| 1. |
- Jiao, Xiang, et al.
(författare)
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PHIP - a novel candidate breast cancer susceptibility locus on 6q14.1
- 2017
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Ingår i: Oncotarget. - : IMPACT JOURNALS LLC. - 1949-2553. ; 8:61, s. 102769-102782
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Tidskriftsartikel (refereegranskat)abstract
- Most non-BRCA1/2 breast cancer families have no identified genetic cause. We used linkage and haplotype analyses in familial and sporadic breast cancer cases to identify a susceptibility locus on chromosome 6q. Two independent genome-wide linkage analysis studies suggested a 3 Mb locus on chromosome 6q and two unrelated Swedish families with a LOD > 2 together seemed to share a haplotype in 6q14.1. We hypothesized that this region harbored a rare high-risk founder allele contributing to breast cancer in these two families. Sequencing of DNA and RNA from the two families did not detect any pathogenic mutations. Finally, 29 SNPs in the region were analyzed in 44,214 cases and 43,532 controls from BCAC, and the original haplotypes in the two families were suggested as low-risk alleles for European and Swedish women specifically. There was also some support for one additional independent moderate-risk allele in Swedish familial samples. The results were consistent with our previous findings in familial breast cancer and supported a breast cancer susceptibility locus at 6q14.1 around the PHIP gene.
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| 2. |
- Shu, Xiang, et al.
(författare)
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Associations of obesity and circulating insulin and glucose with breast cancer risk : a Mendelian randomization analysis
- 2019
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Ingår i: International Journal of Epidemiology. - : OXFORD UNIV PRESS. - 0300-5771 .- 1464-3685. ; 48:3, s. 795-806
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Tidskriftsartikel (refereegranskat)abstract
- Background: In addition to the established association between general obesity and breast cancer risk, central obesity and circulating fasting insulin and glucose have been linked to the development of this common malignancy. Findings from previous studies, however, have been inconsistent, and the nature of the associations is unclear. Methods: We conducted Mendelian randomization analyses to evaluate the association of breast cancer risk, using genetic instruments, with fasting insulin, fasting glucose, 2-h glucose, body mass index (BMI) and BMI-adjusted waist-hip-ratio (WHRadj BMI). We first confirmed the association of these instruments with type 2 diabetes risk in a large diabetes genome-wide association study consortium. We then investigated their associations with breast cancer risk using individual-level data obtained from 98 842 cases and 83 464 controls of European descent in the Breast Cancer Association Consortium. Results: All sets of instruments were associated with risk of type 2 diabetes. Associations with breast cancer risk were found for genetically predicted fasting insulin [odds ratio (OR) = 1.71 per standard deviation (SD) increase, 95% confidence interval (CI) = 1.26-2.31, p = 5.09 x 10(-4)], 2-h glucose (OR = 1.80 per SD increase, 95% CI = 1.3 0-2.49, p = 4.02 x 10(-4)), BMI (OR = 0.70 per 5-unit increase, 95% CI = 0.65-0.76, p = 5.05 x 10(-19)) and WHRadj BMI (OR = 0.85, 95% CI = 0.79-0.91, p = 9.22 x 10(-6)). Stratified analyses showed that genetically predicted fasting insulin was more closely related to risk of estrogen-receptor [ER]-positive cancer, whereas the associations with instruments of 2h glucose, BMI and WHRadj BMI were consistent regardless of age, menopausal status, estrogen receptor status and family history of breast cancer. Conclusions: We confirmed the previously reported inverse association of genetically predicted BMI with breast cancer risk, and showed a positive association of genetically predicted fasting insulin and 2-h glucose and an inverse association of WHRadj BMI with breast cancer risk. Our study suggests that genetically determined obesity and glucose/insulin-related traits have an important role in the aetiology of breast cancer.
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| 3. |
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| 4. |
- Abbasi, Rasha, et al.
(författare)
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IceCube search for neutrinos from GRB 221009A
- 2023
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Ingår i: Proceedings of 38th International Cosmic Ray Conference (ICRC 2023). - : Sissa Medialab Srl.
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Konferensbidrag (refereegranskat)abstract
- GRB 221009A is the brightest Gamma Ray Burst (GRB) ever observed. The observed extremelyhigh flux of high and very-high-energy photons provide a unique opportunity to probe the predictedneutrino counterpart to the electromagnetic emission. We have used a variety of methods to searchfor neutrinos in coincidence with the GRB over several time windows during the precursor, promptand afterglow phases of the GRB. MeV scale neutrinos are studied using photo-multiplier ratescalers which are normally used to search for galactic core-collapse supernovae neutrinos. GeVneutrinos are searched starting with DeepCore triggers. These events don’t have directionallocalization, but instead can indicate an excess in the rate of events. 10 GeV - 1 TeV and >TeVneutrinos are searched using traditional neutrino point source methods which take into accountthe direction and time of events with DeepCore and the entire IceCube detector respectively. The>TeV results include both a fast-response analysis conducted by IceCube in real-time with timewindows of T0 − 1 to T0 + 2 hours and T0 ± 1 day around the time of GRB 221009A, as well asan offline analysis with 3 new time windows up to a time window of T0 − 1 to T0 + 14 days, thelongest time period we consider. The combination of observations by IceCube covers 9 ordersof magnitude in neutrino energy, from MeV to PeV, placing upper limits across the range forpredicted neutrino emission.
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| 5. |
- Ahearn, Thomas U., et al.
(författare)
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Common variants in breast cancer risk loci predispose to distinct tumor subtypes
- 2022
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Ingår i: Breast Cancer Research. - : Springer Nature. - 1465-5411 .- 1465-542X. ; 24:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundGenome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.MethodsAmong 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.ResultsEighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated at p < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.ConclusionThis report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.
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| 6. |
- Beausang, Angela, et al.
(författare)
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"Möjligheten att rädda några av dessa kvinnors liv har inte vägts in"
- 2014
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Ingår i: Dagens Medicin. - : Dagens Medicin.
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Tidskriftsartikel (populärvet., debatt m.m.)abstract
- Namnet på Socialstyrelsens vägledning lyder: Hur upptäcka våldsutsatthet? Ja, det kan man verkligen fråga sig efter att ha läst detta föga vägledande dokument, skriver ett stort antal kritiska debattörer.
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| 7. |
- Docherty, Anna R, et al.
(författare)
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GWAS Meta-Analysis of Suicide Attempt: Identification of 12 Genome-Wide Significant Loci and Implication of Genetic Risks for Specific Health Factors.
- 2023
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Ingår i: The American journal of psychiatry. - : American Psychiatric Association Publishing. - 1535-7228 .- 0002-953X. ; 180:10, s. 723-738
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Tidskriftsartikel (refereegranskat)abstract
- Suicidal behavior is heritable and is a major cause of death worldwide. Two large-scale genome-wide association studies (GWASs) recently discovered and cross-validated genome-wide significant (GWS) loci for suicide attempt (SA). The present study leveraged the genetic cohorts from both studies to conduct the largest GWAS meta-analysis of SA to date. Multi-ancestry and admixture-specific meta-analyses were conducted within groups of significant African, East Asian, and European ancestry admixtures.This study comprised 22 cohorts, including 43,871 SA cases and 915,025 ancestry-matched controls. Analytical methods across multi-ancestry and individual ancestry admixtures included inverse variance-weighted fixed-effects meta-analyses, followed by gene, gene-set, tissue-set, and drug-target enrichment, as well as summary-data-based Mendelian randomization with brain expression quantitative trait loci data, phenome-wide genetic correlation, and genetic causal proportion analyses.Multi-ancestry and European ancestry admixture GWAS meta-analyses identified 12 risk loci at p values <5×10-8. These loci were mostly intergenic and implicated DRD2, SLC6A9, FURIN, NLGN1, SOX5, PDE4B, and CACNG2. The multi-ancestry SNP-based heritability estimate of SA was 5.7% on the liability scale (SE=0.003, p=5.7×10-80). Significant brain tissue gene expression and drug set enrichment were observed. There was shared genetic variation of SA with attention deficit hyperactivity disorder, smoking, and risk tolerance after conditioning SA on both major depressive disorder and posttraumatic stress disorder. Genetic causal proportion analyses implicated shared genetic risk for specific health factors.This multi-ancestry analysis of suicide attempt identified several loci contributing to risk and establishes significant shared genetic covariation with clinical phenotypes. These findings provide insight into genetic factors associated with suicide attempt across ancestry admixture populations, in veteran and civilian populations, and in attempt versus death.
