| 1. |
- Haycock, Philip C., et al.
(author)
-
Association Between Telomere Length and Risk of Cancer and Non-Neoplastic Diseases A Mendelian Randomization Study
- 2017
-
In: JAMA Oncology. - : American Medical Association. - 2374-2437 .- 2374-2445. ; 3:5, s. 636-651
-
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. |
- Locke, Adam E, et al.
(author)
-
Genetic studies of body mass index yield new insights for obesity biology.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 197-401
-
Journal article (peer-reviewed)abstract
- Obesity is heritable and predisposes to many diseases. To understand the genetic basis of obesity better, here we conduct a genome-wide association study and Metabochip meta-analysis of body mass index (BMI), a measure commonly used to define obesity and assess adiposity, in up to 339,224 individuals. This analysis identifies 97 BMI-associated loci (P < 5 × 10(-8)), 56 of which are novel. Five loci demonstrate clear evidence of several independent association signals, and many loci have significant effects on other metabolic phenotypes. The 97 loci account for ∼2.7% of BMI variation, and genome-wide estimates suggest that common variation accounts for >20% of BMI variation. Pathway analyses provide strong support for a role of the central nervous system in obesity susceptibility and implicate new genes and pathways, including those related to synaptic function, glutamate signalling, insulin secretion/action, energy metabolism, lipid biology and adipogenesis.
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| 3. |
- Rydberg Sterner, Therese, et al.
(author)
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The Gothenburg H70 Birth cohort study 2014-16: design, methods and study population.
- 2019
-
In: European journal of epidemiology. - : Springer Science and Business Media LLC. - 1573-7284 .- 0393-2990. ; 34:2, s. 191-209
-
Journal article (peer-reviewed)abstract
- To improve health care for older persons, we need to learn more about ageing, e.g. identify protective factors and early markers for diseases. The Gothenburg H70 Birth Cohort Studies (the H70 studies) are multidisciplinary epidemiological studies examining representative birth cohorts of older populations in Gothenburg, Sweden. So far, six birth cohorts of 70-year-olds have been examined over time, and examinations have been virtually identical between studies. This paper describes the study procedures for the baseline examination of the Birth cohort 1944, conducted in 2014-16. In this study, all men and women born 1944 on specific dates, and registered as residents in Gothenburg, were eligible for participation (n=1839). A total of 1203 (response rate 72.2%; 559 men and 644 women; mean age 70.5years) agreed to participate in the study. The study comprised sampling of blood and cerebrospinal fluid, psychiatric, cognitive, and physical health examinations, examinations of genetics and family history, use of medications, social factors, functional ability and disability, physical fitness and activity, body composition, lung function, audiological and ophthalmological examinations, diet, brain imaging, as well as a close informant interview, and qualitative studies. As in previous examinations, data collection serves as a basis for future longitudinal follow-up examinations. The research gained from the H70 studies has clinical relevance in relation to prevention, early diagnosis, clinical course, experience of illness, understanding pathogenesis and prognosis. Results will increase our understanding of ageing and inform service development, which may lead to enhanced quality of care for older persons.
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| 4. |
- Shungin, Dmitry, et al.
(author)
-
New genetic loci link adipose and insulin biology to body fat distribution.
- 2015
-
In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 518:7538, s. 187-378
-
Journal article (peer-reviewed)abstract
- Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms.
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| 5. |
- Abbafati, Cristiana, et al.
(author)
-
- 2020
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Journal article (peer-reviewed)
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| 6. |
- Bentham, James, et al.
(author)
-
A century of trends in adult human height
- 2016
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In: eLIFE. - 2050-084X. ; 5
-
Journal article (peer-reviewed)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.522.7) and 16.5 cm (13.319.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 7. |
- Bentham, James, et al.
(author)
-
A century of trends in adult human height
- 2016
-
In: eLIFE. - : eLife Sciences Publications Ltd. - 2050-084X. ; 5
-
Journal article (peer-reviewed)abstract
- Being taller is associated with enhanced longevity, and higher education and earnings. We reanalysed 1472 population-based studies, with measurement of height on more than 18.6 million participants to estimate mean height for people born between 1896 and 1996 in 200 countries. The largest gain in adult height over the past century has occurred in South Korean women and Iranian men, who became 20.2 cm (95% credible interval 17.5–22.7) and 16.5 cm (13.3– 19.7) taller, respectively. In contrast, there was little change in adult height in some sub-Saharan African countries and in South Asia over the century of analysis. The tallest people over these 100 years are men born in the Netherlands in the last quarter of 20th century, whose average heights surpassed 182.5 cm, and the shortest were women born in Guatemala in 1896 (140.3 cm; 135.8– 144.8). The height differential between the tallest and shortest populations was 19-20 cm a century ago, and has remained the same for women and increased for men a century later despite substantial changes in the ranking of countries.
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| 8. |
- Chasman, Daniel I., et al.
(author)
-
Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
-
In: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
-
Journal article (peer-reviewed)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 9. |
- Daelman, Bo, et al.
(author)
-
Frailty and cognitive function in middle-aged and older adults with congenital heart disease
- 2024
-
In: Journal of the American College of Cardiology. - : Elsevier. - 0735-1097 .- 1558-3597. ; 83:12, s. 1149-1159
-
Journal article (peer-reviewed)abstract
- Background: Life expectancy of patients with congenital heart disease (CHD) has increased rapidly, resulting in a growing and aging population. Recent studies have shown that older people with CHD have higher morbidity, health care use, and mortality. To maintain longevity and quality of life, understanding their evolving medical and psychosocial challenges is essential.Objectives: The authors describe the frailty and cognitive profile of middle-aged and older adults with CHD to identify predictor variables and to explore the relationship with hospital admissions and outpatient visits.Methods: Using a cross-sectional, multicentric design, we included 814 patients aged ≥40 years from 11 countries. Frailty phenotype was determined using the Fried method. Cognitive function was assessed by the Montreal Cognitive Assessment.Results: In this sample, 52.3% of patients were assessed as robust, 41.9% as prefrail, and 5.8% as frail; 38.8% had cognitive dysfunction. Multinomial regression showed that frailty was associated with older age, female sex, higher physiologic class, and comorbidities. Counterintuitively, patients with mild heart defects were more likely than those with complex lesions to be prefrail. Patients from middle-income countries displayed more prefrailty than those from higher-income countries. Logistic regression demonstrated that cognitive dysfunction was related to older age, comorbidities, and lower country-level income.Conclusions: Approximately one-half of included patients were (pre-)frail, and more than one-third experienced cognitive impairment. Frailty and cognitive dysfunction were identified in patients with mild CHD, indicating that these concerns extend beyond severe CHD. Assessing frailty and cognition routinely could offer valuable insights into this aging population.
