| 1. |
- Haycock, Philip C., et al.
(author)
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Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
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In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
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Journal article (peer-reviewed)abstract
- IMPORTANCE: The causal direction and magnitude of the association between telomere length and incidence of cancer and non-neoplastic diseases is uncertain owing to the susceptibility of observational studies to confounding and reverse causation. OBJECTIVE: To conduct a Mendelian randomization study, using germline genetic variants as instrumental variables, to appraise the causal relevance of telomere length for risk of cancer and non-neoplastic diseases. DATA SOURCES: Genomewide association studies (GWAS) published up to January 15, 2015. STUDY SELECTION: GWAS of noncommunicable diseases that assayed germline genetic variation and did not select cohort or control participants on the basis of preexisting diseases. Of 163 GWAS of noncommunicable diseases identified, summary data from 103 were available. DATA EXTRACTION AND SYNTHESIS: Summary association statistics for single nucleotide polymorphisms (SNPs) that are strongly associated with telomere length in the general population. MAIN OUTCOMES AND MEASURES: Odds ratios (ORs) and 95% confidence intervals (CIs) for disease per standard deviation (SD) higher telomere length due to germline genetic variation. RESULTS: Summary data were available for 35 cancers and 48 non-neoplastic diseases, corresponding to 420 081 cases (median cases, 2526 per disease) and 1 093 105 controls (median, 6789 per disease). Increased telomere length due to germline genetic variation was generally associated with increased risk for site-specific cancers. The strongest associations (ORs [ 95% CIs] per 1-SD change in genetically increased telomere length) were observed for glioma, 5.27 (3.15-8.81); serous low-malignant-potential ovarian cancer, 4.35 (2.39-7.94); lung adenocarcinoma, 3.19 (2.40-4.22); neuroblastoma, 2.98 (1.92-4.62); bladder cancer, 2.19 (1.32-3.66); melanoma, 1.87 (1.55-2.26); testicular cancer, 1.76 (1.02-3.04); kidney cancer, 1.55 (1.08-2.23); and endometrial cancer, 1.31 (1.07-1.61). Associations were stronger for rarer cancers and at tissue sites with lower rates of stem cell division. There was generally little evidence of association between genetically increased telomere length and risk of psychiatric, autoimmune, inflammatory, diabetic, and other non-neoplastic diseases, except for coronary heart disease (OR, 0.78 [ 95% CI, 0.67-0.90]), abdominal aortic aneurysm (OR, 0.63 [ 95% CI, 0.49-0.81]), celiac disease (OR, 0.42 [ 95% CI, 0.28-0.61]) and interstitial lung disease (OR, 0.09 [ 95% CI, 0.05-0.15]). CONCLUSIONS AND RELEVANCE: It is likely that longer telomeres increase risk for several cancers but reduce risk for some non-neoplastic diseases, including cardiovascular diseases.
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| 2. |
- Wuttke, Matthias, et al.
(author)
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A catalog of genetic loci associated with kidney function from analyses of a million individuals
- 2019
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In: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 51:6, s. 957-972
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Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is responsible for a public health burden with multi-systemic complications. Through transancestry meta-analysis of genome-wide association studies of estimated glomerular filtration rate (eGFR) and independent replication (n = 1,046,070), we identified 264 associated loci (166 new). Of these,147 were likely to be relevant for kidney function on the basis of associations with the alternative kidney function marker blood urea nitrogen (n = 416,178). Pathway and enrichment analyses, including mouse models with renal phenotypes, support the kidney as the main target organ. A genetic risk score for lower eGFR was associated with clinically diagnosed CKD in 452,264 independent individuals. Colocalization analyses of associations with eGFR among 783,978 European-ancestry individuals and gene expression across 46 human tissues, including tubulo-interstitial and glomerular kidney compartments, identified 17 genes differentially expressed in kidney. Fine-mapping highlighted missense driver variants in 11 genes and kidney-specific regulatory variants. These results provide a comprehensive priority list of molecular targets for translational research.
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| 3. |
- Carraro, Marco, et al.
(author)
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Performance of in silico tools for the evaluation of p16INK4a (CDKN2A) variants in CAGI
- 2017
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In: Human Mutation. - : Hindawi Limited. - 1059-7794 .- 1098-1004. ; 38:9, s. 1042-1050
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Journal article (peer-reviewed)abstract
- Correct phenotypic interpretation of variants of unknown significance for cancer-associated genes is a diagnostic challenge as genetic screenings gain in popularity in the next-generation sequencing era. The Critical Assessment of Genome Interpretation (CAGI) experiment aims to test and define the state of the art of genotype-phenotype interpretation. Here, we present the assessment of the CAGI p16INK4a challenge. Participants were asked to predict the effect on cellular proliferation of 10 variants for the p16INK4a tumor suppressor, a cyclin-dependent kinase inhibitor encoded by the CDKN2A gene. Twenty-two pathogenicity predictors were assessed with a variety of accuracy measures for reliability in a medical context. Different assessment measures were combined in an overall ranking to provide more robust results. The R scripts used for assessment are publicly available from a GitHub repository for future use in similar assessment exercises. Despite a limited test-set size, our findings show a variety of results, with some methods performing significantly better. Methods combining different strategies frequently outperform simpler approaches. The best predictor, Yang&Zhou lab, uses a machine learning method combining an empirical energy function measuring protein stability with an evolutionary conservation term. The p16INK4a challenge highlights how subtle structural effects can neutralize otherwise deleterious variants.
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| 4. |
- Pattaro, Cristian, et al.
(author)
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Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Journal article (peer-reviewed)abstract
- Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways.
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| 5. |
- Satizabal, Claudia L., et al.
