| 11. |
- Beyerlein, Andreas, et al.
(författare)
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Progression from islet autoimmunity to clinical type 1 diabetes is influenced by genetic factors : Results from the prospective TEDDY study
- 2019
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 56:9, s. 602-605
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Tidskriftsartikel (refereegranskat)abstract
- Background: Progression time from islet autoimmunity to clinical type 1 diabetes is highly variable and the extent that genetic factors contribute is unknown. Methods: In 341 islet autoantibody-positive children with the human leucocyte antigen (HLA) DR3/DR4-DQ8 or the HLA DR4-DQ8/DR4-DQ8 genotype from the prospective TEDDY (The Environmental Determinants of Diabetes in the Young) study, we investigated whether a genetic risk score that had previously been shown to predict islet autoimmunity is also associated with disease progression. Results: Islet autoantibody-positive children with a genetic risk score in the lowest quartile had a slower progression from single to multiple autoantibodies (p=0.018), from single autoantibodies to diabetes (p=0.004), and by trend from multiple islet autoantibodies to diabetes (p=0.06). In a Cox proportional hazards analysis, faster progression was associated with an increased genetic risk score independently of HLA genotype (HR for progression from multiple autoantibodies to type 1 diabetes, 1.27, 95% CI 1.02 to 1.58 per unit increase), an earlier age of islet autoantibody development (HR, 0.68, 95% CI 0.58 to 0.81 per year increase in age) and female sex (HR, 1.94, 95% CI 1.28 to 2.93). Conclusions: Genetic risk scores may be used to identify islet autoantibody-positive children with high-risk HLA genotypes who have a slow rate of progression to subsequent stages of autoimmunity and type 1 diabetes.
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| 12. |
- Bonifacio, Ezio, et al.
(författare)
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Genetic scores to stratify risk of developing multiple islet autoantibodies and type 1 diabetes : A prospective study in children
- 2018
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Ingår i: PLoS Medicine. - : Public Library of Science (PLoS). - 1549-1676. ; 15:4
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Tidskriftsartikel (refereegranskat)abstract
- Background: Around 0.3% of newborns will develop autoimmunity to pancreatic beta cells in childhood and subsequently develop type 1 diabetes before adulthood. Primary prevention of type 1 diabetes will require early intervention in genetically at-risk infants. The objective of this study was to determine to what extent genetic scores (two previous genetic scores and a merged genetic score) can improve the prediction of type 1 diabetes. Methods and findings: The Environmental Determinants of Diabetes in the Young (TEDDY) study followed genetically at-risk children at 3- to 6-monthly intervals from birth for the development of islet autoantibodies and type 1 diabetes. Infants were enrolled between 1 September 2004 and 28 February 2010 and monitored until 31 May 2016. The risk (positive predictive value) for developing multiple islet autoantibodies (pre-symptomatic type 1 diabetes) and type 1 diabetes was determined in 4,543 children who had no first-degree relatives with type 1 diabetes and either a heterozygous HLA DR3 and DR4-DQ8 risk genotype or a homozygous DR4-DQ8 genotype, and in 3,498 of these children in whom genetic scores were calculated from 41 single nucleotide polymorphisms. In the children with the HLA risk genotypes, risk for developing multiple islet autoantibodies was 5.8% (95% CI 5.0%–6.6%) by age 6 years, and risk for diabetes by age 10 years was 3.7% (95% CI 3.0%–4.4%). Risk for developing multiple islet autoantibodies was 11.0% (95% CI 8.7%–13.3%) in children with a merged genetic score of >14.4 (upper quartile; n = 907) compared to 4.1% (95% CI 3.3%–4.9%, P < 0.001) in children with a genetic score of ≤14.4 (n = 2,591). Risk for developing diabetes by age 10 years was 7.6% (95% CI 5.3%–9.9%) in children with a merged score of >14.4 compared with 2.7% (95% CI 1.9%–3.6%) in children with a score of ≤14.4 (P < 0.001). Of 173 children with multiple islet autoantibodies by age 6 years and 107 children with diabetes by age 10 years, 82 (sensitivity, 47.4%; 95% CI 40.1%–54.8%) and 52 (sensitivity, 48.6%, 95% CI 39.3%–60.0%), respectively, had a score >14.4. Scores were higher in European versus US children (P = 0.003). In children with a merged score of >14.4, risk for multiple islet autoantibodies was similar and consistently >10% in Europe and in the US; risk was greater in males than in females (P = 0.01). Limitations of the study include that the genetic scores were originally developed from case–control studies of clinical diabetes in individuals of mainly European decent. It is, therefore, possible that it may not be suitable to all populations. Conclusions: A type 1 diabetes genetic score identified infants without family history of type 1 diabetes who had a greater than 10% risk for pre-symptomatic type 1 diabetes, and a nearly 2-fold higher risk than children identified by high-risk HLA genotypes alone. This finding extends the possibilities for enrolling children into type 1 diabetes primary prevention trials.