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| 8. |
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| 9. |
- Edlund, Anna, et al.
(författare)
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Defective exocytosis and processing of insulin in a cystic fibrosis mouse model
- 2019
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Ingår i: Journal of Endocrinology. - 1479-6805. ; 241:1, s. 45-57
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Tidskriftsartikel (refereegranskat)abstract
- Cystic fibrosis-related diabetes (CFRD) is a common complication for patients with cystic fibrosis (CF), a disease caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR). The cause of CFRD is unclear, but a commonly observed reduction in first-phase insulin secretion suggests defects at the beta cell level. Here we aimed to examine beta- and alpha-cell function in the Cftrtm1EUR/F508del mouse model (C57BL/6J), which carries the most common human mutation in CFTR, the F508del mutation. CFTR expression, beta cell mass, insulin granule distribution, hormone secretion and single cell capacitance changes were evaluated using islets (or beta cells) from F508del mice and age-matched wild-type mice aged 7-10 weeks. Granular pH was measured with DND-189 fluorescence. Serum glucose, insulin and glucagon levels were measured in vivo, and glucose tolerance was assessed using IPGTT. We show increased secretion of proinsulin and concomitant reduced secretion of C-peptide in islets from F508del mice compared to WT mice. Exocytosis and number of docked granules was reduced. We confirmed reduced granular pH by CFTR stimulation. We detected decreased pancreatic beta cell area, but unchanged beta cell number. Moreover, the F508del mutation caused failure to suppress glucagon secretion leading to hyperglucagonemia. In conclusion, F508del mice have beta cell defects resulting in 1) reduced number of docked insulin granules and reduced exocytosis, and 2) potential defective proinsulin cleavage and secretion of immature insulin. These observations provide insight into the functional role of CFTR in pancreatic islets and contribute to increased understanding of the pathogenesis of CFRD.
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| 10. |
- Kalis, Martins, et al.
(författare)
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Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12, s. e29166-
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Tidskriftsartikel (refereegranskat)abstract
- Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.
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| 11. |
- Lyssenko, Valeriya, et al.
(författare)
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Pleiotropic Effects of GIP on Islet Function Involve Osteopontin
- 2011
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 60:9, s. 2424-2433
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-The incretin hormone GIP (glucose-dependent insulinotropic polypeptide) promotes pancreatic beta-cell function by potentiating insulin secretion and beta-cell proliferation. Recently, a combined analysis of several genome-wide association studies (Meta-analysis of Glucose and Insulin-Related Traits Consortium [MAGIC]) showed association to postprandial insulin at the GIP receptor (GIPR) locus. Here we explored mechanisms that could explain the protective effects of GIP on islet function. RESEARCH DESIGN AND METHODS-Associations of GIPR rs10423928 with metabolic and anthropometric phenotypes in both nondiabetic (N = 53,730) and type 2 diabetic individuals (N = 2,731) were explored by combining data from 11 studies.Insulin secretion was measured both in vivo in nondiabetic subjects and in vitro in islets from cadaver donors. Insulin secretion was also measured in response to exogenous GIP. The in vitro measurements included protein and gene expression as well as measurements of beta-cell viability and proliferation. RESULTS-The A allele of GIPR rs10423928 was associated with impaired glucose- and GIP-stimulated insulin secretion and a decrease in BMI, lean body mass, and waist circumference. The decrease in BMI almost completely neutralized the effect of impaired insulin secretion on risk of type 2 diabetes. Expression of GIPR mRNA was decreased in human islets from carriers of the A allele or patients with type 2 diabetes. GIP stimulated osteopontin (OPN) mRNA and protein expression. OPN expression was lower in carriers of the A allele. Both GIP and OPN prevented cytokine-induced reduction in cell viability (apoptosis). In addition, OPN stimulated cell proliferation in insulin-secreting cells. CONCLUSIONS-These findings support beta-cell proliferative and antiapoptotic roles for GIP in addition to its action as an incretin hormone. Identification of a link between GIP and OPN may shed new light on the role of GIP in preservation of functional beta-cell mass in humans. Diabetes 60:2424-2433, 2011
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| 12. |
- Mollet, Inês Guerra Uerra, et al.
(författare)
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Integrator of stress responses calmodulin binding transcription activator 1 (Camta1) Regulates miR-212/miR-132 Expression and insulin secretion
- 2016
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Ingår i: Journal of Biological Chemistry. - 0021-9258. ; 291:35, s. 18440-18452
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Tidskriftsartikel (refereegranskat)abstract
- Altered microRNA profiles have been demonstrated in experimental models of type 2 diabetes, including in islets of the diabetic Goto-Kakizaki (GK) rat. Our bioinformatic analysis of conserved sequences in promoters of microRNAs, previously observed to be up-regulated in GK rat islets, revealed putative CGCG-core motifs on the promoter of the miR-212/miR-132 cluster, overexpression of which has been shown to increase insulin secretion. These motifs are possible targets of calmodulin binding transcription activators Camta1 and Camta2 that have been recognized as integrators of stress responses. We also identified putative NKE elements, possible targets of NK2 homeobox proteins like the essential islet transcription factor Nkx2-2. As Camtas can function as co-activators with NK2 proteins in other tissues, we explored the role of Camta1, Camta2, and Nkx2-2 in the regulation of the miR-212/miR-132 cluster and insulin secretion. We demonstrate that exposure of control Wistar or GK rat islets to 16.7 mM glucose increases miR-212/miR-132 expression but significantly less so in the GK rat. In addition, Camta1, Camta2, and Nkx2-2 were down-regulated in GK rat islets, and knockdown of Camta1 reduced miR-212/miR-132 promoter activity and miR-212/miR-132 expression, even under cAMP elevation. Knockdown of Camta1 decreased insulin secretion in INS-1 832/13 cells and Wistar rat islets but increased insulin content. Furthermore, knockdown of Camta1 reduced K+-induced insulin secretion and voltage-dependent Ca2+ currents. We also demonstrate Camta1 and Nkx2-2 protein interaction. These results indicate that Camta1 is required not only for expression of the miR-212/miR-132 cluster but at multiple levels for regulating beta cell insulin content and secretion.
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| 13. |
- Mueller, Stefanie H., et al.
(författare)
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Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry
- 2023
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Ingår i: Genome Medicine. - : BioMed Central (BMC). - 1756-994X. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes.Methods: We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry.Results: In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C.Conclusions: Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.
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| 14. |
- Nagao, Mototsugu, et al.
(författare)
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Potential Protection Against Type 2 Diabetes in Obesity Through Lower CD36 Expression and Improved Exocytosis in β-Cells
- 2020
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 69:6, s. 1193-1205
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Tidskriftsartikel (refereegranskat)abstract
- Obesity is a risk factor for type 2 diabetes (T2D); however, not all obese individuals develop the disease. In this study, we aimed to investigate the cause of differential insulin secretion capacity of pancreatic islets from donors with T2D and non-T2D (ND), especially obese donors (BMI ≥30 kg/m2). Islets from obese donors with T2D had reduced insulin secretion, decreased β-cell exocytosis, and higher expression of fatty acid translocase CD36. We tested the hypothesis that CD36 is a key molecule in the reduced insulin secretion capacity. Indeed, CD36 overexpression led to decreased insulin secretion, impaired exocytosis, and reduced granule docking. This was accompanied by reduced expression of the exocytotic proteins SNAP25, STXBP1, and VAMP2, likely because CD36 induced downregulation of the insulin receptor substrate (IRS) proteins, suppressed the insulin-signaling phosphatidylinositol 3-kinase/AKT pathway, and increased nuclear localization of the transcription factor FoxO1. CD36 antibody treatment of the human β-cell line EndoC-βH1 increased IRS1 and exocytotic protein levels, improved granule docking, and enhanced insulin secretion. Our results demonstrate that β-cells from obese donors with T2D have dysfunctional exocytosis likely due to an abnormal lipid handling represented by differential CD36 expression. Hence, CD36 could be a key molecule to limit β-cell function in T2D associated with obesity.
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| 15. |
- Wendt, Anna, et al.
