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- Maqdasy, S, et al.
(author)
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Impaired phosphocreatine metabolism in white adipocytes promotes inflammation
- 2022
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 4:2, s. 190-
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Journal article (peer-reviewed)abstract
- The mechanisms promoting disturbed white adipocyte function in obesity remain largely unclear. Herein, we integrate white adipose tissue (WAT) metabolomic and transcriptomic data from clinical cohorts and find that the WAT phosphocreatine/creatine ratio is increased and creatine kinase-B expression and activity is decreased in the obese state. In human in vitro and murine in vivo models, we demonstrate that decreased phosphocreatine metabolism in white adipocytes alters adenosine monophosphate-activated protein kinase activity via effects on adenosine triphosphate/adenosine diphosphate levels, independently of WAT beigeing. This disturbance promotes a pro-inflammatory profile characterized, in part, by increased chemokine (C-C motif) ligand 2 (CCL2) production. These data suggest that the phosphocreatine/creatine system links cellular energy shuttling with pro-inflammatory responses in human and murine white adipocytes. Our findings provide unexpected perspectives on the mechanisms driving WAT inflammation in obesity and may present avenues to target adipocyte dysfunction.
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- Li, Q., et al.
(author)
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Obesity and hyperinsulinemia drive adipocytes to activate a cell cycle program and senesce
- 2021
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In: Nature Medicine. - : Springer Science and Business Media LLC. - 1078-8956 .- 1546-170X. ; 27, s. 1941-1953
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Journal article (peer-reviewed)abstract
- Obesity is considered an important factor for many chronic diseases, including diabetes, cardiovascular disease and cancer. The expansion of adipose tissue in obesity is due to an increase in both adipocyte progenitor differentiation and mature adipocyte cell size. Adipocytes, however, are thought to be unable to divide or enter the cell cycle. We demonstrate that mature human adipocytes unexpectedly display a gene and protein signature indicative of an active cell cycle program. Adipocyte cell cycle progression associates with obesity and hyperinsulinemia, with a concomitant increase in cell size, nuclear size and nuclear DNA content. Chronic hyperinsulinemia in vitro or in humans, however, is associated with subsequent cell cycle exit, leading to a premature senescent transcriptomic and secretory profile in adipocytes. Premature senescence is rapidly becoming recognized as an important mediator of stress-induced tissue dysfunction. By demonstrating that adipocytes can activate a cell cycle program, we define a mechanism whereby mature human adipocytes senesce. We further show that by targeting the adipocyte cell cycle program using metformin, it is possible to influence adipocyte senescence and obesity-associated adipose tissue inflammation. Studies in mature human adipocytes demonstrate that obesity and hyperinsulinemia can induce reentry into the cell cycle and induce senescence.
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| 7. |
- Morgantini, C., et al.
(author)
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Liver macrophages regulate systemic metabolism through non-inflammatory factors
- 2019
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In: Nature Metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 1:4, s. 445-459
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Journal article (peer-reviewed)abstract
- Liver macrophages (LMs) have been proposed to contribute to metabolic disease through secretion of inflammatory cytokines. However, anti-inflammatory drugs lead to only modest improvements in systemic metabolism. Here we show that LMs do not undergo a proinflammatory phenotypic switch in obesity-induced insulin resistance in flies, mice and humans. Instead, we find that LMs produce non-inflammatory factors, such as insulin-like growth factor-binding protein 7 (IGFBP7), that directly regulate liver metabolism. IGFBP7 binds to the insulin receptor and induces lipogenesis and gluconeogenesis via activation of extracellular-signal-regulated kinase (ERK) signalling. We further show that IGFBP7 is subject to RNA editing at a higher frequency in insulin-resistant than in insulin-sensitive obese patients (90% versus 30%, respectively), resulting in an IGFBP7 isoform with potentially higher capacity to bind to the insulin receptor. Our study demonstrates that LMs can contribute to insulin resistance independently of their inflammatory status and indicates that non-inflammatory factors produced by macrophages might represent new drug targets for the treatment of metabolic diseases.
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- Holmer, M, et al.
