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| 2. |
- Klionsky, Daniel J., et al.
(författare)
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Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
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Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
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Forskningsöversikt (refereegranskat)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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| 3. |
- McArdle, P. F., et al.
(författare)
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Agreement between TOAST and CCS ischemic stroke classification: The NINDS SiGN Study
- 2014
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Ingår i: Neurology. - 0028-3878 .- 1526-632X. ; 83:18, s. 1653-60
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: The objective of this study was to assess the level of agreement between stroke subtype classifications made using the Trial of Org 10172 Acute Stroke Treatment (TOAST) and Causative Classification of Stroke (CCS) systems. METHODS: Study subjects included 13,596 adult men and women accrued from 20 US and European genetic research centers participating in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN). All cases had independently classified TOAST and CCS stroke subtypes. Kappa statistics were calculated for the 5 major ischemic stroke subtypes common to both systems. RESULTS: The overall agreement between TOAST and CCS was moderate (agreement rate, 70%; κ = 0.59, 95% confidence interval [CI] 0.58-0.60). Agreement varied widely across study sites, ranging from 28% to 90%. Agreement on specific subtypes was highest for large-artery atherosclerosis (κ = 0.71, 95% CI 0.69-0.73) and lowest for small-artery occlusion (κ = 0.56, 95% CI 0.54-0.58). CONCLUSION: Agreement between TOAST and CCS diagnoses was moderate. Caution is warranted when comparing or combining results based on the 2 systems. Replication of study results, for example, genome-wide association studies, should utilize phenotypes determined by the same classification system, ideally applied in the same manner.
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| 4. |
- Woo, Daniel, et al.
(författare)
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Meta-Analysis of Genome-Wide Association Studies Identifies 1q22 as a Susceptibility Locus for Intracerebral Hemorrhage.
- 2014
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Ingår i: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:4, s. 511-521
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Tidskriftsartikel (refereegranskat)abstract
- Intracerebral hemorrhage (ICH) is the stroke subtype with the worst prognosis and has no established acute treatment. ICH is classified as lobar or nonlobar based on the location of ruptured blood vessels within the brain. These different locations also signal different underlying vascular pathologies. Heritability estimates indicate a substantial genetic contribution to risk of ICH in both locations. We report a genome-wide association study of this condition that meta-analyzed data from six studies that enrolled individuals of European ancestry. Case subjects were ascertained by neurologists blinded to genotype data and classified as lobar or nonlobar based on brain computed tomography. ICH-free control subjects were sampled from ambulatory clinics or random digit dialing. Replication of signals identified in the discovery cohort with p < 1 × 10(-6) was pursued in an independent multiethnic sample utilizing both direct and genome-wide genotyping. The discovery phase included a case cohort of 1,545 individuals (664 lobar and 881 nonlobar cases) and a control cohort of 1,481 individuals and identified two susceptibility loci: for lobar ICH, chromosomal region 12q21.1 (rs11179580, odds ratio [OR] = 1.56, p = 7.0 × 10(-8)); and for nonlobar ICH, chromosomal region 1q22 (rs2984613, OR = 1.44, p = 1.6 × 10(-8)). The replication included a case cohort of 1,681 individuals (484 lobar and 1,194 nonlobar cases) and a control cohort of 2,261 individuals and corroborated the association for 1q22 (p = 6.5 × 10(-4); meta-analysis p = 2.2 × 10(-10)) but not for 12q21.1 (p = 0.55; meta-analysis p = 2.6 × 10(-5)). These results demonstrate biological heterogeneity across ICH subtypes and highlight the importance of ascertaining ICH cases accordingly.
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| 5. |
- Sköldstrom, Pontus, et al.
(författare)
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Towards unified programmability of cloud and carrier infrastructure
- 2014
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Ingår i: Proceedings - 2014 3rd European Workshop on Software-Defined Networks, EWSDN 2014. - 9781479969197 ; , s. 55-60
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Konferensbidrag (refereegranskat)abstract
- The rise of cloud services poses considerable challenges on the control of both cloud and carrier network infrastructures. While traditional telecom network services rely on rather static processes (often involving manual steps), the wide adoption of mobile devices including tablets, smartphones and wearables introduce previously unseen dynamics in the creation, scaling and withdrawal of new services. These phenomena require optimal flexibility in the characterization of services, as well as on the control and orchestration of both carrier and cloud infrastructure. This paper proposes a unified programmability framework addressing: the unification of network and cloud resources, the integrated control and management of cloud and network, the description for programming networked/cloud services, and the provisioning processes of these services. In addition proofs-of-concept are provided based on existing open source control software components. © 2014 IEEE.
