| 161. |
- Hochberg, Georg K A, et al.
(author)
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Structural principles that enable oligomeric small heat-shock protein paralogs to evolve distinct functions.
- 2018
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In: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 359:6378, s. 930-935
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Journal article (peer-reviewed)abstract
- Oligomeric proteins assemble with exceptional selectivity, even in the presence of closely related proteins, to perform their cellular roles. We show that most proteins related by gene duplication of an oligomeric ancestor have evolved to avoid hetero-oligomerization and that this correlates with their acquisition of distinct functions. We report how coassembly is avoided by two oligomeric small heat-shock protein paralogs. A hierarchy of assembly, involving intermediates that are populated only fleetingly at equilibrium, ensures selective oligomerization. Conformational flexibility at noninterfacial regions in the monomers prevents coassembly, allowing interfaces to remain largely conserved. Homomeric oligomers must overcome the entropic benefit of coassembly and, accordingly, homomeric paralogs comprise fewer subunits than homomers that have no paralogs.
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| 162. |
- Jhavar, Sameer, et al.
(author)
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Integration of ERG gene mapping and gene-expression profiling identifies distinct categories of human prostate cancer
- 2009
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In: BJU International. - 1464-4096. ; 103:9, s. 1256-1269
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Journal article (peer-reviewed)abstract
- OBJECTIVE To integrate the mapping of ERG alterations with the collection of expression microarray (EMA) data, as previous EMA analyses have failed to consider the genetic heterogeneity and complex patterns of ERG alteration frequently found in cancerous prostates. MATERIALS AND METHODS We determined genome-wide expression levels with GeneChip Human Exon 1.0 ST arrays (Affymetrix, Santa Clara, CA, USA) using RNA prepared from 35 specimens of prostate cancer from 28 prostates. RESULTS The expression profiles showed clustering, in unsupervised hierarchical analyses, into two distinct prostate cancer categories, with one group strongly associated with indicators of poor clinical outcome. The two categories are not tightly linked to ERG status. By analysis of the data we identified a subgroup of cancers lacking ERG rearrangements that showed an outlier pattern of SPINK1 mRNA expression. There was a major distinction between ERG rearranged and non-rearranged cancers that involves the levels of expression of genes linked to exposure to beta-oestradiol, and to retinoic acid. CONCLUSIONS Expression profiling of prostate cancer samples containing single patterns of ERG alterations can provide novel insights into the mechanism of prostate cancer development, and support the view that factors other than ERG status are the major determinants of poor clinical outcome.
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| 163. |
- Ji, Xuemei, et al.
(author)
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Protein-altering germline mutations implicate novel genes related to lung cancer development
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- Few germline mutations are known to affect lung cancer risk. We performed analyses of rare variants from 39,146 individuals of European ancestry and investigated gene expression levels in 7,773 samples. We find a large-effect association with an ATM L2307F (rs56009889) mutation in adenocarcinoma for discovery (adjusted Odds Ratio=8.82, P=1.18x10(-15)) and replication (adjusted OR=2.93, P=2.22x10(-3)) that is more pronounced in females (adjusted OR=6.81 and 3.19 and for discovery and replication). We observe an excess loss of heterozygosity in lung tumors among ATM L2307F allele carriers. L2307F is more frequent (4%) among Ashkenazi Jewish populations. We also observe an association in discovery (adjusted OR=2.61, P=7.98x10(-22)) and replication datasets (adjusted OR=1.55, P=0.06) with a loss-of-function mutation, Q4X (rs150665432) of an uncharacterized gene, KIAA0930. Our findings implicate germline genetic variants in ATM with lung cancer susceptibility and suggest KIAA0930 as a novel candidate gene for lung cancer risk. In lung cancer, relatively few germline mutations are known to impact risk. Here the authors looked at rare variants in 39,146 individuals and find novel germline mutations associated with risk, as well as implicating ATM and a new candidate gene for lung cancer risk.
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| 164. |
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| 165. |
- Lees, William, et al.