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| 10. |
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| 11. |
- Edberg, Niklas J. T., et al.
(author)
-
Spatial distribution of low-energy plasma around comet 67P/CG from Rosetta measurements
- 2015
-
In: Geophysical Research Letters. - 0094-8276 .- 1944-8007. ; 42:11, s. 4263-4269
-
Journal article (peer-reviewed)abstract
- We use measurements from the Rosetta plasma consortium Langmuir probe and mutual impedance probe to study the spatial distribution of low-energy plasma in the near-nucleus coma of comet 67P/Churyumov-Gerasimenko. The spatial distribution is highly structured with the highest density in the summer hemisphere and above the region connecting the two main lobes of the comet, i.e., the neck region. There is a clear correlation with the neutral density and the plasma to neutral density ratio is found to be approximate to 1-210(-6), at a cometocentric distance of 10km and at 3.1AU from the Sun. A clear 6.2h modulation of the plasma is seen as the neck is exposed twice per rotation. The electron density of the collisionless plasma within 260km from the nucleus falls off with radial distance as approximate to 1/r. The spatial structure indicates that local ionization of neutral gas is the dominant source of low-energy plasma around the comet.
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| 12. |
- Köttgen, Anna, et al.
(author)
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New loci associated with kidney function and chronic kidney disease
- 2010
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:5, s. 376-384
-
Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is a significant public health problem, and recent genetic studies have identified common CKD susceptibility variants. The CKDGen consortium performed a meta-analysis of genome-wide association data in 67,093 individuals of European ancestry from 20 predominantly population-based studies in order to identify new susceptibility loci for reduced renal function as estimated by serum creatinine (eGFRcrea), serum cystatin c (eGFRcys) and CKD (eGFRcrea < 60 ml/min/1.73 m2; n = 5,807 individuals with CKD (cases)). Follow-up of the 23 new genome-wide–significant loci (P < 5 × 10−8) in 22,982 replication samples identified 13 new loci affecting renal function and CKD (in or near LASS2, GCKR, ALMS1, TFDP2, DAB2, SLC34A1, VEGFA, PRKAG2, PIP5K1B, ATXN2, DACH1, UBE2Q2 and SLC7A9) and 7 loci suspected to affect creatinine production and secretion (CPS1, SLC22A2, TMEM60, WDR37, SLC6A13, WDR72 and BCAS3). These results further our understanding of the biologic mechanisms of kidney function by identifying loci that potentially influence nephrogenesis, podocyte function, angiogenesis, solute transport and metabolic functions of the kidney.
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| 13. |
- Parsa, Afshin, et al.
(author)
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Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
- 2013
-
In: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
-
Journal article (peer-reviewed)abstract
- Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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| 14. |
- Pattaro, Cristian, et al.
(author)
-
Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function
- 2016
-
In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
-
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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| 15. |
- Pattaro, Cristian, et al.
(author)
-
Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
-
Journal article (peer-reviewed)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
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| 16. |
- Speliotes, Elizabeth K., et al.
(author)
-
Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index
- 2010
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 42:11, s. 937-948
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Journal article (peer-reviewed)abstract
- Obesity is globally prevalent and highly heritable, but its underlying genetic factors remain largely elusive. To identify genetic loci for obesity susceptibility, we examined associations between body mass index and ~2.8 million SNPs in up to 123,865 individuals with targeted follow up of 42 SNPs in up to 125,931 additional individuals. We confirmed 14 known obesity susceptibility loci and identified 18 new loci associated with body mass index (P < 5 × 10−8), one of which includes a copy number variant near GPRC5B. Some loci (at MC4R, POMC, SH2B1 and BDNF) map near key hypothalamic regulators of energy balance, and one of these loci is near GIPR, an incretin receptor. Furthermore, genes in other newly associated loci may provide new insights into human body weight regulation.
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| 17. |
- Turcot, Valerie, et al.
(author)
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Protein-altering variants associated with body mass index implicate pathways that control energy intake and expenditure in obesity
- 2018
-
In: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 50:1, s. 26-41
-
Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWAS) have identified >250 loci for body mass index (BMI), implicating pathways related to neuronal biology. Most GWAS loci represent clusters of common, noncoding variants from which pinpointing causal genes remains challenging. Here we combined data from 718,734 individuals to discover rare and low-frequency (minor allele frequency (MAF) < 5%) coding variants associated with BMI. We identified 14 coding variants in 13 genes, of which 8 variants were in genes (ZBTB7B, ACHE, RAPGEF3, RAB21, ZFHX3, ENTPD6, ZFR2 and ZNF169) newly implicated in human obesity, 2 variants were in genes (MC4R and KSR2) previously observed to be mutated in extreme obesity and 2 variants were in GIPR. The effect sizes of rare variants are similar to 10 times larger than those of common variants, with the largest effect observed in carriers of an MC4R mutation introducing a stop codon (p.Tyr35Ter, MAF = 0.01%), who weighed similar to 7 kg more than non-carriers. Pathway analyses based on the variants associated with BMI confirm enrichment of neuronal genes and provide new evidence for adipocyte and energy expenditure biology, widening the potential of genetically supported therapeutic targets in obesity.
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| 18. |
- Wilson, Christopher, 1974, et al.
