Page Migration Research Articles

Estimation of the identity of proteolytic aggrecan fragments using PAGE migration and Western immunoblot

To develop calculation models, using Western immunoblot, as a tool for the estimation of proteolytic human aggrecan fragment identity. Seven human aggrecan fragments (calibrators), purified by CsCl gradient centrifugation and identified by Western immunoblot of N- and C-terminals, were used to develop calculation models. The models were used for identification of unknown aggrecan fragments each having one of their N- or C-terminals identified. The calibrator molecular weights (Mw) from sodium dodecyl sulfate (SDS)-gels (m), the Mw of amino acids (a) and the Mw of their carbohydrate substitution (g) were expressed as K = m/(a+g), or as K = 1.085m/(a+g) when compensation for the G1 domain was required. Using these models together with average K-values, 12 out of the 17 immuno-detected aggrecan fragments were calculated to a known protease cleavage site, while five were identified to domain levels. With six neoepitope antibodies together with antibodies against the G1- and G3-domain it was possible to predict the identity of several proteolytic fragments from different regions within the aggrecan monomer.

The analysis and characterisation of immuno-unreactive urinary albumin in healthy volunteers

Objectives: To compare the analysis of different forms of intact albumin in urine from healthy volunteers. To determine contamination by common non-albumin proteins on HPLC analysis of urinary albumin and of purified immuno-unreactive albumin. Design and methods: Overnight urine samples collected from healthy volunteers were analysed for total albumin (immunoreactive plus immuno-unreactive) by HPLC and densitometry following native PAGE separation and for immunoreactive albumin by RIA. The contamination by non-albumin proteins of the HPLC analysis of urinary albumin and of immuno-unreactive albumin preparations was determined by ELISA. Immuno-unreactive albumin was tested for Co 2+-binding capacity. Results and conclusions: HPLC analysis of healthy urine generates higher ACR values than immunological methods due to the presence of immuno-unreactive albumin. Immuno-unreactive albumin cannot be accounted for by the non-albumin urinary proteins tested. Isolated immuno-unreactive albumin is not recognised by antibodies to common urinary proteins or by an array of anti-albumin antibodies and behaves like serum albumin in terms of HPLC elution, native PAGE migration, and cobalt ion binding.

Moving address translation closer to memory in distributed shared-memory multiprocessors

To support a global virtual memory space, an architecture must translate virtual addresses dynamically. In current processors, the translation is done in a TLB (translation lookaside buffer), before or in parallel with the first-level cache access. As processor technology improves at a rapid pace and the working sets of new applications grow insatiably, the latency and bandwidth demands on the TLB are difficult to meet, especially in multiprocessor systems, which run larger applications and are plagued by the TLB consistency problem. We describe and compare five options for virtual address translation in the context of distributed shared memory (DSM) multiprocessors, including CC-NUMAs (cache-coherent non-uniform memory access architectures) and COMAs (cache only memory access architectures). In CC-NUMAs, moving the TLB to shared memory is a bad idea because page placement, migration, and replication are all constrained by the virtual page address, which greatly affects processor node access locality. In the context of COMAs, the allocation of pages to processor nodes is not as critical because memory blocks can dynamically migrate and replicate freely among nodes. As the address translation is done deeper in the memory hierarchy, the frequency of translations drops because of the filtering effect. We also observe that the TLB is very effective when it is merged with the shared-memory, because of the sharing and prefetching effects and because there is no need to maintain TLB consistency. Even if the effectiveness of the TLB merged with the shared memory is very high, we also show that the TLB can be removed in a system with address translation done in memory because the frequency of translations is very low.

Page Migration with Dynamic Space-Sharing Scheduling Policies: The Case of the SGI O2000

In this paper, we claim that memory migration mechanism is a useful approach to improve the execution of parallel applications in dynamic execution environments, but that their performance depends on related system components such as the processor scheduling. To show that, we evaluate the automatic memory migration mechanism provided by IRIX in Origin systems, under different dynamic processor allocation policies when executing OpenMP parallel multiprogrammed Workloads. We have focused the evaluation on the effects of the page migration mechanism on the CPU time consumed by each application, the processor allocation received, and the speedup. Results demonstrate that, if the processor scheduler is memory conscious, that is it maintains as much as possible the system stable, the automarie memory page migration mechanism provided by IRIX improves the CPU time consumed by OpenMP applications.

