Redundant disk arrays: Reliable, parallel secondary storage

During the past decade, advances in processor and memory technology have given rise to increases in computational performance that far outstrip increases in the performance of secondary storage technology. Coupled with emerging small-disk technology, disk arrays provide the cost, volume, and capacity of current disk subsystems, by leveraging parallelism, many times their performance. Unfortunately, arrays of small disks may have much higher failure rates than the single large disks they replace. Redundant arrays of inexpensive disks (RAID) use simple redundancy schemes to provide high data reliability. The data encoding, performance, and reliability of redundant disk arrays are investigated. Organizing redundant data into a disk array is treated as a coding problem. Among alternatives examined, codes as simple as parity are shown to effectively correct single, self-identifying disk failures

The Extragalactic Distance Scale Key Project XXVII. A Derivation of the Hubble Constant Using the Fundamental Plane and Dn-Sigma Relations in Leo I, Virgo, and Fornax

Using published photometry and spectroscopy, we construct the fundamental plane and D_n-Sigma relations in Leo I, Virgo and Fornax. The published Cepheid P-L relations to spirals in these clusters fixes the relation between angular size and metric distance for both the fundamental plane and D_n-Sigma relations. Using the locally calibrated fundamental plane, we infer distances to a sample of clusters with a mean redshift of cz \approx 6000 \kms, and derive a value of H_0=78+- 5+- 9 km/s/Mpc (random, systematic) for the local expansion rate. This value includes a correction for depth effects in the Cepheid distances to the nearby clusters, which decreased the deduced value of the expansion rate by 5% +- 5%. If one further adopts the metallicity correction to the Cepheid PL relation, as derived by the Key Project, the value of the Hubble constant would decrease by a further 6%+- 4%. These two sources of systematic error, when combined with a +- 6% error due to the uncertainty in the distance to the Large Magellanic Cloud, a +- 4% error due to uncertainties in the WFPC2 calibration, and several small sources of uncertainty in the fundamental plane analysis, combine to yield a total systematic uncertainty of +- 11%. We find that the values obtained using either the CMB, or a flow-field model, for the reference frame of the distant clusters, agree to within 1%. The Dn-Sigma relation also produces similar results, as expected from the correlated nature of the two scaling relations. A complete discussion of the sources of random and systematic error in this determination of the Hubble constant is also given, in order to facilitate comparison with the other secondary indicators being used by the Key Project.Comment: 21 pages, 3 figures, Accepted for publication in Ap

Association of Variants in the SPTLC1 Gene With Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation.Objective: To identify the genetic variants associated with juvenile ALS.Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism.Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members.Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway.Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.</p

Genome-wide Analyses Identify KIF5A as a Novel ALS Gene

To identify novel genes associated with ALS, we undertook two lines of investigation. We carried out a genome-wide association study comparing 20,806 ALS cases and 59,804 controls. Independently, we performed a rare variant burden analysis comparing 1,138 index familial ALS cases and 19,494 controls. Through both approaches, we identified kinesin family member 5A (KIF5A) as a novel gene associated with ALS. Interestingly, mutations predominantly in the N-terminal motor domain of KIF5A are causative for two neurodegenerative diseases: hereditary spastic paraplegia (SPG10) and Charcot-Marie-Tooth type 2 (CMT2). In contrast, ALS-associated mutations are primarily located at the C-terminal cargo-binding tail domain and patients harboring loss-of-function mutations displayed an extended survival relative to typical ALS cases. Taken together, these results broaden the phenotype spectrum resulting from mutations in KIF5A and strengthen the role of cytoskeletal defects in the pathogenesis of ALS.Peer reviewe

Association of Variants in the SPTLC1 Gene with Juvenile Amyotrophic Lateral Sclerosis

Importance: Juvenile amyotrophic lateral sclerosis (ALS) is a rare form of ALS characterized by age of symptom onset less than 25 years and a variable presentation. Objective: To identify the genetic variants associated with juvenile ALS. Design, Setting, and Participants: In this multicenter family-based genetic study, trio whole-exome sequencing was performed to identify the disease-associated gene in a case series of unrelated patients diagnosed with juvenile ALS and severe growth retardation. The patients and their family members were enrolled at academic hospitals and a government research facility between March 1, 2016, and March 13, 2020, and were observed until October 1, 2020. Whole-exome sequencing was also performed in a series of patients with juvenile ALS. A total of 66 patients with juvenile ALS and 6258 adult patients with ALS participated in the study. Patients were selected for the study based on their diagnosis, and all eligible participants were enrolled in the study. None of the participants had a family history of neurological disorders, suggesting de novo variants as the underlying genetic mechanism. Main Outcomes and Measures: De novo variants present only in the index case and not in unaffected family members. Results: Trio whole-exome sequencing was performed in 3 patients diagnosed with juvenile ALS and their parents. An additional 63 patients with juvenile ALS and 6258 adult patients with ALS were subsequently screened for variants in the SPTLC1 gene. De novo variants in SPTLC1 (p.Ala20Ser in 2 patients and p.Ser331Tyr in 1 patient) were identified in 3 unrelated patients diagnosed with juvenile ALS and failure to thrive. A fourth variant (p.Leu39del) was identified in a patient with juvenile ALS where parental DNA was unavailable. Variants in this gene have been previously shown to be associated with autosomal-dominant hereditary sensory autonomic neuropathy, type 1A, by disrupting an essential enzyme complex in the sphingolipid synthesis pathway. Conclusions and Relevance: These data broaden the phenotype associated with SPTLC1 and suggest that patients presenting with juvenile ALS should be screened for variants in this gene.