(author)
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Genetic architecture of subcortical brain structures in 38,851 individuals
- 2019
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In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 51:11, s. 1624-
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Journal article (peer-reviewed)abstract
- Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.
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| 6. |
- Wang, Hui, et al.
(author)
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Mitochondria-targeted iridium (III) complexes as two-photon fluorogenic probes of cysteine/homocysteine
- 2018
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In: Sensors and actuators. B, Chemical. - : ELSEVIER SCIENCE SA. - 0925-4005 .- 1873-3077. ; 255, s. 408-415
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Journal article (peer-reviewed)abstract
- Fluorescent imaging of cysteine (Cys) and homocysteine (Hcy) is crucial to understand sulphur metabolism in living cells. Whereas two-photon active cyclometalated Ir(III) complex for detecting Cys/Hcy has been rarely reported. Herein, two novel cyclometalated iridium (III) complexes Ir1-1r2 with different electron-donor were designed, synthesized and fully characterized as well as confirmed by single-crystal X-ray diffraction analysis, which could selectively react with Cys/Hcy, accompanying with an obvious one- and two-photon fluorescence enhancement in vitro. The mechanism for sensing Cys/Hcy was further analyzed in detail by mass spectra and time-dependent density functional theory calculations. It was found that Ir2, bearing ester group, exhibited higher performance on the selective detection of Cys and Hcy compared to In. Notably, the two-photon action cross-section value in the near-infrared region (similar to 800 nm) of Ir2 is significantly enhanced upon the addition of Cys/Hcy. Further application to cellular imaging indicated that Ir2 is membrane permeable and capable of monitoring the changes of intracellular mitochondrial Cys/Hcy. These results support that such two-photon active complexes might provide a promising platform for the detection of mitochondrial Cys/Hcy in living biological systems. (C) 2017 Published by Elsevier B.V.
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| 7. |
- Wang, Hui, et al.
(author)
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Two-Photon Active Organotin(IV) Carboxylate Complexes for Visualization of Anticancer Action
- 2017
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In: ACS Biomaterials Science & Engineering. - : AMER CHEMICAL SOC. - 2373-9878. ; 3:5, s. 836-842
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Journal article (peer-reviewed)abstract
- It is still a challenge that organotin(IV) carboxylate complexes with high-performance two-photon activity for cancer therapy. At present work, two novel organotin carboxylate complexes LSn1 and LSn2, containing coumarin moiety, were rationally designed for two-photon fluorescent imaging and anticancer purpose. The complexes possessed large two-photon action cross-sections and high quantum yields. Living cells evaluation revealed that complexes LSn1 and LSn2 exhibited good biocompatibility and deep tissue penetration over femtosecond laser with wavelength of 840 nm. Furthermore, the antitumor active and as well as possible mechanism of complexes LSn1 and LSn2 have been investigated systematically. The results indicated that complexes LSn1 and LSn2 could induce apoptotic cell death through a mitochondria] dysfunction and ROS elevation pathway. The present work provides a strategy for rationally designing organotin(IV) carboxylate complexes with two-photon activity and antitumor activity.
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| 8. |
- Wang, Wen-qiong, et al.
(author)
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Cheese whey protein recovery by ultrafiltration through transglutaminase (TG) catalysis whey protein cross-linking
- 2016
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In: Food Chemistry. - : Elsevier BV. - 0308-8146. ; 215, s. 31-40
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Journal article (peer-reviewed)abstract
- In whey ultrafiltration (UF) production, two main problems are whey protein recovery and membrane fouling. In this study, membrane coupling protein transglutaminase (TG) catalysis protein cross-linking was investigated under different conditions to find out the best treatment. We found that the optimal conditions for protein recovery involved catalyzing whey protein cross-linking with TG (40 U/g whey proteins) at 40 °C for 60 min at pH 5.0. Under these conditions, the recovery rate was increased 15–20%, lactose rejection rate was decreased by 10%, and relative permeate flux was increase 30–40% compared to the sample without enzyme treatment (control). It was noticeable that the total resistance and cake resistance were decreased after enzyme catalysis. This was mainly due to the increased particle size and decreased zeta potential. Therefore, membrane coupling enzyme catalysis protein cross-linking is a potential means for further use.
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| 9. |
- Xu, Chao-Qun, et al.
(author)
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Genome sequence of Malania oleifera, a tree with great value for nervonic acid production
- 2019
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In: GigaScience. - : Oxford University Press. - 2047-217X. ; 8:2
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Journal article (peer-reviewed)abstract
- Background Malania oleifera, a member of the Olacaceae family, is an IUCN red listed tree, endemic and restricted to the Karst region of southwest China. This tree's seed is valued for its high content of precious fatty acids (especially nervonic acid). However, studies on its genetic makeup and fatty acid biogenesis are severely hampered by a lack of molecular and genetic tools. Findings We generated 51 Gb and 135Gb of raw DNA sequences, using Pacific Biosciences (PacBio) single-molecule real-time and 10x Genomics sequencing, respectively. A final genome assembly, with a scaffold N50 size of 4.65 Mb and a total length of 1.51Gb, was obtained by primary assembly based on PacBio long reads plus scaffolding with 10x Genomics reads. Identified repeats constituted approximate to 82% of the genome, and 24,064 protein-coding genes were predicted with high support. The genome has low heterozygosity and shows no evidence for recent whole genome duplication. Metabolic pathway genes relating to the accumulation of long-chain fatty acid were identified and studied in detail. Conclusions Here, we provide the first genome assembly and gene annotation for M. oleifera. The availability of these resources will be of great importance for conservation biology and for the functional genomics of nervonic acid biosynthesis.
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