(author)
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Observation of the dynamical Casimir effect in a superconducting circuit
- 2011
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In: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 479:7373, s. 376-9
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Journal article (peer-reviewed)abstract
- One of the most surprising predictions of modern quantum theory is that the vacuum of space is not empty. In fact, quantum theory predicts that it teems with virtual particles flitting in and out of existence. Although initially a curiosity, it was quickly realized that these vacuum fluctuations had measurable consequences-for instance, producing the Lamb shift of atomic spectra and modifying the magnetic moment of the electron. This type of renormalization due to vacuum fluctuations is now central to our understanding of nature. However, these effects provide indirect evidence for the existence of vacuum fluctuations. From early on, it was discussed whether it might be possible to more directly observe the virtual particles that compose the quantum vacuum. Forty years ago, it was suggested that a mirror undergoing relativistic motion could convert virtual photons into directly observable real photons. The phenomenon, later termed the dynamical Casimir effect, has not been demonstrated previously. Here we observe the dynamical Casimir effect in a superconducting circuit consisting of a coplanar transmission line with a tunable electrical length. The rate of change of the electrical length can be made very fast (a substantial fraction of the speed of light) by modulating the inductance of a superconducting quantum interference device at high frequencies (>10 gigahertz). In addition to observing the creation of real photons, we detect two-mode squeezing in the emitted radiation, which is a signature of the quantum character of the generation process.
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| 19. |
- Aguilar, J., et al.
(author)
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Search for Leptonic CP Violation with the ESSnuSBplus Project
- 2024
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In: Letters in High Energy Physics. - : Andromeda Publishing And Academic Services LTD. - 2632-2714.
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Journal article (peer-reviewed)abstract
- ESSνSB is a design study for a next-generation long-baseline neutrino experiment that aims at the precise measurement of the CP-violating phase, δCP, in the leptonic sector at the second oscillation maximum. The conceptual design report published from the first phase of the project showed that after 10 years of data taking, more than 70% of the possible δCP range will be covered with 5σ C.L. to reject the no-CP-violation hypothesis. The expected value of δCP precision is smaller than 8◦ for all δCP values. The next phase of the project, the ESSνSB+, aims at using the intense muon flux produced together with neutrinos to measure the neutrino-nucleus cross-section, the dominant term of the systematic uncertainty, in the energy range of 0.2–0.6 GeV, using a Low Energy neutrinos from STORed Muons (LEnuSTORM) and a Low Energy Monitored Neutrino Beam (LEMNB) facilities.
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| 20. |
- Aguilar, J., et al.
(author)
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Study of nonstandard interactions mediated by a scalar field at the ESSnuSB experiment
- 2024
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In: Physical Review D. - : American Physical Society. - 2470-0010 .- 2470-0029. ; 109:11
-
Journal article (peer-reviewed)abstract
- In this paper, we study scalar mediator induced nonstandard interactions (SNSIs) in the context of the ESSnuSB experiment. In particular, we study the capability of ESSnuSB to put bounds on the SNSI parameters and also study the impact of SNSIs in the measurement of the leptonic CP phase δCP. Existence of SNSIs modifies the neutrino mass matrix and this modification can be expressed in terms of three diagonal real parameters (ηee, ημμ, and ηττ) and three off-diagonal complex parameters (ηeμ, ηeτ, and ημτ). Our study shows that the upper bounds on the parameters ημμ and ηττ depend upon how Δm312 is minimized in the theory. However, this is not the case when one tries to measure the impact of SNSIs on δCP. Further, we show that the CP sensitivity of ESSnuSB can be completely lost for certain values of ηee and ημτ for which the appearance channel probability becomes independent of δCP.
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| 21. |
- Aguilar, J., et al.
(author)
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Study of nonstandard interactions mediated by a scalar field at the ESSnuSB experiment
- 2024
-
In: Physical Review D. - : American Physical Society (APS). - 2470-0010 .- 2470-0029. ; 109:11
-
Journal article (peer-reviewed)abstract
- In this paper, we study scalar mediator induced nonstandard interactions (SNSIs) in the context of the ESSnuSB experiment. In particular, we study the capability of ESSnuSB to put bounds on the SNSI parameters and also study the impact of SNSIs in the measurement of the leptonic ?? phase ???. Existence of SNSIs modifies the neutrino mass matrix and this modification can be expressed in terms of three diagonal real parameters (???, ???, and ???) and three off-diagonal complex parameters (???, ???, and ???). Our study shows that the upper bounds on the parameters ??? and ??? depend upon how Δ?231 is minimized in the theory. However, this is not the case when one tries to measure the impact of SNSIs on ???. Further, we show that the ?? sensitivity of ESSnuSB can be completely lost for certain values of ??? and ??? for which the appearance channel probability becomes independent of ???.
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| 22. |
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| 23. |
- Almers, Peter, et al.
(author)
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Exercises
- 2005
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In: Wireless Communications. - 9780470848883 - 047084888X - 0470848871 ; , s. 561-593
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Book chapter (other academic/artistic)
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| 24. |
- Andersson, G., et al.
(author)
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Cyber-security of SCADA systems
- 2012
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In: 2012 IEEE PES Innovative Smart Grid Technologies, ISGT 2012. - : IEEE. - 9781457721588 ; , s. 6175543-
-
Conference paper (peer-reviewed)abstract
- After a general introduction of the VIKING EU FP7 project two specific cyber-attack mechanisms, which have been analyzed in the VIKING project, will be discussed in more detail. Firstly an attack and its consequences on the Automatic Generation Control (AGC) in a power system are investigated, and secondly the cyber security of State Estimators in SCADA systems is scrutinized.
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| 25. |
- Andrade-Talavera, Yuniesky, et al.
(author)
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S100A9 amyloid growth and S100A9 fibril-induced impairment of gamma oscillations in area CA3 of mouse hippocampus ex vivo is prevented by Bri2 BRICHOS
- 2022
-
In: Progress in Neurobiology. - : Elsevier. - 0301-0082 .- 1873-5118. ; 219
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Journal article (peer-reviewed)abstract
- The pro-inflammatory and highly amyloidogenic protein S100A9 is central to the amyloid-neuroinflammatory cascade in neurodegenerative diseases leading to cognitive impairment. Molecular chaperone activity of Bri2 BRICHOS has been demonstrated against a range of amyloidogenic polypeptides. Using a combination of thioflavin T fluorescence kinetic assay, atomic force microscopy and immuno electron microscopy we show here that recombinant Bri2 BRICHOS effectively inhibits S100A9 amyloid growth by capping amyloid fibrils. Using ex-vivo neuronal network electrophysiology in mouse brain slices we also show that both native S100A9 and amyloids of S100A9 disrupt cognition-relevant gamma oscillation power and rhythmicity in hippocampal area CA3 in a time- and protein conformation-dependent manner. Both effects were associated with Toll-like receptor 4 (TLR4) activation and were not observed upon TLR4 blockade. Importantly, S100A9 that had co-aggregated with Bri2 BRICHOS did not elicit degradation of gamma oscillations. Taken together, this work provides insights on the potential influence of S100A9 on cognitive dysfunction in Alzheimer's disease (AD) via gamma oscillation impairment from experimentally-induced gamma oscillations, and further highlights Bri2 BRICHOS as a chaperone against detrimental effects of amyloid self-assembly.