(författare)
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Osteopontin affects insulin vesicle localization and Ca2+ homeostasis in pancreatic beta cells from female mice
- 2017
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetic patients suffer from insulin resistance and reduced insulin secretion. Osteopontin (OPN), a versatile protein expressed in several tissues throughout the body including the islets of Langerhans, has previously been implicated in the development of insulin resistance. Here we have investigated the role of OPN in insulin secretion using an OPN knock out mouse model (OPN-/-). Ultra-structural analyzes of islets from OPN-/- and WT mice indicated weaker cell-cell connections between the islet cells in the OPN-/- mouse compared to WT. Analysis of the insulin granule distribution in the beta cells showed that although OPN-/- and WT beta cells have the same number of insulin granules OPN-/- beta cells have significantly fewer docked granules. Both OPN-/- and WT islets displayed synchronized Ca2+ oscillations indicative of an intact beta cell communication. OPN-/- islets displayed higher intracellular Ca2+ concentrations when stimulated with 16.7 mM glucose than WT islets and the initial dip upon elevated glucose concentrations (which is associated with Ca2+ uptake into ER) was significantly lower in these islets. Glucose-induced insulin secretion was similar in OPN-/- and WT islets. Likewise, non-fasted blood glucose levels were the same in both groups. In summary, deletion of OPN results in several minor beta-cell defects that can be compensated for in a healthy system.
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| 16. |
- Westholm, Efraim, et al.
(författare)
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Interleukin-4 reduces insulin secretion in human islets from healthy but not type-2 diabetic donors
- 2023
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 649, s. 87-92
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Tidskriftsartikel (refereegranskat)abstract
- Type 2 diabetes (T2D) is associated with low-grade inflammation. Here we investigate if the anti-inflammatorycytokine interleukin-4 (IL-4) affects glucose-stimulated insulin secretion (GSIS) in human islets from nondiabetic(ND) and type-2 diabetic (T2D) donors. We first confirmed that GSIS is reduced in islets from T2Ddonors. Treatment with IL-4 for 48 h had no further effect on GSIS in these islets but significantly reduced secretionin ND islets. Acute treatment with IL-4 for 1 h had no effect on GSIS in ND islets which led us to suspect thatIL-4 affects a slow cellular mechanism such as gene transcription. IL-4 has been reported to regulate miR-378a-3pand, indeed, we found that this microRNA was increased with IL-4 treatment. However, overexpression of miR-378a-3p in the human beta cell line EndoC-βH1 did not affect GSIS. MiR-378a-3p is transcribed from the samegene as peroxisome proliferator-activated receptor gamma co-activator 1 beta (PCG-1β) and we found that IL-4treatment showed a clear tendency to increased gene expression of PCG-1β. PCG-1β is a co-activator of peroxisomeproliferator-activated receptor gamma (PPARγ) and, the gene expression of PPARγ was also increased withIL-4 treatment. Our data suggests that the protective role of IL-4 on beta cell survival comes at the cost of loweredinsulin secretion, presumably involving the PPARγ-pathway.
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| 17. |
- Ahlqwist, Anna, et al.
(författare)
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Physical therapy treatment of back complaints on children and adolescents.
- 2008
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Ingår i: Spine. - 1528-1159. ; 33:20
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Tidskriftsartikel (refereegranskat)abstract
- STUDY DESIGN: A randomized controlled trial was performed. OBJECTIVES: To evaluate how 2 different treatment options affect perception of health, pain, and physical functioning over time among children and adolescents with low back pain (LBP). SUMMARY OF BACKGROUND DATA: LBP among children and adolescents has increased. The literature shows that children with LBP also suffer from this condition as adults. Thus, it is important to prevent and treat LBP in children and adolescents. METHODS: Forty-five children and adolescents were consecutively randomized into one of 2 treatment groups and were studied for 12 weeks. Group 1 was given individualized physical therapy and exercise and a standardized self-training program and back education. Group 2 was given self-training program and back education but no individualized therapy. The children and adolescents were tested before and after the treatment period. Child Health Questionnaire Child Form 87, Roland & Morris Disability Questionnaire, Painometer, Back Saver Sit and Reach, and test of trunk muscle endurance were used to evaluate the interventions. RESULTS: Both groups improved statistically significant in most parameters over time. On comparison between the groups the physical function measured by Roland & Morris Disability Questionnaire and the duration of pain measured by Painometer improved statistically significant in Group 1. CONCLUSION: An individual assessment by a knowledgeable physiotherapist and an active treatment model improve how children and adolescents experience their back problems with respect to health and physical function, pain, strength, and mobility, regardless of whether treatment consists of a home exercise program with follow-up or home exercise combined with exercise and treatment supervised by a physiotherapist.
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| 18. |
- Barg, Sebastian, et al.
(författare)
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Delay between fusion pore opening and peptide release from large dense-core vesicles in neuroendocrine cells.
- 2002
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Ingår i: Neuron. - 0896-6273 .- 1097-4199. ; 33:2, s. 287-299
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Tidskriftsartikel (refereegranskat)abstract
- Peptidergic neurotransmission is slow compared to that mediated by classical neurotransmitters. We have studied exocytotic membrane fusion and cargo release by simultaneous capacitance measurements and confocal imaging of single secretory vesicles in neuroendocrine cells. Depletion of the readily releasable pool (RRP) correlated with exocytosis of 10%-20% of the docked vesicles. Some remaining vesicles became releasable after recovery of RRP. Expansion of the fusion pore, seen as an increase in luminal pH, occurred after approximately 0.3 s, and peptide release was delayed by another 1-10 s. We conclude that (1) RRP refilling involves chemical modification of vesicles already in place, (2) the release of large neuropeptides via the fusion pore is negligible and only proceeds after complete fusion, and (3) sluggish peptidergic transmission reflects the time course of vesicle emptying.
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| 19. |
- Bodin, Johanna, et al.
(författare)
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Exposure to bisphenol A, but not phthalates, increases spontaneous diabetes type 1 development in NOD mice
- 2015
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Ingår i: Toxicology Reports. - : Elsevier BV. - 2214-7500. ; 2, s. 99-110
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes mellitus (T1DM) is an autoimmune destruction of insulin producing pancreatic beta-cells due to a genetic predisposition and can be triggered by environmental factors. We have previously shown that bisphenol A (BPA) accelerates the spontaneous development of diabetes in non-obese diabetic (NOD) mice. Here, we hypothesized that oral exposure to a mixture of the endocrine disruptors BPA and phthalates, relevant for human exposure, would accelerate diabetes development compared to BPA alone. NOD mice were exposed to BPA (1 mg/l), a mixture of phthalates (DEHP 1 mg/l, DBP 0.2 mg/l, BBP 10 mg/l and DiBP 20 mg/l) or a combination of BPA and the phthalate mixture through drinking water from conception and throughout life. Previous observations that BPA exposure increased the prevalence of diabetes and insulitis and decreased the number of tissue resident macrophages in pancreas were confirmed, and extended by demonstrating that BPA exposure also impaired the phagocytic activity of peritoneal macrophages. None of these effects were observed after phthalate exposure alone. The phthalate exposure in combination with BPA seemed to dampen the BPA effects on macrophage number and function as well as diabetes development, but not insulitis development. Exposure to BPA alone or in combination with phthalates decreased cytokine release (TNFα, IL-6, IL-10, IFNγ, IL-4) from in vitro stimulated splenocytes and lymph node cells, indicating systemic changes in immune function. In conclusion, exposure to BPA, but not to phthalates or mixed exposure to BPA and phthalates, accelerated diabetes development in NOD mice, apparently in part via systemic immune alterations including decreased macrophage function.
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| 20. |
- Braun, Matthias, et al.
(författare)
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Corelease and differential exit via the fusion pore of GABA, serotonin, and ATP from LDCV in rat pancreatic beta cells
- 2007
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Ingår i: Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 129:3, s. 221-231
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Tidskriftsartikel (refereegranskat)abstract
- The release gamma-aminobutyric acid (GABA) and ATP from rat beta cells was monitored using an electrophysiological assay based on overexpression GABAA or P2X2 receptor ion channels. Exocytosis of LDCVs, detected by carbon fiber amperometry of serotonin, correlated strongly (similar to 80%) with ATP release. The increase in membrane capacitance per ATP release event was 3.4 fF, close to the expected capacitance of an individual LDCV with a diameter of 0.3 mu m. ATP and GABA were coreleased with serotonin with the same probability. Immunogold electron microscopy revealed that similar to 15% of the LDCVs contain GABA. Prespike "pedestals," reflecting exit of granule constituents via the fusion pore, were less frequently observed for ATP than for serotonin or GABA and the relative amplitude (amplitude of foot compared to spike) was smaller: in some cases the ATP-dependent pedestal was missing entirely. An inward tonic current, not dependent on glucose and inhibited by the GABAA receptor antagonist SR95531, was observed in beta cells in clusters of islet cells. Noise analysis indicated that it was due to the activity of individual channels with a conductance of 30 pS, the same as expected for individual GABA(A) Cl- channels with the ionic gradients used. We conclude that (a) LDCVs accumulate ATP and serotonin; (b) regulated release of GABA can be accounted for by exocytosis of a subset of insulin-containing LDCVs; (c) the fusion pore of LDCVs exhibits selectivity and compounds are differentially released depending on their chemical properties (including size); and (d) a glucose-independent nonvesicular form of GABA release exists in beta cells.
