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At least 37 records · Page 2
All sourcesNASA NTRSDOE OSTI
NASA NTRS2000

Homologous recombination as a potential target for caffeine radiosensitization in mammalian cells: reduced caffeine radiosensitization in XRCC2 and XRCC3 mutants

The radiosensitizing effect of caffeine has been associated with the disruption of multiple DNA damage-responsive cell cycle checkpoints, but several lines of evidence also implicate inhibition of DNA repair. The role of DNA repair inhibition in caffeine radiosensitization remains uncharacterized, and it is unknown which repair process, or lesion, is affected. We show that a radiosensitive cell line, mutant for the RAD51 homolog XRCC2 and defective in homologous recombination repair (HRR), displays significantly diminished caffeine radiosensitization that can be restored by expression of XRCC2. Despite the reduced radiosensitization, caffeine effectively abrogates checkpoints in S and G2 phases in XRCC2 mutant cells indicating that checkpoint abrogation is not sufficient for radiosensitization. Another radiosensitive line, mutant for XRCC3 and defective in HRR, similarly shows reduced caffeine radiosensitization. On the other hand, a radiosensitive mutant (irs-20) of DNA-PKcs with a defect in non-homologous end-joining (NHEJ) is radiosensitized by caffeine to an extent comparable to wild-type cells. In addition, rejoining of radiation-induced DNA DSBs, that mainly reflects NHEJ, remains unaffected by caffeine in XRCC2 and XRCC3 mutants, or their wild-type counterparts. These observations suggest that caffeine targets steps in HRR but not in NHEJ and that abrogation of checkpoint response is not sufficient to explain radiosensitization. Indeed, immortalized fibroblasts from AT patients show caffeine radiosensitization despite the checkpoint defects associated with ATM mutation. We propose that caffeine radiosensitization is mediated by inhibition of stages in DNA DSB repair requiring HRR and that checkpoint disruption contributes by allowing these DSBs to transit into irreparable states. Thus, checkpoints may contribute to genomic stability by promoting error-free HRR.

NASA Discipline Radiation Health↗
NASA NTRS2003

An overactivated ATR/CHK1 pathway is responsible for the prolonged G2 accumulation in irradiated AT cells

Induction of checkpoint responses in G1, S, and G2 phases of the cell cycle after exposure of cells to ionizing radiation (IR) is essential for maintaining genomic integrity. Ataxia telangiectasia mutated (ATM) plays a key role in initiating this response in all three phases of the cell cycle. However, cells lacking functional ATM exhibit a prolonged G2 arrest after IR, suggesting regulation by an ATM-independent checkpoint response. The mechanism for this ataxia telangiectasia (AT)-independent G2-checkpoint response remains unknown. We report here that the G2 checkpoint in irradiated human AT cells derives from an overactivation of the ATR/CHK1 pathway. Chk1 small interfering RNA abolishes the IR-induced prolonged G2 checkpoint and radiosensitizes AT cells to killing. These results link the activation of ATR/CHK1 with the prolonged G2 arrest in AT cells and show that activation of this G2 checkpoint contributes to the survival of AT cells.

NASA Discipline Radiation Health↗
NASA NTRS1989

Recoverable distributed shared virtual memory - Memory coherence and storage structures

This paper examines the problem of implementing rollback recovery in multicomputer distributed shared virtual memory environments, in which the shared memory is implemented in software and exists only virtually. A user-transparent checkpointing recovery scheme and new twin-page disk storage management are presented to implement a recoverable distributed shared virtual memory. The checkpointing scheme is integrated with the shared virtual memory management. The twin-page disk approach allows incremental checkpointing without an explicit undo at the time of recovery. A single consistent checkpoint state is maintained on stable disk storage. The recoverable distributed shared virtual memory allows the system to restart computation from a previous checkpoint due to a processor failure without a global restart.

