| 1. |
- Klionsky, Daniel J., et al.
(author)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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In: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Research review (peer-reviewed)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
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| 2. |
- Wang, Zhaoming, et al.
(author)
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Imputation and subset-based association analysis across different cancer types identifies multiple independent risk loci in the TERT-CLPTM1L region on chromosome 5p15.33
- 2014
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In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 23:24, s. 6616-6633
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have mapped risk alleles for at least 10 distinct cancers to a small region of 63 000 bp on chromosome 5p15.33. This region harbors the TERT and CLPTM1L genes; the former encodes the catalytic subunit of telomerase reverse transcriptase and the latter may play a role in apoptosis. To investigate further the genetic architecture of common susceptibility alleles in this region, we conducted an agnostic subset-based meta-analysis (association analysis based on subsets) across six distinct cancers in 34 248 cases and 45 036 controls. Based on sequential conditional analysis, we identified as many as six independent risk loci marked by common single-nucleotide polymorphisms: five in the TERT gene (Region 1: rs7726159, P = 2.10 × 10(-39); Region 3: rs2853677, P = 3.30 × 10(-36) and PConditional = 2.36 × 10(-8); Region 4: rs2736098, P = 3.87 × 10(-12) and PConditional = 5.19 × 10(-6), Region 5: rs13172201, P = 0.041 and PConditional = 2.04 × 10(-6); and Region 6: rs10069690, P = 7.49 × 10(-15) and PConditional = 5.35 × 10(-7)) and one in the neighboring CLPTM1L gene (Region 2: rs451360; P = 1.90 × 10(-18) and PConditional = 7.06 × 10(-16)). Between three and five cancers mapped to each independent locus with both risk-enhancing and protective effects. Allele-specific effects on DNA methylation were seen for a subset of risk loci, indicating that methylation and subsequent effects on gene expression may contribute to the biology of risk variants on 5p15.33. Our results provide strong support for extensive pleiotropy across this region of 5p15.33, to an extent not previously observed in other cancer susceptibility loci.
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| 3. |
- Sampson, Joshua N., et al.
(author)
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Analysis of Heritability and Shared Heritability Based on Genome-Wide Association Studies for 13 Cancer Types
- 2015
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In: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 107:12
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Journal article (peer-reviewed)abstract
- Background: Studies of related individuals have consistently demonstrated notable familial aggregation of cancer. We aim to estimate the heritability and genetic correlation attributable to the additive effects of common single-nucleotide polymorphisms (SNPs) for cancer at 13 anatomical sites. Methods: Between 2007 and 2014, the US National Cancer Institute has generated data from genome-wide association studies (GWAS) for 49 492 cancer case patients and 34 131 control patients. We apply novel mixed model methodology (GCTA) to this GWAS data to estimate the heritability of individual cancers, as well as the proportion of heritability attributable to cigarette smoking in smoking-related cancers, and the genetic correlation between pairs of cancers. Results: GWAS heritability was statistically significant at nearly all sites, with the estimates of array-based heritability, h(l)(2), on the liability threshold (LT) scale ranging from 0.05 to 0.38. Estimating the combined heritability of multiple smoking characteristics, we calculate that at least 24% (95% confidence interval [CI] = 14% to 37%) and 7% (95% CI = 4% to 11%) of the heritability for lung and bladder cancer, respectively, can be attributed to genetic determinants of smoking. Most pairs of cancers studied did not show evidence of strong genetic correlation. We found only four pairs of cancers with marginally statistically significant correlations, specifically kidney and testes (rho = 0.73, SE = 0.28), diffuse large B-cell lymphoma (DLBCL) and pediatric osteosarcoma (rho = 0.53, SE = 0.21), DLBCL and chronic lymphocytic leukemia (CLL) (rho = 0.51, SE = 0.18), and bladder and lung (rho = 0.35, SE = 0.14). Correlation analysis also indicates that the genetic architecture of lung cancer differs between a smoking population of European ancestry and a nonsmoking Asian population, allowing for the possibility that the genetic etiology for the same disease can vary by population and environmental exposures. Conclusion: Our results provide important insights into the genetic architecture of cancers and suggest new avenues for investigation.
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| 4. |
- Chien, Steven W. D., et al.
(author)
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Characterizing Deep-Learning I/O Workloads in TensorFlow
- 2018
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In: Proceedings of PDSW-DISCS 2018: 3rd Joint International Workshop on Parallel Data Storage and Data Intensive Scalable Computing Systems, Held in conjunction with SC 2018: The International Conference for High Performance Computing, Networking, Storage and Analysis. - : Institute of Electrical and Electronics Engineers (IEEE). ; , s. 54-63
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Conference paper (peer-reviewed)abstract
- The performance of Deep-Learning (DL) computing frameworks rely on the rformance of data ingestion and checkpointing. In fact, during the aining, a considerable high number of relatively small files are first aded and pre-processed on CPUs and then moved to accelerator for mputation. In addition, checkpointing and restart operations are rried out to allow DL computing frameworks to restart quickly from a eckpoint. Because of this, I/O affects the performance of DL plications. this work, we characterize the I/O performance and scaling of nsorFlow, an open-source programming framework developed by Google and ecifically designed for solving DL problems. To measure TensorFlow I/O rformance, we first design a micro-benchmark to measure TensorFlow ads, and then use a TensorFlow mini-application based on AlexNet to asure the performance cost of I/O and checkpointing in TensorFlow. To prove the checkpointing performance, we design and implement a burst ffer. find that increasing the number of threads increases TensorFlow ndwidth by a maximum of 2.3 x and 7.8 x on our benchmark environments. e use of the tensorFlow prefetcher results in a complete overlap of mputation on accelerator and input pipeline on CPU eliminating the fective cost of I/O on the overall performance. The use of a burst ffer to checkpoint to a fast small capacity storage and copy ynchronously the checkpoints to a slower large capacity storage sulted in a performance improvement of 2.6x with respect to eckpointing directly to slower storage on our benchmark environment.