(author)
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OGRDB : a reference database of inferred immune receptor genes
- 2020
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In: Nucleic Acids Research. - : Oxford University Press (OUP). - 1362-4962 .- 0305-1048. ; 48:D1, s. 964-970
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Journal article (peer-reviewed)abstract
- High-throughput sequencing of the adaptive immune receptor repertoire (AIRR-seq) is providing unprecedented insights into the immune response to disease and into the development of immune disorders. The accurate interpretation of AIRR-seq data depends on the existence of comprehensive germline gene reference sets. Current sets are known to be incomplete and unrepresentative of the degree of polymorphism and diversity in human and animal populations. A key issue is the complexity of the genomic regions in which they lie, which, because of the presence of multiple repeats, insertions and deletions, have not proved tractable with short-read whole genome sequencing. Recently, tools and methods for inferring such gene sequences from AIRR-seq datasets have become available, and a community approach has been developed for the expert review and publication of such inferences. Here, we present OGRDB, the Open Germline Receptor Database (https://ogrdb.airr-community.org), a public resource for the submission, review and publication of previously unknown receptor germline sequences together with supporting evidence.
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| 166. |
- Li, Li, et al.
(author)
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Insulin induces SOCS-6 expression and its binding to the p85 monomer of phosphoinositide 3-kinase, resulting in improvement in glucose metabolism
- 2004
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In: Journal of Biological Chemistry. - 1083-351X. ; 279:33, s. 34107-34114
-
Journal article (peer-reviewed)abstract
- The suppressors of cytokine signaling ( SOCS) family is thought to act largely as a negative regulator of signaling by cytokines and some growth factors. Surprisingly, the SOCS-6 transgenics had no significant defects in the cytokine signaling and hematopoietic system but displayed significant improvements in glucose metabolism. Insulin stimulation of Akt/protein kinase B was also potentiated. Biochemical analysis showed that, after insulin stimulation, SOCS-6 interacted with the monomeric p85 subunit of class-Ia phosphoinositide ( PI) 3-kinase but not with p85/p110 dimers. Furthermore, SOCS-6 expression is transiently increased by serum and insulin in normal fibroblasts. However, both the mRNA and protein of SOCS-6 were rapidly degraded after induction by insulin. The degradation of the SOCS-6 protein was partially inhibited by a proteasome inhibitor, suggesting a proteasome-mediated degradation mechanism. In contrast, SOCS-6- associated p85 was not degraded and could be recruited to the newly synthesized SOCS-6 molecules in the presence of insulin, suggesting that SOCS-6 expression and its interaction with p85, but not the degradation, is regulated by insulin. The phenotype of SOCS-6 transgenic mice bears a striking resemblance to p85 knock-out mouse models in which glucose metabolism stimulated by insulin is significantly improved despite reduced activation of PI 3-kinase. This suggests that monomeric p85 might play a physiologically important role in attenuating signaling through PI 3-kinase-dependent pathways in unstimulated cells. Therefore, our results indicate that SOCS-6 may provide a dynamically regulated mechanism by which insulin can transiently overcome the negative effects that p85 monomers have on signaling via PI 3-kinase-dependent signaling pathways.
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| 167. |
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| 168. |
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| 169. |
- Maina, David M., et al.
(author)
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Environmental implications of high metal content in soils of a titanium mining zone in Kenya
- 2016
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In: Environmental Science and Pollution Research. - : Springer Science and Business Media LLC. - 0944-1344 .- 1614-7499. ; 23:21, s. 21431-21440
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Journal article (peer-reviewed)abstract
- Mining activities contribute to an increase of specific metal contaminants in soils. This may adversely affect plant life and consequently impact on animal and human health. The objective of this study was to obtain the background metal concentrations in soils around the titanium mining in Kwale County for monitoring its environmental impacts. Forty samples were obtained with half from topsoils and the other from subsoils. X-ray fluorescence spectrometry was used to determine the metal content of the soil samples. High concentrations of Ti, Mn, Fe, and Zr were observed where Ti concentrations ranged from 0.47 to 2.8 %; Mn 0.02 to 3.1 %; Fe 0.89 to 3.1 %; and Zr 0.05 to 0.85 %. Using ratios of elemental concentrations in topsoil to subsoil method and enrichment factors concept, the metals were observed to be of geogenic origin with no anthropogenic input. The high concentrations of Mn and Fe may increase their concentration levels in the surrounding agricultural lands through deposition, thereby causing contamination on the land and the cultivated food crops. The latter can cause adverse human health effects. In addition, titanium mining will produce tailings containing low-level titanium concentrations, which will require proper disposal to avoid increasing titanium concentrations in the soils of the region since it has been observed to be phytotoxic to plants at high concentrations. The results of this study will serve as reference while monitoring the environmental impact by the titanium mining activities.
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| 170. |
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