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| 21. |
- Braun, Matthias, et al.
(författare)
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GABAB-receptor activation inhibits exocytosis in rat pancreatic {beta}-cells by G-protein-dependent activation of calcineurin.
- 2004
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Ingår i: Journal of Physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 559:2, s. 397-409
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Tidskriftsartikel (refereegranskat)abstract
- We have investigated the regulation of hormone secretion from rat pancreatic islets by the GABAB receptors (GABABRs). Inclusion of the specific GABABR antagonist CGP 55845 in the extracellular medium increased glucose-stimulated insulin secretion 1.6-fold but did not affect the release of glucagon and somatostatin. Conversely, addition of the GABABR agonist baclofen inhibited glucose-stimulated insulin secretion by ∼60%. Using RT-PCR, transcription of GABABR1a-c,f and GABABR2 subunits was detected in β-cells. Measurements of membrane currents and cell capacitance were applied to single β-cells to investigate the mechanisms by which GABABR activation inhibits insulin secretion. In perforated-patch measurements, baclofen inhibited exocytosis elicited by 500-ms voltage-clamp depolarizations to 0 mV by ≤ 80% and voltage-gated Ca2+ entry by only ∼30%. Both effects were concentration-dependent with IC50 values of ∼2 μm. The inhibitory action of baclofen was abolished in the presence of CGP 55845. The ability of baclofen to suppress exocytosis was prevented by pre-treatment with pertussis toxin and by inclusion of GDPβS in the intracellular medium, and became irreversible in the presence of GTPγS as expected for a process involving inhibitory G-proteins (Gi/o-proteins). The inhibitory effect of baclofen resulted from activation of the serine/threonine protein phosphatase calcineurin and pre-treatment with cyclosporin A or intracellular application of calcineurin autoinhibitory peptide abolished the effect. Addition of baclofen had no effect on [Ca2+]i and electrical activity in glucose-stimulated β-cells. These data indicate that GABA released from β-cells functions as an autocrine inhibitor of insulin secretion in pancreatic islets and that the effect is principally due to direct suppression of exocytosis.
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| 22. |
- Braun, Matthias, et al.
(författare)
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Regulated Exocytosis of GABA-containing Synaptic-like Microvesicles in Pancreatic {beta}-cells.
- 2004
-
Ingår i: Journal of General Physiology. - : Rockefeller University Press. - 0022-1295 .- 1540-7748. ; 123:3, s. 191-204
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Tidskriftsartikel (refereegranskat)abstract
- We have explored whether {gamma}-aminobutyric acid (GABA) is released by regulated exocytosis of GABA-containing synaptic-like microvesicles (SLMVs) in insulin-releasing rat pancreatic ß-cells. To this end, ß-cells were engineered to express GABAA-receptor Cl--channels at high density using adenoviral infection. Electron microscopy indicated that the average diameter of the SLMVs is 90 nm, that every ß-cell contains ~3,500 such vesicles, and that insulin-containing large dense core vesicles exclude GABA. Quantal release of GABA, seen as rapidly activating and deactivating Cl--currents, was observed during membrane depolarizations from -70 mV to voltages beyond -40 mV or when Ca2+ was dialysed into the cell interior. Depolarization-evoked GABA release was suppressed when Ca2+ entry was inhibited using Cd2+. Analysis of the kinetics of GABA release revealed that GABA-containing vesicles can be divided into a readily releasable pool and a reserve pool. Simultaneous measurements of GABA release and cell capacitance indicated that exocytosis of SLMVs contributes ~1% of the capacitance signal. Mathematical analysis of the release events suggests that every SLMV contains 0.36 amol of GABA. We conclude that there are two parallel pathways of exocytosis in pancreatic ß-cells and that release of GABA may accordingly be temporally and spatially separated from insulin secretion. This provides a basis for paracrine GABAergic signaling within the islet.
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| 23. |
- Christensen, Gitte L., et al.
(författare)
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Bone morphogenetic protein 4 inhibits insulin secretion from rodent beta cells through regulation of calbindin1 expression and reduced voltage-dependent calcium currents
- 2015
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 58:6, s. 1282-1290
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Type 2 diabetes is characterised by progressive loss of pancreatic beta cell mass and function. Therefore, it is of therapeutic interest to identify factors with the potential to improve beta cell proliferation and insulin secretion. Bone morphogenetic protein 4 (BMP4) expression is increased in diabetic animals and BMP4 reduces glucose-stimulated insulin secretion (GSIS). Here, we investigate the molecular mechanism behind this inhibition. Methods BMP4-mediated inhibition of GSIS was investigated in detail using single cell electrophysiological measurements and live cell Ca2+ imaging. BMP4-mediated gene expression changes were investigated by microarray profiling, quantitative PCR and western blotting. Results Prolonged exposure to BMP4 reduced GSIS from rodent pancreatic islets. This inhibition was associated with decreased exocytosis due to a reduced Ca2+ current through voltage-dependent Ca2+ channels. To identify proteins involved in the inhibition of GSIS, we investigated global gene expression changes induced by BMP4 in neonatal rat pancreatic islets. Expression of the Ca2+-binding protein calbindin1 was significantly induced by BMP4. Overexpression of calbindin1 in primary islet cells reduced GSIS, and the effect of BMP4 on GSIS was lost in islets from calbindin1 (Calb1) knockout mice. Conclusions/interpretation We found BMP4 treatment to markedly inhibit GSIS from rodent pancreatic islets in a calbindin1-dependent manner. Calbindin1 is suggested to mediate the effect of BMP4 by buffering Ca2+ and decreasing Ca2+ channel activity, resulting in diminished insulin exocytosis. Both BMP4 and calbindin1 are potential pharmacological targets for the treatment of beta cell dysfunction.
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| 24. |
- Dekker Nitert, Marloes, et al.
(författare)
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CaV1.2 rather than CaV1.3 is coupled to glucose-stimulated insulin secretion in INS-1 832/13 cells.
- 2008
-
Ingår i: Journal of Molecular Endocrinology. - 1479-6813. ; 41:1, s. 1-11
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Tidskriftsartikel (refereegranskat)abstract
- In clonal beta-cell lines and islets from different species, a variety of calcium channels are coupled to glucose-stimulated insulin secretion. The aim of this study was to identify the voltage-gated calcium channels that control insulin secretion in insulinoma (INS)-1 832/13 cells. The mRNA level of Ca(V)1.2 exceeded that of Ca(V)1.3 and Ca(V)2.3 two-fold. Insulin secretion, which rose tenfold in response to 16.7 mM glucose, was completely abolished by 5 microM isradipine that blocks Ca(V)1.2 and Ca(V)1.3. Similarly, the increase in intracellular calcium in response to 15 mM glucose was decreased in the presence of 5 microM isradipine, and the frequency of calcium spikes was decreased to the level seen at 2.8 mM glucose. By contrast, inhibition of Ca(V)2.3 with 100 nM SNX-482 did not significantly affect insulin secretion or intracellular calcium. Using RNA interference, Ca(V)1.2 mRNA and protein levels were knocked down by approximately 65% and approximately 34% respectively, which reduced insulin secretion in response to 16.7 mM glucose by 50%. Similar reductions in calcium currents and cell capacitance were seen in standard whole-cell patch-clamp experiments. The remaining secretion of insulin could be reduced to the basal level by 5 microM isradipine. Calcium influx underlying this residual insulin secretion could result from persisting Ca(V)1.2 expression in transfected cells since knock-down of Ca(V)1.3 did not affect glucose-stimulated insulin secretion. In summary, our results suggest that Ca(V)1.2 is critical for insulin secretion in INS-1 832/13 cells.