Cloning, expression, purification, and characterization of Nocardia sp. GTP cyclohydrolase I

The sequence of the gene from Nocardia sp. NRRL 5646 encoding GTP cyclohydrolase I (GCH), gch, and its adjacent regions was determined. The open reading frame of Nocardia gch contains 684 nucleotides, and the deduced amino acid sequence represents a protein of 227 amino acid residues with a calculated molecular mass of 24,563 Da. The uncommon start codon TTG was identified by matching the N-terminal amino acid sequence of purified Nocardia GCH with the deduced amino acid sequence. A likely ribosomal binding site was identified 9 bp upstream of the translational start site. The 3 ′ end flank region encodes a peptide that shares high homology with dihydropteroate synthases. Nocardia GCH has 73 and 60% identity to the proteins encoded by the putative gch of Mycobacterium tuberculosis and Streptomyces coelicolor, respectively. Nocardia GCH was highly expressed in Escherichia coli cells carrying a pHAT10 based expression vector, and moderately expressed in Mycobacterium smegmatis cells carrying a pSMT3 based expression vector. Enterokinase digestion of recombinant Nocardia GCH, and in-gel digestion of Nocardia GCH and recombinant GCH followed by MALDI-TOF-MS analysis, confirmed that the actual subunit size of the enzyme was 24.5 kDa. Thus, we conclude that the active form of native Nocardia GCH is a decamer. Our earlier incorrect conclusion was that the native enzyme was an octamer derived from the anomalous SDS–PAGE migration of the subunit.

Heat shock protein 72 binds and protects dihydrofolate reductase against oxidative injury

Although heat shock protein Hsp72 confers resistance to oxidative injury, the mechanisms are unknown. These studies demonstrate that Hsp72 protects dihydrofolate reductase (DHFR) against injury caused by the thiol oxidant monochloramine (NH 2Cl). When exposed to NH 2Cl, DHFR catalytic activity is impaired and SDS–PAGE migration retarded. These may be blocked by prior addition of Hsp72 or the folate analog methotrexate. Methotrexate binding to DHFR is diminished by oxidant treatment, preventable by prior Hsp72 incubation. Hsp72 also protects DHFR in IEC-18 cells following oxidant exposure. Hsp72 co-immunoprecipitates with DHFR, especially after partial oxidation. The DHFR–Hsp72 interaction is modulated by cofactor/substrate binding for both Hsp72 (ATP) and DHFR (methotrexate). Thiol oxidation of DHFR increases susceptibility for tryptic proteolysis. Preincubation of DHFR with Hsp72 prevents the NH 2Cl-induced sensitivity to proteolysis. Thus, Hsp72 binds DHFR through enhanced protein–chaperone interactions upon oxidant exposure, a process that may protect against irreversible modification of DHFR catalytic and structural integrity.

OpenMP versus MPI for PDE solvers based on regular sparse numerical operators

Two parallel programming models represented by OpenMP and MPI are compared for PDE solvers based on regular sparse numerical operators. As a typical representative of such an operator, a finite difference approximation of the Euler equations for fluid flow is considered. The comparison of programming models is made with regard to uniform memory access (UMA), non-uniform memory access (NUMA), and self-optimizing NUMA (NUMA-opt) computer architectures. By NUMA-opt, we mean NUMA systems extended with self-optimization algorithms, in order to reduce the non-uniformity of the memory access time. The main conclusions of the study are: (1) that OpenMP is a viable alternative to MPI on UMA and NUMA-opt architectures; (2) that OpenMP is not competitive on NUMA platforms, unless special care is taken to get an initial data placement that matches the algorithm; (3) that for OpenMP to be competitive in the NUMA-opt case, it is not necessary to extend the OpenMP model with additional data distribution directives, nor to include user-level access to the page migration library.

Quantifying contention and balancing memory load on hardware DSM multiprocessors

This paper makes the following contributions: It proposes a new methodology for quantifying remote memory access contention on hardware DSM multiprocessors. The most valuable aspect of this methodology is that it assesses the overhead of contention on real parallel programs running on real hardware. The methodology uses as input the number of accesses from each node of the DSM to each page in memory. A trace of the memory accesses of the program obtained at runtime is used to compute a fairly accurate estimate of the fraction of execution time wasted due to contention. The paper presents also a new algorithm which detects potential hot spots in pages and balances memory load using dynamic page migration. The algorithm attacks indirectly the problem of contention by balancing the remote memory access latency across the nodes of the system. Experiments with five irregular parallel codes on a 128-processor Origin2000 show that the algorithm yields significant performance improvements.