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| 13. |
- Chauhan, Swarup, et al.
(författare)
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MIPAS reduced spectral resolution UTLS-1 mode measurements of temperature, O3, HNO3, N2O, H2O and relative humidity over ice: retrievals and comparison to MLS
- 2009
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Ingår i: Atmospheric Measurement Techniques. - : Copernicus GmbH. - 1867-1381 .- 1867-8548. ; :2, s. 337-353
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Tidskriftsartikel (refereegranskat)abstract
- During several periods since 2005 the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) on Envisat has performed observations dedicated to the region of the upper troposphere/lower stratosphere (UTLS). For the duration of November/December 2005 global distributions of temperature and several trace gases from MIPAS UTLS-1 mode measurements have been retrieved using the IMK/IAA (Institut für Meteorologie und Klimaforschung/Instituto de Astrofísica de Andalucía) scientific processor. In the UTLS region a vertical resolution of 3 km for temperaure, 3 to 4 km for H2O, 2.5 to 3 km for O3, 3.5 km for HNO3 and 3.5 to 2.5 km for N2O has been achieved. The retrieved temperature, H2O, O3, HNO3, N2O, and relative humidity over ice are intercompared with the Microwave Limb Sounder (MLS/Aura) v2.2 data in the pressure range 316 to 0.68 hPa, 316 to 0.68 hPa, 215 to 0.68 hPa, 215 to 3.16 hPa, 100 to 1 hPa and 316 to 10 hPa, respectively. In general, MIPAS and MLS temperatures are biased within ±4 K over the whole pressure and latitude range. Systematic, latitude-independent differences of −2 to −4 K (MIPAS-MLS) at 121 hPa are explained by previously observed biases in the MLS v2.2 temperature retrievals. Temperature differences of −4 K up to 12 K above 10.0 hPa are present both in MIPAS and MLS with respect to ECMWF (European Centre for Medium-Range Weather Forecasts) and are likely due to deficiencies of the ECMWF analysis data. MIPAS and MLS stratospheric volume mixing ratios (vmr) of H2O are biased within ±1 ppmv, with indication of oscillations between 146 and 26 hPa in the MLS dataset. Tropical upper tropospheric values of relative humidity over ice measured by the two instruments differ by ±20% in the pressure range ~146 to 68 hPa. These differences are mainly caused by the MLS temperature biases. Ozone mixing ratios agree within 0.5 ppmv (10 to 20%) between 68 and 14 hPa. At pressures smaller than 10 hPa, MIPAS O3 vmr are higher than MLS by an average of 0.5 ppmv (10%). General agreement between MIPAS and MLS HNO3 is within the range of −1.0 (−10%) to 1.0 ppbv (20%). MIPAS HNO3 is 1.0 ppbv (10%) higher compared to MLS between 46 hPa and 10 hPa over the Northern Hemisphere. Over the tropics at 31.6 hPa MLS shows a low bias of more than 1 ppbv (>50%). In general, MIPAS and MLS N2O vmr agree within 20 to 40 ppbv (20 to 40%). Differences in the range between 100 to 21 hPa are attributed to a known 20% positive bias in MIPAS N2O data.
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| 14. |
- Glatthor, N., et al.
