The next generation of High Energy Physics experiments are expected to generate exabytes of data---two orders of magnitude greater than the current generation. In order to reliably meet peak demands, ...facilities must either plan to provision enough resources to cover the forecasted need, or find ways to elastically expand their computational capabilities. Commercial cloud and allocation-based High Performance Computing (HPC) resources both have explicit and implicit costs that must be considered when deciding when to provision these resources, and to choose an appropriate scale. In order to support such provisioning in a manner consistent with organizational business rules and budget constraints, we have developed a modular intelligent decision support system (IDSS) to aid in the automatic provisioning of resources---spanning multiple cloud providers, multiple HPC centers, and grid computing federations.
Metachromatic leukodystrophy (MLD) and globoid cell leukodystrophy (GLD or Krabbe disease) are severe neurodegenerative lysosomal storage diseases (LSD) caused by arylsulfatase A (ARSA) and ...galactosylceramidase (GALC) deficiency, respectively. Our previous studies established lentiviral gene therapy (GT) as a rapid and effective intervention to provide pervasive supply of therapeutic lysosomal enzymes in CNS tissues of MLD and GLD mice. Here, we investigated whether this strategy is similarly effective in juvenile non‐human primates (NHP). To provide proof of principle for tolerability and biological efficacy of the strategy, we established a comprehensive study in normal NHP delivering a clinically relevant lentiviral vector encoding for the human ARSA transgene. Then, we injected a lentiviral vector coding for the human GALC transgene in Krabbe‐affected rhesus macaques, evaluating for the first time the therapeutic potential of lentiviral GT in this unique LSD model. We showed favorable safety profile and consistent pattern of LV transduction and enzyme biodistribution in the two models, supporting the robustness of the proposed GT platform. We documented moderate inflammation at the injection sites, mild immune response to vector particles in few treated animals, no indication of immune response against transgenic products, and no molecular evidence of insertional genotoxicity. Efficient gene transfer in neurons, astrocytes, and oligodendrocytes close to the injection sites resulted in robust production and extensive spreading of transgenic enzymes in the whole CNS and in CSF, leading to supraphysiological ARSA activity in normal NHP and close to physiological GALC activity in the Krabbe NHP, in which biological efficacy was associated with preliminary indication of therapeutic benefit. These results support the rationale for the clinical translation of intracerebral lentiviral GT to address CNS pathology in MLD, GLD, and other neurodegenerative LSD.
Synopsis
Report on the safety and efficacy of clinically relevant intracerebral gene therapy to deliver lysosomal enzymes in non‐human primates (NHP) and first evidence of efficacy in a Krabbe‐affected NHP recapitulating human globoid cell leukodystrophy.
Two intracerebral injections of low doses of therapeutic lentiviral vectors (LV.hARSA, LV.hGALC) performed in juvenile NHP (to mimic the potential treatment of infantile/early juvenile patients) were well tolerated, with undetectable immune response or genotoxicity related to LV integration.
Efficient gene transfer and transgene expression were observed in oligodendrocytes (in addition to neurons and astrocytes), which are hardly transduced by other vector types.
Stable and widespread supraphysiological and close to physiological enzymatic activities were measured in normal animals and in the Krabbe‐affected NHP, respectively.
Neurobehavioral assessment showed a progressive increase of motor scores in the LV.hGALC‐treated Krabbe NHP, with values close to the mean observed in normal animals at 3 months post‐gene therapy.
The extent of ARSA and GALC activity in CNS tissues post‐gene therapy is expected to provide benefit if achieved in human patients, since ≈ 10% of physiological enzymatic activity would ensure a normal phenotype.
Report on the safety and efficacy of clinically relevant intracerebral gene therapy to deliver lysosomal enzymes in non‐human primates (NHP) and first evidence of efficacy in a Krabbe‐affected NHP recapitulating human globoid cell leukodystrophy.