The NSWAP module for network swap

Swapping between nodes in a cluster of workstations to improve system performance has been discussed by several research papers in the recent past [2] [3]. Studies of workstation usage patterns show that most of the resources in a cluster of workstation are free most of the time even at peak workloads [1]. As a result, there will almost always be idle remote memory for an overloaded node to use as swap space. In addition, faster networks and slowly increasing disk speeds make swapping to remote memory an increasingly attractive option. We present a network swapping system called “nswap” implemented as a loadable kernel module for for the Linux kernel. nswap features a rapid response time even in the case of out of date information about remote hosts, a load balancing scheme through page migrations, and smooth fail-over to disk in case network swap space becomes scarce. The nswap module, conceptually divided into a pseudo-device driver client and a memory server, achieves these goal using a set of protocols described in the poster.

ARS: an adaptive runtime system for locality optimization

Shared memory programs running on Non-Uniform Memory Access (NUMA) machines usually face inherent performance problems stemming from excessive remote memory accesses. A solution, called the Adaptive Runtime System (ARS), is presented in this paper. ARS is designed to adjust the data distribution at runtime through automatic page migrations. It uses memory access histograms gathered by hardware monitors to find access hot spots and, based on this detection, to dynamically and transparently modify the data layout. In this way, incorrectly allocated data can be moved to the most appropriate node and hence data locality can be improved. Simulations show that this allows to achieve a performance gain of as high as 40%.

Scheduler-Activated Dynamic Page Migration for Multiprogrammed DSM Multiprocessors

The performance of multiprogrammed shared-memory multiprocessors suffers often from scheduler interventions that neglect data locality. On cache-coherent distributed shared-memory (DSM) multiprocessors, such scheduler interventions tend to increase the rate of remote memory accesses. This paper presents a novel dynamic page migration algorithm that remedies this problem in iterative parallel programs. The purpose of the algorithm is the early detection of pages that will most likely be accessed remotely by threads associated with them via a thread-to-memory affinity relation. The key mechanism that enables timely identification of these pages is a communication interface between the page migration engine and the operating system scheduler. The algorithm improves previously proposed competitive page migration algorithms in many aspects, including accuracy, timeliness and cost amortization. Most notably, the algorithm is not biased by obsolete memory access history that may be accumulated in the page access counters at runtime. Experiments on the SGI Origin2000 show that the algorithm outperforms by far the best static page placement algorithm and a customized page migration engine implemented in IRIX, the Origin2000 operating system. The algorithm is implemented at user-level and its functionality is orthogonal to the scheduling policy of the operating system.

Optimizing Traffic in DSM Clusters: Fine-Grain Memory Caching versus Page Migration/ Replication

In this paper we compare and contrast two techniques to improve capacity/conflict miss traffic in CC-NUMA DSM clusters. Page migration/replication optimizes read-write accesses to a page used by a single processor by migrating the page to that processor and replicates all read-shared pages in the sharers' local memories. R-NUMA optimizes read-write accesses to any page by allowing a processor to cache that page in its main memory. Page migration/replication requires less hardware complexity compared with R-NUMA, but has limited applicability and incurs much higher overheads even with tuned hardware/software support. In this paper we compare and contrast page migration/replication and R-NUMA on simulated clusters of symmetric multiprocessors executing shared-memory applications. Our results show that: (1) both page migration/replication and R-NUMA significantly improve the system performance over first-touch migration in many applications, (2) page migration/replication has limited opportunity and cannot eliminate all the capacity/conflict misses even with fast hardware support and unlimited amount of memory, (3) R-NUMA always performs best given a page cache large enough to fit an application's primary working set and subsumes page migration/replication, (4) R-NUMA benefits more from hardware support to accelerate page operations than page migration/replication, and (5) integrating page migration/replication into R-NUMA to help reduce the hardware cost requires sophisticated mechanisms and policies to select candidates for page migration/replication