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| 26. |
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| 27. |
- André, Camilla, et al.
(author)
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Recurrence and survival after standard versus oncoplastic breast-conserving surgery for breast cancer
- 2021
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In: BJS Open. - : Oxford University Press. - 2474-9842. ; 5:1
-
Journal article (peer-reviewed)abstract
- Background: Oncoplastic techniques in breast-conserving surgery (BCS) are used increasingly for larger tumours. This large cohort study aimed to assess oncological outcomes after oncoplastic BCS (OPS) versus standard BCS.Methods: Data for all women who had BCS in three centres in Stockholm during 2010-2016 were extracted from the Swedish National Breast Cancer Register. All patients with T2-3 tumours, all those receiving neoadjuvant treatment, and an additional random sample of women with T1 tumours were selected. Medical charts were reviewed for local recurrences and surgical technique according to the Hoffman-Wallwiener classification. Date and cause of death were retrieved from the Swedish Cause of Death Register.Results: The final cohort of 4178 breast cancers in 4135 patients was categorized into three groups according to surgical technique: 3720 for standard BCS, 243 simple OPS, and 215 complex OPS. Median duration of follow up was 64 (range 24-110) months. Node-positive and large tumours were more common in OPS than in standard BCS (P < 0.001). There were 61 local recurrences: 57 (1.5 per cent), 1 (0.4 per cent) and 3 (1.4 per cent) in the standard BCS, simple OPS and complex OPS groups respectively (P = 0.368). Overall, 297 patients died, with an unadjusted 5-year overall survival rate of 94.7, 93.1 and 92.6 per cent respectively (P = 0.350). Some 102 deaths were from breast cancer, with unadjusted 5-year cancer-specific survival rates of 97.9, 98.3 and 95.0 per cent respectively (P = 0.056).Discussion: Oncoplastic BCS is a safe surgical option, even for larger node-positive tumours, with low recurrence and excellent survival rates.
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| 28. |
- André, Frida, et al.
(author)
-
The prevalence of gaming and gambling in a child and adolescent psychiatry unit
- 2022
-
In: Journal of Public Health Research. - : SAGE Publications. - 2279-9028 .- 2279-9036. ; 11:2
-
Journal article (peer-reviewed)abstract
- Background:Gaming and gambling are frequently reported from child and adolescent psychiatry and school health care. Swedish epidemiological data show that 1.3% of the population meet the criteria for gambling disorder. Risk factors are male gender, young age, single status and being born outside Sweden. Both problem gaming and gambling are associated with compulsion, psychiatric and physical symptoms, impaired cognitive development and school performance. Based on the limited knowledge and the need for more research into these behaviours among young individuals, the present study aimed to look at the prevalence of gaming and gambling in patients at the child and adolescent psychiatry department (CAP) in Skåne, a region in the south of Sweden.Design and methods:The overall aim is to explore gaming and gambling in a child and youth population. Children aged 8–18 years (N = 144) from CAP in Skåne were assessed with two self-screening instruments: GASA (Game Addiction Scale for Adolescents) and NODS-CLiP (NORC Diagnostic Screen for Gambling Problems). Information were collected regarding type of care, housing situation and diagnosis.Results:Thirty-three percent of the study participants showed problem/addictive gaming. Fifty-two percent of the males in the study showed problem/addictive gaming. Forty-four percent of the subjects with ADHD showed problem/addictive gaming. Eleven percent of the study participants showed problem gambling.Conclusions:The present study reports hitherto unreported figures of problem gaming and gambling. Our results show the importance of screening children and adolescents for these conditions when admitting subjects to CAP in/outpatient care.
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| 29. |
- André, Mats, et al.
(author)
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Lower hybrid waves at comet 67P/Churyumov-Gerasimenko
- 2017
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In: Monthly notices of the Royal Astronomical Society. - : OXFORD UNIV PRESS. - 0035-8711 .- 1365-2966. ; 469, s. S29-S38
-
Journal article (peer-reviewed)abstract
- We investigate the generation of waves in the lower hybrid frequency range by density gradients in the near plasma environment of comet 67P/Churyumov-Gerasimenko. When the plasma is dominated by water ions from the comet, a situation with magnetized electrons and unmagnetized ions is favourable for the generation of lower hybrid waves. These waves can transfer energy between ions and electrons and reshape the plasma environment of the comet. We consider cometocentric distances out to a few hundred km. We find that when the electron motion is not significantly interrupted by collisions with neutrals, large average gradients within tens of km of the comet, as well as often observed local large density gradients at larger distances, are often likely to be favourable for the generation of lower hybrid waves. Overall, we find that waves in the lower hybrid frequency range are likely to be common in the near plasma environment.
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| 30. |
- André, Samuel, 1986-, et al.
(author)
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Managing Fluctuating Requirements by Platforms Defined in the Interface Between Technology and Product Development
- 2014
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In: Advances in Transdisciplinary Engineering: Moving Integrated Product Development to Service Clouds in the Global Economy. - Amsterdam : IOS Press. - 9781614994404 - 9781614994398 ; , s. 424-433
-
Conference paper (peer-reviewed)abstract
- Product platforms play an important role for the efficient customisation and variant forming of products in many companies. In this paper four different companies ranging from OEM to B2B suppliers have been interviewed on how they engage in technology and product development, create and maintain product platforms and how they respond to the changing requirements on the platforms and on the products and product families derived from them. The objective is to find how product platforms are used to meet the demands of efficient product customisation. The companies all have identifiable product platforms and established processes for product development. However, there are differences in how they define technology development, how the platforms are created, maintained, replaced and what the platforms contain. The introduction of new technology into the platforms and how the platforms are used from a Lean product development perspective has been of interest in the survey as reported in the paper.
