| 1. |
- Urdiales, Tomás, et al.
(författare)
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Association between ethnic background and COVID-19 morbidity, mortality and vaccination in England : a multistate cohort analysis using the UK Biobank
- 2023
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Ingår i: BMJ Open. - : BMJ. - 2044-6055. ; 13:9, s. 074367-
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: Despite growing evidence suggesting increased COVID-19 mortality among people from ethnic minorities, little is known about milder forms of SARS-CoV-2 infection. We sought to explore the association between ethnic background and the probability of testing, testing positive, hospitalisation, COVID-19 mortality and vaccination uptake. DESIGN: A multistate cohort analysis. Participants were followed between 8 April 2020 and 30 September 2021. SETTING: The UK Biobank, which stores medical data on around half a million people who were recruited between 2006 and 2010. PARTICIPANTS: 405 541 subjects were eligible for analysis, limited to UK Biobank participants living in England. 23 891 (6%) of participants were non-white. PRIMARY AND SECONDARY OUTCOME MEASURES: The associations between ethnic background and testing, testing positive, hospitalisation and COVID-19 mortality were studied using multistate survival analyses. The association with single and double-dose vaccination was also modelled. Multistate models adjusted for age, sex and socioeconomic deprivation were fitted to estimate adjusted HRs (aHR) for each of the multistate transitions. RESULTS: 18 172 (4.5%) individuals tested positive, 3285 (0.8%) tested negative and then positive, 1490 (6.9% of those tested positive) were hospitalised, and 129 (0.6%) tested positive at the moment of hospital admission (ie, direct hospitalisation). Finally, 662 (17.4%) died after admission. Compared with white participants, Asian participants had an increased risk of negative to positive transition (aHR 1.24 (95% CI 1.02 to 1.52)), testing positive (95% CI 1.44 (1.33 to 1.55)) and direct hospitalisation (1.61 (95% CI 1.28 to 2.03)). Black participants had an increased risk of hospitalisation following a positive test (1.71 (95% CI 1.29 to 2.27)) and direct hospitalisation (1.90 (95% CI 1.51 to 2.39)). Although not the case for Asians (aHR 1.00 (95% CI 0.98 to 1.02)), black participants had a reduced vaccination probability (0.63 (95% CI 0.62 to 0.65)). In contrast, Chinese participants had a reduced risk of testing negative (aHR 0.64 (95% CI 0.57 to 0.73)), of testing positive (0.40 (95% CI 0.28 to 0.57)) and of vaccination (0.78 (95% CI 0.74 to 0.83)). CONCLUSIONS: We identified inequities in testing, vaccination and COVID-19 outcomes according to ethnicity in England. Compared with whites, Asian participants had increased risks of infection and admission, and black participants had almost double hospitalisation risk, and a 40% lower vaccine uptake.
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| 2. |
- Alsted, Thomas J., et al.
(författare)
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Contraction-induced lipolysis is not impaired by inhibition of hormone-sensitive lipase in skeletal muscle
- 2013
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Ingår i: Journal of Physiology. - : Wiley. - 1469-7793 .- 0022-3751. ; 591:20, s. 5141-5155
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Tidskriftsartikel (refereegranskat)abstract
- In skeletal muscle hormone-sensitive lipase (HSL) has long been accepted to be the principal enzyme responsible for lipolysis of intramyocellular triacylglycerol (IMTG) during contractions. However, this notion is based on in vitro lipase activity data, which may not reflect the in vivo lipolytic activity. We investigated lipolysis of IMTG in soleus muscles electrically stimulated to contract ex vivo during acute pharmacological inhibition of HSL in rat muscles and in muscles from HSL knockout (HSL-KO) mice. Measurements of IMTG are complicated by the presence of adipocytes located between the muscle fibres. To circumvent the problem with this contamination we analysed intramyocellular lipid droplet content histochemically. At maximal inhibition of HSL in rat muscles, contraction-induced breakdown of IMTG was identical to that seen in control muscles (P < 0.001). In response to contractions IMTG staining decreased significantly in both HSL-KO and WT muscles (P < 0.05). In vitro TG hydrolase activity data revealed that adipose triglyceride lipase (ATGL) and HSL collectively account for approximate to 98% of the TG hydrolase activity in mouse skeletal muscle, other TG lipases accordingly being of negligible importance for lipolysis of IMTG. The present study is the first to demonstrate that contraction-induced lipolysis of IMTG occurs in the absence of HSL activity in rat and mouse skeletal muscle. Furthermore, the results suggest that ATGL is activated and plays a major role in lipolysis of IMTG during muscle contractions.
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| 3. |
- Graae, Anne-Sofie, et al.
