| 1. |
- Repouskou, Anastasia, et al.
(författare)
-
Long term transcriptional and behavioral effects in mice developmentally exposed to a mixture of endocrine disruptors associated with delayed human neurodevelopment
- 2020
-
Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 10, s. 1-8
-
Tidskriftsartikel (refereegranskat)abstract
- Accumulating evidence suggests that gestational exposure to endocrine disrupting chemicals (EDCs) may interfere with normal brain development and predispose for later dysfunctions. The current study focuses on the exposure impact of mixtures of EDCs that better mimics the real-life situation. We herein describe a mixture of phthalates, pesticides and bisphenol A (mixture N1) detected in pregnant women of the SELMA cohort and associated with language delay in their children. To study the long-term impact of developmental exposure to N1 on brain physiology and behavior we administered this mixture to mice throughout gestation at doses 0x, 0.5x, 10x, 100x and 500x the geometric mean of SELMA mothers' concentrations, and examined their offspring in adulthood. Mixture N1 exposure increased active coping during swimming stress in both sexes, increased locomotion and reduced social interaction in male progeny. The expression of corticosterone receptors, their regulator Fkbp5, corticotropin releasing hormone and its receptor, oxytocin and its receptor, estrogen receptor beta, serotonin receptors (Htr1a, Htr2a) and glutamate receptor subunit Grin2b, were modified in the limbic system of adult animals, in a region-specific, sexually-dimorphic and experience-dependent manner. Principal component analysis revealed gene clusters associated with the observed behavioral responses, mostly related to the stress axis. This integration of epidemiology-based data with an experimental model increases the evidence that prenatal exposure to EDC mixtures impacts later life brain functions.
|
|
| 2. |
- Bikos, Vasilis, et al.
(författare)
-
An Immunogenetic Signature of Ongoing Antigen Interactions in Splenic Marginal Zone Lymphoma Expressing IGHV1-2*04 Receptors
- 2016
-
Ingår i: Clinical Cancer Research. - 1078-0432 .- 1557-3265. ; 22:8, s. 2032-2040
-
Tidskriftsartikel (refereegranskat)abstract
- Purpose: Prompted by the extensive biases in the immunoglobulin (IG) gene repertoire of splenic marginal-zone lymphoma (SMZL), supporting antigen selection in SMZL ontogeny, we sought to investigate whether antigen involvement is also relevant post-transformation. Experimental Design: We conducted a large-scale subcloning study of the IG rearrangements of 40 SMZL cases aimed at assessing intraclonal diversification (ID) due to ongoing somatic hypermutation (SHM). Results: ID was identified in 17 of 21 (81%) rearrangements using the immunoglobulin heavy variable (IGHV) 1-2*04 gene versus 8 of 19 (40%) rearrangements utilizing other IGHV genes (P = 0.001). ID was also evident in most analyzed IG light chain gene rearrangements, albeit was more limited compared with IG heavy chains. Identical sequence changes were shared by subclones from different patients utilizing the IGHV1-2*04 gene, confirming restricted ongoing SHM profiles. Non-IGHV1-2*04 cases displayed both a lower number of ongoing SHMs and a lack of shared mutations (per group of cases utilizing the same IGHV gene). Conclusions: These findings support ongoing antigen involvement in a sizable portion of SMZL and further argue that IGHV1-2*04 SMZL may represent a distinct molecular subtype of the disease.
|
|
| 3. |
- Delis, Costas, et al.
(författare)
-
AtHESPERIN : a novel regulator of circadian rhythms with poly(A)-degrading activity in plants
- 2016
-
Ingår i: RNA Biology. - : Informa UK Limited. - 1547-6286 .- 1555-8584. ; 13:1, s. 68-82
-
Tidskriftsartikel (refereegranskat)abstract
- We report the identification and characterization of a novel gene, AtHesperin (AtHESP) that codes for a deadenylase in Arabidopsis thaliana. The gene is under circadian clock-gene regulation and has similarity to the mammalian Nocturnin. AtHESP can efficiently degrade poly(A) substrates exhibiting allosteric kinetics. Size exclusion chromatography and native electrophoresis coupled with kinetic analysis support that the native enzyme is oligomeric with at least 3 binding sites. Knockdown and overexpression of AtHESP in plant lines affects the expression and rhythmicity of the clock core oscillator genes TOC1 and CCA1. This study demonstrates an evolutionary conserved poly(A)-degrading activity in plants and suggests deadenylation as a mechanism involved in the regulation of the circadian clock. A role of AtHESP in stress response in plants is also depicted.
|
|
| 4. |
- Papadopoulou, Anastasia, et al.