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| 6. |
- Chroinin, Danielle Ni, et al.
(författare)
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Statin Therapy and Outcome After Ischemic Stroke : Systematic Review and Meta-Analysis of Observational Studies and Randomized Trials
- 2013
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Ingår i: Stroke. - 0039-2499 .- 1524-4628. ; 44:2, s. 448-456
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Forskningsöversikt (refereegranskat)abstract
- Background and Purpose-Although experimental data suggest that statin therapy may improve neurological outcome after acute cerebral ischemia, the results from clinical studies are conflicting. We performed a systematic review and meta-analysis investigating the relationship between statin therapy and outcome after ischemic stroke. Methods-The primary analysis investigated statin therapy at stroke onset (prestroke statin use) and good functional outcome (modified Rankin score 0 to 2) and death. Secondary analyses included the following: (1) acute poststroke statin therapy (<= 72 hours after stroke), and (2) thrombolysis-treated patients. Results-The primary analysis included 113 148 subjects (27 studies). Among observational studies, statin treatment at stroke onset was associated with good functional outcome at 90 days (pooled odds ratio [OR], 1.41; 95% confidence interval [CI], 1.29-1.56; P<0.001), but not 1 year (OR, 1.12; 95% CI, 0.9-1.4; P=0.31), and with reduced fatality at 90 days (pooled OR, 0.71; 95% CI, 0.62-0.82; P<0.001) and 1 year (OR, 0.80;95% CI, 0.67-0.95; P=0.01). In the single randomized controlled trial reporting 90-day functional outcome, statin treatment was associated with good outcome (OR, 1.5; 95% CI, 1.0-2.24; P=0.05). No reduction in fatality was observed on meta-analysis of data from 3 randomized controlled trials (P=0.9). In studies restricted to of thrombolysis-treated patients, an association between statins and increased fatality at 90 days was observed (pooled OR, 1.25; 95% CI, 1.02-1.52; P=0.03, 3 studies, 4339 patients). However, this association was no longer present after adjusting for age and stroke severity in the largest study (adjusted OR, 1.14; 95% CI, 0.90-1.44; 4012 patients). Conclusion-In the largest meta-analysis to date, statin therapy at stroke onset was associated with improved outcome, a finding not observed in studies restricted to thrombolysis-treated patients. Randomized trials of statin therapy in acute ischemic stroke are needed.
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| 7. |
- Devan, William J., et al.
(författare)
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Heritability Estimates Identify a Substantial Genetic Contribution to Risk and Outcome of Intracerebral Hemorrhage
- 2013
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:6, s. 1578-1583
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Previous studies suggest that genetic variation plays a substantial role in occurrence and evolution of intracerebral hemorrhage (ICH). Genetic contribution to disease can be determined by calculating heritability using family-based data, but such an approach is impractical for ICH because of lack of large pedigree-based studies. However, a novel analytic tool based on genome-wide data allows heritability estimation from unrelated subjects. We sought to apply this method to provide heritability estimates for ICH risk, severity, and outcome. Methods-We analyzed genome-wide genotype data for 791 ICH cases and 876 controls, and determined heritability as the proportion of variation in phenotype attributable to captured genetic variants. Contribution to heritability was separately estimated for the APOE (encoding apolipoprotein E) gene, an established genetic risk factor, and for the rest of the genome. Analyzed phenotypes included ICH risk, admission hematoma volume, and 90-day mortality. Results-ICH risk heritability was estimated at 29% (SE, 11%) for non-APOE loci and at 15% (SE, 10%) for APOE. Heritability for 90-day ICH mortality was 41% for non-APOE loci and 10% (SE, 9%) for APOE. Genetic influence on hematoma volume was also substantial: admission volume heritability was estimated at 60% (SE, 70%) for non-APOE loci and at 12% (SE, 4%) for APOE. Conclusions-Genetic variation plays a substantial role in ICH risk, outcome, and hematoma volume. Previously reported risk variants account for only a portion of inherited genetic influence on ICH pathophysiology, pointing to additional loci yet to be identified.
