Runtime support for load balancing of parallel adaptive and irregular applications

Applications critical to today\u27s engineering research often must make use of the increased memory and processing power of a parallel machine. While advances in architecture design are leading to more and more powerful parallel systems, the software tools needed to realize their full potential are in a much less advanced state. In particular, efficient, robust, and high-performance runtime support software is critical in the area of dynamic load balancing. While the load balancing of loosely synchronous codes, such as field solvers, has been studied extensively for the past 15 years, there exists a class of problems, known as asynchronous and highly adaptive , for which the dynamic load balancing problem remains open. as we discuss, characteristics of this class of problems render compile-time or static analysis of little benefit, and complicate the dynamic load balancing task immensely.;We make two contributions to this area of research. The first is the design and development of a runtime software toolkit, known as the Parallel Runtime Environment for Multi-computer Applications, or PREMA, which provides interprocessor communication, a global namespace, a framework for the implementation of customized scheduling policies, and several such policies which are prevalent in the load balancing literature. The PREMA system is designed to support coarse-grained domain decompositions with the goals of portability, flexibility, and maintainability in mind, so that developers will quickly feel comfortable incorporating it into existing codes and developing new codes which make use of its functionality. We demonstrate that the programming model and implementation are efficient and lead to the development of robust and high-performance applications.;Our second contribution is in the area of performance modeling. In order to make the most effective use of the PREMA runtime software, certain parameters governing its execution must be set off-line. Optimal values for these parameters may be determined through repeated executions of the target application; however, this is not always possible, particularly in large-scale environments and long-running applications. We present an analytic model that allows the user to quickly and inexpensively predict application performance and fine-tune applications built on the PREMA platform

Towards a multi-arm multi-stage platform trial of disease modifying approaches in Parkinson's disease

An increase in the efficiency of clinical trial conduct has been successfully demonstrated in the oncology field, by the use of multi-arm, multi-stage trials allowing the evaluation of multiple therapeutic candidates simultaneously, and seamless recruitment to Phase 3 for those candidates passing an interim signal of efficacy. Replicating this complex innovative trial design in diseases such as Parkinson's disease is appealing but in addition to the challenges associated with any trial assessing a single potentially disease modifying intervention in PD, a multi-arm platform trial must also specifically consider the heterogeneous nature of PD, alongside the desire to potentially test multiple treatments with different mechanisms of action. In a multi-arm trial, there is a need to appropriately stratify treatment arms to ensure each are comparable with a shared placebo/standard of care arm, however in PD there may be a preference to enrich an arm with a subgroup of patients that may be most likely to respond to a specific treatment approach. The solution to this conundrum lies in having clearly defined criteria for inclusion in each treatment arm as well as an analysis plan that takes account of pre-defined subgroups of interest, alongside evaluating the impact of each treatment on the broader population of PD patients. Beyond this, there must be robust processes of treatment selection, and consensus derived measures to confirm target engagement and interim assessments of efficacy, as well as consideration of the infrastructure needed to support recruitment, and the long-term funding and sustainability of the platform. This has to incorporate the diverse priorities of clinicians, triallists, regulatory authorities and above all the views of people with Parkinson's disease

Secondary somatic mutations restoring RAD51C and RAD51D associated with acquired resistance to the PARP inhibitor rucaparib in high-grade ovarian carcinoma

High-grade epithelial ovarian carcinomas (OC) containing mutated BRCA1 or BRCA2 (BRCA1/2) homologous recombination (HR) genes are sensitive to platinum-based chemotherapy and poly(ADP-ribose) polymerase inhibitors (PARPi), while restoration of HR function due to secondary mutations in BRCA1/2 has been recognized as an important resistance mechanism. We sequenced core HR pathway genes in 12 pairs of pre-treatment and post-progression tumor biopsy samples collected from patients in ARIEL2 Part 1, a phase 2 study of the PARPi rucaparib as treatment for platinum-sensitive, relapsed OC. In six of 12 pre-treatment biopsies, a truncation mutation in BRCA1, RAD51C or RAD51D was identified. In five of six paired post-progression biopsies, one or more secondary mutations restored the open reading frame. Four distinct secondary mutations and spatial heterogeneity were observed for RAD51C. In vitro complementation assays and a patient-derived xenograft (PDX), as well as predictive molecular modeling, confirmed that resistance to rucaparib was associated with secondary mutations