(författare)
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Global peroxyacetyl nitrate (PAN) retrieval in the upper troposphere from limb emission spectra of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS)
- 2007
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 7:11, s. 2775-2787
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Tidskriftsartikel (refereegranskat)abstract
- We use limb emission spectra of the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) onboard the ENVIronmental SATellite (ENVISAT) to derive the first global distribution of peroxyacetyl nitrate (PAN) in the upper troposphere. PAN is generated in tropospheric air masses polluted by fuel combustion or biomass burning and acts as a reservoir and carrier of NOx in the cold free troposphere. PAN exhibits continuum-like broadband structures in the mid-infrared region and was retrieved in a contiguous analysis window covering the wavenumber region 775–800 cm−1. The interfering species CCl4, HCFC-22, H2O, ClONO2, CH3CCl3 and C2H2 were fitted along with PAN, whereas pre-fitted profiles were used to model the contribution of other contaminants like ozone. Sensitivity tests consisting in retrieval without consideration of PAN demonstrated the existence of PAN signatures in MIPAS spectra obtained in polluted air masses. The analysed dataset consists of 10 days between 4 October and 1 December 2003. This period covers the end of the biomass burning season in South America and South and East Africa, in which generally large amounts of pollutants are produced and distributed over wide areas of the southern hemispheric free troposphere. Indeed, elevated PAN amounts of 200–700 pptv were measured in a large plume extending from Brasil over the Southern Atlantic, Central and South Africa, the South Indian Ocean as far as Australia at altitudes between 8 and 16 km. Enhanced PAN values were also found in a much more restricted area between northern subtropical Africa and India. The most significant northern midlatitude PAN signal was detected in an area at 8 km altitude extending from China into the Chinese Sea. The average mid and high latitude PAN amounts found at 8 km were around 125 pptv in the northern, but only between 50 and 75 pptv in the southern hemisphere. The PAN distribution found in the southern hemispheric tropics and subtropics is highly correlated with the jointly fitted acetylene (C2H2), which is another pollutant produced by biomass burning, and agrees reasonably well with the CO plume detected during end of September 2003 at the 275 hPa level (~10 km) by the Measurement of Pollution in the Troposphere (MOPITT) instrument on the Terra satellite. Similar southern hemispheric PAN amounts were also observed by previous airborne measurements performed in September/October 1992 and 1996 above the South Atlantic and the South Pacific, respectively.
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| 15. |
- Hippich, Markus, et al.
(författare)
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Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:4, s. 847-857
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Tidskriftsartikel (refereegranskat)abstract
- The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes–associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6–3.02]) and for diabetes (HR 2.92 [95% CI 2.05–4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.
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| 16. |
- Krång, Anna Sara, 1972, et al.
(författare)
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Transition from sea to land: Olfactory function and constraints in the terrestrial hermit crab Coenobita clypeatus
- 2012
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Ingår i: Proceedings of the Royal Society of London. Biological Sciences. - : The Royal Society. - 0962-8452 .- 1471-2954. ; 279:1742, s. 3510-3519
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Tidskriftsartikel (refereegranskat)abstract
- The ability to identify chemical cues in the environment is essential to most animals. Apart from marine larval stages, anomuran land hermit crabs (Coenobita) have evolved different degrees of terrestriality, and thus represent an excellent opportunity to investigate adaptations of the olfactory system needed for a successful transition from aquatic to terrestrial life. Although superb processing capacities of the central olfactory system have been indicated in Coenobita and their olfactory system evidently is functional on land, virtually nothing was known about what type of odourants are detected. Here, we used electroantennogram (EAG) recordings in Coenobita clypeatus and established the olfactory response spectrum. Interestingly, different chemical groups elicited EAG responses of opposite polarity, which also appeared for Coenobita compressus and the closely related marine hermit crab Pagurus bernhardus. Furthermore, in a two-choice bioassay with C. clypeatus, we found that water vapour was critical for natural and synthetic odourants to induce attraction or repulsion. Strikingly, also the physiological response was found much greater at higher humidity in C. clypeatus, whereas no such effect appeared in the terrestrial vinegar fly Drosophila melanogaster. In conclusion, our results reveal that the Coenobita olfactory system is restricted to a limited number of water-soluble odourants, and that high humidity is most critical for its function.
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| 17. |
- Lestinsky, M., et al.
(författare)
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CRYRING@ESR: present status and future research
- 2015
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Ingår i: Physica Scripta. - 0031-8949 .- 1402-4896. ; T166
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Tidskriftsartikel (refereegranskat)abstract
- The former storage ring CRYRING has been shipped from the Manne Siegbahn Laboratory in Stockholm to Darmstadt as a Swedish in-kind contribution to FAIR. At its new location downstream of ESR all ion species presently accessible in ESR can be transferred to CRYRING, in which ions with rigidities between 1.44 and 0.054 Tm can be stored. The original Swedish layout has been modified by reconfiguring the sequence of straight sections and by slightly increasing the circumference to ESR/2. Ions can be injected from ESR or from an independent 300 keV/u RFQ test injector. The instrumentation of the ring includes an RF drift tube system for acceleration and deceleration (1 T s(-1), with a possibility for an upgrade to 7 T s(-1)), electron cooling, a free experimental section, and both fast and slow extraction of ions. We report on the present progress of this project, give a prospective timeline, and summarize the new research which will be enabled by this project. First beam for commissioning of the storage ring is expected for 2015, final bakeout to restore ultrahigh vacuum conditions in 2016 and ion beams injected through ESR in similar to 2017.
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| 18. |
- Paul, Dirk S., et al.