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| 31. |
- André, Samuel, 1986-, et al.
(author)
-
The design platform – a coherent platform description of heterogeneous design assets for suppliers of highly customised systems
- 2017
-
In: Journal of engineering design (Print). - : Taylor & Francis. - 0954-4828 .- 1466-1837. ; 28:10-12, s. 599-626
-
Journal article (peer-reviewed)abstract
- Companies developing highly customised products are continuously faced with fluctuating requirements during the early and late stages of the product development (PD) process. This differs from companies that develop end-consumer products, which uses fixed specifications and where product platforms have been a successful enabler for efficient customisation. However, in the past, product platforms have not been able to fully support companies working in an engineer-to-order business environment. This article outlines the results from a three-year collaborative research project between academics within the area of engineering design and practitioners from the engineer-to-order industry. The research introduces a design platform (DP) that aims to support the development of customised products when traditional platform concepts do not suffice. The platform approach provides a coherent environment for heterogeneous design assets to be used in PD by supporting both the design activity and the finished solutions. The needs and abilities regarding such a platform were investigated through a series of interviews and workshops at four companies. Then, the DP was modelled and support tools were developed. Finally, company representatives evaluated the complete DP and its applications, reporting promising results.
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| 32. |
- Aquila, Andrew, et al.
(author)
-
Time-resolved protein nanocrystallography using an X-ray free-electron laser
- 2012
-
In: Optics Express. - 1094-4087. ; 20:3, s. 2706-2716
-
Journal article (peer-reviewed)abstract
- We demonstrate the use of an X-ray free electron laser synchronized with an optical pump laser to obtain X-ray diffraction snapshots from the photoactivated states of large membrane protein complexes in the form of nanocrystals flowing in a liquid jet. Light-induced changes of Photosystem I-Ferredoxin co-crystals were observed at time delays of 5 to 10 µs after excitation. The result correlates with the microsecond kinetics of electron transfer from Photosystem I to ferredoxin. The undocking process that follows the electron transfer leads to large rearrangements in the crystals that will terminally lead to the disintegration of the crystals. We describe the experimental setup and obtain the first time-resolved femtosecond serial X-ray crystallography results from an irreversible photo-chemical reaction at the Linac Coherent Light Source. This technique opens the door to time-resolved structural studies of reaction dynamics in biological systems.
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| 33. |
- Araújo, José, et al.
(author)
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A down-sampled controller to reduce network usage with guaranteed closed-loop performance
- 2014
-
In: Decision and Control (CDC), 2014 IEEE 53rd Annual Conference on. - : IEEE conference proceedings. - 9781479977468 ; , s. 6849-6856
-
Conference paper (peer-reviewed)abstract
- We propose and evaluate a down-sampled controller which reduces the network usage while providing a guaranteed desired linear quadratic control performance. This method is based on fast and slow sampling intervals, as the closed-system benefits by being brought quickly to steady-state conditions while behaving satisfactorily when being actuated at a slow rate once at those conditions. This mechanism is shown to provide large savings with respect to network usage when compared to traditional periodic time-triggered control and other aperiodic controllers proposed in the literature.
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| 34. |
- Arike, Liisa, et al.
(author)
-
Protein Turnover in Epithelial Cells and Mucus along the Gastrointestinal Tract Is Coordinated by the Spatial Location and Microbiota
- 2020
-
In: Cell Reports. - : Elsevier BV. - 2211-1247. ; 30:4, s. 1077-1087
-
Journal article (peer-reviewed)abstract
- The gastrointestinal tract is covered by a single layer of epithelial cells that, together with the mucus layers, protect the underlying tissue from microbial invasion. The epithelium has one of the highest turnover rates in the body. Using stable isotope labeling, high-resolution mass spectrometry, and computational analysis, we report a comprehensive dataset of the turnover of more than 3,000 and the expression of more than 5,000 intestinal epithelial cell proteins, analyzed under conventional and germ-free conditions across five different segments in mouse intestine. The median protein half-life is shorter in the small intestine than in the colon. Differences in protein turnover rates along the intestinal tract can be explained by distinct physiological and immune-related functions between the small and large intestine. An absence of microbiota results in an approximately 1 day longer protein half-life in germ-free animals.
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| 35. |
- Aulchenko, Yurii S, et al.
(author)
-
Loci influencing lipid levels and coronary heart disease risk in 16 European population cohorts
- 2009
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 41:1, s. 47-55
-
Journal article (peer-reviewed)abstract
- Recent genome-wide association (GWA) studies of lipids have been conducted in samples ascertained for other phenotypes, particularly diabetes. Here we report the first GWA analysis of loci affecting total cholesterol (TC), low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol and triglycerides sampled randomly from 16 population-based cohorts and genotyped using mainly the Illumina HumanHap300-Duo platform. Our study included a total of 17,797-22,562 persons, aged 18-104 years and from geographic regions spanning from the Nordic countries to Southern Europe. We established 22 loci associated with serum lipid levels at a genome-wide significance level (P < 5 x 10(-8)), including 16 loci that were identified by previous GWA studies. The six newly identified loci in our cohort samples are ABCG5 (TC, P = 1.5 x 10(-11); LDL, P = 2.6 x 10(-10)), TMEM57 (TC, P = 5.4 x 10(-10)), CTCF-PRMT8 region (HDL, P = 8.3 x 10(-16)), DNAH11 (LDL, P = 6.1 x 10(-9)), FADS3-FADS2 (TC, P = 1.5 x 10(-10); LDL, P = 4.4 x 10(-13)) and MADD-FOLH1 region (HDL, P = 6 x 10(-11)). For three loci, effect sizes differed significantly by sex. Genetic risk scores based on lipid loci explain up to 4.8% of variation in lipids and were also associated with increased intima media thickness (P = 0.001) and coronary heart disease incidence (P = 0.04). The genetic risk score improves the screening of high-risk groups of dyslipidemia over classical risk factors.
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| 36. |
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| 37. |
- Berndt, Sonja I., et al.
