| 1. |
- Hansson, Björn, et al.
(författare)
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Adipose cell size changes are associated with a drastic actin remodeling
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Adipose tissue plays a major role in regulating whole-body insulin sensitivity and energy metabolism. To accommodate surplus energy, the tissue rapidly expands by increasing adipose cell size (hypertrophy) and cell number (hyperplasia). Previous studies have shown that enlarged, hypertrophic adipocytes are less responsive to insulin, and that adipocyte size could serve as a predictor for the development of type 2 diabetes. In the present study, we demonstrate that changes in adipocyte size correlate with a drastic remodeling of the actin cytoskeleton. Expansion of primary adipocytes following 2 weeks of high-fat diet (HFD)-feeding in C57BL6/J mice was associated with a drastic increase in filamentous (F)-actin as assessed by fluorescence microscopy, increased Rho-kinase activity, and changed expression of actin-regulating proteins, favoring actin polymerization. At the same time, increased cell size was associated with impaired insulin response, while the interaction between the cytoskeletal scaffolding protein IQGAP1 and insulin receptor substrate (IRS)-1 remained intact. Reversed feeding from HFD to chow restored cell size, insulin response, expression of actin-regulatory proteins and decreased the amount of F-actin filaments. Together, we report a drastic cytoskeletal remodeling during adipocyte expansion, a process which could contribute to deteriorating adipocyte function.
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| 2. |
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| 3. |
- Hammar, Björn, et al.
(författare)
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A Novel Type of Autosomal Dominant Episodic Nystagmus Segregating with a Variant in the FRMD5 Gene
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Ingår i: Neuro-Ophthalmology. - 0165-8107.
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Tidskriftsartikel (refereegranskat)abstract
- To describe the phenotype of a novel form of autosomal dominant episodic nystagmus and to identify the potential genetic aetiology. We identified several individuals in a large Swedish family affected by episodic nystagmus. In total, 39 family members from five generations were invited to participate in the study, of which 17 were included (12 affected and 5 unaffected). The phenotype of the nystagmus was described based on data collected from family members through questionnaires, interviews, clinical examinations and from video recordings of ongoing episodes of nystagmus. Whole genome sequencing (WGS) and further Sanger sequencing for segregation of the identified candidate variants was performed in eight participants (six affected and two unaffected). The 12 affected participants showed a phenotype with episodic nystagmus of early onset. A vertical jerk nystagmus with variable amplitude and frequency was characterized in the analysed video material. No other eye pathology or other disease that could explain the episodic nystagmus was identified among the family participants. Genetic analysis identified a missense variant (p.Ser375Phe) in the gene FRMD5, which segregated with the disease in the eight individuals analysed, from three generations. We describe a novel autosomal dominant form of early onset episodic nystagmus and suggest the FRMD5 gene as a strong candidate gene for this disorder.
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| 4. |
- Hellner, Britt Marie, et al.
(författare)
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Systematiskt arbete för äldres säkerhet : om fall, trafikolyckor och bränder
- 2007
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Bok (refereegranskat)abstract
- Äldre personer är överrepresenterade i nästan alla olyckor. Förutom stort personligt lidande för individen leder skadorna ofta till omfattande kostnader för samhället. Därför har Räddningsverket och IMS/Socialstyrelsen tilsammans med forskare vid Umeå Universitet, Karlstad Universitet, Krolinska Insitutet, FoU Välfärd Örebro samt Vägverket gemensamt sammaställt denna bok. Syftet är att inspirera och vägleda ett systematiskt arbete i samhället för att öka säkerheten och minska skadorna till följd av olyckor bland äldre. Boken riktar sig till verksamma inom vård och omsorg för äldre, tjänstemän och politiker på olika nivåer i samhället
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| 5. |
- Huang, Xiaoli, et al.