(författare)
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Increased DNA methylation variability in type 1 diabetes across three immune effector cell types
- 2016
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- The incidence of type 1 diabetes (T1D) has substantially increased over the past decade, suggesting a role for non-genetic factors such as epigenetic mechanisms in disease development. Here we present an epigenome-wide association study across 406,365 CpGs in 52 monozygotic twin pairs discordant for T1D in three immune effector cell types. We observe a substantial enrichment of differentially variable CpG positions (DVPs) in T1D twins when compared with their healthy co-twins and when compared with healthy, unrelated individuals. These T1D-associated DVPs are found to be temporally stable and enriched at gene regulatory elements. Integration with cell type-specific gene regulatory circuits highlight pathways involved in immune cell metabolism and the cell cycle, including mTOR signalling. Evidence from cord blood of newborns who progress to overt T1D suggests that the DVPs likely emerge after birth. Our findings, based on 772 methylomes, implicate epigenetic changes that could contribute to disease pathogenesis in T1D.
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| 19. |
- Sharma, Ashok, et al.
(författare)
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Identification of non-HLA genes associated with development of islet autoimmunity and type 1 diabetes in the prospective TEDDY cohort
- 2018
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411. ; 89, s. 90-100
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Tidskriftsartikel (refereegranskat)abstract
- Traditional linkage analysis and genome-wide association studies have identified HLA and a number of non-HLA genes as genetic factors for islet autoimmunity (IA) and type 1 diabetes (T1D). However, the relative risk associated with previously identified non-HLA genes is usually very small as measured in cases/controls from mixed populations. Genetic associations for IA and T1D may be more accurately assessed in prospective cohorts. In this study, 5806 subjects from the TEDDY (The Environmental Determinants of Diabetes in the Young) study, an international prospective cohort study, were genotyped for 176,586 SNPs on the ImmunoChip. Cox proportional hazards analyses were performed to discover the SNPs associated with the risk for IA, T1D, or both. Three regions were associated with the risk of developing any persistent confirmed islet autoantibody: one known region near SH2B3 (HR = 1.35, p = 3.58 × 10-7) with Bonferroni-corrected significance and another known region near PTPN22 (HR = 1.46, p = 2.17 × 10-6) and one novel region near PPIL2 (HR = 2.47, p = 9.64 × 10-7) with suggestive evidence (p < 10-5). Two known regions (PTPN22: p = 2.25 × 10-6, INS; p = 1.32 × 10-7) and one novel region (PXK/PDHB: p = 8.99 × 10-6) were associated with the risk for multiple islet autoantibodies. First appearing islet autoantibodies differ with respect to association. Two regions (INS: p = 5.67 × 10-6 and TTC34/PRDM16: 6.45 × 10-6) were associated if the fist appearing autoantibody was IAA and one region (RBFOX1: p = 8.02 × 10-6) was associated if the first appearing autoantibody was GADA. The analysis of T1D identified one region already known to be associated with T1D (INS: p = 3.13 × 10-7) and three novel regions (RNASET2, PLEKHA1, and PPIL2; 5.42 × 10-6 > p > 2.31 × 10-6). These results suggest that a number of low frequency variants influence the risk of developing IA and/or T1D and these variants can be identified by large prospective cohort studies using a survival analysis approach.
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| 20. |
- Steck, T., et al.
(författare)
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Bias determination and precision validation of ozone profiles from MIPAS-Envisat retrieved with the IMK-IAA processor
- 2007
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Ingår i: Atmospheric Chemistry And Physics. - : Copernicus GmbH. - 1680-7316 .- 1680-7324. ; 7:13, s. 3639-3662
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Tidskriftsartikel (refereegranskat)abstract
- This paper characterizes vertical ozone profiles retrieved with the IMK-IAA (Institute for Meteorology and Climate Research, Karlsruhe – Instituto de Astrofisica de Andalucia) science-oriented processor from high spectral resolution data (until March 2004) measured by the Michelson Interferometer for Passive Atmospheric Sounding (MIPAS) aboard the environmental satellite Envisat. Bias determination and precision validation is performed on the basis of correlative measurements by ground-based lidars, Fourier transform infrared spectrometers, and microwave radiometers as well as balloon-borne ozonesondes, the balloon-borne version of MIPAS, and two satellite instruments (Halogen Occultation Experiment and Polar Ozone and Aerosol Measurement III). Percentage mean differences between MIPAS and the comparison instruments for stratospheric ozone are generally within ±10%. The precision in this altitude region is estimated at values between 5 and 10% which gives an accuracy of 15 to 20%. Below 18 km, the spread of the percentage mean differences is larger and the precision degrades to values of more than 20% depending on altitude and latitude. The main reason for the degraded precision at low altitudes is attributed to undetected thin clouds which affect MIPAS retrievals, and to the influence of uncertainties in the water vapor concentration.
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