| 1. |
- 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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| 2. |
- Deng, Min, et al.
(författare)
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Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis
- 2013
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 45:6, s. 697-
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Tidskriftsartikel (refereegranskat)abstract
- To identify susceptibility genes for amyotrophic lateral sclerosis (ALS), we conducted a genome-wide association study (GWAS) in 506 individuals with sporadic ALS and 1,859 controls of Han Chinese ancestry. Ninety top SNPs suggested by the current GWAS and 6 SNPs identified by previous GWAS were analyzed in an independent cohort of 706 individuals with ALS and 1,777 controls of Han Chinese ancestry. We discovered two new susceptibility loci for ALS at 1q32 (CAMK1G, rs6703183, P-combined = 2.92 x 10(-8), odds ratio (OR) = 1.31) and 22p11 (CABIN1 and SUSD2, rs8141797, P-combined = 2.35 x 10(-9), OR = 1.52). These two loci explain 12.48% of the overall variance in disease risk in the Han Chinese population. We found no association evidence for the previously reported loci in the Han Chinese population, suggesting genetic heterogeneity of disease susceptibility for ALS between ancestry groups. Our study identifies two new susceptibility loci and suggests new pathogenic mechanisms of ALS.
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| 3. |
- Weinstein, John N., et al.
(författare)
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The cancer genome atlas pan-cancer analysis project
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:10, s. 1113-1120
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Forskningsöversikt (refereegranskat)abstract
- The Cancer Genome Atlas (TCGA) Research Network has profiled and analyzed large numbers of human tumors to discover molecular aberrations at the DNA, RNA, protein and epigenetic levels. The resulting rich data provide a major opportunity to develop an integrated picture of commonalities, differences and emergent themes across tumor lineages. The Pan-Cancer initiative compares the first 12 tumor types profiled by TCGA. Analysis of the molecular aberrations and their functional roles across tumor types will teach us how to extend therapies effective in one cancer type to others with a similar genomic profile. © 2013 Nature America, Inc. All rights reserved.
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| 5. |
- Dong, Yaa-Hui, et al.
(författare)
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Use of Inhaled Corticosteroids in Patients With COPD and the Risk of TB and Influenza A Systematic Review and Meta-analysis of Randomized Controlled Trials
- 2014
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Ingår i: Chest. - : Elsevier BV. - 1931-3543 .- 0012-3692. ; 145:6, s. 1286-1297
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Tidskriftsartikel (refereegranskat)abstract
- Background: The use of inhaled corticosteroids (ICSs) is associated with an increased risk of pneumonia in patients with COPD. However the risks of other respiratory infections such as TB and influenza remain unclear. Methods: Through a comprehensive literature search of MEDLINE EMBASE CINAHL Cochrane Library and ClinicalTrials.gov from inception to July 2013 we identified randomized controlled trials of ICS therapy lasting at least 6 months. We conducted meta-analyses by the Peto Mantel-Haenszel and Bayesian approaches to generate summary estimates comparing ICS with non-ICS treatment on the risk of TB and influenza. Results: Twenty-five trials (22,898 subjects) for TB and 26 trials (23,616 subjects) for influenza were included. Compared with non-ICS treatment ICS treatment was associated with a significantly higher risk of TB (Peto OR 2.29 95% CI 1.04-5.03) but not influenza (Peto OR 1.24 95% CI 0.94-1.63). Results were similar with each meta-analytic approach. Furthermore the number needed to harm to cause one additional TB event was lower for patients with COPD treated with ICSs in endemic areas than for those in nonendemic areas (909 vs 1,667 respectively). Conclusions: This study raises safety concerns about the risk of TB and influenza associated with ICS use in patients with COPD which deserve further investigation.
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| 6. |
- Lango Allen, Hana, et al.
(författare)
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Hundreds of variants clustered in genomic loci and biological pathways affect human height.
- 2010
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Ingår i: Nature. - : Springer Science and Business Media LLC. - 1476-4687 .- 0028-0836. ; 467:7317, s. 832-8
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Tidskriftsartikel (refereegranskat)abstract
- Most common human traits and diseases have a polygenic pattern of inheritance: DNA sequence variants at many genetic loci influence the phenotype. Genome-wide association (GWA) studies have identified more than 600 variants associated with human traits, but these typically explain small fractions of phenotypic variation, raising questions about the use of further studies. Here, using 183,727 individuals, we show that hundreds of genetic variants, in at least 180 loci, influence adult height, a highly heritable and classic polygenic trait. The large number of loci reveals patterns with important implications for genetic studies of common human diseases and traits. First, the 180 loci are not random, but instead are enriched for genes that are connected in biological pathways (P = 0.016) and that underlie skeletal growth defects (P<0.001). Second, the likely causal gene is often located near the most strongly associated variant: in 13 of 21 loci containing a known skeletal growth gene, that gene was closest to the associated variant. Third, at least 19 loci have multiple independently associated variants, suggesting that allelic heterogeneity is a frequent feature of polygenic traits, that comprehensive explorations of already-discovered loci should discover additional variants and that an appreciable fraction of associated loci may have been identified. Fourth, associated variants are enriched for likely functional effects on genes, being over-represented among variants that alter amino-acid structure of proteins and expression levels of nearby genes. Our data explain approximately 10% of the phenotypic variation in height, and we estimate that unidentified common variants of similar effect sizes would increase this figure to approximately 16% of phenotypic variation (approximately 20% of heritable variation). Although additional approaches are needed to dissect the genetic architecture of polygenic human traits fully, our findings indicate that GWA studies can identify large numbers of loci that implicate biologically relevant genes and pathways.