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| 25. |
- Eftring, Håkan, et al.
(författare)
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Tips for creating inclusive classrooms at LTH
- 2023
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Ingår i: LTH:s 12:e Pedagogiska inspirationskonferens. - 2003-3761 .- 2003-377X. ; , s. 45-47
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Konferensbidrag (övrigt vetenskapligt/konstnärligt)abstract
- All people are different. All teachers are different. All students are different. They have different life situations, different study situations, and different preferences, conditions, and abilities. How can we take this diversity into account when we plan our teaching and exams? What situations should we prepare for? How can we help students focus on their learning and not on unnecessary obstacles we unconsciously introduce? If we make small efforts upfront, this lets us avoid much larger efforts later on when we are confronted with the reality of students in our class and their different needs.At this round table, let us discuss diversity in teaching and learning. During fall 2023, a pilot of the course “The Inclusive Classroom” was run at LTH, the Faculty of Engineering at Lund University. We present the compiled, most important take-aways of participants and instructors, in addition to individual case-studies. In a nutshell: There are a lot of easy things you can do that can already have large effects, and you are not alone: LTH has many resources to support you. Please join a supportive, engaged community and learn from and with us!
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| 26. |
- Eliasson, Lena, et al.
(författare)
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Diabetes : Partners for life
- 2016
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Ingår i: eLife. - 2050-084X. ; 5, s. 1-2
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Tidskriftsartikel (refereegranskat)abstract
- The hormones insulin and glucagon both play important roles in the development of diabetes.
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| 27. |
- Eliasson, Lena, et al.
(författare)
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Lessons from basic pancreatic beta cell research in type-2 diabetes and vascular complications
- 2017
-
Ingår i: Diabetology International. - : Springer Science and Business Media LLC. - 2190-1686 .- 2190-1678. ; 8:2, s. 139-152
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Forskningsöversikt (refereegranskat)abstract
- The changes in life-style with increased access of food and reduced physical activity have resulted in the global epidemic of obesity. Consequently, individuals with type 2 diabetes and cardiovascular disease have also escalated. A central organ in the development of diabetes is the pancreas, and more specifically the pancreatic beta cells within the islets of Langerhans. Beta cells have been assigned the important task of secreting insulin when blood glucose is increased to lower the glucose level. An early sign of diabetes pathogenesis is lack of first phase insulin response and reduced second phase secretion. In this review, which is based on the foreign investigator award lecture given at the JSDC meeting in Sendai in October 2016, we discuss a possible cellular explanation for the reduced first phase insulin response and how this can be influenced by lipids. Moreover, since patients with cardiovascular disease and high levels of cholesterol are often treated with statins, we summarize recent data regarding effects on statins on glucose homeostasis and insulin secretion. Finally, we suggest microRNAs (miRNAs) as central players in the adjustment of beta cell function during the development of diabetes. We specifically discuss miRNAs regarding their involvement in insulin secretion regulation, differential expression in type 2 diabetes, and potential as biomarkers for prediction of diabetes and cardiovascular complications.
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| 28. |
- Esguerra, Jonathan L.S., et al.
(författare)
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MicroRNAs in islet hormone secretion
- 2018
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Ingår i: Diabetes, Obesity and Metabolism. - : Wiley. - 1462-8902. ; 20:Suppl 2, s. 11-19
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Forskningsöversikt (refereegranskat)abstract
- Pancreatic islet hormone secretion is central in the maintenance of blood glucose homeostasis. During development of hyperglycaemia, the β-cell is under pressure to release more insulin to compensate for increased insulin resistance. Failure of the β-cells to secrete enough insulin results in type 2 diabetes (T2D). MicroRNAs (miRNAs) are short non-coding RNA molecules suitable for rapid regulation of the changes in target gene expression needed in β-cell adaptations. Moreover, miRNAs are involved in the maintenance of α-cell and β-cell phenotypic identities via cell-specific, or cell-enriched expression. Although many of the abundant miRNAs are highly expressed in both cell types, recent research has focused on the role of miRNAs in β-cells. It has been shown that highly abundant miRNAs, such as miR-375, are involved in several cellular functions indispensable in maintaining β-cell phenotypic identity, almost acting as “housekeeping genes” in the context of hormone secretion. Despite the abundance and importance of miR-375, it has not been shown to be differentially expressed in T2D islets. On the contrary, the less abundant miRNAs such as miR-212/miR-132, miR-335, miR-130a/b and miR-152 are deregulated in T2D islets, wherein the latter three miRNAs were shown to play key roles in regulating β-cell metabolism. In this review, we focus on β-cell function and describe miRNAs involved in insulin biosynthesis and processing, glucose uptake and metabolism, electrical activity and Ca2+-influx and exocytosis of the insulin granules. We present current status on miRNA regulation in α-cells, and finally we discuss the involvement of miRNAs in β-cell dysfunction underlying T2D pathogenesis.
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| 29. |
- Esguerra, Jonathan, et al.
(författare)
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Regulation of Pancreatic Beta Cell Stimulus-Secretion Coupling by microRNAs.
- 2014
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 5:4, s. 1018-1031
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Forskningsöversikt (refereegranskat)abstract
- Increased blood glucose after a meal is countered by the subsequent increased release of the hypoglycemic hormone insulin from the pancreatic beta cells. The cascade of molecular events encompassing the initial sensing and transport of glucose into the beta cell, culminating with the exocytosis of the insulin large dense core granules (LDCVs) is termed "stimulus-secretion coupling." Impairment in any of the relevant processes leads to insufficient insulin release, which contributes to the development of type 2 diabetes (T2D). The fate of the beta cell, when exposed to environmental triggers of the disease, is determined by the possibility to adapt to the new situation by regulation of gene expression. As established factors of post-transcriptional regulation, microRNAs (miRNAs) are well-recognized mediators of beta cell plasticity and adaptation. Here, we put focus on the importance of comprehending the transcriptional regulation of miRNAs, and how miRNAs are implicated in stimulus-secretion coupling, specifically those influencing the late stages of insulin secretion. We suggest that efficient beta cell adaptation requires an optimal balance between transcriptional regulation of miRNAs themselves, and miRNA-dependent gene regulation. The increased knowledge of the beta cell transcriptional network inclusive of non-coding RNAs such as miRNAs is essential in identifying novel targets for the treatment of T2D.
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| 30. |
- Gao, Rui, et al.
(författare)
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α-cell electrophysiology and the regulation of glucagon secretion
- 2023
-
Ingår i: The Journal of endocrinology. - 1479-6805. ; 258:2
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Forskningsöversikt (refereegranskat)abstract
- Glucagon is the principal glucose-elevating hormone that forms the first-line defence against hypoglycaemia. Along with insulin, glucagon also plays a key role in maintaining systemic glucose homeostasis. The cells that secrete glucagon, pancreatic α-cells, are electrically excitable cells and use electrical activity to couple its hormone secretion to changes in ambient glucose levels. Exactly how glucose regulates α-cells has been a topic of debate for decades but it is clear that electrical signals generated by the cells play an important role in glucagon secretory response. Decades of studies have already revealed the key players involved in the generation of these electrical signals and possible mechanisms controlling them to tune glucagon release. This has offered the opportunity to fully understand the enigmatic α-cell physiology. In this review, we describe the current knowledge on cellular electrophysiology and factors regulating excitability, glucose sensing, and glucagon secretion. We also discuss α-cell pathophysiology and the perspective of addressing glucagon secretory defects in diabetes for developing better diabetes treatment, which bears the hope of eliminating hypoglycaemia as a clinical problem in diabetes care.
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| 31. |
- Glavaski-Joksimovic, Aleksandra, et al.