(author)
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Genome-wide meta-analysis identifies 11 new loci for anthropometric traits and provides insights into genetic architecture
- 2013
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:5, s. 501-U69
-
Journal article (peer-reviewed)abstract
- Approaches exploiting trait distribution extremes may be used to identify loci associated with common traits, but it is unknown whether these loci are generalizable to the broader population. In a genome-wide search for loci associated with the upper versus the lower 5th percentiles of body mass index, height and waist-to-hip ratio, as well as clinical classes of obesity, including up to 263,407 individuals of European ancestry, we identified 4 new loci (IGFBP4, H6PD, RSRC1 and PPP2R2A) influencing height detected in the distribution tails and 7 new loci (HNF4G, RPTOR, GNAT2, MRPS33P4, ADCY9, HS6ST3 and ZZZ3) for clinical classes of obesity. Further, we find a large overlap in genetic structure and the distribution of variants between traits based on extremes and the general population and little etiological heterogeneity between obesity subgroups.
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| 38. |
- Bugaytsova, Jeanna, et al.
(author)
-
pH regulated H. pylori adherence : implications for persistent infection and disease
-
Other publication (other academic/artistic)abstract
- Helicobacter pylori’s BabA adhesin binds strongly to gastric mucosal ABH/Leb glycans on the stomach epithelium and overlying mucus, materials continuously shed into the acidic gastric lumen. Here we report that this binding is acid labile, acid inactivation is fully reversible; and acid lability profiles vary with BabA sequence and correlate with disease patterns. Isogenic H. pylori strains from the gastric antrum and more acidic corpus were identified that differed in acid lability of receptor binding and in sequence near BabA’s carbohydrate binding domain. We propose that reversible acid inactivation of receptor binding helps H. pylori avoid clearance by mucosal shedding, and that strain differences in acid lability affect tissue tropism and the spectrum of associated gastric diseases.
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| 39. |
- Canbäck, Björn, et al.
(author)
-
The Littorina sequence database (LSD) - an online resource for genomic data.
- 2012
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In: Molecular Ecology Resources. - : Wiley. - 1755-098X .- 1755-0998. ; 12, s. 142-148
-
Journal article (peer-reviewed)abstract
- We present an interactive, searchable expressed sequence tag database for the periwinkle snail Littorina saxatilis, an upcoming model species in evolutionary biology. The database is the result of a hybrid assembly between Sanger and 454 sequences, 1290 and 147 491 sequences respectively. Normalized and non-normalized cDNA was obtained from different ecotypes of L. saxatilis collected in the UK and Sweden. The Littorina sequence database (LSD) contains 26 537 different contigs, of which 2453 showed similarity with annotated proteins in UniProt. Querying the LSD permits the selection of the taxonomic origin of blast hits for each contig, and the search can be restricted to particular taxonomic groups. The database allows access to UniProt annotations, blast output, protein family domains (PFAM) and Gene Ontology. The database will allow users to search for genetic markers and identifying candidate genes or genes for expression analyses. It is open for additional deposition of sequence information for L. saxatilis and other species of the genus Littorina. The LSD is available at http://mbio-serv2.mbioekol.lu.se/Littorina/.
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| 40. |
- Chang, C. W. Sandbo, et al.
(author)
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Generating Multimode Entangled Microwaves with a Superconducting Parametric Cavity
- 2018
-
In: Physical Review Applied. - 2331-7019. ; 10:4
-
Journal article (peer-reviewed)abstract
- We demonstrate the generation of multimode entangled states of propagating microwaves. The entangled states are generated by our parametrically pumping a multimode superconducting cavity. By combining different pump frequencies, applied simultaneously to the device, we can produce different entanglement structures in a programable fashion. The Gaussian output states are fully characterized by our measuring the full covariance matrices of the modes. The covariance matrices are absolutely calibrated by our using an in situ microwave calibration source, a shot-noise tunnel junction. Applying a variety of entanglement measures, we demonstrate both full inseparability and genuine tripartite entanglement of the states. Our method is easily extensible to more modes.
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| 41. |
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| 42. |
- Chen, Gefei, et al.
(author)
-
Bri2 BRICHOS client specificity and chaperone activity are governed by assembly state
- 2017
-
In: Nature Communications. - : Nature Publishing Group. - 2041-1723. ; 8
-
Journal article (peer-reviewed)abstract
- . Protein misfolding and aggregation is increasingly being recognized as a cause of disease. In Alzheimer's disease the amyloid-beta peptide (A beta) misfolds into neurotoxic oligomers and assembles into amyloid fibrils. The Bri2 protein associated with Familial British and Danish dementias contains a BRICHOS domain, which reduces A beta fibrillization as well as neurotoxicity in vitro and in a Drosophila model, but also rescues proteins from irreversible nonfibrillar aggregation. How these different activities are mediated is not known. Here we show that Bri2 BRICHOS monomers potently prevent neuronal network toxicity of A beta, while dimers strongly suppress A beta fibril formation. The dimers assemble into high-molecular-weight oligomers with an apparent two-fold symmetry, which are efficient inhibitors of non-fibrillar protein aggregation. These results indicate that Bri2 BRICHOS affects qualitatively different aspects of protein misfolding and toxicity via different quaternary structures, suggesting a means to generate molecular chaperone diversity.
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| 43. |
- Cohen, Samuel I A, et al.
(author)
-
A molecular chaperone breaks the catalytic cycle that generates toxic Aβ oligomers.
- 2015
-
In: Nature Structural & Molecular Biology. - : Springer Science and Business Media LLC. - 1545-9985 .- 1545-9993. ; 22:3, s. 207-213
-
Journal article (peer-reviewed)abstract
- Alzheimer's disease is an increasingly prevalent neurodegenerative disorder whose pathogenesis has been associated with aggregation of the amyloid-β peptide (Aβ42). Recent studies have revealed that once Aβ42 fibrils are generated, their surfaces effectively catalyze the formation of neurotoxic oligomers. Here we show that a molecular chaperone, a human Brichos domain, can specifically inhibit this catalytic cycle and limit human Aβ42 toxicity. We demonstrate in vitro that Brichos achieves this inhibition by binding to the surfaces of fibrils, thereby redirecting the aggregation reaction to a pathway that involves minimal formation of toxic oligomeric intermediates. We verify that this mechanism occurs in living mouse brain tissue by cytotoxicity and electrophysiology experiments. These results reveal that molecular chaperones can help maintain protein homeostasis by selectively suppressing critical microscopic steps within the complex reaction pathways responsible for the toxic effects of protein misfolding and aggregation.