(författare)
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ADAMTS9 Regulates Skeletal Muscle Insulin Sensitivity Through Extracellular Matrix Alterations
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:3, s. 502-514
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Tidskriftsartikel (refereegranskat)abstract
- The ADAMTS9 rs4607103 C allele is one of the few gene variants proposed to increase the risk of type 2 diabetes through an impairment of insulin sensitivity. We show that the variant is associated with increased expression of the secreted ADAMTS9 and decreased insulin sensitivity and signaling in human skeletal muscle. In line with this, mice lacking Adamts9 selectively in skeletal muscle have improved insulin sensitivity. The molecular link between ADAMTS9 and insulin signaling was characterized further in a model where ADAMTS9 was overexpressed in skeletal muscle. This selective over expression resulted in decreased insulin signaling presumably mediated through alterations of the integrin 131 signaling pathway and disruption of the intracellular cytoskeletal organization. Furthermore, this led to impaired mitochondria! function in mouse muscle-an observation found to be of translational character because humans carrying the ADAMTS9 risk allele have decreased expression of mitochondrial markers. Finally, we found that the link between ADAMTS9 overexpression and impaired insulin signaling could be due to accumulation of harmful lipid intermediates. Our findings contribute to the understanding of the molecular mechanisms underlying insulin resistance and type 2 diabetes and point to inhibition of ADAMTS9 as a potential novel mode of treating insulin resistance.
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| 4. |
- Jeppesen, Jacob, et al.
(författare)
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FAT/CD36 is localized in sarcolemma and in vesicle-like structures in subsarcolemma regions but not in mitochondria.
- 2010
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Ingår i: Journal of Lipid Research. - 0022-2275 .- 1539-7262. ; 51:6, s. 1504-12
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Tidskriftsartikel (refereegranskat)abstract
- The primary aim of the present study was to investigate in which cellular compartments fatty acid trans-locase CD36 (FAT/CD36) is localized. Intact and fully functional skeletal muscle mitochondria were isolated from lean and obese female Zucker rats and from 10 healthy male individuals. FAT/CD36 could not be detected in the isolated mitochondria, whereas the mitochondrial marker F(1)ATPase-beta was clearly detected using immunoblotting. Lack of markers for other membrane structures indicated that the mitochondria were not contaminated with membranes known to contain FAT/CD36. In addition, fluorescence immunocytochemistry was performed on single muscle fibers dissected from soleus muscle of lean and obese Zucker rats and from the vastus lateralis muscle from humans. Costaining against FAT/CD36 and MitoNEET clearly show that FAT/CD36 is highly present in sarcolemma and it also associates with some vesicle-like intracellular compartments. However, FAT/CD36 protein was not detected in mitochondrial membranes, supporting the biochemical findings. Based on the presented data, FAT/CD36 seems to be abundantly expressed in sarcolemma and in vesicle-like structures throughout the muscle cell. However, FAT/CD36 is not present in mitochondria in rat or human skeletal muscle. Thus, the functional role of FAT/CD36 in lipid transport seems primarily to be allocated to the plasma membrane in skeletal muscle.
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| 5. |
- Mojtaba Ghiasi, Seyed, et al.
(författare)
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The Endoplasmic Reticulum Chaperone Glucose-Regulated Protein 94 is Essential for Proinsulin Handling
- 2019
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 68:4, s. 747-760
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Tidskriftsartikel (refereegranskat)abstract
- Although endoplasmic reticulum (ER) chaperone binding to mutant proinsulin has been reported, the role of protein chaperones in the handling of wild-type proinsulin is under-investigated. Here, we have explored the importance of glucose regulated protein 94 (GRP94), a prominent ER chaperone known to fold insulin-like growth factors, in proinsulin handling within β-cells. We found that GRP94 co-immunoprecipitated with proinsulin and that inhibition of GRP94 function and/or expression reduced glucose-dependent insulin secretion, shortened proinsulin half-life and lowered intracellular proinsulin and insulin levels. This phenotype was accompanied by post-ER proinsulin misprocessing and higher numbers of enlarged insulin granules that contained amorphic material with reduced immunogold staining for mature insulin. Insulin granule exocytosis was two-fold accelerated but the secreted insulin had diminished bioactivity. Moreover, GRP94 knockdown or knockout in β-cells selectively activated Protein Kinase R-like Endoplasmic Reticulum Kinase (PERK), without increasing apoptosis levels. Finally, GRP94 mRNA was overexpressed in islets from T2D patients. We conclude that GRP94 is a chaperone crucial for proinsulin handling and insulin secretion.
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| 6. |
- Prats, Clara, et al.
