| 1. |
- Mahajan, Anubha, et al.
(författare)
-
Fine-mapping type 2 diabetes loci to single-variant resolution using high-density imputation and islet-specific epigenome maps
- 2018
-
Ingår i: Nature Genetics. - : NATURE PUBLISHING GROUP. - 1061-4036 .- 1546-1718. ; 50:11, s. 1505-
-
Tidskriftsartikel (refereegranskat)abstract
- We expanded GWAS discovery for type 2 diabetes (T2D) by combining data from 898,130 European-descent individuals (9% cases), after imputation to high-density reference panels. With these data, we (i) extend the inventory of T2D-risk variants (243 loci,135 newly implicated in T2D predisposition, comprising 403 distinct association signals); (ii) enrich discovery of lower-frequency risk alleles (80 index variants with minor allele frequency <5%,14 with estimated allelic odds ratio >2); (iii) substantially improve fine-mapping of causal variants (at 51 signals, one variant accounted for >80% posterior probability of association (PPA)); (iv) extend fine-mapping through integration of tissue-specific epigenomic information (islet regulatory annotations extend the number of variants with PPA >80% to 73); (v) highlight validated therapeutic targets (18 genes with associations attributable to coding variants); and (vi) demonstrate enhanced potential for clinical translation (genome-wide chip heritability explains 18% of T2D risk; individuals in the extremes of a T2D polygenic risk score differ more than ninefold in prevalence).
|
|
| 2. |
- Hastoy, B., et al.
(författare)
-
Electrophysiological properties of human beta-cell lines EndoC-beta H1 and -beta H2 conform with human beta-cells
- 2018
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 8
-
Tidskriftsartikel (refereegranskat)abstract
- Limited access to human islets has prompted the development of human beta cell models. The human beta cell lines EndoC-beta H1 and EndoC-beta H2 are increasingly used by the research community. However, little is known of their electrophysiological and secretory properties. Here, we monitored parameters that constitute the glucose-triggering pathway of insulin release. Both cell lines respond to glucose (6 and 20 mM) with 2- to 3-fold stimulation of insulin secretion which correlated with an elevation of [Ca2+](i), membrane depolarisation and increased action potential firing. Similar to human primary beta cells, K-ATP channel activity is low at 1mM glucose and is further reduced upon increasing glucose concentration; an effect that was mimicked by the K-ATP channel blocker tolbutamide. The upstroke of the action potentials reflects the activation of Ca2+ channels with some small contribution of TTX-sensitive Na+ channels. The repolarisation involves activation of voltage-gated Kv2.2 channels and large-conductance Ca2+-activated K+ channels. Exocytosis presented a similar kinetics to human primary beta cells. The ultrastructure of these cells shows insulin vesicles composed of an electrondense core surrounded by a thin clear halo. We conclude that the EndoC-beta H1 and -beta H2 cells share many features of primary human beta-cells and thus represent a useful experimental model.
|
|
| 3. |
- Almquist, Joachim, 1980, et al.
(författare)
-
Unraveling the Pharmacokinetic Interaction of Ticagrelor and MEDI2452 (Ticagrelor Antidote) by Mathematical Modeling
- 2016
-
Ingår i: CPT: Pharmacometrics and Systems Pharmacology. - : Wiley. - 2163-8306. ; 5:6, s. 313-323
-
Tidskriftsartikel (refereegranskat)abstract
- The investigational ticagrelor-neutralizing antibody fragment, MEDI2452, is developed to rapidly and specifically reverse the antiplatelet effects of ticagrelor. However, the dynamic interaction of ticagrelor, the ticagrelor active metabolite (TAM), and MEDI2452, makes pharmacokinetic (PK) analysis nontrivial and mathematical modeling becomes essential to unravel the complex behavior of this system. We propose a mechanistic PK model, including a special observation model for post-sampling equilibration, which is validated and refined using mouse in vivo data from four studies of combined ticagrelor-MEDI2452 treatment. Model predictions of free ticagrelor and TAM plasma concentrations are subsequently used to drive a pharmacodynamic (PD) model that successfully describes platelet aggregation data. Furthermore, the model indicates that MEDI2452-bound ticagrelor is primarily eliminated together with MEDI2452 in the kidneys, and not recycled to the plasma, thereby providing a possible scenario for the extrapolation to humans. We anticipate the modeling work to improve PK and PD understanding, experimental design, and translational confidence.
|
|
| 4. |
- Arvidsson, Susann, 1965-, et al.
(författare)
-
Callers' perceptions of their contact with a rheumatology telephone helpline
- 2019
-
Ingår i: Musculoskeletal Care. - Oxford : Wiley. - 1478-2189 .- 1557-0681. ; 17:1, s. 105-112
-
Tidskriftsartikel (refereegranskat)abstract
- Background Telephone helplines are useful for improving patients' access to healthcare services and reducing the need for frequent face-to-face contact with healthcare professionals. Little is known about how people who phone a helpline perceive the encounter. Objectives The aims of the present study were to describe the variation in how callers perceive their encounter with a rheumatology telephone helpline. Methods The study had a descriptive, qualitative design and used a phenomenographic approach, comprising 27 semi-structured telephone interviews with callers to Rheuma Direct, a rheumatology telephone helpline with specially trained nurses. The callers comprised 22 women and five men, aged 22-89 years (mean 54 years). Results The callers phoned Rheuma Direct when they had problems obtaining answers to questions on the internet or from healthcare professionals. Three descriptive categories emerged: constructive dialogue, specialized competence and applicability. The callers perceived that it was a constructive dialogue when they were able to discuss their concerns with someone, received emotional support, felt reassured and were satisfied with the information provided. They perceived specialized competence when the nurses were experienced and skilful, the advice provided complemented previously received information and when they had more knowledge after the call. The callers perceived that Rheuma Direct had applicability because it was easy to access and they could make different choices before, during and after the telephone call. Conclusions Callers to a rheumatology telephone helpline perceived it as a valuable complement to other sources of information, and felt that it could provide them with the tools to manage their disease better, as well as future contacts with healthcare professionals.
|
|
| 5. |
- Bjarnegård, Niclas, 1964-, et al.