Canonical Wnt signals combined with suppressed TGFβ/BMP pathways promote renewal of the native human colonic epithelium

Background: A defining characteristic of the human intestinal epithelium is that it is the most rapidly renewing tissue in the body. However, the processes underlying tissue renewal and the mechanisms that govern their coordination have proved difficult to study in the human gut. Objective: To investigate the regulation of stem cell-driven tissue renewal by canonical Wnt and TGFβ/bone morphogenetic protein (BMP) pathways in the native human colonic epithelium. Design: Intact human colonic crypts were isolated from mucosal tissue samples and placed into 3D culture conditions optimised for steady-state tissue renewal. High affinity mRNA in situ hybridisation and immunohistochemistry were complemented by functional genomic and bioimaging techniques. The effects of signalling pathway modulators on the status of intestinal stem cell biology, crypt cell proliferation, migration, differentiation and shedding were determined. Results: Native human colonic crypts exhibited distinct activation profiles for canonical Wnt, TGFβ and BMP pathways. A population of intestinal LGR5/OLFM4-positive stem/progenitor cells were interspersed between goblet-like cells within the crypt-base. Exogenous and crypt cell-autonomous canonical Wnt signals supported homeostatic intestinal stem/progenitor cell proliferation and were antagonised by TGFβ or BMP pathway activation. Reduced Wnt stimulation impeded crypt cell proliferation, but crypt cell migration and shedding from the crypt surface were unaffected and resulted in diminished crypts. Conclusions: Steady-state tissue renewal in the native human colonic epithelium is dependent on canonical Wnt signals combined with suppressed TGFβ/BMP pathways. Stem/progenitor cell proliferation is uncoupled from crypt cell migration and shedding, and is required to constantly replenish the crypt cell population

The biguanide polyamine analog verlindamycin promotes differentiation in neuroblastoma via induction of antizyme

Deregulated polyamine biosynthesis is emerging as a common feature of neuroblastoma and drugs targeting this metabolic pathway such as DFMO are in clinical and preclinical development. The polyamine analog verlindamycin inhibits the polyamine biosynthesis pathway enzymes SMOX and PAOX, as well as the histone demethylase LSD1. Based on our previous research in acute myeloid leukemia (AML), we reasoned verlindamycin may also unblock neuroblastoma differentiation when combined with all-trans-retinoic acid (ATRA). Indeed, co-treatment with verlindamycin and ATRA strongly induced differentiation regardless of MYCN status, but in MYCN-expressing cells, protein levels were strongly diminished. This process was not transcriptionally regulated but was due to increased degradation of MYCN protein, at least in part via ubiquitin-independent, proteasome-dependent destruction. Here we report that verlindamycin effectively induces the expression of functional tumor suppressor—antizyme via ribosomal frameshifting. Consistent with previous results describing the function of antizyme, we found that verlindamycin treatment led to the selective targeting of ornithine decarboxylase (the rate-limiting enzyme for polyamine biosynthesis) as well as key oncoproteins, such as cyclin D and Aurora A kinase. Retinoid-based multimodal differentiation therapy is one of the few interventions that extends relapse-free survival in MYCN-associated high-risk neuroblastoma and these results point toward the potential use of verlindamycin in this regimen.Output Status: Forthcoming/Available Onlin

The Long-Baseline Neutrino Experiment: Exploring Fundamental Symmetries of the Universe