Wu, Kun-Lung↗
NASA NTRS1993

Relaxing consistency in recoverable distributed shared memory

Relaxed memory consistency models have recently been proposed to tolerate memory access latency in both hardware and software distributed shared memory systems. In recoverable shared memory multiprocessors, relaxing consistency has the added benefit of reducing the number of checkpoints needed to avoid rollback propagation. In this paper, we introduce new checkpointing algorithms that take advantage of relaxed consistency to reduce the performance overhead of checkpointing. We also introduce a scheme based on lazy relaxed consistency, that reduces both checkpointing overhead and the overhead of avoiding error propagation in systems with error latency. Multiprocessor address traces are used to evaluate the relaxed consistency approach to checkpointing with distributed shared memory.

Janssens, Bob↗
NASA NTRS1993

Relaxing consistency in recoverable distributed shared memory

Relaxed memory consistency models tolerate increased memory access latency in both hardware and software distributed shared memory systems. In recoverable systems, relaxing consistency has the added benefit of reducing the number of checkpoints needed to avoid rollback propagation. In this paper, we introduce new checkpointing algorithms that take advantage of relaxed consistency to reduce the performance overhead of checkpointing. We also introduce a scheme based on lazy relaxed consistency, that reduces both checkpointing overhead and the overhead of avoiding error propagation in systems with error latency. We use multiprocessor address traces to evaluate the relaxed consistency approach to checkpointing with distributed shared memory.

Janssens, Bob↗
NASA NTRS1990

Error recovery in shared memory multiprocessors using private caches

The problem of recovering from processor transient faults in shared memory multiprocesses systems is examined. A user-transparent checkpointing and recovery scheme using private caches is presented. Processes can recover from errors due to faulty processors by restarting from the checkpointed computation state. Implementation techniques using checkpoint identifiers and recovery stacks are examined as a means of reducing performance degradation in processor utilization during normal execution. This cache-based checkpointing technique prevents rollback propagation, provides rapid recovery, and can be integrated into standard cache coherence protocols. An analytical model is used to estimate the relative performance of the scheme during normal execution. Extensions to take error latency into account are presented.

Wu, Kun-Lung↗
NASA NTRS1990

Recoverable distributed shared virtual memory

The problem of rollback recovery in distributed shared virtual environments, in which the shared memory is implemented in software in a loosely coupled distributed multicomputer system, is examined. A user-transparent checkpointing recovery scheme and a new twin-page disk storage management technique are presented for implementing recoverable distributed shared virtual memory. The checkpointing scheme can be integrated with the memory coherence protocol for managing the shared virtual memory. The twin-page disk design allows checkpointing to proceed in an incremental fashion without an explicit undo at the time of recovery. The recoverable distributed shared virtual memory allows the system to restart computation from a checkpoint without a global restart.

Wu, Kun-Lung↗
NASA NTRS1991

Experimental evaluation of multiprocessor cache-based error recovery

Several variations of cache-based checkpointing for rollback error recovery in shared-memory multiprocessors have been recently developed. By modifying the cache replacement policy, these techniques use the inherent redundancy in the memory hierarchy to periodically checkpoint the computation state. Three schemes, different in the manner in which they avoid rollback propagation, are evaluated. By simulation with address traces from parallel applications running on an Encore Multimax shared-memory multiprocessor, the performance effect of integrating the recovery schemes in the cache coherence protocol are evaluated. The results indicate that the cache-based schemes can provide checkpointing capability with low performance overhead but uncontrollable high variability in the checkpoint interval.