(author)
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Associations between subcutaneous adipocyte hypertrophy and nonalcoholic fatty liver disease
- 2022
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 12:1, s. 20519-
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Journal article (peer-reviewed)abstract
- Adipocyte hypertrophy and expression of adipokines in subcutaneous adipose tissue (SAT) have been linked to steatosis, nonalcoholic steatohepatitis (NASH) and fibrosis in morbidly obese (BMI ≥ 40 kg/m2) subjects. It is unknown if this is also true for subjects with NAFLD with lesser degrees of obesity (BMI < 35 kg/m2). Thirty-two subjects with biopsy-proven NAFLD and 15 non-diabetic controls matched for BMI underwent fine-needle biopsies of SAT. Adipocyte volume was calculated. RNA-sequencing of SAT was performed in a subset of 20 NAFLD patients. Adipocyte volume and gene expression levels were correlated to the presence of NASH or significant fibrosis. Subjects with NAFLD had larger adipocyte volume compared with controls, (1939 pL, 95% CI 1130–1662 vs. 854 pL, 95% CI 781–926, p < 0.001). There was no association between adipocyte volume and the presence of NASH. Gene expression of adipokines previously described to correlate with NASH in morbid obesity, was not associated with NASH or fibrosis. Our results suggest that persons with NAFLD have larger SAT adipocytes compared with controls and that adipocytes are involved in the pathophysiology of hepatic steatosis in NAFLD. However, adipocyte volume was not associated with NASH or fibrosis in NAFLD subjects with varying degrees of obesity.
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- Aouadi, M, et al.
(author)
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Career pathways, part 2
- 2020
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In: Nature metabolism. - : Springer Science and Business Media LLC. - 2522-5812. ; 2:8, s. 651-652
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Journal article (peer-reviewed)
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| 24. |
- Aouadi, S, et al.
(author)
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ICMCTF 2014 : Preface
- 2014
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In: Thin Solid Films. - : Elsevier. - 0040-6090 .- 1879-2731. ; 572, s. 1-1
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Journal article (peer-reviewed)abstract
- The 41st International Conference on Metallurgical Coatings andThin Films (ICMCTF), sponsored by the Advanced Surface EngineeringDivision (ASED) of the American Vacuum Society (AVS), was heldfrom April 28 to May 2, 2014 in San Diego, California, USA.The week's technical program consisted of 37 technical sessions,which were organized into 13 symposia. The conference opened witha Plenary Lecture by Prof. Sybrand van der Zwaag, Materials Scienceand Engineering at the faculty of Aerospace Engineering at the TUDelft, The Netherlands, on “Self-healing Materials: an Alternative Approachto Create More Durable/Reliable Materials and Products”. TheExhibition Keynote Lecture was presented by Prof. Timothy P. Weihs,Department of Materials Science and Engineering at the Johns HopkinsUniversity, Baltimore, MD, USA, on “Driving Commercial Applicationsand Exploring Scientific Questions with Reactive Multilayer Foils”.During the conference week, a well subscribed poster session wasattended by a large and appreciative attendee audience. An expansivelarge two-day interactive industrial exhibition, with more than 50booths,was held inwhich companies displayed theirmost recent developmentsin vacuumscience and plasma-based deposition technologies.In addition to the technical symposia sessions, there were threefocused topical sessions, and six specialized short courses offered.Professor Jindrich Musil from the faculty of Applied Sciences atthe University of Bohemia, Plzeň, Czech Republic, was the recipientof the 2014 ASED R.F. Bunshah Annual Award; he presented the HonoraryLecture, “Advanced Hard Nanocomposite Coatings with UniqueProperties”. The award recognizes and honors Prof. Musil's seminalcontributions to the development of advanced nanocomposite coatingswith enhanced hardness, oxidation resistance, toughness, and crackresistance.The ASED Annual ICMCTF Graduate Student Awards werepresented to Shiyu Liu (Gold Medal), University of Cambridge, UK;Samantha K. Lawrence (Silver Medal), Purdue University, WestLafayette, IN, USA; and Trevor Hardcastle (Bronze Medal), Universityof Leeds, UK.The electronic submission and handling of manuscripts via theElsevier Editorial System (EES), including the selection of reviewersand evaluation ofmanuscripts,were identical to the procedures appliedto manuscripts submitted as regular contributions for publication ininternational scientific journals. Following the tradition practiced since1987, the accepted manuscripts are published in the archival journalsSurface and Coatings Technology and Thin Solid Films. ICMCTF 2014proceedings are open-access to the participants for one year via theElsevier journals' web sites.The organization of this conference and the preparation of proceedingsvolumes would have been impossible without the tremendouseffort and dedication of many individuals, including the General Chair,Yip-Wah Chung, Northwestern University, USA, and the ProgramChair, Claus Rebholz, the University of Cyprus, the team of symposiaand session chairs that made possible the realization of an exciting technicalprogram. We especially thank all the authors and presenters fortheir contributions; we also thank the hundreds of reviewers for theirtimely submission of high quality reports. To our sponsors,we acknowledge,appreciate, and thank these companies for their most generousand continuing support.The 42nd International Conference on Metallurgical Coatings andThin Films (ICMCTF 2015) will be held in San Diego, California, April20–24, 2015, with Claus Rebholz, University of Cyprus, as the GeneralChair and Suneel Kodambaka, the University of California at Los Angeles, as the Program Chair.