(författare)
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Survival, migration, and differentiation of Sox1-GFP embryonic stem cells in coculture with an auditory brainstem slice preparation
- 2008
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Ingår i: Cloning and Stem Cells. - : Mary Ann Liebert. - 1536-2302 .- 1557-7457. ; 10:1, s. 75-87
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Tidskriftsartikel (refereegranskat)abstract
- The poor regeneration capability of the mammalian hearing organ has initiated different approaches to enhance its functionality after injury. To evaluate a potential neuronal repair paradigm in the inner ear and cochlear nerve we have previously used embryonic neuronal tissue and stem cells for implantation in vivo and in vitro. At present, we have used in vitro techniques to study the survival and differentiation of Sox1-green fluorescent protein (GFP) mouse embryonic stem (ES) cells as a monoculture or as a coculture with rat auditory brainstem slices. For the coculture, 300 mu m-thick brainstem slices encompassing the cochlear nucleus and cochlear nerve were prepared from postnatal SD rats. The. slices were propagated using the membrane interface method and the cochlear nuclei were prelabeled with DiI. After some days in culture a suspension of Sox1 cells was deposited next to the brainstem slice. Following. deposition Sox1 cells migrated toward the brainstem and onto the cochlear nucleus. GFP was not detectable in undifferentiated ES cells but became evident during neural differentiation.. Up to 2 weeks after transplantation the cocultures were fixed. The undifferentiated cells were evaluated with antibodies against progenitor cells whereas the differentiated cells were determined with neuronal and glial markers. The morphological and immunohistochemical data indicated that Sox1 cells in monoculture differentiated into a higher percentage of glial cells than neurons. However, when a coculture was used a significantly lower percentage of Sox1 cells differentiated into glial cells. The results demonstrate that a coculture of Sox1 cells and auditory brainstem present a useful model to study stem cell differentiation.
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| 32. |
- Gschwendtner, Dda, et al.
(författare)
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The AWAKE Run 2 Programme and Beyond
- 2022
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Ingår i: Symmetry. - : MDPI AG. - 2073-8994. ; 14:8
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Tidskriftsartikel (refereegranskat)abstract
- Plasma wakefield acceleration is a promising technology to reduce the size of particle accelerators. The use of high energy protons to drive wakefields in plasma has been demonstrated during Run 1 of the AWAKE programme at CERN. Protons of energy 400 GeV drove wakefields that accelerated electrons to 2 GeV in under 10 m of plasma. The AWAKE collaboration is now embarking on Run 2 with the main aims to demonstrate stable accelerating gradients of 0.5-1 GV/m, preserve emittance of the electron bunches during acceleration and develop plasma sources scalable to 100s of metres and beyond. By the end of Run 2, the AWAKE scheme should be able to provide electron beams for particle physics experiments and several possible experiments have already been evaluated. This article summarises the programme of AWAKE Run 2 and how it will be achieved as well as the possible application of the AWAKE scheme to novel particle physics experiments.
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| 33. |
- Hansson, Anna, et al.
(författare)
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Synthesis of Dihalo-Substituted Analogues of Tröger’s Base from ortho- and meta-Substituted Anilines.
- 2003
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Ingår i: European Journal of Organic Chemistry. - : Wiley. - 1434-193X .- 1099-0690. ; 2003:16, s. 3179-3188
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Tidskriftsartikel (refereegranskat)abstract
- For the first time, ortho- and meta-halo-substituted anilines were successfully condensed with formaldehyde to dihalo-substituted analogues of Trögers base. By using paraformaldehyde and TFA, yields of 2-85% of these potential supramolecular building blocks were obtained. Even the inconceivable achievement of condensing anilines unsubstituted in para-position to analogues of Trögers base was successful. Adding our present results to our previous, makes it now possible to synthesize analogues of Trögers base halo-substituted in almost any desired position in each of its two aromatic rings. In addition the first X-ray structure of a dihalo-substituted analogue of Trögers base, 3,9-dibromo-4,10-dimethyl-6H,12H-5,11-methanodibenzo[b,f][1,5]diazocine (17), is presented. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
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| 34. |
- Hilbert, Kevin, et al.
(författare)
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Cortical and Subcortical Brain Alterations in Specific Phobia and Its Animal and Blood-Injection-Injury Subtypes: A Mega-Analysis From the ENIGMA Anxiety Working Group.
- 2024
-
Ingår i: The American Journal of Psychiatry. - 1535-7228. ; 181:8, s. 728-740
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Tidskriftsartikel (refereegranskat)abstract
- Specific phobia is a common anxiety disorder, but the literature on associated brain structure alterations exhibits substantial gaps. The ENIGMA Anxiety Working Group examined brain structure differences between individuals with specific phobias and healthy control subjects as well as between the animal and blood-injection-injury (BII) subtypes of specific phobia. Additionally, the authors investigated associations of brain structure with symptom severity and age (youths vs. adults).Data sets from 31 original studies were combined to create a final sample with 1,452 participants with phobia and 2,991 healthy participants (62.7% female; ages 5-90). Imaging processing and quality control were performed using established ENIGMA protocols. Subcortical volumes as well as cortical surface area and thickness were examined in a preregistered analysis.Compared with the healthy control group, the phobia group showed mostly smaller subcortical volumes, mixed surface differences, and larger cortical thickness across a substantial number of regions. The phobia subgroups also showed differences, including, as hypothesized, larger medial orbitofrontal cortex thickness in BII phobia (N=182) compared with animal phobia (N=739). All findings were driven by adult participants; no significant results were observed in children and adolescents.Brain alterations associated with specific phobia exceeded those of other anxiety disorders in comparable analyses in extent and effect size and were not limited to reductions in brain structure. Moreover, phenomenological differences between phobia subgroups were reflected in diverging neural underpinnings, including brain areas related to fear processing and higher cognitive processes. The findings implicate brain structure alterations in specific phobia, although subcortical alterations in particular may also relate to broader internalizing psychopathology.
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| 35. |
- Juan-Mateu, Jon Agraves, et al.
(författare)
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Neuron-enriched RNA-binding Proteins Regulate Pancreatic Beta Cell Function and Survival
- 2017
-
Ingår i: Journal of Biological Chemistry. - 1083-351X. ; 292:8, s. 3466-3480
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Tidskriftsartikel (refereegranskat)abstract
- Pancreatic beta cell failure is the central event leading to diabetes. Beta cells share many phenotypic traits with neurons, and proper beta cell function relies on the activation of several neuronal-like transcription programs. Regulation of gene expression by alternative splicing plays a pivotal role in brain, where it affects neuronal development, function and disease. The role of alternative splicing in beta cells remains unclear, but recent data indicate that splicing alterations modulated by both inflammation and susceptibility genes for diabetes contribute to beta cell dysfunction and death. Here we used RNA sequencing to compare the expression of splicing-regulatory RNA-binding proteins in human islets, brain and other human tissues, and identified a cluster of splicing regulators that are expressed in both beta cells and brain. Four of them, namely Elavl4, Nova2, Rbox1 and Rbfox2 were selected for subsequent functional studies in insulin-producing rat INS-1E, human EndoC-βH1 cells, and in primary rat beta cells. Silencing of Elavl4 and Nova2 increased beta cell apoptosis, while silencing of Rbfox1 and Rbfox2 increased insulin content and secretion. Interestingly, Rbfox1 silencing modulates the splicing of the actin-remodeling protein gelsolin, increasing gelsolin expression and leading to faster glucose-induced actin depolymerization and increased insulin release. Taken together, these findings indicate that beta cells share common splicing regulators and programs with neurons. These splicing regulators play key roles in insulin release and beta cell survival and their dysfunction may contribute to the loss of functional beta cell mass in diabetes.
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| 36. |
- Karagiannopoulos, Alexandros, et al.
(författare)
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Human pancreatic islet miRNA-mRNA networks of altered miRNAs due to glycemic status
- 2022
-
Ingår i: iScience. - : Elsevier BV. - 2589-0042. ; 25:4
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are short non-coding RNAs that regulate gene expression via mRNA targeting, playing important roles in the pancreatic islets. We aimed to identify molecular pathways and genomic regulatory regions associated with altered miRNA expression due to glycemic status, which could contribute to the development of type 2 diabetes (T2D). To this end, miRNAs were identified by a combination of differential miRNA expression and correlation analysis in human islet samples from donors with normal and elevated blood glucose levels. Analysis and clustering of highly correlated, experimentally validated gene targets of these miRNAs revealed two islet-specific clusters, which were associated with key aspects of islet functions and included a high number of T2D-related genes. Finally, cis-eQTLs and public GWAS data integration uncovered suggestive genomic signals of association with insulin secretion and T2D. The miRNA-driven network-based approach presented in this study contributes to a better understanding of impaired insulin secretion in T2D pathogenesis.
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| 37. |
- Margarita, Cristiana, et al.