On page migration and other relaxed task systems

This paper is concerned with the page migration (or file migration) problem (Black and Sleator, Technical Report CMU-CS-89-201, Department of Computer Science, Carnegie-Mellon University, 1989) as part of a large class of on-line problems. The page migration problem deals with the management of pages residing in a network of processors. In the classical problem there is only one copy of each page which is accessed by different processors over time. The page is allowed to be migrated between processors. However a migration incurs higher communication cost than an access (proportionally to the page size). The problem is that of deciding when and where to migrate the page in order to lower access costs. A more general setting is the k- page migration problem where we wish to maintain k copies of the page. The page migration problems are concerned with a dilemma common to many on-line problems: determining when it is beneficial to make configuration changes. We deal with the relaxed task systems model which captures a large class of problems of this type, that can be described as the generalization of some original task system problem (Borodin et al., J. ACM 39(4) (1992) 745–763). Given a c-competitive algorithm for a task system we show how to obtain a deterministic O(c 2) and randomized O(c) competitive algorithms for the corresponding relaxed task system. The result implies deterministic algorithms for k- page migration by using k-server (Manasse et al., J. Algorithms 11(2) (1990) 208–230) algorithms, and for network leasing by using generalized Steiner tree algorithms (Awerbuch et al., Proc 7th Ann. ACM-SIAM Symp. on Discrete Algorithms, January 1996, pp. 68–74), as well as providing solutions for natural generalizations of other problems (e.g. storage rearrangement (Fiat et al., Proc. 36th Ann. IEEE Symp. on Foundations of Computer Science, October 1995, pp. 392–403). We further study some special cases of the k-page migration problem and get optimal deterministic algorithms. For the classical page migration problem we present a deterministic algorithm that achieves a competitive ratio of ∼4.086, improving upon the previously best competitive ratio of 7 (Awerbuch et al., Proc. 25th ACM Symp. on Theory of Computing, May 1993, pp. 164–173). (The current lower bound on the problem is ∼3.148 (Chrobak et al., J. Algorithms 24(1) (1997) 124–157).)

Domain II of m-calpain is a Ca 2+-dependent cysteine protease

Calpain, a Ca 2+-dependent cytosolic cysteine protease, proteolytically modulates specific substrates involved in Ca 2+-mediated intracellular events, such as signal transduction, cell cycle, differentiation, and apoptosis. The 3D structure of m-calpain, in the absence of Ca 2+, revealed that the two subdomains (domains IIa and IIb) of the protease domain (II) have an ‘open’ conformation, probably due to interactions with other domains. Although the presence of an EF-hand structure was once predicted in the protease domain, no explicit Ca 2+-binding structure was identified in the 3D structure. Therefore, it is predicted that if the protease domain is excised from the calpain molecule, it will have a Ca 2+-independent protease activity. In this study, we have characterized a truncated human m-calpain that consists of only the protease domain. Unexpectedly, the proteolytic activity was Ca 2+-dependent, very weak, and not effectively inhibited by calpastatin, a calpain inhibitor. Ca 2+-dependent modification of the protease domain by the cysteine protease inhibitor, E-64c, was clearly observed as a SDS–PAGE migration change, indicating that the conformational changes of this domain are a result of Ca 2+ binding. These results suggest that the Ca 2+ binding to domain II, as well as to domains III, IV, and VI, is critical in the process of complete activation of calpain.

A Transparent Runtime Data Distribution Engine for OpenMP

This paper makes two important contributions. First, the paper investigates the performance implications of data placement in OpenMP programs running on modern NUMA multiprocessors. Data locality and minimization of the rate of remote memory accesses are critical for sustaining high performance on these systems. We show that due to the low remote‐to‐local memory access latency ratio of contemporary NUMA architectures, reasonably balanced page placement schemes, such as round‐robin or random distribution, incur modest performance losses. Second, the paper presents a transparent, user‐level page migration engine with an ability to gain back any performance loss that stems from suboptimal placement of pages in iterative OpenMP programs. The main body of the paper describes how our OpenMP runtime environment uses page migration for implementing implicit data distribution and redistribution schemes without programmer intervention. Our experimental results verify the effectiveness of the proposed framework and provide a proof of concept that it is not necessary to introduce data distribution directives in OpenMP and warrant the simplicity or the portability of the programming model.

Characterization of Sendai virus M protein mutants that can partially interfere with virus particle production

Substitution of Val(113) in Sendai virus (SeV) M protein generates non-functional polypeptides, characterized by their exclusion from virus particles and by their ability to interfere with virus particle production. These phenotypic traits correlate with a single-band PAGE migration profile, in contrast to wild-type M (M(wt )), which separates into two species, one of which is a phosphorylated form. The single-band migration is likely to result from a conformational change, as evidenced by the lack of maturation of a native epitope and by a particular tryptic digestion profile, and not from the phosphorylation of all M molecules, an assumption consistent with the PAGE migration feature. One of the M mutants (HA-M(30 ), an M protein carrying Thr(112)Met and Val(113) Glu substitutions tagged with an influenza virus haemagglutinin epitope) was characterized further in the context of SeV infection, i.e. under conditions of co-expression with M(wt). HA-M (30) is shown (i) to bind mainly to membrane fractions, (ii) not to co-precipitate M(wt), as HA-M(wt) does, (iii) to interfere with the binding of nucleocapsids to membranes and (iv) to accumulate in perinuclear regions, in contrast to HA-M(wt ), which is also found at the cell periphery. Such mutants constitute potential tools for the identification of critical steps in paramyxovirus assembly and budding.