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| 32. |
- Eriksson, Fredrik, et al.
(author)
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Atomic scale interface engineering by modulated ion-assisted deposition applied to soft x-ray multilayer optics
- 2008
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In: Applied Optics. - 1559-128X .- 2155-3165. ; 47:23, s. 4196-4204
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Journal article (peer-reviewed)abstract
- Cr/Sc and Ni/V multilayers, intended as normal incidence soft x-ray mirrors and Brewster angle polarizers, have been synthesized by employing a novel modulated low-energy and high-flux ion assistance as a means of engineering the interfaces between the subnanometer layers on an atomic scale during magnetron sputter deposition. To reduce both roughness and intermixing, the ion energy was modulated within each layer. The flat and abrupt interfaces yielded soft x-ray mirrors with near-normal incidence reflectances of R = 20.7% at the Sc 2p absorption edge and R = 2.7% at the V 2p absorption edge. Multilayers optimized for the Brewster angle showed a reflectance of R = 26.7% and an extinction ratio of Rs/Rp=5450 for Cr/Sc and R = 10% and Rs/Rp=4190 for Ni/V. Transmission electron microscopy investigations showed an amorphous Cr/Sc structure with an accumulating high spatial frequency roughness. For Ni/V the initial growth mode is amorphous and then turns crystalline after ~1/3 of the total thickness, with an accumulating low spatial frequency roughness as a consequence. Elastic recoil detection analyses showed that N was the major impurity in both Cr/Sc and Ni/V with concentrations of 15 at. % and 9 at. %, respectively, but also O (3 at. % and 1.3 at. %) and C (0.5 at. % and 1.9 at. %) were present. Simulations of the possible normal incidence reflective properties in the soft x-ray range of 100-600 eV are given, predicting that reflectivities of more than 31% for Cr/Sc and 5.8% for Ni/V can be achieved if better control of the impurities and the deposition process is employed. The simulations also show that Cr/Sc is a good candidate for mirrors for the photon energies between the absorption edges of B (E = 188 eV) and Sc (E = 398.8 eV).
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| 34. |
- Flach, RJR, et al.
(author)
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Endothelial protein kinase MAP4K4 promotes vascular inflammation and atherosclerosis
- 2015
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6, s. 8995-
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Journal article (peer-reviewed)abstract
- Signalling pathways that control endothelial cell (EC) permeability, leukocyte adhesion and inflammation are pivotal for atherosclerosis initiation and progression. Here we demonstrate that the Sterile-20-like mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4), which has been implicated in inflammation, is abundantly expressed in ECs and in atherosclerotic plaques from mice and humans. On the basis of endothelial-specific MAP4K4 gene silencing and gene ablation experiments in Apoe−/− mice, we show that MAP4K4 in ECs markedly promotes Western diet-induced aortic macrophage accumulation and atherosclerotic plaque development. Treatment of Apoe−/− and Ldlr−/− mice with a selective small-molecule MAP4K4 inhibitor also markedly reduces atherosclerotic lesion area. MAP4K4 silencing in cultured ECs attenuates cell surface adhesion molecule expression while reducing nuclear localization and activity of NFκB, which is critical for promoting EC activation and atherosclerosis. Taken together, these results reveal that MAP4K4 is a key signalling node that promotes immune cell recruitment in atherosclerosis.
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| 35. |
- Gorishnyy, T.Z., et al.