(författare)
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The Molecular Basis for Inhibition of Stemlike Cancer Cells by Salinomycin
- 2018
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Ingår i: ACS Central Science. - : American Chemical Society (ACS). - 2374-7943 .- 2374-7951. ; 4:6, s. 760-767
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Tidskriftsartikel (refereegranskat)abstract
- Tumors are phenotypically heterogeneous and include subpopulations of cancer cells with stemlike properties. The natural product salinomycin, a K+-selective ionophore, was recently found to exert selectivity against such cancer stem cells. This selective effect is thought to be due to inhibition of the Wnt signaling pathway, but the mechanistic basis remains unclear. Here, we develop a functionally competent fluorescent conjugate of salinomycin to investigate the molecular mechanism of this compound. By subcellular imaging, we demonstrate a rapid cellular uptake of the conjugate and accumulation in the endoplasmic reticulum (ER). This localization is connected to induction of Ca2+ release from the ER into the cytosol. Depletion of Ca2+ from the ER induces the unfolded protein response as shown by global mRNA analysis and Western blot analysis of proteins in the pathway. In particular, salinomycin-induced ER Ca2+ depletion up-regulates C/EBP homologous protein (CHOP), which inhibits Wnt signaling by down-regulating β-catenin. The increased cytosolic Ca2+ also activates protein kinase C, which has been shown to inhibit Wnt signaling. These results reveal that salinomycin acts in the ER membrane of breast cancer cells to cause enhanced Ca2+ release into the cytosol, presumably by mediating a counter-flux of K+ ions. The clarified mechanistic picture highlights the importance of ion fluxes in the ER as an entry to inducing phenotypic effects and should facilitate rational development of cancer treatments.
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| 6. |
- Krawczyk, Katarzyna, et al.
(författare)
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Myocardin Family Members Drive Formation of Caveolae.
- 2015
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 10:8
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Tidskriftsartikel (refereegranskat)abstract
- Caveolae are membrane organelles that play roles in glucose and lipid metabolism and in vascular function. Formation of caveolae requires caveolins and cavins. The make-up of caveolae and their density is considered to reflect cell-specific transcriptional control mechanisms for caveolins and cavins, but knowledge regarding regulation of caveolae genes is incomplete. Myocardin (MYOCD) and its relative MRTF-A (MKL1) are transcriptional coactivators that control genes which promote smooth muscle differentiation. MRTF-A communicates changes in actin polymerization to nuclear gene transcription. Here we tested if myocardin family proteins control biogenesis of caveolae via activation of caveolin and cavin transcription. Using human coronary artery smooth muscle cells we found that jasplakinolide and latrunculin B (LatB), substances that promote and inhibit actin polymerization, increased and decreased protein levels of caveolins and cavins, respectively. The effect of LatB was associated with reduced mRNA levels for these genes and this was replicated by the MRTF inhibitor CCG-1423 which was non-additive with LatB. Overexpression of myocardin and MRTF-A caused 5-10-fold induction of caveolins whereas cavin-1 and cavin-2 were induced 2-3-fold. PACSIN2 also increased, establishing positive regulation of caveolae genes from three families. Full regulation of CAV1 was retained in its proximal promoter. Knock down of the serum response factor (SRF), which mediates many of the effects of myocardin, decreased cavin-1 but increased caveolin-1 and -2 mRNAs. Viral transduction of myocardin increased the density of caveolae 5-fold in vitro. A decrease of CAV1 was observed concomitant with a decrease of the smooth muscle marker calponin in aortic aneurysms from mice (C57Bl/6) infused with angiotensin II. Human expression data disclosed correlations of MYOCD with CAV1 in a majority of human tissues and in the heart, correlation with MKL2 (MRTF-B) was observed. The myocardin family of transcriptional coactivators therefore drives formation of caveolae and this effect is largely independent of SRF.
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| 9. |
- Ludvigsson, Johnny, et al.
(författare)
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GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus
- 2012
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Ingår i: New England Journal of Medicine. - : Massachusetts Medical Society. - 0028-4793 .- 1533-4406. ; 366:5, s. 433-442
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The 65-kD isoform of glutamic acid decarboxylase (GAD65) is a major autoantigen in type 1 diabetes. We hypothesized that alum-formulated GAD65 (GAD-alum) can preserve beta-cell function in patients with recent-onset type 1 diabetes.METHODS: We studied 334 patients, 10 to 20 years of age, with type 1 diabetes, fasting C-peptide levels of more than 0.3 ng per milliliter (0.1 nmol per liter), and detectable serum GAD65 autoantibodies. Within 3 months after diagnosis, patients were randomly assigned to receive one of three study treatments: four doses of GAD-alum, two doses of GAD-alum followed by two doses of placebo, or four doses of placebo. The primary outcome was the change in the stimulated serum C-peptide level (after a mixed-meal tolerance test) between the baseline visit and the 15-month visit. Secondary outcomes included the glycated hemoglobin level, mean daily insulin dose, rate of hypoglycemia, and fasting and maximum stimulated C-peptide levels.RESULTS: The stimulated C-peptide level declined to a similar degree in all study groups, and the primary outcome at 15 months did not differ significantly between the combined active-drug groups and the placebo group (P=0.10). The use of GAD-alum as compared with placebo did not affect the insulin dose, glycated hemoglobin level, or hypoglycemia rate. Adverse events were infrequent and mild in the three groups, with no significant differences.CONCLUSIONS: Treatment with GAD-alum did not significantly reduce the loss of stimulated C peptide or improve clinical outcomes over a 15-month period.
