| 1. |
|
|
| 2. |
- Klionsky, Daniel J., et al.
(författare)
-
Guidelines for the use and interpretation of assays for monitoring autophagy
- 2012
-
Ingår i: Autophagy. - : Informa UK Limited. - 1554-8635 .- 1554-8627. ; 8:4, s. 445-544
-
Forskningsöversikt (refereegranskat)abstract
- In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.
|
|
| 3. |
- Breznau, Nate, et al.
(författare)
-
Observing many researchers using the same data and hypothesis reveals a hidden universe of uncertainty
- 2022
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 119:44
-
Tidskriftsartikel (refereegranskat)abstract
- This study explores how researchers analytical choices affect the reliability of scientific findings. Most discussions of reliability problems in science focus on systematic biases. We broaden the lens to emphasize the idiosyncrasy of conscious and unconscious decisions that researchers make during data analysis. We coordinated 161 researchers in 73 research teams and observed their research decisions as they used the same data to independently test the same prominent social science hypothesis: that greater immigration reduces support for social policies among the public. In this typical case of social science research, research teams reported both widely diverging numerical findings and substantive conclusions despite identical start conditions. Researchers expertise, prior beliefs, and expectations barely predict the wide variation in research outcomes. More than 95% of the total variance in numerical results remains unexplained even after qualitative coding of all identifiable decisions in each teams workflow. This reveals a universe of uncertainty that remains hidden when considering a single study in isolation. The idiosyncratic nature of how researchers results and conclusions varied is a previously underappreciated explanation for why many scientific hypotheses remain contested. These results call for greater epistemic humility and clarity in reporting scientific findings.
|
|
| 4. |
- Kehoe, Laura, et al.
(författare)
-
Make EU trade with Brazil sustainable
- 2019
-
Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 364:6438, s. 341-
-
Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)
|
|
| 5. |
- Palsdottir, Vilborg, 1979, et al.
(författare)
-
Interactions Between the Gravitostat and the Fibroblast Growth Factor System for the Regulation of Body Weight
- 2019
-
Ingår i: Endocrinology. - : The Endocrine Society. - 0013-7227 .- 1945-7170. ; 160:5, s. 1057-1064
-
Tidskriftsartikel (refereegranskat)abstract
- Both fibroblast growth factors (FGFs), by binding to FGF receptors (FGFRs), and activation of the gravitostat, by artificial loading, decrease the body weight (BW). Previous studies demonstrate that both the FGF system and loading have the capacity to regulate BW independently of leptin. The aim of the current study was to determine the possible interactions between the effect of increased loading and the FGF system for the regulation of BW. We observed that the BW-reducing effect of increased loading was abolished in mice treated with a monoclonal antibody directed against FGFR1c, suggesting interactions between the two systems. As serum levels of endocrine FGF21 and hepatic FGF21 mRNA were increased in the loaded mice compared with the control mice, we first evaluated the loading response in FGF21 over expressing mice with constant high FGF21 levels. Leptin treatment, but not increased loading, decreased the BW in the FGF21-overexpressing mice, demonstrating that specifically the loading effect is attenuated in the presence of high activity in the FGF system. However, as FGF21 knockout mice displayed a normal loading response on BW, FGF21 is neither mediating nor essential for the loading response. In conclusion, the BW-reducing effect of increased loading but not of leptin treatment is blocked by high activity in the FGF system. We propose that both the gravitostat and the FGF system regulate BW independently of leptin and that pharmacologically enhanced activity in the FGF system reduces the sensitivity of the grayitostat.
|
|
| 6. |
- Albuquerque, Daniel, et al.
(författare)
-
LES simulation of oscillating natural ventilation driven by vortex shedding in isolated buildings
- 2020
-
Ingår i: Proceedings of Building Simulation 2019: 16th Conference of IBPSA. - : IBPSA. - 9781775052012 ; , s. 644-649
-
Konferensbidrag (refereegranskat)abstract
- A recently published study presented a new type of natural ventilation (NV) flow, named pumping ventilation. The oscilatory mechanism of vortex shedding that occurs at the wake region of an isolated building drives this new type of ventilation in rooms with two (or more) openings facing the leeward or windward side of an isolated building. This paper presents a validated Large Eddy Simulation (LES) study of oscillating/pumping NV in an isolated building using three different separations (s') between its two windows. LES is validated using an experimental database from measurements performed at the University of Gavle boundary layer wind tunnel (WT). The measurements use a cubic model with 0.45m side representing a three-story building at a 1/20 scale that allows the use of bottom-hung windows. LES results show a good agreement with the measured non-dimensional ventilation rates. A dimensionless analysis shows the dominant frequencies of the pumping flow, are close to the Strouhal frequency.
|
|
| 7. |
- Albuquerque, Daniel P., et al.
(författare)
-
Experimental and numerical investigation of pumping ventilation on the leeward side of a cubic building
- 2020
-
Ingår i: Building and Environment. - : Elsevier. - 0360-1323 .- 1873-684X. ; 179
-
Tidskriftsartikel (refereegranskat)abstract
- Unstable interaction between shear layers that form in the wake of an isolated building exposed to wind can drive natural pumping ventilation in windward and leeward facing rooms with two or more horizontally separated openings. This paper presents an experimental and numerical study of pumping ventilation in a three-story cubic building with two leeward openings in its middle floor. Reduced-scaled measurements were performed in the University of Gävle atmospheric-boundary-layer wind tunnel. The ventilation mechanism was investigated using smoke visualization, hot wire anemometry and particle image velocimetry. Effective ventilation rates were obtained using a tracer gas decay method. Experimental results confirmed that pumping ventilation is a 3D oscillatory unstable phenomenon with periodic behavior over several oscillation cycles. Measured flowrates show a linear relation between the effective ventilation rate and window separation. The numerical simulations used two turbulence modeling approaches: unsteady Reynolds-averaged Navier-Stokes (URANS) and large eddy simulation (LES). Both URANS and LES could predict vortex shedding frequency with an error below 5%. LES showed a good agreement with the measured ventilation rates, with an error below 10%, while URANS underestimated ventilation rates by at least 40%. The ventilation efficiency, obtained by LES, ranged between 0.60 and 0.75 (for the case with larger window separation). The results show that LES may be a suitable simulation approach for pumping ventilation. In contrast, URANS cannot simulate pumping ventilation.
|
|
| 8. |
- Améen, Caroline, 1975, et al.
(författare)
-
Activation of peroxisome proliferator-activated receptor alpha increases the expression and activity of microsomal triglyceride transfer protein in the liver
- 2005
-
Ingår i: J Biol Chem. ; 280:2, s. 1224-9
-
Tidskriftsartikel (refereegranskat)abstract
- Microsomal triglyceride transfer protein (MTP) is rate-limiting in the assembly and secretion of lipoproteins containing apolipoprotein (apo) B. Previously we demonstrated that Wy 14,643 (Wy), a peroxisome proliferator-activated receptor (PPAR) alpha agonist, increases apoB-100 secretion despite decreased triglyceride synthesis. In this study, we sought to determine whether PPARalpha activation increases MTP expression and activity. Treatment with Wy increased hepatic MTP expression and activity in rats and mice and increased MTP expression in primary cultures of rat and mouse hepatocytes. Addition of actinomycin D blocked this increase and the MTP promoter (-136 to +67) containing a conserved DR1 element was activated by Wy, showing that PPARalpha activates transcription of the gene. Wy did not affect MTP expression in the intestine or in cultured hepatocytes from PPARalpha-null mice. A retinoid X receptor agonist (9-cis-retinoic acid), but not a PPARgamma agonist (rosiglitazone), increased MTP mRNA expression in cultured hepatocytes from both wild type and PPARalpha-null mice. In rat hepatocytes incubated with Wy, MTP mRNA levels increased between 6 and 24 h, and MTP protein expression and apoB-100 secretion increased between 24 and 72 h. In conclusion, PPARalpha activation stimulates hepatic MTP expression via increased transcription of the Mtp gene. This effect is paralleled by a change in apoB-100 secretion, indicating that the effect of Wy on apoB-100 secretion is mediated by increased expression of MTP.
|
|
| 9. |
- Améen, Caroline, 1975, et al.
(författare)
-
Effects of gender and GH secretory pattern on sterol regulatory element-binding protein-1c and its target genes in rat liver.