(författare)
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Dissipative Cyclic Reaction Networks : Mechanistic Insights into a Minor Enantiomer Recycling Process
- 2024
-
Ingår i: ChemSystemsChem. - 2570-4206. ; 6:2
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Tidskriftsartikel (refereegranskat)abstract
- An analysis of an out-of-equilibrium cyclic reaction network which continuously converts a minor undesired product enantiomer to the desired major enantiomer by irreversible addition of chemical fuel and irreversible elimination of spent fuel is presented. The reaction network is maintained as long as fuel is added; interrupted fuel addition drives the system towards equilibrium, but the cyclic process restarts upon resumed fuel addition, as demonstrated by three consecutive fuel cycles. The process is powered by the hydrolysis of methyl cyanoformate to HCN and monomethyl carbonic acid, which decomposes to CO2 and MeOH. The time it takes to reach steady state depends on the rate of conversion of the fuel and decreases with increased conversion rate. Three catalysts, one metal catalyst and two enzymes, together constitute an efficient regulation system allowing control of the forward, backward and waste-forming steps, thereby assuring the production of high yields of products with high enantiopurity.
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| 38. |
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| 39. |
- Mårtensson, Ulrika, et al.
(författare)
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Deletion of the G protein-coupled receptor 30 impairs glucose tolerance, reduces bone growth, increases blood pressure, and eliminates estradiol-stimulated insulin release in female mice.
- 2009
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 150:2, s. 687-98
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Tidskriftsartikel (refereegranskat)abstract
- In vitro studies suggest that the G protein-coupled receptor (GPR) 30 is a functional estrogen receptor. However, the physiological role of GPR30 in vivo is unknown, and it remains to be determined whether GPR30 is an estrogen receptor also in vivo. To this end, we studied the effects of disrupting the GPR30 gene in female and male mice. Female GPR30((-/-)) mice had hyperglycemia and impaired glucose tolerance, reduced body growth, increased blood pressure, and reduced serum IGF-I levels. The reduced growth correlated with a proportional decrease in skeletal development. The elevated blood pressure was associated with an increased vascular resistance manifested as an increased media to lumen ratio of the resistance arteries. The hyperglycemia and impaired glucose tolerance in vivo were associated with decreased insulin expression and release in vivo and in vitro in isolated pancreatic islets. GPR30 is expressed in islets, and GPR30 deletion abolished estradiol-stimulated insulin release both in vivo in ovariectomized adult mice and in vitro in isolated islets. Our findings show that GPR30 is important for several metabolic functions in female mice, including estradiol-stimulated insulin release.
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| 40. |
- Nagao, Mototsugu, et al.
(författare)
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Selectively Bred Diabetes Models : GK Rats, NSY Mice, and ON Mice
- 2020
-
Ingår i: Animal Models of Diabetes. Methods in Molecular Biology. - New York, NY : Springer US. - 1940-6029. - 9781071603857 - 9781071603840 ; 2128, s. 25-54
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Bokkapitel (refereegranskat)abstract
- The polygenic background of selectively bred diabetes models mimics the etiology of type 2 diabetes. So far, three different rodent models (Goto-Kakizaki rats, Nagoya-Shibata-Yasuda mice, and Oikawa-Nagao mice) have been established in the diabetes research field by continuous selective breeding for glucose tolerance from outbred rodent stocks. The origin of hyperglycemia in these rodents is mainly insulin secretion deficiency from the pancreatic β-cells and mild insulin resistance in insulin target organs. In this chapter, we summarize backgrounds and phenotypes of these rodent models to highlight their importance in diabetes research. Then, we introduce experimental methodologies to evaluate β-cell exocytosis as a putative common defect observed in these rodent models.
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| 41. |
- Nordén, Anna, et al.
(författare)
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Vem äger företagen? : En kartläggning av kvinnors ägande av svenska företag
- 2023
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Från inledningen: I den här rapporten tar vi ett unikt grepp kring kvinnors och mäns ägande av företag i Sverige. Att äga ett företag ger ägaren makt över företaget. Det skapar förutsättningar att ta beslut som är anpassade till dem själva. Att äga ett företag ger också en möjlighet att ta ut inkomst för näringsverksamhet eller utdelning. Vilket innebär skattemässiga fördelar.Den genomsnittliga kvinnan som kan och vill äga företag ska ha samma förutsättningar att göra det som den genomsnittliga mannen. Så är det inte idag. De ojämlikheter som finns i ägandet tyder på strukturella hinder som kan kopplas till flera faktorer som uppväxt, utbildning, nätverk, diskriminering och tillgångtill kapital.Sett från ett bredare perspektiv handlar ägande om att skapa förutsättningar för ett bättre samhälle. Ett diversifierat ägande av företag gör det enklare att skapa produkter och tjänster för alla. Det handlar om att öka förmågan att lösa komplexa problem och att skapa nya innovationer.I denna rapport studerar vi ägande av företag och jämför framförallt kvinnor och män. Vi utökar analysen för att försöka fånga en del av den heterogenitet som finns inom dessa grupper och tittar på ålder samt om företagsägaren eller hens föräldrar är födda i Sverige eller inte.
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| 42. |
- Ofori, Jones, et al.
(författare)
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Human Islet MicroRNA-200c Is Elevated in Type 2 Diabetes and Targets the Transcription Factor ETV5 to Reduce Insulin Secretion
- 2022
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 71:2, s. 275-284
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs (miRNAs) are part of deregulated insulin secretion in type 2 diabetes (T2D) development. Rodent models have suggested miR-200c to be involved, but the role and potential as therapeutic target of this miRNA in human islets are not clear. Here we report increased expression of miR-200c in islets from T2D as compared with nondiabetic (ND) donors and display results showing reduced glucose-stimulated insulin secretion in EndoC-βH1 cells overexpressing miR-200c. We identify transcription factor ETV5 as the top rank target of miR-200c in human islets using TargetScan in combination with Pearson correlation analysis of miR-200c and mRNA expression data from the same human donors. Among other targets were JAZF1, as earlier shown in miR-200 knockout mice. Accordingly, linear model analysis of ETV5 and JAZF1 gene expression showed reduced expression of both genes in islets from human T2D donors. Western blot analysis confirmed the reduced expression of ETV5 on the protein level in EndoC-βH1 cells overexpressing miR-200c, and luciferase assay validated ETV5 as a direct target of miR-200c. Finally, LNA knockdown of miR-200c increased glucose-stimulated insulin secretion in islets from T2D donors approximately threefold. Our data reveal a vital role of the miR-200c–ETV5 axis in β-cell dysfunction and pathophysiology of T2D.
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| 43. |
- Ofori, Jones K, et al.
(författare)
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The highly expressed calcium-insensitive synaptotagmin-11 and synaptotagmin-13 modulate insulin secretion
- 2022
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Ingår i: Acta Physiologica. - : Wiley. - 1748-1708 .- 1748-1716. ; 236:1
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Tidskriftsartikel (refereegranskat)abstract
- Aim SYT11 and SYT13, two calcium-insensitive synaptotagmins, are downregulated in islets from type 2 diabetic donors, but their function in insulin secretion is unknown. To address this, we investigated the physiological role of these two synaptotagmins in insulin-secreting cells. Methods Correlations between gene expression levels were performed using previously described RNA-seq data on islets from 188 human donors. SiRNA knockdown was performed in EndoC-beta H1 and INS-1 832/13 cells. Insulin secretion was measured with ELISA. Patch-clamp was used for single-cell electrophysiology. Confocal microscopy was used to determine intracellular localization. Results Human islet expression of the transcription factor PDX1 was positively correlated with SYT11 (p = 2.4e(-10)) and SYT13 (p < 2.2e(-16)). Syt11 and Syt13 both co-localized with insulin, indicating their localization in insulin granules. Downregulation of Syt11 in INS-1 832/13 cells (siSYT11) resulted in increased basal and glucose-induced insulin secretion. Downregulation of Syt13 (siSYT13) decreased insulin secretion induced by glucose and K+. Interestingly, the cAMP-raising agent forskolin was unable to enhance insulin secretion in siSYT13 cells. There was no difference in insulin content, exocytosis, or voltage-gated Ca2+ currents in the two models. Double knockdown of Syt11 and Syt13 (DKD) resembled the results in siSYT13 cells. Conclusion SYT11 and SYT13 have similar localization and transcriptional regulation, but they regulate insulin secretion differentially. While downregulation of SYT11 might be a compensatory mechanism in type-2 diabetes, downregulation of SYT13 reduces the insulin secretory response and overrules the compensatory regulation of SYT11 in a way that could aggravate the disease.