(författare)
-
Gestational diabetes mellitus is associated with TCF7L2 gene polymorphisms independent of HLA-DQB1*0602 genotypes and islet cell autoantibodies.
- 2011
-
Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 28:9, s. 1018-1027
-
Tidskriftsartikel (refereegranskat)abstract
- Aims: To test whether the TCF7L2 gene was associated with gestational diabetes, whether the association between TCF7L2 and gestational diabetes was independent of HLA-DQB1*0602 and islet cell autoantibodies, as well as maternal age, number of pregnancies, family history of diabetes and the HLA-DQB1 genotypes, and to test whether the distribution of HLA-DQB1 alleles was affected by country of birth. Methods: We genotyped the rs7903146, rs12255372 and rs7901695 single nucleotide polymorphisms of the TCF7L2 gene in 826 mothers with gestational diabetes and in 1185 healthy control subjects in the Diabetes Prediction in Skåne Study. The mothers were also typed for HLA-DQB1 genotypes and tested for islet cell autoantibodies against GAD65, insulinoma-associated antigen-2 and insulin. Results: The heterozygous genotypes CT, GT and TC of the rs7903146 (T is risk for Type 2 diabetes), rs12255372 (T is risk for Type 2 diabetes) and rs7901695 (C is risk for Type 2 diabetes), respectively, as well as the homozygous genotypes TT, TT and CC of the rs7903146, rs12255372 and rs7901695, respectively, were strongly associated with gestational diabetes (P < 0.0001). These associations remained statistically significant after adjusting for maternal age, number of pregnancies, family history of diabetes and HLA-DQ genotypes and were independent of the presence of islet cell autoantibodies. No interaction was observed between TCF7L2 and HLA-DQB1*0602, which was shown to be negatively associated with gestational diabetes in mothers born in Sweden (P = 0.010). Conclusions: The TCF7L2 was associated with susceptibility for gestational diabetes independently of the presence of HLA-DQB1*0602 and islet cell autoantibodies and other factors such as maternal age, number of pregnancies, family history of diabetes and other HLA-DQ genotypes. The HLA-DQB1*0602 was negatively associated with gestational diabetes in mothers born in Sweden.
|
|
| 5. |
- Papadopoulou, Anastasia, et al.
(författare)
-
HLA-DQB1 genotypes and islet cell autoantibodies against GAD65 and IA-2 in relation to development of diabetes post partum in women with gestational diabetes mellitus.
- 2012
-
Ingår i: Diabetes Research and Clinical Practice. - : Elsevier BV. - 1872-8227 .- 0168-8227. ; 95, s. 260-264
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS: To study HLA-DQB1 genes and islet cell autoantibodies against glutamic acid decarboxylase 65 (GADA) and insulinoma antigen-2 (IA-2A) in relation to diabetes post partum in mothers with diagnosed gestational diabetes mellitus (GDM). METHODS: During 2003-2004, women undergoing a 75g oral glucose tolerance test (OGTT) during pregnancy were invited to participate in the Mamma Study. Cut-off level defining GDM was a 2-h capillary blood glucose of 7.8mmol/L. 1-2 years after delivery a 75g OGTT was performed, GADA and IA-2A were measured and HLA-DQB1 genes analysed. Data were available for 452 mothers with previous GDM and 168 randomly selected control subjects. RESULTS: HLA-DQB1*0602 was negatively associated with GDM (p=0.033) and with development of diabetes post partum (p=0.017), whereas high risk HLA were not associated with GDM or with diabetes. The presence of GADA post partum was positively associated with diabetes post partum (p=0.0009), but not with impaired glucose tolerance. CONCLUSIONS: Mothers with GDM and HLA-DQB1*0602 were less likely to develop diabetes after pregnancy, and type 1 diabetes associated high risk HLA genes did not predict type 1 diabetes post partum. Additionally, GADA were positively associated with diabetes development.