- 2004
-
Ingår i: American journal of physiology. Endocrinology and metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 287:6
-
Tidskriftsartikel (refereegranskat)abstract
- We investigated whether the sexually dimorphic secretory pattern of growth hormone (GH) in the rat regulates hepatic gene expression of sterol regulatory element-binding protein-1c (SREBP-1c) and its target genes. SREBP-1c, fatty acid synthase (FAS), and glycerol-3-phosphate acyltransferase (GPAT) mRNA were more abundant in female than in male livers, whereas acetyl-CoA carboxylase-1 (ACC1) and stearoyl-CoA desaturase-1 (SCD-1) were similarly expressed in both sexes. Hypophysectomized female rats were given GH as a continuous infusion or as two daily injections for 7 days to mimic the female- and male-specific GH secretory patterns, respectively. The female pattern of GH administration increased the expression of SREBP-1c, ACC1, FAS, SCD-1, and GPAT mRNA, whereas the male pattern of GH administration increased only SCD-1 mRNA. FAS and SCD-1 protein levels were regulated in a similar manner by GH. Incubation of primary rat hepatocytes with GH increased SCD-1 mRNA levels and decreased FAS and GPAT mRNA levels but had no effect on SREBP-1c mRNA. GH decreased hepatic liver X receptor-alpha (LXRalpha) mRNA levels both in vivo and in vitro. Feminization of the GH plasma pattern in male rats by administration of GH as a continuous infusion decreased insulin sensitivity and increased expression of FAS and GPAT mRNA but had no effect on SREBP-1c, ACC1, SCD-1, or LXRalpha mRNA. In conclusion, FAS and GPAT are specifically upregulated by the female secretory pattern of GH. This regulation is not a direct effect of GH on hepatocytes and does not involve changed expression of SREBP-1c or LXRalpha mRNA but is associated with decreased insulin sensitivity.
|
|
| 10. |
- Azzu, V., et al.
(författare)
-
Suppression of insulin-induced gene 1 (INSIG1) function promotes hepatic lipid remodelling and restrains NASH progression
- 2021
-
Ingår i: Molecular Metabolism. - : Elsevier BV. - 2212-8778. ; 48
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: Non-alcoholic fatty liver disease (NAFLD) is a silent pandemic associated with obesity and the metabolic syndrome, and also increases cardiovascular- and cirrhosis-related morbidity and mortality. A complete understanding of adaptive compensatory metabolic programmes that modulate non-alcoholic steatohepatitis (NASH) progression is lacking. Methods and results: Transcriptomic analysis of liver biopsies in patients with NASH revealed that NASH progression is associated with rewiring of metabolic pathways, including upregulation of de novo lipid/cholesterol synthesis and fatty acid remodelling. The modulation of these metabolic programmes was achieved by activating sterol regulatory element-binding protein (SREBP) transcriptional networks; however, it is still debated whether, in the context of NASH, activation of SREBPs acts as a pathogenic driver of lipotoxicity, or rather promotes the biosynthesis of protective lipids that buffer excessive lipid accumulation, preventing inflammation and fibrosis. To elucidate the pathophysiological role of SCAP/SREBP in NASH and wound-healing response, we used an Insig1 deficient (with hyper-efficient SREBPs) murine model challenged with a NASH-inducing diet. Despite enhanced lipid and cholesterol biosynthesis, Insig1 KO mice had similar systemic metabolism and insulin sensitivity to Het/WT littermates. Moreover, activating SREBPs resulted in remodelling the lipidome, decreased hepatocellular damage, and improved wound-healing responses. Conclusions: Our study provides actionable knowledge about the pathways and mechanisms involved in NAFLD pathogenesis, which may prove useful for developing new therapeutic strategies. Our results also suggest that the SCAP/SREBP/INSIG1 trio governs transcriptional programmes aimed at protecting the liver from lipotoxic insults in NASH. (C) 2021 Published by Elsevier GmbH. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
|
|
| 11. |
- Bjursell, Mikael, 1977, et al.
(författare)
-
Opposing effects of adiponectin receptors 1 and 2 on energy metabolism
- 2007
-
Ingår i: DIABETES. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:3, s. 583-593
-
Tidskriftsartikel (refereegranskat)abstract
- The adipocyte-derived hormone adiponectin regulates glucose and lipid metabolism and influences the risk for developing obesity, type 2 diabetes, and cardiovascular disease. Adiponectin binds to two different seven-transmembrane domain receptors termed AdipoR1 and AdipoR2. To study the physiological importance of these receptors, AdipoR1 gene knockout mice (AdipoR1−/−) and AdipoR2 gene knockout mice (AdipoR2−/−) were generated. AdipoR1−/− mice showed increased adiposity associated with decreased glucose tolerance, spontaneous locomotor activity, and energy expenditure. However, AdipoR2−/− mice were lean and resistant to high-fat diet–induced obesity associated with improved glucose tolerance and higher spontaneous locomotor activity and energy expenditure and reduced plasma cholesterol levels. Thus, AdipoR1 and AdipoR2 are clearly involved in energy metabolism but have opposing effects.
|
|
| 12. |
- Bohlooly-Yeganeh, Mohammad, 1966, et al.
(författare)
-
Growth hormone overexpression in the central nervous system results in hyperphagia-induced obesity associated with insulin resistance and dyslipidemia.
- 2005
-
Ingår i: Diabetes. - 0012-1797 .- 1939-327X. ; 54:1, s. 51-62
-
Tidskriftsartikel (refereegranskat)abstract
- It is well known that peripherally administered growth hormone (GH) results in decreased body fat mass. However, GH-deficient patients increase their food intake when substituted with GH, suggesting that GH also has an appetite stimulating effect. Transgenic mice with an overexpression of bovine GH in the central nervous system (CNS) were created to investigate the role of GH in CNS. This study shows that overexpression of GH in the CNS differentiates the effect of GH on body fat mass from that on appetite. The transgenic mice were not GH-deficient but were obese and showed increased food intake as well as increased hypothalamic expression of agouti-related protein and neuropeptide Y. GH also had an acute effect on food intake following intracerebroventricular injection of C57BL/6 mice. The transgenic mice were severely hyperinsulinemic and showed a marked hyperplasia of the islets of Langerhans. In addition, the transgenic mice displayed alterations in serum lipid and lipoprotein levels and hepatic gene expression. In conclusion, GH overexpression in the CNS results in hyperphagia-induced obesity indicating a dual effect of GH with a central stimulation of appetite and a peripheral lipolytic effect.
|
|
| 13. |
- Bortolini, Giacomo, 1996-, et al.
(författare)
-
The spatially resolved star formation history of the dwarf spiral galaxy NGC 5474
- 2024
-
Ingår i: Monthly notices of the Royal Astronomical Society. - 0035-8711 .- 1365-2966. ; 527:3, s. 5339-5355
-
Tidskriftsartikel (refereegranskat)abstract
- We study the resolved stellar populations and derive the star formation history of NGC 5474, a peculiar star-forming dwarf galaxy at a distance of ∼7 Mpc, using Hubble Space Telescope Advanced Camera for Surveys data from the Legacy Extragalactic UV Survey (LEGUS) programme. We apply an improved colour–magnitude diagram fitting technique based on the code SFERA and use the latest PARSEC–COLIBRI stellar models. Our results are the following. The off-centre bulge-like structure, suggested to constitute the bulge of the galaxy, is dominated by star formation (SF) activity initiated 14 Gyr ago and lasted at least up to 1 Gyr ago. Nevertheless, this component shows clear evidence of prolonged SF activity (lasting until ∼10 Myr ago). We estimate the total stellar mass of the bulge-like structure to be (5.0 ± 0.3) × 108 M⊙. Such a mass is consistent with published suggestions that this structure is in fact an independent system orbiting around and not within NGC 5474’s disc. The stellar overdensity located to the South–West of the bulge-like structure shows a significant SF event older than 1 Gyr, while it is characterized by two recent peaks of SF, around ∼10 and ∼100 Myr ago. In the last Gyr, the behaviour of the stellar disc is consistent with what is known in the literature as ‘gasping’. The synchronized burst at 10–35 Myr in all components might hint to the recent gravitational interaction between the stellar bulge-like structure and the disc of NGC 5474.
|
|
| 14. |
- Calzetti, Daniela, et al.