(författare)
-
Vascular characteristics in young women-Effect of extensive endurance training or a sedentary lifestyle
- 2018
-
Ingår i: Acta Physiologica. - : Wiley. - 1748-1716 .- 1748-1708. ; 223:2
-
Tidskriftsartikel (refereegranskat)abstract
- Aim: To explore whether high-level endurance training in early age has an influence on the arterial wall properties in young women. Methods: Forty-seven athletes (ATH) and 52 controls (CTR), all 17-25 years of age, were further divided into runners (RUN), whole-body endurance athletes (WBA), sedentary controls (SC) and normally active controls (AC). Two-dimensional ultrasound scanning of the carotid arteries was conducted to determine local common carotid artery (CCA) geometry and wall distensibility. Pulse waves were recorded with a tonometer to determine regional pulse wave velocity (PWV) and pulse pressure waveform. Results: Carotid-radial PWV was lower in WBA than in RUN (P < .05), indicating higher arterial distensibility along the arm. Mean arterial pressure was lower in ATH than in CTR and in RUN than in WBA (P < .05). Synthesized aortic augmentation index (AI at 75) was lower among ATH than among CTR (-12.8 ± 1.6 vs -2.6 ± 1.2%, P < .001) and in WBA than in RUN (-16.4 ± 2.5 vs -10.7 ± 2.0%, P < .05), suggesting a diminished return of reflection waves to the aorta during systole. Carotid-femoral PWV and intima-media thickness (IMT), lumen diameter and radial distensibility of the CCA were similar in ATH and CTR. Conclusion: Elastic artery distensibility and carotid artery IMT are not different in young women with extensive endurance training over several years and in those with sedentary lifestyle. On the other hand, our data suggest that long-term endurance training is associated with potentially favourable peripheral artery adaptation, especially in sports where upper body work is added. This adaptation, if persisting later in life, could contribute to lower cardiovascular risk.
|
|
| 6. |
- Caltagirone, Claudia, et al.
(författare)
-
Solvatochromic fluorescent BODIPY derivative as imaging agent in camptothecin loaded hexosomes for possible theranostic applications
- 2015
-
Ingår i: RSC Advances. - : Royal Society of Chemistry (RSC). - 2046-2069. ; 5:30, s. 23443-23449
-
Tidskriftsartikel (refereegranskat)abstract
- We here discuss the potential theranostic nanomedicine application of an innovative formulation consisting of monoolein-based nanoparticles with a two-dimensional hexagonal inner structure stabilized in water using a mixture of PEO132-PPO50-PEO132 block copolymers with and without conjugated folate for targeting. The proposed tumor-cell targeted formulation was shown to be able to simultaneously host the model anticancer drug camptothecin and a pyrene-modified BODIPY fluorophore, based on dynamic light scattering, small-angle X-ray scattering, and cryogenic transmission electron microscopy. The photophysical properties of the fluorophore were studied in solution in various solvents. A marked fluorescent solvatochromism, whose origin was explained by time-dependent density functional theory theoretical calculations, was observed. Fluorescence microscopy showed that HeLa cells readily internalize these nanoparticles, and that the fluorophore localizes within the lipid droplets. In addition, cytotoxicity test revealed that these nanoparticles are not toxic at the concentration used for the imaging analysis.
|
|
| 7. |
- Dabkowska, A. P., et al.
(författare)
-
Temperature responsive lipid liquid crystal layers with embedded nanogels
- 2017
-
Ingår i: Chemical Communications. - : Royal Society of Chemistry. - 1359-7345 .- 1364-548X. ; 53:8, s. 1417-1420
-
Tidskriftsartikel (refereegranskat)abstract
- Polymer nanogels are embedded within layers consisting of a nonlamellar liquid crystalline lipid phase to act as thermoresponsive controllers of layer compactness and hydration. As the nanogels change from the swollen to the collapsed state via a temperature trigger, they enable on-demand release of water from the mixed polymer-lipid layer while the lipid matrix remains intact. Combining stimuli-responsive polymers with responsive lipid-based mesophase systems opens up new routes in biomedical applications such as functional biomaterials, bioanalysis and drug delivery.
|
|
| 8. |
- Dalen, Love, et al.
(författare)
-
Identifying Bird Remains Using Ancient DNA Barcoding
- 2017
-
Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 8:6
-
Tidskriftsartikel (refereegranskat)abstract
- Bird remains that are difficult to identify taxonomically using morphological methods, are common in the palaeontological record. Other types of challenging avian material include artefacts and food items from endangered taxa, as well as remains from aircraft strikes. We here present a DNA-based method that enables taxonomic identification of bird remains, even from material where the DNA is heavily degraded. The method is based on the amplification and sequencing of two short variable parts of the 16S region in the mitochondrial genome. To demonstrate the applicability of this approach, we evaluated the method on a set of Holocene and Late Pleistocene postcranial bird bones from several palaeontological and archaeological sites in Europe with good success.
|
|
| 9. |
|
|
| 10. |
|
|