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| 10. |
- Naumovska, Magdalena, et al.
(författare)
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Mapping the architecture of the temporal artery with photoacoustic imaging for diagnosing giant cell arteritis
- 2022
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Ingår i: Photoacoustics. - : Elsevier BV. - 2213-5979. ; 27
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Tidskriftsartikel (refereegranskat)abstract
- Photoacoustic (PA) imaging is rapidly emerging as a promising clinical diagnostic tool. One of the main applications of PA imaging is to image vascular networks in humans. This relies on the signal obtained from oxygenated and deoxygenated hemoglobin, which limits imaging of the vessel wall itself. Giant cell arteritis (GCA) is a treatable, but potentially sight- and life-threatening disease, in which the artery wall is infiltrated by leukocytes. Early intervention can prevent complications making prompt diagnosis of importance. Temporal artery biopsy is the gold standard for diagnosing GCA. We present an approach to imaging the temporal artery using multispectral PA imaging. Employing minimally supervised spectral analysis, we produce histology-like images where the artery wall is clearly discernible from the lumen and further differentiate between PA spectra from biopsies diagnosed as GCA- and GCA+ in 77 patients.
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| 11. |
- Wickerts, Sanna, 1992, et al.
(författare)
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Prospective Life-Cycle Modeling of Quantum Dot Nanoparticles for Use in Photon Upconversion Devices
- 2021
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Ingår i: ACS Sustainable Chemistry & Engineering. - : American Chemical Society (ACS). - 2168-0485. ; 9:14, s. 5187-5195
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Tidskriftsartikel (refereegranskat)abstract
- Quantum dot nanoparticles (NPs) can be used in several applications, for example, photon upconversion devices that increase the electricity output of solar modules. In order to facilitate life cycle assessment (LCA) studies of such applications, this study provides ready-to-use LCA unit process data for four NPs suitable for photon upconversion applications: cadmium selenide, cadmium sulfide, lead selenide, and lead sulfide. The data is provided for two prospective scenarios: one optimistic and one pessimistic. An impact assessment is conducted in order to assess the NPs’ climate change performance, where solvent-related processes such as steam production for recycling and hazardous waste treatment are shown to be hotspots. To show the applicability of the data, a prospective assessment of a solar module with an upconversion layer is conducted to investigate whether it is preferable from a climate perspective to install more solar modules or equip existing ones with upconversion devices, leading to more electricity produced in both cases. The assessment shows that solar modules need to become 0.05–2 percentage points more efficient per gram of NPs applied, depending on the scenario, in order for the upconversion layer to be preferable.
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| 12. |
- Öhman, Jenny, et al.
(författare)
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Ticagrelor induces adenosine triphosphate release from human red blood cells.
- 2012
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; 418:4, s. 754-758
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Tidskriftsartikel (refereegranskat)abstract
- RATIONALE: The novel P2Y(12) antagonist ticagrelor inhibits ADP-induced platelet aggregation more rapidly and more potently than clopidogrel. Clinical trials have revealed dyspnea and asymptomatic ventricular pauses as side effects of ticagrelor. The mechanism behind these side effects is not known, but it is plausible that they are mediated by adenosine. OBJECTIVE: Ticagrelor is known to increase adenosine concentrations by inhibiting red blood cell reuptake, but the potency of this effect may be too low to fully explain the adenosine related effects. The purpose of the present study was to determine whether ticagrelor has other effects on red blood cells (RBCs) that could contribute to explain the pleiotropic effects seen with ticagrelor treatment. METHODS AND RESULTS: Using a luciferase-based bioluminescence assay, we studied ATP release in human blood. Human RBCs responded to ticagrelor in vitro by releasing substantial amounts of ATP in a dose-dependent manner (IC(50) 14μM). The rapid effect indicates release through membrane channels, which was supported by a depolarizing effect of ticagrelor and inhibition of ATP release by anion channel blockers. CONCLUSION: In conclusion, our data show that, in vitro, ticagrelor can induce ATP release from human RBCs, which is subsequently degraded to adenosine. Further studies are warranted to determine what role this mechanism may play in the clinical effects of ticagrelor.
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