(författare)
-
Revisiting Attenuation Curves : The Case of NGC 3351
- 2021
-
Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 913:1
-
Tidskriftsartikel (refereegranskat)abstract
- Multiwavelength images from the far-UV (similar to 0.15 mu m) to the submillimeter of the central region of the galaxy NGC 3351 are analyzed to constrain its stellar populations and dust attenuation. Despite hosting a similar to 1 kpc circumnuclear starburst ring, NGC 3351 deviates from the IRX-beta relation, the relation between the infrared-to-UV luminosity ratio and the UV continuum slope beta that other starburst galaxies follow. To understand the reason for the deviation, we leverage the high angular resolution of archival near-UV-to-near-IR Hubble Space Telescope images to divide the ring into similar to 60-180 pc size regions and model each individually. We find that the UV slope of the combined intrinsic (dust-free) stellar populations in the central region is redder than what is expected for a young model population. This is due to the region's complex star formation history, which boosts the near-UV emission relative to the far-UV. The resulting net attenuation curve has a UV slope that lies between those of the starburst attenuation curve (Calzetti et al. 2000) and the Small Magellanic Cloud extinction curve; the total-to-selective attenuation value, R'(V) = 4.93, is larger than both. As found for other star-forming galaxies, the stellar continuum of NGC 3351 is less attenuated than the ionized gas, with E(B - V)(star) = 0.40 E(B - V)(gas). The combination of the red intrinsic stellar population and the new attenuation curve fully accounts for the location of the central region of NGC 3351 on the IRX-beta diagram. Thus, the observed characteristics result from the complex mixture of stellar populations and dust column densities in the circumnuclear region. Despite being a sample of one, these findings highlight the difficulty of defining attenuation curves of general applicability outside the regime of centrally concentrated starbursts.
|
|
| 15. |
- Carlsson, Björn, et al.
(författare)
-
Review article: the emerging role of genetics in precision medicine for patients with non-alcoholic steatohepatitis.
- 2020
-
Ingår i: Alimentary pharmacology & therapeutics. - : Wiley. - 1365-2036 .- 0269-2813. ; 51:12, s. 1305-1320
-
Forskningsöversikt (refereegranskat)abstract
- Non-alcoholic steatohepatitis (NASH) is a severe form of non-alcoholic fatty liver disease (NAFLD) characterised by liver fat accumulation, inflammation and progressive fibrosis. Emerging data indicate that genetic susceptibility increases risks of NAFLD, NASH and NASH-related cirrhosis.To review NASH genetics and discuss the potential for precision medicine approaches to treatment.PubMed search and inclusion of relevant literature.Single-nucleotide polymorphisms in PNPLA3, TM6SF2, GCKR, MBOAT7 and HSD17B13 are clearly associated with NASH development or progression. These genetic variants are common and have moderate-to-large effect sizes for development of NAFLD, NASH and hepatocellular carcinoma (HCC). The genes play roles in lipid remodelling in lipid droplets, hepatic very low-density lipoprotein (VLDL) secretion and de novo lipogenesis. The PNPLA3 I148M variant (rs738409) has large effects, with approximately twofold increased odds of NAFLD and threefold increased odds of NASH and HCC per allele. Obesity interacts with PNPLA3 I148M to elevate liver fat content and increase rates of NASH. Although the isoleucine-to-methionine substitution at amino acid position 148 of the PNPLA3 enzyme inactivates its lipid remodelling activity, the effect of PNPLA3 I148M results from trans-repression of another lipase (ATGL/PNPLA2) by sequestration of a shared cofactor (CGI-58/ABHD5), leading to decreased hepatic lipolysis and VLDL secretion. In homozygous Pnpla3 I148M knock-in rodent models of NAFLD, targeted PNPLA3 mRNA knockdown reduces hepatic steatosis, inflammation and fibrosis.The emerging genetic and molecular understanding of NASH paves the way for novel interventions, including precision medicines that can modulate the activity of specific genes associated with NASH.
|
|
| 16. |
- Carrilho da Graça, Guilherme, et al.
(författare)
-
Pumping ventilation of corner and single sided rooms with two openings
- 2021
-
Ingår i: Building and Environment. - : Elsevier. - 0360-1323 .- 1873-684X. ; 205
-
Tidskriftsartikel (refereegranskat)abstract
- Corner rooms with two or more open windows in perpendicular facades can be naturally ventilated in cross-ventilation or pumping ventilation. These two airflow regimes also occur in rooms with two openings in the same façade, in the form of single sided pumping or cross sided ventilation. This paper presents an experimental and numerical simulation study of the scale and occurrence of these two flow regimes for rooms in a rectangular building exposed to wind. Flow visualization and tracer gas measurement of effective airflow were performed in an atmospheric boundary layer wind tunnel using a rectangular model of a three-story building (1/20 scale) with a ventilated middle floor. Experimental results show that pumping ventilation occurs when the wind is perpendicular to the façade (single sided rooms) or aligned with the building corner (corner rooms). In addition to these two perfectly aligned wind directions, pumping also occurs for a range of incoming wind angles: ±19° for single sided; and ±9° for corner rooms. As a result, for isolated rectangular buildings that have, at least, one single sided and two corner rooms in each facade, pumping ventilation can potentially occur in two or more rooms for 62 % of incoming wind directions. To investigate the transition between steady cross-ventilation and unsteady pumping ventilation, three-dimensional computational fluid dynamics large eddy simulations were performed to obtain wind generated pressures in the ventilation openings. Results show that the transition from cross-ventilation to pumping occurs when the steady pressure becomes smaller than the unsteady component. These results are used to develop a pressure based simplified model for corner ventilation that can predict effective airflow from external wind generated pressures with an average error below 10.2 %. © 2021 Elsevier Ltd
|
|
| 17. |
- de Bem, Andreza Fabro, et al.
(författare)
-
Animal Models of Metabolic Disorders in the Study of Neurodegenerative Diseases : An Overview
- 2021
-
Ingår i: Frontiers in Neuroscience. - : Frontiers Media SA. - 1662-4548 .- 1662-453X. ; 14
-
Forskningsöversikt (refereegranskat)abstract
- The incidence of metabolic disorders, as well as of neurodegenerative diseases—mainly the sporadic forms of Alzheimer’s and Parkinson’s disease—are increasing worldwide. Notably, obesity, diabetes, and hypercholesterolemia have been indicated as early risk factors for sporadic forms of Alzheimer’s and Parkinson’s disease. These conditions share a range of molecular and cellular features, including protein aggregation, oxidative stress, neuroinflammation, and blood-brain barrier dysfunction, all of which contribute to neuronal death and cognitive impairment. Rodent models of obesity, diabetes, and hypercholesterolemia exhibit all the hallmarks of these degenerative diseases, and represent an interesting approach to the study of the phenotypic features and pathogenic mechanisms of neurodegenerative disorders. We review the main pathological aspects of Alzheimer’s and Parkinson’s disease as summarized in rodent models of obesity, diabetes, and hypercholesterolemia.
|
|
| 18. |
- Disney-Hogg, Linden, et al.
(författare)
-
Impact of atopy on risk of glioma : a Mendelian randomisation study
- 2018
-
Ingår i: BMC Medicine. - : BioMed Central. - 1741-7015. ; 16
-
Tidskriftsartikel (refereegranskat)abstract
- Background: An inverse relationship between allergies with glioma risk has been reported in several but not all epidemiological observational studies. We performed an analysis of genetic variants associated with atopy to assess the relationship with glioma risk using Mendelian randomisation (MR), an approach unaffected by biases from temporal variability and reverse causation that might have affected earlier investigations.Methods: Two-sample MR was undertaken using genome-wide association study data. We used single nucleotide polymorphisms (SNPs) associated with atopic dermatitis, asthma and hay fever, IgE levels, and self-reported allergy as instrumental variables. We calculated MR estimates for the odds ratio (OR) for each risk factor with glioma using SNP-glioma estimates from 12,488 cases and 18,169 controls, using inverse-variance weighting (IVW), maximum likelihood estimation (MLE), weighted median estimate (WME) and mode-based estimate (MBE) methods. Violation of MR assumptions due to directional pleiotropy were sought using MR-Egger regression and HEIDI-outlier analysis.Results: Under IVW, MLE, WME and MBE methods, associations between glioma risk with asthma and hay fever, self-reported allergy and IgE levels were non-significant. An inverse relationship between atopic dermatitis and glioma risk was found by IVW (OR 0.96, 95% confidence interval (CI) 0.93-1.00, P = 0.041) and MLE (OR 0.96, 95% CI 0.94-0.99, P = 0.003), but not by WME (OR 0.96, 95% CI 0.91-1.01, P = 0.114) or MBE (OR 0.97, 95% CI 0.92-1.02, P = 0.194).Conclusions: Our investigation does not provide strong evidence for relationship between atopy and the risk of developing glioma, but findings do not preclude a small effect in relation to atopic dermatitis. Our analysis also serves to illustrate the value of using several MR methods to derive robust conclusions.
|
|
| 19. |
- Du, Jiaying, et al.