The higher energy and luminosity from the LHC in Run 2 have put increased pressure on CMS computing resources. Extrapolating to even higher luminosities (and thus higher event complexities and ...trigger rates) beyond Run 3, it becomes clear that simply scaling up the the current model of CMS computing alone will become economically unfeasible. High Performance Computing (HPC) facilities, widely used in scientific computing outside of HEP, have the potential to help fill the gap. Here we describe the U.S.CMS efforts to integrate US HPC resources into CMS Computing via the HEPCloud project at Fermilab. We present advancements in our ability to use NERSC resources at scale and efforts to integrate other HPC sites as well. We present experience in the elastic use of HPC resources, quickly scaling up use when so required by CMS workflows. We also present performance studies of the CMS multi-threaded framework on both Haswell and KNL HPC resources.
HEPCloud is rapidly becoming the primary system for provisioning compute resources for all Fermilab-affiliated experiments. In order to reliably meet the peak demands of the next generation of High ...Energy Physics experiments, Fermilab must plan to elastically expand its computational capabilities to cover the forecasted need. Commercial cloud and allocation-based High Performance Computing (HPC) resources both have explicit and implicit costs that must be considered when deciding when to provision these resources, and at which scale. In order to support such provisioning in a manner consistent with organizational business rules and budget constraints, we have developed a modular intelligent decision support system (IDSS) to aid in the automatic provisioning of resources spanning multiple cloud providers, multiple HPC centers, and grid computing federations. In this paper, we discuss the goals and architecture of the HEPCloud Facility, the architecture of the IDSS, and our early experience in using the IDSS for automated facility expansion both at Fermi and Brookhaven National Laboratory.
Scientific communities have been in the forefront of adopting new technologies and methodologies in the computing. Scientific computing has influenced how science is done today, achieving ...breakthroughs that were impossible to achieve several decades ago. For the past decade several such communities in the Open Science Grid (OSG) and the European Grid Infrastructure (EGI) have been using GlideinWMS to run complex application workflows to effectively share computational resources over the grid. GlideinWMS is a pilot-based workload management system (WMS) that creates on demand, a dynamically sized overlay HTCondor batch system on grid resources. At present, the computational resources shared over the grid are just adequate to sustain the computing needs. We envision that the complexity of the science driven by "Big Data" will further push the need for computational resources. To fulfill their increasing demands and/or to run specialized workflows, some of the big communities like CMS are investigating the use of cloud computing as Infrastructure-As-A-Service (IAAS) with GlideinWMS as a potential alternative to fill the void. Similarly, communities with no previous access to computing resources can use GlideinWMS to setup up a batch system on the cloud infrastructure. To enable this, the architecture of GlideinWMS has been extended to enable support for interfacing GlideinWMS with different Scientific and commercial cloud providers like HLT, FutureGrid, FermiCloud and Amazon EC2. In this paper, we describe a solution for cloud bursting with GlideinWMS. The paper describes the approach, architectural changes and lessons learned while enabling support for cloud infrastructures in GlideinWMS.
Context:
Mutations within the PROP1 gene represent one of the main causes of familial combined pituitary hormone deficiency (CPHD). However, most of the cases are sporadic with an unknown genetic ...cause.
Objective:
The aim of this study was the search for low penetrance variations within and around a conserved regulatory element in the intron 1 of PROP1, contributing to a multifactorial form of the disease in sporadic patients.
Methods and Patients:
A fragment of 570 bp encompassing the conserved region was sequenced in 107 CPHD patients and 294 controls, and an association study was performed with the four identified variants, namely c.109+435G>A (rs73346254), c.109+463C>T (rs4498267), c.109+768C>G (rs4431364), and c.109+915_917ins/delTAG (rs148607624). The functional role of the associated polymorphisms was evaluated by luciferase reporter gene expression analyses and EMSA.