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| 44. |
- Panagiotou, Styliani, et al.
(författare)
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OSBP-mediated PI(4)P-cholesterol exchange at endoplasmic reticulum-secretory granule contact sites controls insulin secretion
- 2024
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Ingår i: Cell Reports. - : Cell Press. - 2211-1247. ; 43:4
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Tidskriftsartikel (refereegranskat)abstract
- Insulin is packaged into secretory granules that depart the Golgi and undergo a maturation process that involves changes in the protein and lipid composition of the granules. Here, we show that insulin secretory granules form physical contacts with the endoplasmic reticulum and that the lipid exchange protein oxysterol-binding protein (OSBP) is recruited to these sites in a Ca2+-dependent manner. OSBP binding to insulin granules is positively regulated by phosphatidylinositol-4 (PI4)-kinases and negatively regulated by the PI4 phosphate (PI(4)P) phosphatase Sac2. Loss of Sac2 results in excess accumulation of cholesterol on insulin granules that is normalized when OSBP expression is reduced, and both acute inhibition and small interfering RNA (siRNA)-mediated knockdown of OSBP suppress glucose-stimulated insulin secretion without affecting insulin production or intracellular Ca2+ signaling. In conclusion, we show that lipid exchange at endoplasmic reticulum (ER)-granule contact sites is involved in the exocytic process and propose that these contacts act as reaction centers with multimodal functions during insulin granule maturation.
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| 45. |
- Rönn, Tina, et al.
(författare)
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Genes with epigenetic alterations in human pancreatic islets impact mitochondrial function, insulin secretion, and type 2 diabetes
- 2023
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Ingår i: Nature Communications. - : Springer Nature. - 2041-1723. ; 14:1
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Tidskriftsartikel (refereegranskat)abstract
- Epigenetic dysregulation may influence disease progression. Here we explore whether epigenetic alterations in human pancreatic islets impact insulin secretion and type 2 diabetes (T2D). In islets, 5,584 DNA methylation sites exhibit alterations in T2D cases versus controls and are associated with HbA1c in individuals not diagnosed with T2D. T2D-associated methylation changes are found in enhancers and regions bound by β-cell-specific transcription factors and associated with reduced expression of e.g. CABLES1, FOXP1, GABRA2, GLR1A, RHOT1, and TBC1D4. We find RHOT1 (MIRO1) to be a key regulator of insulin secretion in human islets. Rhot1-deficiency in β-cells leads to reduced insulin secretion, ATP/ADP ratio, mitochondrial mass, Ca2+, and respiration. Regulators of mitochondrial dynamics and metabolites, including L-proline, glycine, GABA, and carnitines, are altered in Rhot1-deficient β-cells. Islets from diabetic GK rats present Rhot1-deficiency. Finally, RHOT1methylation in blood is associated with future T2D. Together, individuals with T2D exhibit epigenetic alterations linked to mitochondrial dysfunction in pancreatic islets.
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| 46. |
- Sæþórsdóttir, Anna Dóra, et al.
(författare)
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From boiling to frozen? The rise and fall of international tourism to iceland in the era of overtourism
- 2020
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Ingår i: Environments - MDPI. - : MDPI AG. - 2076-3298. ; 7:8, s. 1-19
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Tidskriftsartikel (refereegranskat)abstract
- Overtourism has emerged as a common concept to describe the perceived negative impacts that large numbers of tourists can have on destinations. Iceland is one of the destinations which has been most associated with the concept of overtourism. Tourism in Iceland grew rapidly from 2010 to 2019, much higher than in most other countries, with Iceland reaching a ranking as high as thirteenth on a list of countries with the highest ratio of tourists per inhabitant. The increase in visitors to the country has had various impacts on Iceland’s economy, society and environment. This paper provides an overview of the different ways in which overtourism has revealed itself at a national level in Iceland. The implications of supposed overtourism are shown to be complex, with management responses limited by their relative focus.
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| 47. |
- Sæthórsdóttir, Anna Dóra, et al.
(författare)
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Overtourism in Iceland : Fantasy or reality?
- 2020
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Ingår i: Sustainability (Switzerland). - 2071-1050. ; 12:18
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Tidskriftsartikel (refereegranskat)abstract
- Iceland has been one of the main destinations that have been incorporated into the discourse of overtourism. However, Iceland is different to many other supposed overtourism destinations in that its tourism is based on natural areas. Nevertheless, destination discourses can play an important part in influencing tourist decision-making and government and industry policy making. A media analysis was conducted of 507 online media articles on overtourism in Iceland that were published in 2018, with the main themes being identified via content analysis. The results indicated that the media discourse represented only a partial picture of overtourism and the crowding phenomenon in Iceland, with mechanisms to respond to crowding, the satisfaction level of tourists with their Icelandic nature experience, and local people's support for tourism being underreported. Some of the findings reflect that of other media analyses. However, there are considerable discontinuities between media representations and discourses of overtourism in Iceland, which highlight the importance of national-or destination-level media analysis. The media analysis illustrates the need for a better understanding of different destination discourses and their influence.
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| 48. |
- Salunkhe, Vishal A., et al.
(författare)
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Dual Effect of Rosuvastatin on Glucose Homeostasis Through Improved Insulin Sensitivity and Reduced Insulin Secretion
- 2016
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Ingår i: EBioMedicine. - : Elsevier. - 2352-3964. ; 10, s. 185-194
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Tidskriftsartikel (refereegranskat)abstract
- Statins are beneficial in the treatment of cardiovascular disease (CVD), but these lipid-lowering drugs are associated with increased incidence of new on-set diabetes. The cellular mechanisms behind the development of diabetes by statins are elusive. Here we have treated mice on normal diet (ND) and high fat diet (HFD) with rosuvastatin. Under ND rosuvastatin lowered blood glucose through improved insulin sensitivity and increased glucose uptake in adipose tissue. In vitro rosuvastatin reduced insulin secretion and insulin content in islets. In the beta cell Ca(2+) signaling was impaired and the density of granules at the plasma membrane was increased by rosuvastatin treatment. HFD mice developed insulin resistance and increased insulin secretion prior to administration of rosuvastatin. Treatment with rosuvastatin decreased the compensatory insulin secretion and increased glucose uptake. In conclusion, our data shows dual effects on glucose homeostasis by rosuvastatin where insulin sensitivity is improved, but beta cell function is impaired.
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| 49. |
- Salunkhe, Vishal A., et al.
(författare)
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MiR-335 overexpression impairs insulin secretion through defective priming of insulin vesicles
- 2017
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Ingår i: Physiological Reports. - : Wiley. - 2051-817X. ; 5:21
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Tidskriftsartikel (refereegranskat)abstract
- MicroRNAs contribute to the maintenance of optimal cellular functions by fine-tuning protein expression levels. In the pancreatic β-cells, imbalances in the exocytotic machinery components lead to impaired insulin secretion and type 2 diabetes (T2D). We hypothesize that dysregulated miRNA expression exacerbates β-cell dysfunction, and have earlier shown that islets from the diabetic GK-rat model have increased expression of miRNAs, including miR-335- 5p (miR-335). Here, we aim to determine the specific role of miR-335 during development of T2D, and the influence of this miRNA on glucose-stimulated insulin secretion and Ca2+-dependent exocytosis. We found that the expression of miR-335 negatively correlated with secretion index in human islets of individuals with prediabetes. Overexpression of miR-335 in human KndoC- (βH\ and in rat INS-1 832/13 cells (OE335) resulted in decreased glucose-sti- mulated insulin secretion, and OE335 cells showed concomitant reduction in three exocytotic proteins: SNAP25, Syntaxin-binding protein 1 (STXBPl), and synaptotagmin 11 (SYTll). Single-cell capacitance measurements, complemented with TIRF microscopy of the granule marker NPY-mEGFP demonstrated a significant reduction in exocytosis in OE335 cells. The reduction was not associated with defective docking or decreased Ca2+ current More likely, it is a direct consequence of impaired priming of already docked granules. Earlier reports have proposed reduced granular priming as the cause of reduced first-phase insulin secretion during prediabetes. Here, we show a specific role of miR-335 in regulating insulin secretion during this transition period. Moreover, we can conclude that miR-335 has the capacity to modulate insulin secretion and Ca2+-dependent exocytosis through effects on granular priming.
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| 50. |
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