(författare)
-
Perception of Delay in Computer Input Devices Establishing a Baseline for Signal Processing of Motion Sensor Systems
- 2016
-
Ingår i: The 3rd EAI International Conference on IoT Technologies for HealthCare HealthyIoT'16. - Västeraås, Sweden : Springer International Publishing. ; , s. 107-112
-
Konferensbidrag (refereegranskat)abstract
- New computer input devices in healthcare applications using small embedded sensors need firmware filters to run smoothly and to provide a better user experience. Therefore, it has to be investigated how much delay can be tolerated for signal processing before the users perceive a delay when using a computer input device. This paper is aimed to find out a threshold of unperceived delay by performing user tests with 25 participants. A communication retarder was used to create delays from 0 to 100 ms between a receiving computer and three different USB-connected computer input devices. A wired mouse, a wifi mouse and a head-mounted mouse were used as input devices. The results of the user tests show that delays up to 50ms could be tolerated and are not perceived as delay, or depending on the used device still perceived as acceptable.
|
|
| 20. |
- Du, Jiaying, et al.
(författare)
-
The effects of perceived USB-delay for sensor and embedded system development
- 2016
-
Ingår i: Proceedings of the Annual International Conference of the IEEE Engineering in Medicine and Biology Society, EMBSVolume 2016. - 9781457702204 ; , s. 2492-2495
-
Konferensbidrag (refereegranskat)abstract
- Perceiving delay in computer input devices is a problem which gets even more eminent when being used in healthcare applications and/or in small, embedded systems. Therefore, the amount of delay found as acceptable when using computer input devices was investigated in this paper. A device was developed to perform a benchmark test for the perception of delay. The delay can be set from 0 to 999 milliseconds (ms) between a receiving computer and an available USB-device. The USB-device can be a mouse, a keyboard or some other type of USB-connected input device. Feedback from performed user tests with 36 people form the basis for the determination of time limitations for the USB data processing in microprocessors and embedded systems without users' noticing the delay. For this paper, tests were performed with a personal computer and a common computer mouse, testing the perception of delays between 0 and 500 ms. The results of our user tests show that perceived delays up to 150 ms were acceptable and delays larger than 300 ms were not acceptable at all.
|
|
| 21. |
- Dutta, Tanmoy, 1998, et al.
(författare)
-
Mitochondrial amidoxime-reducing component 1 p.Ala165Thr increases protein degradation mediated by the proteasome.
- 2024
-
Ingår i: Liver international : official journal of the International Association for the Study of the Liver. - 1478-3223 .- 1478-3231. ; 44:5, s. 1219-1232
-
Tidskriftsartikel (refereegranskat)abstract
- Metabolic dysfunction-associated steatotic liver disease (MASLD) is a global health concern with no effective and specific drug treatment available. The rs2642438 minor allele in mitochondrial amidoxime-reducing component 1 (MARC1) results in an aminoacidic substitution (p.Ala165Thr) and associates with protection against MASLD. However, the mechanisms behind this protective effect are unknown. In this study, we examined the consequences of this aminoacidic substitution on protein stability and subcellular localization.We overexpressed the human MARC1 A165 (wild-type) or 165T (mutant) invivo in mice and invitro in human hepatoma cells (HepG2 and HuH-7), generated several mutants at position 165 by insitu mutagenesis and then examined protein levels. We also generated HepG2 cells stably overexpressing MARC1 A165 or 165T to test the effect of this substitution on MARC1 subcellular localization.MARC1 165T overexpression resulted in lower protein levels than A165 both invivo and invitro. Similarly, any mutant at position 165 showed lower protein levels compared to the wild-type protein. We showed that the 165T mutant protein is polyubiquitinated and its degradation is accelerated through lysine-48 ubiquitin-mediated proteasomal degradation. We also showed that the 165T substitution does not affect the MARC1 subcellular localization.This study shows that alanine at position 165 in MARC1 is crucial for protein stability, and the threonine substitution at this position leads to a hypomorphic protein variant due to lower protein levels. Our result supports the notion that lowering hepatic MARC1 protein level may be a successful therapeutic strategy for treating MASLD.
|
|
| 22. |
|
|
| 23. |
- Dutton, Edward, 1980-, et al.
(författare)
-
The myth of the stupid believer : The negative religiousness-IQ nexus is not on general intelligence (g) and is likely a product of the relations between IQ and Autism Spectrum traits
- 2020
-
Ingår i: Journal of religion and health. - : Springer. - 0022-4197 .- 1573-6571. ; 59:3, s. 1567-1579
-
Tidskriftsartikel (refereegranskat)abstract
- Numerous studies have found a negative relationship between religiousness and IQ. It is in the region of - 0.2, according to meta-analyses. The reasons for this relationship are, however, unknown. It has been suggested that higher intelligence leads to greater attraction to science, or that it helps to override evolved cognitive dispositions such as for religiousness. Either way, such explanations assume that the religion-IQ nexus is on general intelligence (g), rather than some subset of specialized cognitive abilities. In other words, they assume it is a Jensen effect. Two large datasets comparing groups with different levels of religiousness show that their IQ differences are not on g and must, therefore, be attributed to specialized abilities. An analysis of the specialized abilities on which the religious and non-religious groups differ reveals no clear pattern. We cautiously suggest that this may be explicable in terms of autism spectrum disorder traits among people with high IQ scores, because such traits are negatively associated with religiousness.
|
|
| 24. |
- Edvardsson, Ulrika, 1967, et al.
(författare)
-
PPARalpha activation increases triglyceride mass and adipose differentiation-related protein in hepatocytes.
- 2006
-
Ingår i: Journal of lipid research. - 0022-2275. ; 47:2, s. 329-40
-
Tidskriftsartikel (refereegranskat)abstract
- Adipose differentiation-related protein (ADRP) is a lipid droplet-associated protein that is expressed in various tissues. In mice treated with the peroxisome proliferator-activated receptor alpha (PPARalpha) agonist Wy14,643 (Wy), hepatic mRNA and protein levels of ADRP as well as hepatic triglyceride content increased. Also in primary mouse hepatocytes, Wy increased ADRP expression and intracellular triglyceride mass. The triglyceride mass increased in spite of unchanged triglyceride biosynthesis and increased palmitic acid oxidation. However, Wy incubation decreased the secretion of newly synthesized triglycerides, whereas apolipoprotein B secretion increased. Thus, decreased availability of triglycerides for VLDL assembly could help to explain the cellular accumulation of triglycerides after Wy treatment. We hypothesized that this effect could be mediated by increased ADRP expression. Similar to PPARalpha activation, adenovirus-mediated ADRP overexpression in mouse hepatocytes enhanced cellular triglyceride mass and decreased the secretion of newly synthesized triglycerides. In ADRP-overexpressing cells, Wy incubation resulted in a further decrease in triglyceride secretion. This effect of Wy was not attributable to decreased cellular triglycerides after increased fatty acid oxidation because the triglyceride mass in Wy-treated ADRP-overexpressing cells was unchanged. In summary, PPARalpha activation prevents the availability of triglycerides for VLDL assembly and increases hepatic triglyceride content in part by increasing the expression of ADRP.
|
|
| 25. |
|
|
| 26. |
- Ericson, E., et al.