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| 8. |
- Falcone, Guido J., et al.
(författare)
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Burden of Risk Alleles for Hypertension Increases Risk of Intracerebral Hemorrhage
- 2012
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 43:11, s. 2877-2883
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Genetic variation influences risk of intracerebral hemorrhage (ICH). Hypertension (HTN) is a potent risk factor for ICH and several common genetic variants (single nucleotide polymorphisms [SNPs]) associated with blood pressure levels have been identified. We sought to determine whether the cumulative burden of blood pressure-related SNPs is associated with risk of ICH and pre-ICH diagnosis of HTN. Methods-We conducted a prospective multicenter case-control study in 2272 subjects of European ancestry (1025 cases and 1247 control subjects). Thirty-nine SNPs reported to be associated with blood pressure levels were identified from the National Human Genome Research Institute genomewide association study catalog. Single-SNP association analyses were performed for the outcomes ICH and pre-ICH HTN. Subsequently, weighted and unweighted genetic risk scores were constructed using these SNPs and entered as the independent variable in logistic regression models with ICH and pre-ICH HTN as the dependent variables. Results-No single SNP was associated with either ICH or pre-ICH HTN. The blood pressure-based unweighted genetic risk score was associated with risk of ICH (OR, 1.11; 95% CI, 1.02-1.21; P=0.01) and the subset of ICH in deep regions (OR, 1.18; 95% CI, 1.07-1.30; P=0.001), but not with the subset of lobar ICH. The score was associated with a history of HTN among control subjects (OR, 1.17; 95% CI, 1.04-1.31; P=0.009) and ICH cases (OR, 1.15; 95% CI, 1.01-1.31; P=0.04). Similar results were obtained when using a weighted score. Conclusion-Increasing numbers of high blood pressure-related alleles are associated with increased risk of deep ICH as well as with clinically identified HTN. (Stroke. 2012; 43: 2877-2883.)
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| 9. |
- Anderson, Christopher D., et al.
(författare)
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Common Variants Within Oxidative Phosphorylation Genes Influence Risk of Ischemic Stroke and Intracerebral Hemorrhage
- 2013
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Ingår i: Stroke: a journal of cerebral circulation. - 1524-4628. ; 44:3, s. 612-619
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Tidskriftsartikel (refereegranskat)abstract
- Background and Purpose-Previous studies demonstrated association between mitochondrial DNA variants and ischemic stroke (IS). We investigated whether variants within a larger set of oxidative phosphorylation (OXPHOS) genes encoded by both autosomal and mitochondrial DNA were associated with risk of IS and, based on our results, extended our investigation to intracerebral hemorrhage (ICH). Methods-This association study used a discovery cohort of 1643 individuals, a validation cohort of 2432 individuals for IS, and an extension cohort of 1476 individuals for ICH. Gene-set enrichment analysis was performed on all structural OXPHOS genes, as well as genes contributing to individual respiratory complexes. Gene-sets passing gene-set enrichment analysis were tested by constructing genetic scores using common variants residing within each gene. Associations between each variant and IS that emerged in the discovery cohort were examined in validation and extension cohorts. Results-IS was associated with genetic risk scores in OXPHOS as a whole (odds ratio [OR], 1.17; P=0.008) and complex I (OR, 1.06; P=0.050). Among IS subtypes, small vessel stroke showed association with OXPHOS (OR, 1.16; P=0.007), complex I (OR, 1.13; P=0.027), and complex IV (OR, 1.14; P=0.018). To further explore this small vessel association, we extended our analysis to ICH, revealing association between deep hemispheric ICH and complex IV (OR, 1.08; P=0.008). Conclusions-This pathway analysis demonstrates association between common genetic variants within OXPHOS genes and stroke. The associations for small vessel stroke and deep ICH suggest that genetic variation in OXPHOS influences small vessel pathobiology. Further studies are needed to identify culprit genetic variants and assess their functional consequences. (Stroke. 2013;44:612-619.)
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