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| 9. |
- Wang, Yi-Qiang, et al.
(författare)
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Analysis of expressed sequence tags from Ginkgo mature foliage in China
- 2010
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Ingår i: TREE GENET GENOMES. - : Springer Science and Business Media LLC. - 1614-2942 .- 1614-2950. ; 6:3, s. 357-365
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Tidskriftsartikel (refereegranskat)abstract
- Ginkgo biloba L. is a tree native to China, which has large importance within medicine and horticulture. The extracts from Ginkgo mature leaves with rich flavonoids and terpenoids are commonly used for a variety of folk remedies. We constructed a cDNA library derived from mature leaves of Ginkgo, which consisted of 8.12 x 10(5) clones with the insert length of 500-2,000 bp. We performed an analysis of expressed sequence tags (ESTs) and obtained partial sequences from 2,039 clones, which represented 1,437 unigenes consisting of 249 contigs and 1,188 singletons. The 2,039 ESTs were submitted to GenBank (dbEST) at NCBI and were assigned GenBank accession numbers from GE647881 to GE649919. The 1,235 cDNA clones out of 2,039 (60.1%) were assigned putative functions, and the remaining 804 clones were not similar to any known gene sequences in the databases. The five largest categories of Ginkgo clones were: "energy" (19.4%), "disease/defense" (16%), "metabolism" (11.3%), "unclassified proteins" (12.5%), and "secondary metabolism" (9%). The highly expressed transcripts in the cDNA library were some genes related to photosynthesis, disease/defense, and flavonoid biosynthesis, including ribulose-bisphosphate carboxylase small-chain gene, pathogenesis-related protein gene, light-harvesting chlorophyll a/b binding protein of photosystem gene, catalase gene, and phenylcoumaran benzylic ether reductase gene et al. Many genes with ESTs similar to photosynthesis, secondary metabolism, and stress-response genes were characterized. The analysis of ESTs indicates that it is a useful approach for isolating Ginkgo genes homologous to known genes. Our results provide new information about mature leaf-specific transcripts of Ginkgo.
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| 10. |
- Zhang, Wei, et al.
(författare)
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Activation of nuclear factor-kappa B pathway is responsible for tumor necrosis factor-a-induced up-regulation of endothelin B2 receptor expression in vascular smooth muscle cells in vitro
- 2012
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Ingår i: Toxicology Letters. - : Elsevier BV. - 1879-3169 .- 0378-4274. ; 209:2, s. 107-112
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Tidskriftsartikel (refereegranskat)abstract
- The endothelin B2 (ETB2) receptors are induced in vascular smooth muscle cells (VSMCs) in cardiovascular diseases. We tested if in vitro short-term exposure to the pro-inflammatory cytokine tumor necrosis factor-alpha (TNF-alpha) could up-regulate ETB2 receptors in rat mesenteric arteries, and if this effect is through activation of intracellular nuclear factor-kappa B (NF-kappa B) pathway. The mesenteric arteries were dissected from male Sprague-Dawley rats and the endothelium was removed. The arteries were co-incubated with TNF-alpha in serum-free Dulbecco's modified Eagle's medium. Real-time reverse transcription-PCR, Western blot and immunohistochemical staining were employed to assess the mRNA/protein expression of ETB2 receptors and activation of NF-kappa B pathway. The results showed that, during organ culture. TNF-alpha concentration-dependently enhanced ET52 receptors expression at both mRNA and protein levels, paralleled with activation of NF-kappa B pathway in VSMC. The up-regulated ETB2 receptor expression and NF-kappa B activation could be effectively suppressed by general transcriptional inhibitor actinomycin D, or either of the selective I kappa B kinase inhibitors wedelolactone and IMD-0354. Conclusively, the activation of intracellular NF-kappa B pathway is responsible for the up-regulation of ETB2 receptors induced by short-term exposure to TNF-alpha. This could partly explain the toxic effects of TNF-alpha on VSMCs that account for cardiovascular diseases. (C) 2011 Elsevier Ireland Ltd. All rights reserved.
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