|
|
| 6. |
- Papadopoulou, Anastasia
(författare)
-
The genetic background of gestational diabetes mellitus
- 2011
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The aims of this work is to better determine the genetic background of gestational diabetes (GDM) and to examine how specific genes affect the development of diabetes post partum. In the DiPiS (Diabetes Prediction in Skåne) study we typed for HLA-DQB1 alleled, the transcription factor 7-like 2(TCF7L2) rs7903146, rs12255372 and rs7901695 SNPs, the 1858 C>T SNP of the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene and we tested for the presence of islet cell autoantibodies against glutamic acid decarboxylase 65 (GAD65), insulinoma-associated antigen 2 (IA-2) and insulin in women who had been diagnosed with GDM at least once during 2000-2004. The HLA-DQB1*0602 allele which is considered to be protective for type 1 diabetes had a negative association with GDM even when excluding the autoantibody positive GDM women. There was a positive association between the type 2 diabetes associated TCF7L2 and GDM, regardless of the presence of islet cell autoantibodies or of HLA-DQB1*0602. The 1858 C>T SNP of the PTPN22 gene, which is considered a risk SNP for type 1 diabetes as well as other autoimmune disorders, had no association with GDM. The HLA-DQB1*0602 had even a negative association with diabetes post partum in a group of GDM women diagnosed during 2003-2005 in the Mamma study in which we had follow-up data one to two years after delivery. We conclude that GDM is a heterogeneous disorder which shares clinical features and genetic predisposition with both type 1 and type 2 diabetes. This is strengthened by the fact that GDM women have an increased risk to develop type 2 or even type 1 diabetes years after delivery.
|
|
| 7. |
- Papadopoulou, Anastasia, et al.
(författare)
-
The type 1 diabetes protective HLA DQB1*0602 allele is less frequent in gestational diabetes mellitus.
- 2009
-
Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 52, s. 1339-1342
-
Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: We tested whether gestational diabetes mellitus (GDM) is associated with HLA-DQ genotypes. METHODS: A total of 764 mothers with non-autoimmune (GAD65, insulinoma-associated protein 2 [IA-2] and insulin autoantibody-negative) GDM were ascertained between September 2000 and August 2004 in the population-based Diabetes Prediction in Skåne (DiPiS) study. HLA-DQB1 genotypes were determined in these mothers and in 1191 randomly selected non-diabetic control mothers also negative for islet autoantibodies. The data were analysed in relation to maternal age, country of birth, number of pregnancies/siblings and pregnancy weight gain. RESULTS: The frequency of type 1 diabetes high-risk HLA-DQ alleles (DQB1*0201, DQB1*0302) did not differ between GDM mothers and controls. In contrast, the low-risk DQB1*0602 allele was less prevalent (OR 0.64, 95% CI = 0.51-0.80, p = 0.0006) in GDM than in control mothers. The difference in DQB1*0602 frequency between GDM mothers and controls remained after multiple logistic regression analysis correcting for maternal age, country of birth, number of pregnancies/siblings and weight gain during pregnancy (OR 0.67, 95% CI 0.51-0.88, p = 0.009). CONCLUSIONS/INTERPRETATION: The negative association between mothers who have non-autoimmune GDM and HLA-DQ*0602 suggest that this allele may protect not only from type 1 diabetes but also from GDM.
|
|
| 8. |
- TEDDY study group, The, et al.
(författare)
-
The environmental determinants of diabetes in the young (TEDDY) study: Study design
- 2007
-
Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 8:5, s. 286-298
-
Tidskriftsartikel (refereegranskat)abstract
- The primary objective of this multicenter, multinational, epidemiological study is the identification of infectious agents, dietary factors, or other environmental exposures that are associated with increased risk of autoimmunity and type 1 diabetes mellitus (T1DM). Factors affecting specific phenotypic manifestations such as early age of onset or rate of progression or with protection from the development of T1DM will also be identified. The Environmental Determinants of Diabetes in the Young (TEDDY) is an observational cohort study in which newborns who are younger than 4 months and have high-risk human leukocyte antigen alleles in the general population or are first-degree relatives (FDRs) of patients affected with T1DM will be enrolled. Six clinical centers in the USA and Europe will screen 361 588 newborns, of which it is anticipated that 17 804 will be eligible for enrollment with just over 7800 followed. Recruitment will occur over 5 yr, with children being followed to the age of 15 yr. Identification of such factors will lead to a better understanding of disease pathogenesis and result in new strategies to prevent, delay, or reverse T1DM.
|
|