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| 44. |
- de Zwarte, Sonja M. C., et al.
(author)
-
The association between familial risk and brain abnormalities is disease specific : an ENIGMA-relatives study of schizophrenia and bipolar disorder
- 2019
-
In: Biological Psychiatry. - : Elsevier. - 0006-3223 .- 1873-2402. ; 86:7, s. 545-556
-
Journal article (peer-reviewed)abstract
- BACKGROUND: Schizophrenia and bipolar disorder share genetic liability, and some structural brain abnormalities are common to both conditions. First-degree relatives of patients with schizophrenia (FDRs-SZ) show similar brain abnormalities to patients, albeit with smaller effect sizes. Imaging findings in first-degree relatives of patients with bipolar disorder (FDRs-BD) have been inconsistent in the past, but recent studies report regionally greater volumes compared with control subjects.METHODS: We performed a meta-analysis of global and subcortical brain measures of 6008 individuals (1228 FDRs-SZ, 852 FDRs-BD, 2246 control subjects, 1016 patients with schizophrenia, 666 patients with bipolar disorder) from 34 schizophrenia and/or bipolar disorder family cohorts with standardized methods. Analyses were repeated with a correction for intracranial volume (ICV) and for the presence of any psychopathology in the relatives and control subjects.RESULTS: FDRs-BD had significantly larger ICV (d = +0.16, q < .05 corrected), whereas FDRs-SZ showed smaller thalamic volumes than control subjects (d = -0.12, q < .05 corrected). ICV explained the enlargements in the brain measures in FDRs-BD. In FDRs-SZ, after correction for ICV, total brain, cortical gray matter, cerebral white matter, cerebellar gray and white matter, and thalamus volumes were significantly smaller; the cortex was thinner (d < -0.09, q < .05 corrected); and third ventricle was larger (d = +0.15, q < .05 corrected). The findings were not explained by psychopathology in the relatives or control subjects.CONCLUSIONS: Despite shared genetic liability, FDRs-SZ and FDRs-BD show a differential pattern of structural brain abnormalities, specifically a divergent effect in ICV. This may imply that the neurodevelopmental trajectories leading to brain anomalies in schizophrenia or bipolar disorder are distinct.
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| 45. |
- Demirkan, Ayse, et al.
(author)
-
Genetic architecture of circulating lipid levels
- 2011
-
In: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 19:7, s. 813-819
-
Journal article (peer-reviewed)abstract
- Serum concentrations of low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), triglycerides (TGs) and total cholesterol (TC) are important heritable risk factors for cardiovascular disease. Although genome-wide association studies (GWASs) of circulating lipid levels have identified numerous loci, a substantial portion of the heritability of these traits remains unexplained. Evidence of unexplained genetic variance can be detected by combining multiple independent markers into additive genetic risk scores. Such polygenic scores, constructed using results from the ENGAGE Consortium GWAS on serum lipids, were applied to predict lipid levels in an independent population-based study, the Rotterdam Study-II (RS-II). We additionally tested for evidence of a shared genetic basis for different lipid phenotypes. Finally, the polygenic score approach was used to identify an alternative genome-wide significance threshold before pathway analysis and those results were compared with those based on the classical genome-wide significance threshold. Our study provides evidence suggesting that many loci influencing circulating lipid levels remain undiscovered. Cross-prediction models suggested a small overlap between the polygenic backgrounds involved in determining LDL-C, HDL-C and TG levels. Pathway analysis utilizing the best polygenic score for TC uncovered extra information compared with using only genome-wide significant loci. These results suggest that the genetic architecture of circulating lipids involves a number of undiscovered variants with very small effects, and that increasing GWAS sample sizes will enable the identification of novel variants that regulate lipid levels.
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| 46. |
- Demirkan, Ayse, et al.
(author)
-
Genome-Wide Association Study Identifies Novel Loci Associated with Circulating Phospho- and Sphingolipid Concentrations
- 2012
-
In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:2, s. e1002490-
-
Journal article (peer-reviewed)abstract
- Phospho- and sphingolipids are crucial cellular and intracellular compounds. These lipids are required for active transport, a number of enzymatic processes, membrane formation, and cell signalling. Disruption of their metabolism leads to several diseases, with diverse neurological, psychiatric, and metabolic consequences. A large number of phospholipid and sphingolipid species can be detected and measured in human plasma. We conducted a meta-analysis of five European family-based genome-wide association studies (N = 4034) on plasma levels of 24 sphingomyelins (SPM), 9 ceramides (CER), 57 phosphatidylcholines (PC), 20 lysophosphatidylcholines (LPC), 27 phosphatidylethanolamines (PE), and 16 PE-based plasmalogens (PLPE), as well as their proportions in each major class. This effort yielded 25 genome-wide significant loci for phospholipids (smallest P-value = 9.88 x 10(-204)) and 10 loci for sphingolipids (smallest P-value = 3.10 x 10(-57)). After a correction for multiple comparisons (P-value, 2.2 x 10(-9)), we observed four novel loci significantly associated with phospholipids (PAQR9, AGPAT1, PKD2L1, PDXDC1) and two with sphingolipids (PLD2 and APOE) explaining up to 3.1% of the variance. Further analysis of the top findings with respect to within class molar proportions uncovered three additional loci for phospholipids (PNLIPRP2, PCDH20, and ABDH3) suggesting their involvement in either fatty acid elongation/saturation processes or fatty acid specific turnover mechanisms. Among those, 14 loci (KCNH7, AGPAT1, PNLIPRP2, SYT9, FADS1-2-3, DLG2, APOA1, ELOVL2, CDK17, LIPC, PDXDC1, PLD2, LASS4, and APOE) mapped into the glycerophospholipid and 12 loci (ILKAP, ITGA9, AGPAT1, FADS1-2-3, APOA1, PCDH20, LIPC, PDXDC1, SGPP1, APOE, LASS4, and PLD2) to the sphingolipid pathways. In large meta-analyses, associations between FADS1-2-3 and carotid intima media thickness, AGPAT1 and type 2 diabetes, and APOA1 and coronary artery disease were observed. In conclusion, our study identified nine novel phospho- and sphingolipid loci, substantially increasing our knowledge of the genetic basis for these traits.