Janssens, Bob↗
NASA NTRS2000

JavaGenes and Condor: Cycle-Scavenging Genetic Algorithms

A genetic algorithm code, JavaGenes, was written in Java and used to evolve pharmaceutical drug molecules and digital circuits. JavaGenes was run under the Condor cycle-scavenging batch system managing 100-170 desktop SGI workstations. Genetic algorithms mimic biological evolution by evolving solutions to problems using crossover and mutation. While most genetic algorithms evolve strings or trees, JavaGenes evolves graphs representing (currently) molecules and circuits. Java was chosen as the implementation language because the genetic algorithm requires random splitting and recombining of graphs, a complex data structure manipulation with ample opportunities for memory leaks, loose pointers, out-of-bound indices, and other hard to find bugs. Java garbage-collection memory management, lack of pointer arithmetic, and array-bounds index checking prevents these bugs from occurring, substantially reducing development time. While a run-time performance penalty must be paid, the only unacceptable performance we encountered was using standard Java serialization to checkpoint and restart the code. This was fixed by a two-day implementation of custom checkpointing. JavaGenes is minimally integrated with Condor; in other words, JavaGenes must do its own checkpointing and I/O redirection. A prototype Java-aware version of Condor was developed using standard Java serialization for checkpointing. For the prototype to be useful, standard Java serialization must be significantly optimized. JavaGenes is approximately 8700 lines of code and a few thousand JavaGenes jobs have been run. Most jobs ran for a few days. Results include proof that genetic algorithms can evolve directed and undirected graphs, development of a novel crossover operator for graphs, a paper in the journal Nanotechnology, and another paper in preparation.

Globus, Al↗
NASA NTRS2001

The radioresistance to killing of A1-5 cells derives from activation of the Chk1 pathway

Checkpoints respond to DNA damage by arresting the cell cycle to provide time for facilitating repair. In mammalian cells, the G(2) checkpoint prevents the Cdc25C phosphatase from removing inhibitory phosphate groups from the mitosis-promoting kinase Cdc2. Both Chk1 and Chk2, the checkpoint kinases, can phosphorylate Cdc25C and inactivate its in vitro phosphatase activity. Therefore, both Chk1 and Chk2 are thought to regulate the activation of the G(2) checkpoint. Here we report that A1-5, a transformed rat embryo fibroblast cell line, shows much more radioresistance associated with a much stronger G(2) arrest response when compared with its counterpart, B4, although A1-5 and B4 cells have a similar capacity for nonhomologous end-joining DNA repair. These phenotypes of A1-5 cells are accompanied by a higher Chk1 expression and a higher phosphorylation of Cdc2. On the other hand, Chk2 expression increases slightly following radiation; however, it has no difference between A1-5 and B4 cells. Caffeine or UCN-01 abolishes the extreme radioresistance with the strong G(2) arrest and at the same time reduces the phosphorylation of Cdc2 in A1-5 cells. In addition, Chk1 but not Chk2 antisense oligonucleotide sensitizes A1-5 cells to radiation-induced killing and reduces the G(2) arrest of the cells. Taken together these results suggest that the Chk1/Cdc25C/Cdc2 pathway is the major player for the radioresistance with G(2) arrest in A1-5 cells.

NASA Discipline Radiation Health↗
NASA NTRS1989

Cache-based error recovery for shared memory multiprocessor systems

A multiprocessor cache-based checkpointing and recovery scheme for of recovering from transient processor errors in a shared-memory multiprocessor with private caches is presented. New implementation techniques that use checkpoint identifiers and recovery stacks to reduce performance degradation in processor utilization during normal execution are examined. This cache-based checkpointing technique prevents rollback propagation, provides for rapid recovery, and can be integrated into standard cache coherence protocols. An analytical model is used to estimate the relative performance of the scheme during normal execution. Extensions that take error latency into account are presented.

Wu, Kun-Lung↗
NASA NTRS2011

Differential Processing of Low and High LET Radiation Induced DNA Damage: Investigation of Switch from ATM to ATR Signaling

