyp1-liposomal vaccines were characterized with respect to size, protein encapsulation rates and retention of their physical characteristics after incorporation into the DMN patch. DMN mechanical strength and skin penetration ability were tested. A vaccine composed of LiHyp1, CpG and liposomes and subcutaneously injected or a vaccine containing antigen and CpG in DMN patches, without liposomes, induced high antibody responses and significant levels of protection against L. donovani parasite infection. This study progresses the development of an efficacious leishmania vaccine by detailing promising vaccine formulations and skin delivery technologies and it addresses protective efficacy of a liposome-based dissolvable microneedle patch vaccine system

Phase II study of gemcitabine and vindesine in patients with previously untreated non-resectable non-small-cell lung cancer

Because both vindesine and gemcitabine are active drugs in advanced non-small-cell lung cancer (NSCLC), with different modes of action and only partly overlapping toxicity, a phase II study was performed. Gemcitabine 1000 mg m−2 was given on days 1, 8 and 15 every 4 weeks, while vindesine 3 mg m−2 was administered weekly for 7 weeks, then every 2 weeks. A total of 42 patients with nonresectable NSCLC were included. The median age of patients was 56 years; 57% were men, 52% had adenocarcinoma, 31% squamous cell carcinoma and 17% had large-cell carcinoma. The performance status ranged from 0 to 2 with 83% in performance status 1. The majority (55%) had stage IV disease, while 40% had stage III B and 5% stage III A disease. WHO grade 3–4 leucopenia occurred in five patients (12%) and 9% had grade 4 neutropenia. Thrombocytopenia grade 3–4 was observed in six patients (15%). There were no septic death or bleeding episodes. One patient had a transient WHO grade 4 increase in bilirubin, and four patients had a decrease in glomerular filtration rate below the normal limit; one of these patients developed a non-reversible renal insufficiency. Ten patients (24%) complained of dyspnoea of uncertain mechanism, possibly involving bronchoconstriction. There were one complete and seven partial responses among 40 assessable patients (20%, 95% confidence limits 9–36%). Median response duration was 31 weeks (range 11–83 weeks) and median survival time 31 weeks (range 2–171 weeks). The current combination of gemcitabine and vindesine does not appear to be promising for further examination because of the toxicity and somewhat disappointing activity. © 1999 Cancer Research Campaig

Using a Non-Image-Based Medium-Throughput Assay for Screening Compounds Targeting N-myristoylation in Intracellular Leishmania Amastigotes

We have refined a medium-throughput assay to screen hit compounds for activity against N-myristoylation in intracellular amastigotes of Leishmania donovani. Using clinically-relevant stages of wild type parasites and an Alamar blue-based detection method, parasite survival following drug treatment of infected macrophages is monitored after macrophage lysis and transformation of freed amastigotes into replicative extracellular promastigotes. The latter transformation step is essential to amplify the signal for determination of parasite burden, a factor dependent on equivalent proliferation rate between samples. Validation of the assay has been achieved using the anti-leishmanial gold standard drugs, amphotericin B and miltefosine, with EC50 values correlating well with published values. This assay has been used, in parallel with enzyme activity data and direct assay on isolated extracellular amastigotes, to test lead-like and hit-like inhibitors of Leishmania Nmyristoyl transferase (NMT). These were derived both from validated in vivo inhibitors of Trypanosoma brucei NMT and a recent high-throughput screen against L. donovani NMT. Despite being a potent inhibitor of L. donovani NMT, the activity of the lead T. brucei NMT inhibitor (DDD85646) against L. donovani amastigotes is relatively poor. Encouragingly, analogues of DDD85646 show improved translation of enzyme to cellular activity. In testing the high-throughput L. donovani hits, we observed macrophage cytotoxicity with compounds from two of the four NMT-selective series identified, while all four series displayed low enzyme to cellular translation, also seen here with the T. brucei NMT inhibitors. Improvements in potency and physicochemical properties will be required to deliver attractive lead-like Leishmania NMT inhibitors

Molecular markers of anti-malarial drug resistance in Central, West and East African children with severe malaria.

BACKGROUND: The Plasmodium falciparum multidrug resistance 1 (PfMDR1), P. falciparum Ca(2+)-ATPase (PfATP6) and Kelch-13 propeller domain (PfK13) loci are molecular markers of parasite susceptibility to anti-malarial drugs. Their frequency distributions were determined in the isolates collected from children with severe malaria originating from three African countries. METHODS: Samples from 287 children with severe malaria [(Gabon: n = 114); (Ghana: n = 89); (Kenya: n = 84)] were genotyped for pfmdr1, pfatp6 and pfk13 loci by DNA sequencing and assessing pfmdr1 copy number variation (CNV) by real-time PCR. RESULTS: Pfmdr1-N86Y mutation was detected in 48, 10 and 10% in Lambaréné, Kumasi and Kisumu, respectively. At codon 184, the prevalence of the mutation was 73% in Lambaréné, 63% in Kumasi and 49% Kisumu. The S1034C and N1042D variants were absent at all three sites, while the frequency of the D1246Y mutation was 1, 3 and 13% in Lambaréné, Kumasi and Kisumu, respectively. Isolates with two pfmdr1 gene copy number predominantly harboured the N86Y wild-type allele and were mostly found in Kumasi (10%) (P < 0.0001). Among the main pfmdr1 haplotypes (NFD, NYD and YFD), NYD was associated with highest parasitaemia (P = 0.04). At the pfatp6 locus, H243Y and A623E mutations were observed at very low frequency at all three sites. The prevalence of the pfatp6 E431K variant was 6, 18 and 17% in Lambaréné, Kumasi and Kisumu, respectively. The L263E and S769N mutations were absent in all isolates. The pfk13 variants associated with artemisinin resistance in Southeast Asia were not observed. Eleven novel substitutions in the pfk13 locus occurring at low frequency were observed. CONCLUSIONS: Artemisinins are still highly efficacious in large malaria-endemic regions though declining efficacy has occurred in Southeast Asia. The return of chloroquine-sensitive strains following the removal of drug pressure is observed. However, selection of wild-type alleles in the multidrug-resistance gene and the increased gene copy number is associated with reduced lumefantrine sensitivity. This study indicates a need to constantly monitor drug resistance to artemisinin in field isolates from malaria-endemic countries