The preponderance of matter over antimatter in the early Universe, the dynamics of the supernova bursts that produced the heavy elements necessary for life and whether protons eventually decay --- these mysteries at the forefront of particle physics and astrophysics are key to understanding the early evolution of our Universe, its current state and its eventual fate. The Long-Baseline Neutrino Experiment (LBNE) represents an extensively developed plan for a world-class experiment dedicated to addressing these questions. LBNE is conceived around three central components: (1) a new, high-intensity neutrino source generated from a megawatt-class proton accelerator at Fermi National Accelerator Laboratory, (2) a near neutrino detector just downstream of the source, and (3) a massive liquid argon time-projection chamber deployed as a far detector deep underground at the Sanford Underground Research Facility. This facility, located at the site of the former Homestake Mine in Lead, South Dakota, is approximately 1,300 km from the neutrino source at Fermilab -- a distance (baseline) that delivers optimal sensitivity to neutrino charge-parity symmetry violation and mass ordering effects. This ambitious yet cost-effective design incorporates scalability and flexibility and can accommodate a variety of upgrades and contributions. With its exceptional combination of experimental configuration, technical capabilities, and potential for transformative discoveries, LBNE promises to be a vital facility for the field of particle physics worldwide, providing physicists from around the globe with opportunities to collaborate in a twenty to thirty year program of exciting science. In this document we provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess.Comment: Major update of previous version. This is the reference document for LBNE science program and current status. Chapters 1, 3, and 9 provide a comprehensive overview of LBNE's scientific objectives, its place in the landscape of neutrino physics worldwide, the technologies it will incorporate and the capabilities it will possess. 288 pages, 116 figure

A broadly implementable research course in phage discovery and genomics for first-year undergraduate students

Engaging large numbers of undergraduates in authentic scientific discovery is desirable but difficult to achieve. We have developed a general model in which faculty and teaching assistants from diverse academic institutions are trained to teach a research course for first-year undergraduate students focused on bacteriophage discovery and genomics. The course is situated within a broader scientific context aimed at understanding viral diversity, such that faculty and students are collaborators with established researchers in the field. The Howard Hughes Medical Institute (HHMI) Science Education Alliance Phage Hunters Advancing Genomics and Evolutionary Science (SEA-PHAGES) course has been widely implemented and has been taken by over 4,800 students at 73 institutions. We show here that this alliance-sourced model not only substantially advances the field of phage genomics but also stimulates students\u27 interest in science, positively influences academic achievement, and enhances persistence in science, technology, engineering, and mathematics (STEM) disciplines. Broad application of this model by integrating other research areas with large numbers of early-career undergraduate students has the potential to be transformative in science education and research training

Izu-Bonin-Mariana Rear Arc: The Missing Half of the Subduction Factory

4GT) lies in the western part of the Izu fore-arc basin, ~60 km east of the arc-front volcano Aogashima, ~170 km west of the axis of the Izu-Bonin Trench, 1.5 km west of Ocean Drilling Program (ODP) Site 792, and at 1776 meters below sea level (mbsl). It was drilled as a 150 m deep geotechnical test hole for potential future deep drilling (5500 meters below seafloor [mbsf]) at proposed Site IBM-4 using the D/V Chikyu. Core from Site U1436 yielded a rich record of Late Pleistocene explosive volcanism, including distinctive black glassy mafic ash layers that may record large-volume eruptions on the Izu arc front. Because of the importance of this discovery, Site U1436 was drilled in three additional holes (U1436B, U1436C, and U1436D), as part of a contingency operation, in an attempt to get better recovery on the black glassy mafic ash layers and enclosing sediments and to better constrain the thickness of the mafic ash layers. IODP Site U1437 is located in the Izu rear arc, ~330 km west of the axis of the IzuBonin Trench and ~90 km west of the arc-front volcanoes Myojinsho and Myojin Knoll, at 2117 mbsl. The primary scientific objective for Site U1437 was to characterize “the missing half of the subduction factory”; this was because numerous ODP/Integrated Ocean Drilling Program sites had been drilled in the arc to fore-arc region (i.e., ODP Site 782A Leg 126), but this was the first site to be drilled in the rear part of the Izu arc. A complete view of the arc system is needed to understand the formation of oceanic arc crust and its evolution into continental crust. Site U1437 on the rear arc had excellent core recovery in Holes U1437B and U1437D, and we succeeded in hanging the longest casing ever in the history of R/V JOIDES Resolution scientific drilling (1085.6 m) in Hole U1437E and cored to 1806.5 mbsf