(författare)
-
Hepatic patatin-like phospholipase domain-containing 3 levels are increased in I148M risk allele carriers and correlate with NAFLD in humans
- 2022
-
Ingår i: Hepatology communications.. - : Ovid Technologies (Wolters Kluwer Health). - 2471-254X. ; 6:10, s. 2689-2701
-
Tidskriftsartikel (refereegranskat)abstract
- In nonalcoholic fatty liver disease (NAFLD) the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 variant is a contributor. In mice, the Pnpla3 148M variant accumulates on lipid droplets and probably leads to sequestration of a lipase cofactor leading to impaired mobilization of triglycerides. To advance our understanding of the localization and abundance of PNPLA3 protein in humans, we used liver biopsies from patients with NAFLD to investigate the link to NAFLD and the PNPLA3 148M genotype. We experimentally qualified an antibody against human PNPLA3. Hepatic PNPLA3 protein fractional area and localization were determined by immunohistochemistry in biopsies from a well-characterized NAFLD cohort of 67 patients. Potential differences in hepatic PNPLA3 protein levels among patients related to degree of steatosis, lobular inflammation, ballooning, and fibrosis, and PNPLA3 I148M gene variants were assessed. Immunohistochemistry staining in biopsies from patients with NAFLD showed that hepatic PNPLA3 protein was predominantly localized to the membranes of small and large lipid droplets in hepatocytes. PNPLA3 protein levels correlated strongly with steatosis grade (p = 0.000027) and were also significantly higher in patients with lobular inflammation (p = 0.009), ballooning (p = 0.022), and significant fibrosis (stage 2-4, p = 0.014). In addition, PNPLA3 levels were higher in PNPLA3 rs738409 148M (CG, GG) risk allele carriers compared to 148I (CC) nonrisk allele carriers (p = 0.0029). Conclusion: PNPLA3 protein levels were associated with increased hepatic lipid content and disease severity in patients with NAFLD and were higher in PNPLA3 rs738409 (148M) risk allele carriers. Our hypothesis that increased hepatic levels of PNPLA3 may be part of the pathophysiological mechanism of NAFLD is supported.
|
|
| 27. |
- Forsgård, Richard A., 1987-, et al.
(författare)
-
Two-Week Aflibercept or Erlotinib Administration Does Not Induce Changes in Intestinal Morphology in Male Sprague-Dawley Rats But Aflibercept Affects Serum and Urine Metabolic Profiles
- 2019
-
Ingår i: Translational Oncology. - : Elsevier. - 1944-7124 .- 1936-5233. ; 12:8, s. 1122-1130
-
Tidskriftsartikel (refereegranskat)abstract
- Gastrointestinal toxicity is a frequently observed adverse event during cancer treatment with traditional chemotherapeutics. Currently, traditional chemotherapeutics are often combined with targeted biologic agents. These biologics, however, possess a distinct toxicity profile, and they may also exacerbate the adverse effects of traditional chemotherapeutics. In this study, we aimed to characterize the gastrointestinal and metabolic changes after a 2-week treatment period with aflibercept, an antiangiogenic VEGFR decoy, and with erlotinib, a tyrosine-kinase inhibitor. Male rats were treated either with aflibercept or erlotinib for 2 weeks. During the 2-week treatment period, the animals in the aflibercept group received twosubcutaneous doses of 25 mg/kg aflibercept. The erlotinib group got 10 mg/kg of erlotinib by oral gavage every other day. The control groups were treated similarly but received either saline injections or oral gavage of water. Intestinal toxicity was assessed by measuring intestinal permeability and by histological analyses of intestinal tissues. Metabolic changes were measured with H-1 nuclear magnetic resonance in serum and urine. Neither aflibercept nor erlotinib induced changes in intestinal permeability or intestinal tissue morphology. However, aflibercept treatment resulted in stunted body weight gain and altered choline, amino acid, and lipid metabolism. Two-week treatment with aflibercept or erlotinib alone does not induce observable changes in gastrointestinal morphology and function. However, observed aflibercept-treatment related metabolic changes suggest alterations in intestinal microbiota, nutrient intake, and adipose tissue function. The metabolic changes are also interesting in respect to the systemic effects of aflibercept and their possible associations with adverse events caused by aflibercept administration.
|
|
| 28. |
|
|
| 29. |
- Gennemark, Peter, et al.
(författare)
-
An oral antisense oligonucleotide for PCSK9 inhibition
- 2021
-
Ingår i: Science Translational Medicine. - : AMER ASSOC ADVANCEMENT SCIENCE. - 1946-6234 .- 1946-6242. ; 13:593
-
Tidskriftsartikel (refereegranskat)abstract
- Inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce low-density lipoprotein (LDL) cholesterol and are used for treatment of dyslipidemia. Current PCSK9 inhibitors are administered via subcutaneous injection. We present a highly potent, chemically modified PCSK9 antisense oligonucleotide (ASO) with potential for oral delivery. Past attempts at oral delivery using earlier-generation ASO chemistries and transient permeation enhancers provided encouraging data, suggesting that improving potency of the ASO could make oral delivery a reality. The constrained ethyl chemistry and liver targeting enabled by N-acetylgalactosamine conjugation make this ASO highly potent. A single subcutaneous dose of 90 mg reduced PCSK9 by >90% in humans with elevated LDL cholesterol and a monthly subcutaneous dose of around 25 mg is predicted to reduce PCSK9 by 80% at steady state. To investigate the feasibility of oral administration, the ASO was coformulated in a tablet with sodium caprate as permeation enhancer. Repeated oral daily dosing in dogs resulted in a bioavailability of 7% in the liver (target organ), about fivefold greater than the plasma bioavailability. Target engagement after oral administration was confirmed by intrajejunal administration of a rat-specific surrogate ASO in solution with the enhancer to rats and by plasma PCSK9 and LDL cholesterol lowering in cynomolgus monkey after tablet administration. On the basis of an assumption of 5% liver bioavailability after oral administration in humans, a daily dose of 15 mg is predicted to reduce circulating PCSK9 by 80% at steady state, supporting the development of the compound for oral administration to treat dyslipidemia.
|
|
| 30. |
- Golub, Malgorzata, et al.
(författare)
-
A framework for ensemble modelling of climate change impacts on lakes worldwide : the ISIMIP Lake Sector
- 2022
-
Ingår i: Geoscientific Model Development. - : Copernicus Publications. - 1991-959X .- 1991-9603. ; 15:11, s. 4597-4623
-
Tidskriftsartikel (refereegranskat)abstract
- Empirical evidence demonstrates that lakes and reservoirs are warming across the globe. Consequently, there is an increased need to project future changes in lake thermal structure and resulting changes in lake biogeochemistry in order to plan for the likely impacts. Previous studies of the impacts of climate change on lakes have often relied on a single model forced with limited scenario-driven projections of future climate for a relatively small number of lakes. As a result, our understanding of the effects of climate change on lakes is fragmentary, based on scattered studies using different data sources and modelling protocols, and mainly focused on individual lakes or lake regions. This has precluded identification of the main impacts of climate change on lakes at global and regional scales and has likely contributed to the lack of lake water quality considerations in policy-relevant documents, such as the Assessment Reports of the Intergovernmental Panel on Climate Change (IPCC). Here, we describe a simulation protocol developed by the Lake Sector of the Inter-Sectoral Impact Model Intercomparison Project (ISIMIP) for simulating climate change impacts on lakes using an ensemble of lake models and climate change scenarios for ISIMIP phases 2 and 3. The protocol prescribes lake simulations driven by climate forcing from gridded observations and different Earth system models under various representative greenhouse gas concentration pathways (RCPs), all consistently bias-corrected on a 0.5 degrees x 0.5 degrees global grid. In ISIMIP phase 2, 11 lake models were forced with these data to project the thermal structure of 62 well-studied lakes where data were available for calibration under historical conditions, and using uncalibrated models for 17 500 lakes defined for all global grid cells containing lakes. In ISIMIP phase 3, this approach was expanded to consider more lakes, more models, and more processes. The ISIMIP Lake Sector is the largest international effort to project future water temperature, thermal structure, and ice phenology of lakes at local and global scales and paves the way for future simulations of the impacts of climate change on water quality and biogeochemistry in lakes.
|
|
| 31. |
|
|
| 32. |
|
|
| 33. |
- Jones, Benedict C, et al.
(författare)
-
To which world regions does the valence-dominance model of social perception apply?