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| 47. |
- Ding, Ming, et al.
(author)
-
Dairy consumption, systolic blood pressure, and risk of hypertension : Mendelian randomization study
- 2017
-
In: The BMJ. - : BMJ Publishing Group Ltd. - 1756-1833 .- 0959-8138. ; 356
-
Journal article (peer-reviewed)abstract
- OBJECTIVE To examine whether previous observed inverse associations of dairy intake with systolic blood pressure and risk of hypertension were causal. DESIGN Mendelian randomization study using the single nucleotide polymorphism rs4988235 related to lactase persistence as an instrumental variable. SETTING CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology) Consortium. PARTICIPANTS Data from 22 studies with 171 213 participants, and an additional 10 published prospective studies with 26 119 participants included in the observational analysis. MAIN OUTCOME MEASURES The instrumental variable estimation was conducted using the ratio of coefficients approach. Using metaanalysis, an additional eight published randomized clinical trials on the association of dairy consumption with systolic blood pressure were summarized. RESULTS Compared with the CC genotype (CC is associated with complete lactase deficiency), the CT/TT genotype (TT is associated with lactose persistence, and CT is associated with certain lactase deficiency) of LCT-13910 (lactase persistence gene) rs4988235 was associated with higher dairy consumption (0.23 (about 55 g/day), 95% confidence interval 0.17 to 0.29) serving/day; P<0.001) and was not associated with systolic blood pressure (0.31, 95% confidence interval -0.05 to 0.68 mm Hg; P=0.09) or risk of hypertension (odds ratio 1.01, 95% confidence interval 0.97 to 1.05; P=0.27). Using LCT-13910 rs4988235 as the instrumental variable, genetically determined dairy consumption was not associated with systolic blood pressure (beta=1.35, 95% confidence interval -0.28 to 2.97 mm Hg for each serving/day) or risk of hypertension (odds ratio 1.04, 0.88 to 1.24). Moreover, meta-analysis of the published clinical trials showed that higher dairy intake has no significant effect on change in systolic blood pressure for interventions over one month to 12 months (intervention compared with control groups: beta=-0.21, 95% confidence interval -0.98 to 0.57 mm Hg). In observational analysis, each serving/day increase in dairy consumption was associated with -0.11 (95% confidence interval -0.20 to -0.02 mm Hg; P=0.02) lower systolic blood pressure but not risk of hypertension (odds ratio 0.98, 0.97 to 1.00; P=0.11). CONCLUSION The weak inverse association between dairy intake and systolic blood pressure in observational studies was not supported by a comprehensive instrumental variable analysis and systematic review of existing clinical trials.
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| 48. |
- do Nascimento, Allan Andre, et al.
(author)
-
Tube-based Model Predictive Control for Dynamic Positioning of Marine Vessels
- 2019
-
In: IFAC PAPERSONLINE. - : ELSEVIER. - 2405-8963. ; , s. 33-38
-
Conference paper (peer-reviewed)abstract
- This paper focuses on the design of a robust model predictive control law for dynamic positioning (DP) of marine vessels in the presence of actuator saturation and environmental disturbances. The proposed solution is a tube-based MPC ensuring robustness and constraint fulfillment. Formulation of the tube-based MPC relies on a sufficient robust invariant set condition, along with a linear matrix inequality (LMI) synthesis procedure, and an efficient analytical Pontryagin set difference computation. Simulation results show the effectiveness and satisfactory behaviour of the proposed controller.
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| 49. |
- Do, Ron, et al.
(author)
-
Common variants associated with plasma triglycerides and risk for coronary artery disease
- 2013
-
In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 45:11, s. 1345-
-
Journal article (peer-reviewed)abstract
- Triglycerides are transported in plasma by specific triglyceride-rich lipoproteins; in epidemiological studies, increased triglyceride levels correlate with higher risk for coronary artery disease (CAD). However, it is unclear whether this association reflects causal processes. We used 185 common variants recently mapped for plasma lipids (P < 5 x 10(-8) for each) to examine the role of triglycerides in risk for CAD. First, we highlight loci associated with both low-density lipoprotein cholesterol (LDL-C) and triglyceride levels, and we show that the direction and magnitude of the associations with both traits are factors in determining CAD risk. Second, we consider loci with only a strong association with triglycerides and show that these loci are also associated with CAD. Finally, in a model accounting for effects on LDL-C and/or high-density lipoprotein cholesterol (HDL-C) levels, the strength of a polymorphism's effect on triglyceride levels is correlated with the magnitude of its effect on CAD risk. These results suggest that triglyceride-rich lipoproteins causally influence risk for CAD.
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| 50. |
- Dokken, Jørgen S., et al.
(author)
-
A multimesh finite element method for the Navier-Stokes equations based on projection methods
- 2020
-
In: Computer Methods in Applied Mechanics and Engineering. - : Elsevier. - 0045-7825 .- 1879-2138. ; 368
-
Journal article (peer-reviewed)abstract
- The multimesh finite element method is a technique for solving partial differential equations on multiple non-matching meshes by enforcing interface conditions using Nitsche's method. Since the non-matching meshes can result in arbitrarily cut cells, additional stabilization terms are needed to obtain a stable method. In this contribution we extend the multimesh finite element method to the Navier-Stokes equations based on the incremental pressure-correction scheme. For each step in the pressure-correction scheme, we derive a multimesh finite element formulation with suitable stabilization terms. The proposed scheme is implemented for arbitrary many overlapping two dimensional domains, yielding expected spatial and temporal convergence rates for the Taylor-Green problem, and demonstrates good agreement for the drag and lift coefficients for the Turek-Schfifer benchmark (DFG benchmark 2D-3). Finally, we illustrate the capabilities of the proposed scheme by optimizing the layout of obstacles in a two dimensional channel.
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