Reliability-oriented resource management for High-Performance Computing

Reliability is an increasingly pressing issue for High-Performance Computing systems, as failures are a threat to large-scale applications, for which an even single run may incur significant energy and billing costs. Currently, application developers need to address reliability explicitly, by integrating application-specific checkpoint/restore mechanisms. However, the application alone cannot exploit system knowledge, which is not the case for system-wide resource management systems. In this paper, we propose a reliability-oriented policy that can increase significantly component reliability by combining checkpoint/restore mechanisms exploitation and proactive resource management policies

Late-Stage Metastatic Melanoma Emerges through a Diversity of Evolutionary Pathways

UNLABELLED: Understanding the evolutionary pathways to metastasis and resistance to immune-checkpoint inhibitors (ICI) in melanoma is critical for improving outcomes. Here, we present the most comprehensive intrapatient metastatic melanoma dataset assembled to date as part of the Posthumous Evaluation of Advanced Cancer Environment (PEACE) research autopsy program, including 222 exome sequencing, 493 panel-sequenced, 161 RNA sequencing, and 22 single-cell whole-genome sequencing samples from 14 ICI-treated patients. We observed frequent whole-genome doubling and widespread loss of heterozygosity, often involving antigen-presentation machinery. We found KIT extrachromosomal DNA may have contributed to the lack of response to KIT inhibitors of a KIT-driven melanoma. At the lesion-level, MYC amplifications were enriched in ICI nonresponders. Single-cell sequencing revealed polyclonal seeding of metastases originating from clones with different ploidy in one patient. Finally, we observed that brain metastases that diverged early in molecular evolution emerge late in disease. Overall, our study illustrates the diverse evolutionary landscape of advanced melanoma. SIGNIFICANCE: Despite treatment advances, melanoma remains a deadly disease at stage IV. Through research autopsy and dense sampling of metastases combined with extensive multiomic profiling, our study elucidates the many mechanisms that melanomas use to evade treatment and the immune system, whether through mutations, widespread copy-number alterations, or extrachromosomal DNA. See related commentary by Shain, p. 1294. This article is highlighted in the In This Issue feature, p. 1275

Global urban environmental change drives adaptation in white clover

Urbanization transforms environments in ways that alter biological evolution. We examined whether urban environmental change drives parallel evolution by sampling 110,019 white clover plants from 6169 populations in 160 cities globally. Plants were assayed for a Mendelian antiherbivore defense that also affects tolerance to abiotic stressors. Urban-rural gradients were associated with the evolution of clines in defense in 47% of cities throughout the world. Variation in the strength of clines was explained by environmental changes in drought stress and vegetation cover that varied among cities. Sequencing 2074 genomes from 26 cities revealed that the evolution of urban-rural clines was best explained by adaptive evolution, but the degree of parallel adaptation varied among cities. Our results demonstrate that urbanization leads to adaptation at a global scale

Education and employment: The future for Aboriginal people: With responses from: Peta Goldburg, Roderic Lacey and Maurice Ryan

Article includes responses from: Peta Goldburg, Roderic Lacey and Maurice Rya

Genome-Wide Association Mapping in Dogs Enables Identification of the Homeobox Gene, <i>NKX2-8</i>, as a Genetic Component of Neural Tube Defects in Humans

<div><p>Neural tube defects (NTDs) is a general term for central nervous system malformations secondary to a failure of closure or development of the neural tube. The resulting pathologies may involve the brain, spinal cord and/or vertebral column, in addition to associated structures such as soft tissue or skin. The condition is reported among the more common birth defects in humans, leading to significant infant morbidity and mortality. The etiology remains poorly understood but genetic, nutritional, environmental factors, or a combination of these, are known to play a role in the development of NTDs. The variable conditions associated with NTDs occur naturally in dogs, and have been previously reported in the Weimaraner breed. Taking advantage of the strong linkage-disequilibrium within dog breeds we performed genome-wide association analysis and mapped a genomic region for spinal dysraphism, a presumed NTD, using 4 affected and 96 unaffected Weimaraners. The associated region on canine chromosome 8 (<i>p_genome</i> = 3.0×10⁻⁵), after 100,000 permutations, encodes 18 genes, including <i>NKX2-8</i>, a homeobox gene which is expressed in the developing neural tube. Sequencing <i>NKX2-8</i> in affected Weimaraners revealed a G to AA frameshift mutation within exon 2 of the gene, resulting in a premature stop codon that is predicted to produce a truncated protein. The exons of <i>NKX2-8</i> were sequenced in human patients with spina bifida and rare variants (rs61755040 and rs10135525) were found to be significantly over-represented (p = 0.036). This is the first documentation of a potential role for <i>NKX2-8</i> in the etiology of NTDs, made possible by investigating the molecular basis of naturally occurring mutations in dogs.</p></div

Manhattan plots of GWAS results for NTDs in Weimaraners (4 cases, 96 controls; λ = 1.03).

<p><b>A</b>. Raw p-values. Y axis: −log 10 of the raw p-values; X axis: SNPs color coded by chromosome. The lowest p-values are on chromosome 8. <b>B</b>. 100K Max (T) permutation results. Y axis: −log 10 of the permuted p-value; X axis: SNPs color coded by chromosome. The red line denotes genome wide significance (p≤0.05; −log 10≥1.3). <b>C</b>. Chi-square and allele frequencies for affected dogs by Mb on chromosome 8. The interval with the highest chi-square association (χ² = 119) and allele frequency = 1 within affected dogs is boxed, defining the critical interval. <i>NKX2-8</i> is located within this interval.</p

Comparison of the protein sequence of <i>NKX2-8</i> between human, unaffected dog, spinal dysraphism Weimaraner, cat, cow, bat, wild boar, mouse, tree-shrew, chicken and zebra fish.

<p>Two functional domains: a homeobox (A) and an NK specific domain (B) are boxed. A truncated protein (arrow), the result of the frameshift mutation (grey shaded) in spinal dysraphism affected Weimaraners, is missing the NK specific domain. Locations for missense variants rs61755040 (asterisk) and rs10135525 (double asterisk), found in human patients with spina bifida, are shaded within the protein sequence. These variants reside within evolutionary conserved domains.</p

Chromatograms of <i>NKX2-8</i> exon 2 sequence where a mutation of G to AA was found in an affected Weimaraner.

<p>From left to right: Unaffected Weimaraners have a genotype of “GG”; affected Weimaraners have a genotype of “AA”; carrier Weimaraners have a genotype of “AG”.</p