- 2021
-
Ingår i: Nature Human Behaviour. - : Springer Science and Business Media LLC. - 2397-3374. ; 5:1, s. 159-169
-
Tidskriftsartikel (refereegranskat)abstract
- Over the past 10 years, Oosterhof and Todorov's valence-dominance model has emerged as the most prominent account of how people evaluate faces on social dimensions. In this model, two dimensions (valence and dominance) underpin social judgements of faces. Because this model has primarily been developed and tested in Western regions, it is unclear whether these findings apply to other regions. We addressed this question by replicating Oosterhof and Todorov's methodology across 11 world regions, 41 countries and 11,570 participants. When we used Oosterhof and Todorov's original analysis strategy, the valence-dominance model generalized across regions. When we used an alternative methodology to allow for correlated dimensions, we observed much less generalization. Collectively, these results suggest that, while the valence-dominance model generalizes very well across regions when dimensions are forced to be orthogonal, regional differences are revealed when we use different extraction methods and correlate and rotate the dimension reduction solution. PROTOCOL REGISTRATION: The stage 1 protocol for this Registered Report was accepted in principle on 5 November 2018. The protocol, as accepted by the journal, can be found at https://doi.org/10.6084/m9.figshare.7611443.v1 .
|
|
| 34. |
- Jung, Dooseok Escher, et al.
(författare)
-
Universal Upper End of the Stellar Initial Mass Function in the Young and Compact LEGUS Clusters
- 2023
-
Ingår i: Astrophysical Journal. - 0004-637X .- 1538-4357. ; 954:2
-
Tidskriftsartikel (refereegranskat)abstract
- We investigate the variation in the upper end of the stellar initial mass function (uIMF) in 375 young and compact star clusters in five nearby galaxies within ∼5 Mpc. All the young stellar clusters (YSCs) in the sample have ages ≲ 4 Myr and masses above 500 M⊙, according to standard stellar models. The YSC catalogs were produced from Hubble Space Telescope images obtained as part of the Legacy ExtraGalactic UV Survey (LEGUS) Hubble treasury program. They are used here to test whether the uIMF is universal or changes as a function of the cluster's stellar mass. We perform this test by measuring the Hα luminosity of the star clusters as a proxy for their ionizing photon rate, and charting its trend as a function of cluster mass. Large cluster numbers allow us to mitigate the stochastic sampling of the uIMF. The advantage of our approach relative to previous similar attempts is the use of cluster catalogs that have been selected independently of the presence of Hα emission, thus removing a potential sample bias. We find that the uIMF, as traced by the Hα emission, shows no dependence on cluster mass, suggesting that the maximum stellar mass that can be produced in star clusters is universal, in agreement with previous findings.
|
|
| 35. |
- Karlsson, D., et al.
(författare)
-
Inhibition of SGLT2 Preserves Function and Promotes Proliferation of Human Islets Cells In Vivo in Diabetic Mice
- 2022
-
Ingår i: Biomedicines. - : MDPI AG. - 2227-9059. ; 10:2
-
Tidskriftsartikel (refereegranskat)abstract
- Dapagliflozin is a sodium-glucose co-transporter 2 (SGLT2) inhibitor used for the treatment of diabetes. This study examines the effects of dapagliflozin on human islets, focusing on alpha and beta cell composition in relation to function in vivo, following treatment of xeno-transplanted diabetic mice. Mouse beta cells were ablated by alloxan, and dapagliflozin was provided in the drinking water while controls received tap water. Body weight, food and water intake, plasma glucose, and human C-peptide levels were monitored, and intravenous arginine/glucose tolerance tests (IVarg GTT) were performed to evaluate islet function. The grafted human islets were isolated at termination and stained for insulin, glucagon, Ki67, caspase 3, and PDX-1 immunoreactivity in dual and triple combinations. In addition, human islets were treated in vitro with dapagliflozin at different glucose concentrations, followed by insulin and glucagon secretion measurements. SGLT2 inhibition increased the animal survival rate and reduced plasma glucose, accompanied by sustained human C-peptide levels and improved islet response to glucose/arginine. SGLT2 inhibition increased both alpha and beta cell proliferation (Ki67+glucagon+ and Ki67+insulin+) while apoptosis was reduced (caspase3+glucagon+ and caspase3+insulin+). Alpha cells were fewer following inhibition of SGLT2 with increased glucagon/PDX-1 double-positive cells, a marker of alpha to beta cell transdifferentiation. In vitro treatment of human islets with dapagliflozin had no apparent impact on islet function. In summary, SGLT2 inhibition supported human islet function in vivo in the hyperglycemic milieu and potentially promoted alpha to beta cell transdifferentiation, most likely through an indirect mechanism. © 2022 by the authors. Licensee MDPI, Basel, Switzerland.
|
|
| 36. |
- Kelly, Patrick L., et al.
(författare)
-
Constraints on the Hubble constant from supernova Refsdal's reappearance
- 2023
-
Ingår i: Science. - 0036-8075 .- 1095-9203. ; 380:6649
-
Tidskriftsartikel (refereegranskat)abstract
- The gravitationally lensed supernova Refsdal appeared in multiple images produced through gravitational lensing by a massive foreground galaxy cluster. After the supernova appeared in 2014, lens models of the galaxy cluster predicted that an additional image of the supernova would appear in 2015, which was subsequently observed. We use the time delays between the images to perform a blinded measurement of the expansion rate of the Universe, quantified by the Hubble constant (H0). Using eight cluster lens models, we infer kilometers per second per megaparsec. Using the two models most consistent with the observations, we find kilometers per second per megaparsec. The observations are best reproduced by models that assign dark-matter halos to individual galaxies and the overall cluster.
|
|
| 37. |
- Kostrzewski, T., et al.
(författare)
-
Modelling human liver fibrosis in the context of non-alcoholic steatohepatitis using a microphysiological system
- 2021
-
Ingår i: Communications Biology. - : Springer Science and Business Media LLC. - 2399-3642. ; 4:1
-
Tidskriftsartikel (refereegranskat)abstract
- Kostrzewski et al. introduce an in vitro microphysiological model of non-alcoholic steatohepatitis (NASH), consisting of co-cultured primary human liver cells. The authors characterised the transcriptomic, inflammatory and fibrotic phenotype of the model and show that major features of NASH can be recapitulated and therapeutic interventions mimicked. Non-alcoholic steatohepatitis (NASH) is a common form of chronic liver disease characterised by lipid accumulation, infiltration of immune cells, hepatocellular ballooning, collagen deposition and liver fibrosis. There is a high unmet need to develop treatments for NASH. We have investigated how liver fibrosis and features of advanced clinical disease can be modelled using an in vitro microphysiological system (MPS). The NASH MPS model comprises a co-culture of primary human liver cells, which were cultured in a variety of conditions including+/- excess sugar, fat, exogenous TGF beta or LPS. The transcriptomic, inflammatory and fibrotic phenotype of the model was characterised and compared using a system biology approach to identify conditions that mimic more advanced clinical disease. The transcriptomic profile of the model was shown to closely correlate with the profile of patient samples and the model displayed a quantifiable fibrotic phenotype. The effects of Obeticholic acid and Elafibranor, were evaluated in the model, as wells as the effects of dietary intervention, with all able to significantly reduce inflammatory and fibrosis markers. Overall, we demonstrate how the MPS NASH model can be used to model different aspects of clinical NASH but importantly demonstrate its ability to model advanced disease with a quantifiable fibrosis phenotype.
|
|
| 38. |
- Köckemann, Uwe, 1983-, et al.
(författare)
-
Open-source data collection and data sets for activity recognition in smart homes
- 2020
-
Ingår i: Sensors. - : MDPI AG. - 1424-8220. ; 20:3
-
Tidskriftsartikel (refereegranskat)abstract
- As research in smart homes and activity recognition is increasing, it is of ever increasing importance to have benchmarks systems and data upon which researchers can compare methods. While synthetic data can be useful for certain method developments, real data sets that are open and shared are equally as important. This paper presents the E-care@home system, its installation in a real home setting, and a series of data sets that were collected using the E-care@home system. Our first contribution, the E-care@home system, is a collection of software modules for data collection, labeling, and various reasoning tasks such as activity recognition, person counting, and configuration planning. It supports a heterogeneous set of sensors that can be extended easily and connects collected sensor data to higher-level Artificial Intelligence (AI) reasoning modules. Our second contribution is a series of open data sets which can be used to recognize activities of daily living. In addition to these data sets, we describe the technical infrastructure that we have developed to collect the data and the physical environment. Each data set is annotated with ground-truth information, making it relevant for researchers interested in benchmarking different algorithms for activity recognition.
|
|
| 39. |
- Lee, S. D., et al.