Results:
A statistically significant increased frequency was observed in the patients for rs73346254A (P = 5 × 10−4) and rs148607624delTAG (P = 0.01) alleles. Among all the possible allele combinations, only the haplotype bearing both risk alleles showed a significantly higher frequency in the patients vs. controls (P = 4.7 × 10−4) and conferred a carrier risk of 4.19 (P = 1.2 × 10−4). This haplotype determined a significant decrease of the luciferase activity in comparison with a basal promoter and the other allelic combinations in GH4C and MCF7 cells (P = 4.6 × 10−6; P = 5.5 × 10−4, respectively). The EMSA showed a differential affinity for nuclear proteins for the alternative alleles of the two associated variations.
Conclusions:
Variations with a functional significance conferring susceptibility to CPHD have been identified in the PROP1 gene, indicating a multifactorial origin of this disorder in sporadic cases.
The Diverse use of Clouds by CMS Andronis, Anastasios; Bauer, Daniela; Chaze, Olivier ...
Journal of physics. Conference series,
12/2015, Volume:
664, Issue:
2
Journal Article
Peer reviewed
Open access
The resources CMS is using are increasingly being offered as clouds. In Run 2 of the LHC the majority of CMS CERN resources, both in Meyrin and at the Wigner Computing Centre, will be presented as ...cloud resources on which CMS will have to build its own infrastructure. This infrastructure will need to run all of the CMS workflows including: Tier 0, production and user analysis. In addition, the CMS High Level Trigger will provide a compute resource comparable in scale to the total offered by the CMS Tier 1 sites, when it is not running as part of the trigger system. During these periods a cloud infrastructure will be overlaid on this resource, making it accessible for general CMS use. Finally, CMS is starting to utilise cloud resources being offered by individual institutes and is gaining experience to facilitate the use of opportunistically available cloud resources. We present a snap shot of this infrastructure and its operation at the time of the CHEP2015 conference.
Background
: Mutations in the gene encoding the pituitary transcription factor POU1F1 (Pit-1, pituitary transcription factor-1) have been described in combined pituitary hormone deficiency (CPHD).
...Aim
: The aim of this study was the characterisation of the molecular defect causing CPHD in a patient born to consanguineous parents.
Subject and methods
: The case of a 12.5-yr-old girl presenting with severe growth failure at diagnosis (−3 SD score at 3 months) and deficiency of GH, PRL, and TSH was investigated for the presence of
POU1F1
gene mutations by denaturing high performance liquid chromatography analysis.
Results
: A novel mutation adjacent to the IVS2 splicing acceptor site (IVS2-3insA) was identified in the patient at the homozygous state. Analysis of patient’s lymphocyte mRNA and an
in vitro
splicing assay revealed the presence of 2 aberrant splicing products: a) deletion of the first 71 nucleotides of exon 3, altering the open reading frame and generating a premature stop codon, b) total exon 3 skipping resulting in an in frame deleted mRNA encoding a putative protein lacking part of the transactivation domain and of the POU-specific homeodomain. Notably, the patient’s relatives heterozygous for the mutation had PRL levels under the normal range with no evident clinical symptoms.
Conclusions
: The IVS2-3insA mutation, responsible for CPHD at the homozygous state, causes the presence of 2 aberrant splicing products encoding non-functional products. In the heterozygotes one normal allele might not guarantee a complete pituitary function.
The CMS High Level Trigger is a compute farm of more than 10,000 cores. During data taking this resource is heavily used and is an integral part of the experiment's triggering system. However, ...outside of data taking periods this resource is largely unused. We describe why CMS wants to use the HLT as a cloud resource (outside of data taking periods) and how this has been achieved. In doing this we have turned a single-use cluster into an agile resource for CMS production computing. While we are able to use the HLT as a production cloud resource, there is still considerable further work that CMS needs to carry out before this resource can be used with the desired agility. This report, therefore, represents a snapshot of this activity at the time of CHEP 2013.
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