(author)
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Optimization of wear-resistant coating architectures using finite element analysis
- 2003
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In: Journal of Vacuum Science & Technology. A. Vacuum, Surfaces, and Films. - : American Vacuum Society. - 0734-2101 .- 1520-8559. ; 21:1, s. 332-339
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Journal article (peer-reviewed)abstract
- The design of successful wear-resistant coating architectures requires simultaneous consideration of several factors. In particular, coatings which consist of CrN layers of varying thickness separated by thin Cr layers have the highest wear resistance for both aluminum and steel substrate materials, but a methodology was needed to optimize both the overall coating design and the individual layer thicknesses. This paper provides an initial step toward the development of future application specific coating designs and improved coating design methodologies.
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| 37. |
- Jalabert, A, et al.
(author)
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Profiling of ob/ob mice skeletal muscle exosome-like vesicles demonstrates combined action of miRNAs, proteins and lipids to modulate lipid homeostasis in recipient cells
- 2021
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In: Scientific reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1, s. 21626-
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Journal article (peer-reviewed)abstract
- We have determined the lipid, protein and miRNA composition of skeletal muscle (SkM)-released extracellular vesicles (ELVs) from Ob/ob (OB) vs wild-type (WT) mice. The results showed that atrophic insulin-resistant OB-SkM released less ELVs than WT-SkM, highlighted by a RAB35 decrease and an increase in intramuscular cholesterol content. Proteomic analyses of OB-ELVs revealed a group of 37 proteins functionally connected, involved in lipid oxidation and with catalytic activities. OB-ELVs had modified contents for phosphatidylcholine (PC 34-4, PC 40-3 and PC 34-0), sphingomyelin (Sm d18:1/18:1) and ceramides (Cer d18:1/18:0) and were enriched in cholesterol, likely to alleviated intracellular accumulation. Surprisingly many ELV miRNAs had a nuclear addressing sequence, and targeted genes encoding proteins with nuclear activities. Interestingly, SkM-ELV miRNA did not target mitochondria. The most significant function targeted by the 7 miRNAs altered in OB-ELVs was lipid metabolism. In agreement, OB-ELVs induced lipid storage in recipient adipocytes and increased lipid up-take and fatty acid oxidation in recipient muscle cells. In addition, OB-ELVs altered insulin-sensitivity and induced atrophy in muscle cells, reproducing the phenotype of the releasing OB muscles. These data suggest for the first time, a cross-talk between muscle cells and adipocytes, through the SkM-ELV route, in favor of adipose tissue expansion.
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| 42. |
- Sondergaard, JN, et al.
(author)
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CCT3-LINC00326 axis regulates hepatocarcinogenic lipid metabolism
- 2022
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In: Gut. - : BMJ. - 1468-3288 .- 0017-5749. ; 71:10, s. 2081-2092
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Journal article (peer-reviewed)abstract
- To better comprehend transcriptional phenotypes of cancer cells, we globally characterised RNA-binding proteins (RBPs) to identify altered RNAs, including long non-coding RNAs (lncRNAs).DesignTo unravel RBP-lncRNA interactions in cancer, we curated a list of ~2300 highly expressed RBPs in human cells, tested effects of RBPs and lncRNAs on patient survival in multiple cohorts, altered expression levels, integrated various sequencing, molecular and cell-based data.ResultsHigh expression of RBPs negatively affected patient survival in 21 cancer types, especially hepatocellular carcinoma (HCC). After knockdown of the top 10 upregulated RBPs and subsequent transcriptome analysis, we identified 88 differentially expressed lncRNAs, including 34 novel transcripts. CRISPRa-mediated overexpression of four lncRNAs had major effects on the HCC cell phenotype and transcriptome. Further investigation of four RBP-lncRNA pairs revealed involvement in distinct regulatory processes. The most noticeable RBP-lncRNA connection affected lipid metabolism, whereby the non-canonical RBP CCT3 regulated LINC00326 in a chaperonin-independent manner. Perturbation of the CCT3-LINC00326 regulatory network led to decreased lipid accumulation and increased lipid degradation in cellulo as well as diminished tumour growth in vivo.ConclusionsWe revealed that RBP gene expression is perturbed in HCC and identified that RBPs exerted additional functions beyond their tasks under normal physiological conditions, which can be stimulated or intensified via lncRNAs and affected tumour growth.
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