(författare)
-
IDOL regulates systemic energy balance through control of neuronal VLDLR expression
- 2019
-
Ingår i: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:11
-
Tidskriftsartikel (refereegranskat)abstract
- Liver X receptors limit cellular lipid uptake by stimulating the transcription of inducible degrader of the low-density lipoprotein receptor (IDOL), an E3 ubiquitin ligase that targets lipoprotein receptors for degradation. The function of IDOL in systemic metabolism is incompletely understood. Here we show that loss of IDOL in mice protects against the development of dietinduced obesity and metabolic dysfunction by altering food intake and thermogenesis. Unexpectedly, analysis of tissue-specific knockout mice revealed that IDOL affects energy balance, not through its actions in peripheral metabolic tissues (liver, adipose tissue, endothelium, intestine, and skeletal muscle) but by controlling lipoprotein receptor abundance in neurons. Single-cell RNA sequencing of the hypothalamus demonstrated that IDOL deletion altered gene expression linked to the control of metabolism. Finally, we identified very low-density lipoprotein receptor (VLDLR) rather than low-density lipoprotein receptor (LDLR) as the primary mediator of the effects of IDOL on energy balance. These data identify a role for the neuronal IDOL-VLDLR pathway in metabolic homoeostasis and diet-induced obesity.
|
|
| 40. |
|
|
| 41. |
- Lindén, Daniel, 1971
(författare)
-
Growth hormone and PPARa in the regulation of lipoprotein metabolism
- 2002
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In humans, apolipoprotein B (apoB)-100 is produced in the liver and apoB-48 is formed in the intestine. In the rat, however, the two forms of apoB are produced in the liver, leading to the formation of VLDL consisting of either apoB-48 or apoB-100. The mRNA for apoB-48 is produced by insertion of a stop codon in the mRNA for apoB-100, an enzyme-dependent event called apoB mRNA editing. From previous results, it is clear that growth hormone (GH) treatment in vivo stimulates the VLDL secretion in both rats and humans. However, during GH treatment, the liver is exposed to increased levels of insulin and fatty acids, which have been shown to increase VLDL secretion. Using primary rat hepatic cell cultures, GH incubation increased the apoB mRNA editing and triglyceride synthesis and decreased the apoB-100 secretion. Moreover, GH increased the secretion of apoB-48-VLDL and combined incubation with oleic acid had an additive effect. The importance of increased insulin secretion for the effect of GH in vivo was investigated in hypophysectomised (Hx) rats. Increased insulin levels did not mediate the observed effects of GH on serum lipoprotein levels. However, GH treatment increased the hepatic triglyceride secretion rate, an effect that was blunted by insulin treatment. Both GH and insulin increased the expression of lipogenic enzymes in Hx rats, indicating that these effects of GH could be mediated via increased insulin secretion. GH was found to decrease the expression of peroxisome proliferator-activated receptor a (PPARa) both in hepatocyte cultures and in Hx rats. In spite of decreased PPARa levels, GH increased the expression of liver fatty acid binding protein. The importance of PPARa for VLDL production was investigated in PPARa null mice. PPARa-deficient hepatocytes had an increased capacity for apoB and VLDL secretion. Female, in contrast to male PPARa null mice had increased hepatic triglyceride secretion rate and serum apoB levels. Moreover, when fed a high-fat diet, male PPARa null mice displayed increased serum apoB and LDL cholesterol levels.In summary, GH was found to have direct effects on apoB and VLDL production and secretion and increased insulin levels could not explain most of the effects of GH in vivo. GH decreased PPARa expression both in vitro and in vivo. PPARa null mice have higher secretion and serum levels of apoB-containing lipoproteins.
|
|
| 42. |
- Lindén, Daniel, 1971, et al.
(författare)
-
Influence of peroxisome proliferator-activated receptor alpha agonists on the intracellular turnover and secretion of apolipoprotein (Apo) B-100 and ApoB-48.
- 2002
-
Ingår i: The Journal of biological chemistry. - 0021-9258. ; 277:25, s. 23044-53
-
Tidskriftsartikel (refereegranskat)abstract
- The peroxisome proliferator-activated receptor (PPAR) alpha agonist WY 14,643 increased the secretion of apolipoprotein (apo) B-100, but not that of apoB-48, and decreased triglyceride biosynthesis and secretion from primary rat hepatocytes. These effects resulted in decreased secretion of apoB-100-very low density lipoprotein (VLDL) and an increased secretion of apoB-100 on low density lipoproteins/intermediate density lipoproteins. ApoB-48-VLDL was also replaced by more dense particles. The proteasomal inhibitor lactacystin did not influence the recovery of apoB-100 or apoB-48 in primary rat hepatocytes, indicating that co-translational (proteasomal) degradation is of less importance in these cells. Treatment with WY 14,643 made the recovery of apoB-100 sensitive to lactacystin, most likely reflecting the decreased biosynthesis of triglycerides. The PPAR alpha agonist induced a significant increase in the accumulation of pulse-labeled apoB-100 even after a short pulse (2-5 min). There was also an increase in apoB-100 nascent polypeptides, indicating that the co-translational degradation of apoB-100 was inhibited. However, a minor influence on an early posttranslation degradation cannot be excluded. This decreased co-translational degradation of apoB-100 explained the increased secretion of the protein. The levels of apoB-48 remained unchanged during these pulse-chase experiments, and albumin production was not affected, indicating a specific effect of PPAR alpha agonists on the co-translational degradation of apoB-100. These findings explain the difference in the rate of secretion of the two apoB proteins seen after PPAR alpha activation. PPAR alpha agonists increased the expression and biosynthesis of liver fatty acid-binding protein (LFABP). Increased expression of LFABP by transfection of McA-RH7777 cells increased the secretion of apoB-100, decreased triglyceride biosynthesis and secretion, and increased PPAR alpha mRNA levels. These findings suggest that PPAR alpha and LFABP could interact to amplify the effect of endogenous PPAR alpha agonists on the assembly of VLDL.
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
- Lindén, Daniel, 1971, et al.
(författare)
-
Pnpla3 silencing with antisense oligonucleotides ameliorates nonalcoholic steatohepatitis and fibrosis in Pnpla3 I148M knock-in mice.
- 2019
-
Ingår i: Molecular metabolism. - : Elsevier BV. - 2212-8778. ; 22:April, s. 49-61
-
Tidskriftsartikel (refereegranskat)abstract
- Nonalcoholic fatty liver disease (NAFLD) is becoming a leading cause of advanced chronic liver disease. The progression of NAFLD, including nonalcoholic steatohepatitis (NASH), has a strong genetic component, and the most robust contributor is the patatin-like phospholipase domain-containing 3 (PNPLA3) rs738409 encoding the 148M protein sequence variant. We hypothesized that suppressing the expression of the PNPLA3 148M mutant protein would exert a beneficial effect on the entire spectrum of NAFLD.We examined the effects of liver-targeted GalNAc3-conjugated antisense oligonucleotide (ASO)-mediated silencing of Pnpla3 in a knock-in mouse model in which we introduced the human PNPLA3 I148M mutation.ASO-mediated silencing of Pnpla3 reduced liver steatosis (p=0.038) in homozygous Pnpla3 148M/M knock-in mutant mice but not in wild-type littermates fed a steatogenic high-sucrose diet. In mice fed a NASH-inducing diet, ASO-mediated silencing of Pnpla3 reduced liver steatosis score and NAFLD activity score independent of the Pnpla3 genotype, while reductions in liver inflammation score (p=0.018) and fibrosis stage (p=0.031) were observed only in the Pnpla3 knock-in 148M/M mutant mice. These responses were accompanied by reduced liver levels of Mcp1 (p=0.026) and Timp2 (p=0.007) specifically in the mutant knock-in mice. This may reduce levels of chemokine attracting inflammatory cells and increase the collagenolytic activity during tissue regeneration.This study provides the first evidence that a Pnpla3 ASO therapy can improve all features of NAFLD, including liver fibrosis, and suppress the expression of a strong innate genetic risk factor, Pnpla3 148M, which may open up a precision medicine approach in NASH.
|
|
| 46. |
- Lindén, Daniel, 1971, et al.