PTP-SL and STEP protein tyrosine phosphatases regulate the activation of the extracellular signal-regulated kinases ERK1 and ERK2 by association through a kinase interaction motif.

Protein kinases and phosphatases regulate the activity of extracellular signal-regulated kinases 1 and 2 (ERK1/2) by controlling the phosphorylation of specific residues. We report the physical and functional association of ERK1/2 with the PTP-SL and STEP protein tyrosine phosphatases (PTPs). Upon binding, the N-terminal domains of PTP-SL and STEP were phosphorylated by ERK1/2, whereas these PTPs dephosphorylated the regulatory phosphotyrosine residues of ERK1/2 and inactivated them. A sequence of 16 amino acids in PTP-SL was identified as being critical for ERK1/2 binding and termed kinase interaction motif (KIM) (residues 224-239); it was shown to be required for phosphorylation of PTP-SL by ERK1/2 at Thr253. Co-expression of ERK2 with catalytically active PTP-SL in COS-7 cells impaired the EGF-induced activation of ERK2, whereas a PTP-SL mutant, lacking PTP activity, increased the ERK2 response to EGF. This effect was dependent on the presence of the KIM on PTP-SL. Furthermore, ERK1/2 activity was downregulated in 3T3 cells stably expressing PTP-SL. Our findings demonstrate the existence of a conserved ERK1/2 interaction motif within the cytosolic non-catalytic domains of PTP-SL and STEP, which is required for the regulation of ERK1/2 activity and for phosphorylation of the PTPs by these kinases. Our findings suggest that PTP-SL and STEP act as physiological regulators of the ERK1/2 signaling pathway.

Tropomyosin in Preimplantation Mouse Development: Identification, Expression, and Organization during Cell Division and Polarization

Tropomyosin is an actin-binding cytoskeletal protein which has been extensively characterized in a variety of cell types and tissues, with the exception of very early developmental stages during which cellular polarization first occurs. We have identified five polypeptides in mouse preimplantation conceptuses which show many of the characteristics of tropomyosin. They form the major portion of the heat-stable cytoskeletal protein fraction of blastomeres and have the characteristic isoelectric and SDS–PAGE migration characteristics on 1-D and 2-D gels. All five polypeptides were synthesized in late 2- and 4-cell, and all 8-cell stages, with three of the five polypeptides showing lower synthetic levels in fertilized eggs and early 2-cell conceptuses. These heat-stable proteins showed specific differences from proteins isolated from mouse 3T3 fibroblasts by the same method, namely higherMrisoforms were not represented, also some of the isoforms can be labeled by incorporation of [14C]proline. The cellular distribution of tropomyosin in early stage conceptuses was examined using monoclonal and affinity-purified polyclonal antibodies. Tropomyosin becomes associated both with the blastomere cortex postfertilization and with the cleavage furrow during cytokinesis. The interphase cortical association is uniform until the 8-cell stage, when tropomyosin becomes associated with the developing apical pole and is excluded from the basolateral cortex. This polar localization is inherited along with the pole at the 8- to 16-cell division, but experiments in which cell division is artificially prolonged show that tropomyosin localization does not represent a permanent marking of the pole. We conclude that the early mouse conceptus contains a unique and specific set of tropomyosins which respond to polarizing signals.

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Page Migration Algorithms Using Work Functions

The page migration problem occurs during management of a globally addressed shared memory in a multiprocessor system. Each physical page of memory is located at a given processor, and memory references to that page by other processors are charged a cost equal to the network distance. At times the page may migrate between processors, at a cost equal to the distance times a page size factor,D. The problem is to schedule movements online so as to minimize the total cost of memory references. Page migration can also be viewed as a restriction of the 1-server with excursions problem. This paper presents a collection of algorithms and lower bounds for the page migration problem in various settings. Competitive analysis is used. The competitiveness of an online algorithm is the worst case ratio of its cost to the optimum cost on any sequence of requests. Randomized (2+1/2D)-competitive online algorithms are given for trees and products of trees, including the mesh and the hypercube, and for uniform spaces whenD=1,2. These algorithms are shown to be optimal. A lower bound of8527on the competitiveness of any deterministic algorithm (in arbitrary spaces) withD=1 is shown, disproving a conjecture of Black and Sleator. Deterministic (2+1/2D)-competitive algorithms are given for products of continuous trees under the L1metric, such as Rnwith the Manhattan metric. A deterministic algorithm for Rnunder any norm is presented and is shown to have competitive ratio tending to 1+φ=2.618…. The paper makes extensive use of the concept of a work function, a tool which provides a systematic approach to many competitive analysis problems.