The members of the phosphatidylinositol kinase-like kinase family of proteins namely ataxia-telangiectasia mutated (ATM) and ATM- and Rad3-related (ATR) are directly responsible for the maintenance of genomic integrity by mounting DDR through signaling and facilitating the recruitment of repair factors at the sites of DNA damage along with coordinating the deployment of cell cycle checkpoints to permit repair by phosphorylating Checkpoint kinase Chk1, Chk2 and p53. High LET radiation from GCR (Galactic Cosmic Rays) consisting mainly of protons and high energy and charged (HZE) particles from SPE (Solar Particle Event) pose a major health risk for astronauts on their space flight missions. The determination of these risks and the design of potential safeguards require sound knowledge of the biological consequences of lesion induction and the capability of the cells to counter them. We here strive to determine the coordination of ATM and ATR kinases at the break sites directly affecting checkpoint signaling and DNA repair and whether differential processing of breaks induced by low and high LET radiation leads to possible augmentation of swap of these damage sensors at the sites of DNA damage. Exposure of cells to IR triggers rapid autophosphorylation of serine-1981 that causes dimer dissociation and initiates monomer formation of ATM. ATM kinase activity depends on the disruption of the dimer, which allows access and phosphorylation of downstream ATM substrates like Chk2. Evidence suggests that ATM is activated by the alterations in higher-order chromatin structure although direct binding of ATM to DSB ends may be a crucial step in its activation. On the other hand, in case of ATR, RPA (replication protein A)-coated ssDNA (single-stranded DNA) generated as a result of stalled DNA replication or during processing of chromosomal lesions is crucial for the localization of ATR to sites of DNA damage in association with ATR-interacting protein (ATRIP). Although the majority of RPA-coated ssDNA is generally present only during DNA replication, ATR activation in G1 and G2-phase might still require formation of RPA-coated ssDNA, probably initiated by the MRN-CtIP complex and then extended by the Exo1- or BLM-dependent mechanisms at the sites of DSBs. Evidence accumulates that activation of ATM and ATR are oppositely regulated by the length of single stranded overhangs generated at the break sites by processes mentioned above and these stretches of single stranded overhangs hold the clue for ATM to ATR switch at broken DNA ends. We irradiated 82-6hTERT human fibroblast cells with low LET gamma-rays and high LET Fe and Si particles. Preliminary results with cells exposed to 1Gy gamma-rays show that the kinetics of pChk2-pT68 foci formation is comparable to that of gamma-H2AX although they appear to recede quicker. The number and intensity of observed foci reaches a maximum at 30 min and 60 min post IR for Chk2-pT68 and gamma-H2AX foci respectively and all Chk2-pT68 foci colocalize with gamma-H2AX foci. The kinetics of Chk1-pS345 and ATRIP are being determined. Results of Chk2-pT68 foci kinetics was also corroborated by western blot experiments, although phosphorylation was detected as early as 10 min and started receding 30 min post IR with 2Gy of gamma-rays. On the other hand, level of ATR-pS428 reached its maximum between 60 and 120 min and was maintained until the last measured time point of 4 hours post IR as determined by western blotting. Experiments performed with high LET Fe and Si particles will be reported.

Saha, Janapriya↗
NASA NTRS1978

On the append and continue features in NASTRAN

The APPEND feature is described which is applicable in the case of real eigenvalue analysis. This feature permitted the addition of new eigenvalues and eigenvectors to those already computed in a previously checkpointed run without re-executing the entire problem. The next feature was the CONTINUE feature which was applicable in the case of transient analysis of coupled equations. This feature enabled the integration of coupled equations to be continued beyond the last output time for which the solution was obtained in a previously checkpointed run (without re-executing the entire problem). These two features are illustrated by suitable examples.

Pamidi, P. R.↗
NASA NTRS1991

Memory management and compiler support for rapid recovery from failures in computer systems

This paper describes recent developments in the use of memory management and compiler technology to support rapid recovery from failures in computer systems. The techniques described include cache coherence protocols for user transparent checkpointing in multiprocessor systems, compiler-based checkpoint placement, compiler-based code modification for multiple instruction retry, and forward recovery in distributed systems utilizing optimistic execution.

Fuchs, W. K.↗
NASA NTRS1992

Scheduling message processing for reducing rollback propagation

Traditional checkpointing and rollback recovery techniques for parallel systems have typically assumed the communication pattern is specified by program behavior. In this paper we exploit the property that the communication pattern can often be changed at run-time without affecting program correctness. A scheduling algorithm for message processing and its implementation for reducing rollback propagation are described. The algorithm incorporates a user-transparent prioritized scheme based upon the run-time communication and checkpointing history. Communication trace-driven simulation for several parallel programs written in the Chare Kernel language demonstrates that the probability of rollback propagation can be reduced at the cost of slight additional performance degradation.