(författare)
-
Therapeutic opportunities for the treatment of NASH with genetically validated targets.
- 2023
-
Ingår i: Journal of hepatology. - 1600-0641. ; 79:4, s. 1056-1064
-
Tidskriftsartikel (refereegranskat)abstract
- The identification of genetic variants associated with fatty liver disease (FLD) from genome wide association studies (GWASs) started in 2008 when single nucleotide polymorphisms in PNPLA3, the gene encoding patatin-like phospholipase domain-containing 3, were found to be associated with altered hepatic fat content. Since then, several genetic variants associated with protection from or increased risk of FLD have been identified. The identification of these variants has allowed insight into the metabolic pathways causing FLD and to identify therapeutic targets to treat the disease. In this mini-review we will examine the therapeutic opportunities derived from genetically validated targets in FLD, including PNPLA3 and HSD17β13, where oligonucleotide-based therapies are currently being evaluated in clinical trials for the treatment of non-alcoholic steatohepatitis (NASH).
|
|
| 47. |
- Lindén, Malin, et al.
(författare)
-
FET family fusion oncoproteins target the SWI/SNF chromatin remodeling complex
- 2019
-
Ingår i: EMBO Reports. - : EMBO. - 1469-221X .- 1469-3178. ; 20
-
Tidskriftsartikel (refereegranskat)abstract
- Members of the human FET family of RNA-binding proteins, comprising FUS, EWSR1, and TAF15, are ubiquitously expressed and engage at several levels of gene regulation. Many sarcomas and leukemias are characterized by the expression of fusion oncogenes with FET genes as 5′ partners and alternative transcription factor-coding genes as 3′ partners. Here, we report that the N terminus of normal FET proteins and their oncogenic fusion counterparts interact with the SWI/SNF chromatin remodeling complex. In contrast to normal FET proteins, increased fractions of FET oncoproteins bind SWI/SNF, indicating a deregulated and enhanced interaction in cancer. Forced expression of FET oncogenes caused changes of global H3K27 trimethylation levels, accompanied by altered gene expression patterns suggesting a shift in the antagonistic balance between SWI/SNF and repressive polycomb group complexes. Thus, deregulation of SWI/SNF activity could provide a unifying pathogenic mechanism for the large group of tumors caused by FET fusion oncoproteins. These results may help to develop common strategies for therapy. © 2019 The Authors. Published under the terms of the CC BY 4.0 license
|
|
| 48. |
- Lindgren, Anna, et al.
(författare)
-
Adiponectin receptor 2 deficiency results in reduced atherosclerosis in the brachiocephalic artery in apolipoprotein e deficient mice.
- 2013
-
Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 8:11
-
Tidskriftsartikel (refereegranskat)abstract
- Adiponectin has been shown to have beneficial cardiovascular effects and to signal through the adiponectin receptors, AdipoR1 and AdipoR2. The original aim of this study was to investigate the effect of combined AdipoR1 and AdipoR2 deficiency (AdipoR1(-/-)AdipoR2(-/-)) on atherosclerosis. However, we made the interesting observation that AdipoR1 (-/-) AdipoR2 (-/-) leads to embryonic lethality demonstrating the critical importance of the adiponectin signalling system during development. We then investigated the effect of AdipoR2-ablation on the progression of atherosclerosis in apolipoprotein E deficient (ApoE (-/-) ) mice. AdipoR2(-/-)ApoE(-/-) mice fed an atherogenic diet had decreased plaque area in the brachiocephalic artery compared with AdipoR2 (+/+) ApoE(-/-) littermate controls as visualized in vivo using an ultrasound biomicroscope and confirmed by histological analyses. The decreased plaque area in the brachiocephalic artery could not be explained by plasma cholesterol levels or inflammatory status. However, accumulation of neutral lipids was decreased in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice after incubation with oxidized LDL. This effect was associated with lower CD36 and higher ABCA1 mRNA levels in peritoneal macrophages from AdipoR2(-/-)ApoE(-/-) mice compared with AdipoR2(+/+)ApoE(-/-) controls after incubation with oxidized LDL. In summary, we show that adiponectin receptors are crucial during embryonic development and that AdipoR2-deficiency slows down the progression of atherosclerosis in the brachiocephalic artery of ApoE-deficient mice.
|
|
| 49. |
- Liu, K., et al.
(författare)
-
Multiomics analysis of naturally efficacious lipid nanoparticle coronas reveals high-density lipoprotein is necessary for their function
- 2023
-
Ingår i: Nature Communications. - 2041-1723. ; 14:1
-
Tidskriftsartikel (refereegranskat)abstract
- In terms of lipid nanoparticle (LNP) engineering, the relationship between particle composition, delivery efficacy, and the composition of the biocoronas that form around LNPs, is poorly understood. To explore this we analyze naturally efficacious biocorona compositions using an unbiased screening workflow. First, LNPs are complexed with plasma samples, from individual lean or obese male rats, and then functionally evaluated in vitro. Then, a fast, automated, and miniaturized method retrieves the LNPs with intact biocoronas, and multiomics analysis of the LNP-corona complexes reveals the particle corona content arising from each individual plasma sample. We find that the most efficacious LNP-corona complexes were enriched with high-density lipoprotein (HDL) and, compared to the commonly used corona-biomarker Apolipoprotein E, corona HDL content was a superior predictor of in-vivo activity. Using technically challenging and clinically relevant lipid nanoparticles, these methods reveal a previously unreported role for HDL as a source of ApoE and, form a framework for improving LNP therapeutic efficacy by controlling corona composition. ApoE is known to be important for lipid nanoparticle function. Here, the authors shows that efficacious coronal ApoE originates from high-density lipoprotein (HDL) particles and, enhances hepatic delivery, making HDL a superior biomarker for lipid nanoparticle potency.
|
|
| 50. |
- Ljungberg, Anna, 1977, et al.
(författare)
-
Importance of PPAR alpha for the effects of growth hormone on hepatic lipid and lipoprotein metabolism
- 2007
-
Ingår i: Growth Horm IGF Res. - : Elsevier BV. - 1096-6374. ; 17:2, s. 154-64
-
Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Growth hormone (GH) enhances lipolysis in adipose tissue, thereby increasing the flux of fatty acids to other tissues. Moreover, GH increases hepatic triglyceride synthesis and secretion in rats and decreases the action of peroxisome proliferator-activated receptor (PPAR)alpha. PPARalpha is activated by fatty acids and regulates hepatic lipid metabolism in rodents. The aim of this study was to investigate the importance of PPARalpha for the effects of GH on hepatic gene expression and lipoprotein metabolism. DESIGN: Bovine GH was given as a continuous infusion (5mg/kg/day) for 7 days to PPARalpha-null and wild-type (wt) mice. Plasma and liver lipids and hepatic gene expression were measured. In separate experiments, hepatic triglyceride secretion was measured. RESULTS: GH treatment decreased hepatic triglyceride content and increased hepatic triglyceride secretion rate and serum cholesterol levels. Furthermore, GH increased hepatic acylCoA:diacylglycerol acyltransferase (DGAT)2 mRNA levels, but decreased the hepatic mRNA expression of acyl-CoA oxidase, medium-chain acyl-CoA dehydrogenase and PPARgamma1. All these GH effects were independent of PPARalpha. However, the effect of GH on Cyp4a10, PPARgamma2, and DGAT1 was different between the genotypes. GH treatment decreased Cyp4a10 mRNA expression in wt mice, but increased the expression in PPARalpha-null mice. In contrast, GH decreased the expression of DGAT1 and PPARgamma2 in PPARalpha-null mice, but not in wt mice. CONCLUSIONS: Most of the effects of GH on lipid and lipoprotein metabolism were independent of PPARalpha. However, GH had unique effects on Cyp4a10, DGAT1, and PPARgamma2 gene expression in PPARalpha-null mice showing cross-talk between GH and PPARalpha signalling in vivo.
|
|