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| 5. |
- Chien, Steven W.D., et al.
(author)
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Improving Cloud Storage Network Bandwidth Utilization of Scientific Applications
- 2023
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In: Proceedings of the 7th Asia-Pacific Workshop on Networking, APNET 2023. - : Association for Computing Machinery (ACM). ; , s. 172-173
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Conference paper (peer-reviewed)abstract
- Cloud providers began to provide managed services to attract scientific applications, which have been traditionally executed on supercomputers. One example is AWS FSx for Lustre, a fully managed parallel file system (PFS) released in 2018. However, due to the nature of scientific applications, the frontend storage network bandwidth is left completely idle for the majority of its lifetime. Furthermore, the pricing model does not match the scalability requirement. We propose iFast, a novel host-side caching mechanism for scientific applications that improves storage bandwidth utilization and end-to-end application performance: by overlapping compute and data writeback through inexpensive local storage. iFast supports the Massage Passing Interface (MPI) library that is widely used by scientific applications and is implemented as a preloaded library. It requires no change to applications, the MPI library, or support from cloud operators. We demonstrate how iFast can accelerate the end-to-end time of a representative scientific application Neko, by 13-40%.
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| 6. |
- Chien, Steven W. D., et al.
(author)
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Tf-Darshan : Understanding Fine-grained I/O Performance in Machine Learning Workloads
- 2020
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In: Proceedings - IEEE International Conference on Cluster Computing, ICCC. - : Institute of Electrical and Electronics Engineers Inc.. ; , s. 359-370
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Conference paper (peer-reviewed)abstract
- Machine Learning applications on HPC systems have been gaining popularity in recent years. The upcoming large scale systems will offer tremendous parallelism for training through GPUs. However, another heavy aspect of Machine Learning is I/O, and this can potentially be a performance bottleneck. TensorFlow, one of the most popular Deep-Learning platforms, now offers a new profiler interface and allows instrumentation of TensorFlow operations. However, the current profiler only enables analysis at the TensorFlow platform level and does not provide system-level information. In this paper, we extend TensorFlow Profiler and introduce tf-Darshan, both a profiler and tracer, that performs instrumentation through Darshan. We use the same Darshan shared instrumentation library and implement a runtime attachment without using a system preload. We can extract Darshan profiling data structures during TensorFlow execution to enable analysis through the TensorFlow profiler. We visualize the performance results through TensorBoard, the web-based TensorFlow visualization tool. At the same time, we do not alter Darshan's existing implementation. We illustrate tf-Darshan by performing two case studies on ImageNet image and Malware classification. We show that by guiding optimization using data from tf-Darshan, we increase POSIX I/O bandwidth by up to 19% by selecting data for staging on fast tier storage. We also show that Darshan has the potential of being used as a runtime library for profiling and providing information for future optimization.
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| 7. |
- Markidis, Stefano, et al.
(author)
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PolyPIC : The polymorphic-particle-in-cell method for fluid-kinetic coupling
- 2018
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In: Frontiers in Physics. - : Frontiers Media S.A.. - 2296-424X. ; 6:OCT
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Journal article (peer-reviewed)abstract
- Particle-in-Cell (PIC) methods are widely used computational tools for fluid and kinetic plasma modeling. While both the fluid and kinetic PIC approaches have been successfully used to target either kinetic or fluid simulations, little was done to combine fluid and kinetic particles under the same PIC framework. This work addresses this issue by proposing a new PIC method, PolyPIC, that uses polymorphic computational particles. In this numerical scheme, particles can be either kinetic or fluid, and fluid particles can become kinetic when necessary, e.g., particles undergoing a strong acceleration. We design and implement the PolyPIC method, and test it against the Landau damping of Langmuir and ion acoustic waves, two stream instability and sheath formation. We unify the fluid and kinetic PIC methods under one common framework comprising both fluid and kinetic particles, providing a tool for adaptive fluid-kinetic coupling in plasma simulations.
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| 8. |
- Olshevsky, Viacheslav, et al.
(author)
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Automated Classification of Plasma Regions Using 3D Particle Energy Distributions
- 2021
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In: Journal of Geophysical Research - Space Physics. - : American Geophysical Union (AGU). - 2169-9380 .- 2169-9402. ; 126:10
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Journal article (peer-reviewed)abstract
- We investigate the properties of the ion sky maps produced by the Dual Ion Spectrometers (DIS) from the Fast Plasma Investigation (FPI). We have trained a convolutional neural network classifier to predict four regions crossed by the Magnetospheric Multiscale Mission (MMS) on the dayside magnetosphere: solar wind, ion foreshock, magnetosheath, and magnetopause using solely DIS spectrograms. The accuracy of the classifier is >98%. We use the classifier to detect mixed plasma regions, in particular to find the bow shock regions. A similar approach can be used to identify the magnetopause crossings and reveal regions prone to magnetic reconnection. Data processing through the trained classifier is fast and efficient and thus can be used for classification for the whole MMS database.
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