Wang, Yi-Min↗
NASA NTRS1995

Ensuring correct rollback recovery in distributed shared memory systems

Distributed shared memory (DSM) implemented on a cluster of workstations is an increasingly attractive platform for executing parallel scientific applications. Checkpointing and rollback techniques can be used in such a system to allow the computation to progress in spite of the temporary failure of one or more processing nodes. This paper presents the design of an independent checkpointing method for DSM that takes advantage of DSM's specific properties to reduce error-free and rollback overhead. The scheme reduces the dependencies that need to be considered for correct rollback to those resulting from transfers of pages. Furthermore, in-transit messages can be recovered without the use of logging. We extend the scheme to a DSM implementation using lazy release consistency, where the frequency of dependencies is further reduced.

Janssens, Bob↗
NASA NTRS2001

Evidence for factors modulating radiation-induced G2-delay: potential application as radioprotectors

Manipulation of checkpoint response to DNA damage can be developed as a means for protecting astronauts from the adverse effects of unexpected, or background exposures to ionizing radiation. To achieve this goal reagents need to be developed that protect cells from radiation injury by prolonging checkpoint response, thus promoting repair. We present evidence for a low molecular weight substance excreted by cells that dramatically increases the duration of the G2-delay. This compound is termed G2-Arrest Modulating Activity (GAMA). A rat cell line (A1-5) generated by transforming rat embryo fibroblasts with a temperature sensitive form of p53 plus H-ras demonstrates a dramatic increase in radiation resistance after exposure to low LET radiation that is not associated with an increase in the efficiency of rejoining of DNA double strand breaks. Radioresistance in this cell line correlates with a dramatic increase in the duration of the G2 arrest that is modulated by a GAMA produced by actively growing cells. The properties of GAMA suggest that it is a low molecular weight heat-stable peptide. Further characterization of this substance and elucidation of its mechanism of action may allow the development of a biological response modifier with potential applications as a radioprotector. GAMA may be useful for protecting astronauts from radiation injury as preliminary evidence suggests that it is able to modulate the response of cells exposed to heavy ion radiation, similar to that encountered in outer space.

NASA Discipline Radiation Health↗
NASA NTRS2017

Radiation Hardening by Software Techniques on FPGAs: Flight Experiment Evaluation and Results

We present our work on implementing Radiation Hardening by Software (RHBSW) techniques on the Xilinx Virtex5 FPGAs PowerPC 440 processors on the SpaceCube 2.0 platform. The techniques have been matured and tested through simulation modeling, fault emulation, laser fault injection and now in a flight experiment, as part of the Space Test Program- Houston 4-ISS SpaceCube Experiment 2.0 (STP-H4-ISE 2.0). This work leverages concepts such as heartbeat monitoring, control flow assertions, and checkpointing, commonly used in the High Performance Computing industry, and adapts them for use in remote sensing embedded systems. These techniques are extremely low overhead (typically <1.3%), enabling a 3.3x gain in processing performance as compared to the equivalent traditionally radiation hardened processor. The recently concluded STP-H4 flight experiment was an opportunity to upgrade the RHBSW techniques for the Virtex5 FPGA and demonstrate them on-board the ISS to achieve TRL 7. This work details the implementation of the RHBSW techniques, that were previously developed for the Virtex4-based SpaceCube 1.0 platform, on the Virtex5-based SpaceCube 2.0 flight platform. The evaluation spans the development and integration with flight software, remotely uploading the new experiment to the ISS SpaceCube 2.0 platform, and conducting the experiment continuously for 16 days before the platform was decommissioned. The experiment was conducted on two PowerPCs embedded within the Virtex5 FPGA devices and the experiment collected 19,400 checkpoints, processed 253,482 status messages, and incurred 0 faults. These results are highly encouraging and future work is looking into longer duration testing as part of the STP-H5 flight experiment.

Hybrid Flight Architectures↗