(författare)
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Decrease in intramuscular lipid droplets and translocation of HSL in response to muscle contraction and epinephrine
- 2006
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Ingår i: Journal of Lipid Research. - 1539-7262. ; 47:11, s. 2392-2399
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Tidskriftsartikel (refereegranskat)abstract
- A better understanding of skeletal muscle lipid metabolism is needed to identify the molecular mechanisms relating intramuscular triglyceride (IMTG) to muscle metabolism and insulin sensitivity. An increasing number of proteins have been reported to be associated with intracellular triglyceride (TG), among them the PAT family members: perilipin, ADRP ( for adipocyte differentiation-related protein), and TIP47 ( for tail-interacting protein of 47 kDa). Hormone-sensitive lipase (HSL) is thought to be the major enzyme responsible for IMTG hydrolysis in skeletal muscle. In adipocytes, regulation of HSL by intracellular redistribution has been demonstrated. The existence of such regulatory mechanisms in skeletal muscle has long been hypothesized but has never been demonstrated. The aim of this study was to characterize the PAT family proteins associated with IMTG and to investigate the effect of epinephrine stimulation or muscle contraction on skeletal muscle TG content and HSL intracellular distribution. Rat soleus muscles were either incubated with epinephrine or electrically stimulated for 15 min. Single muscle fibers were used for morphological analysis by confocal and transmission electron microscopy. We show a decrease in IMTG in response to both lipolytic stimuli. Furthermore, we identify two PAT family proteins, ADRP and TIP47, associated with IMTG. Finally, we demonstrate HSL translocation to IMTG and ADRP after stimulation with epinephrine or contraction.
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| 7. |
- Wright, Graham D., et al.
(författare)
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Recognising the importance and impact of Imaging Scientists: Global guidelines for establishing career paths within core facilities
- 2024
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Ingår i: JOURNAL OF MICROSCOPY. - 0022-2720 .- 1365-2818. ; 294:3, s. 397-410
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Tidskriftsartikel (refereegranskat)abstract
- In the dynamic landscape of scientific research, imaging core facilities are vital hubs propelling collaboration and innovation at the technology development and dissemination frontier. Here, we present a collaborative effort led by Global BioImaging (GBI), introducing international recommendations geared towards elevating the careers of Imaging Scientists in core facilities. Despite the critical role of Imaging Scientists in modern research ecosystems, challenges persist in recognising their value, aligning performance metrics and providing avenues for career progression and job security. The challenges encompass a mismatch between classic academic career paths and service-oriented roles, resulting in a lack of understanding regarding the value and impact of Imaging Scientists and core facilities and how to evaluate them properly. They further include challenges around sustainability, dedicated training opportunities and the recruitment and retention of talent. Structured across these interrelated sections, the recommendations within this publication aim to propose globally applicable solutions to navigate these challenges. These recommendations apply equally to colleagues working in other core facilities and research institutions through which access to technologies is facilitated and supported. This publication emphasises the pivotal role of Imaging Scientists in advancing research programs and presents a blueprint for fostering their career progression within institutions all around the world. In the exciting world of scientific research, imaging core facilities are essential hubs where scientists use advanced technologies to conduct experiments and uncover fascinating discoveries. What makes these facilities remarkable is that multiple scientists can access and utilise a variety of instruments for a wide range of multidisciplinary research projects, fostering collaboration and innovation. At the forefront of this scientific adventure are Imaging Scientists, experts who play a crucial role in planning experiments, preparing materials, adapting and acquiring technologies, collecting data, training and supporting researchers, analysing images and forming conclusions. Despite their pivotal contributions, there are challenges in recognising the importance of Imaging Scientists and ensuring they have ample opportunities to advance in their careers. These challenges include a mismatch between the typical academic career path and the unique roles and responsibilities of Imaging Scientists, a lack of widespread understanding of their value plus financial constraints, insufficient training opportunities, and difficulties in attracting and retaining talented individuals. To address these issues, Global BioImaging (GBI; www.globalbioimaging.org) has brought together Imaging Scientists from around the world to develop a generally applicable set of recommendations in three key areas: highlighting the significance and value of Imaging Scientists, making it easier to recruit and retain them, and supporting their ongoing learning and professional growth. A notable concept is to reimagine the traditional separation between academic roles and technical support roles. GBI envisions that these recommendations will not only benefit imaging facilities but also prove valuable for research institutions housing diverse technologies organised into core facilities. Recognising the diverse nature of research performing institutions globally, the GBI community sees this guide as a starting point that will initiate dialogue and instigate change, which should be periodically updated as the needs of Imaging Scientists change. This initial version lays a solid foundation for future enhancements, contributing to the acknowledgement and support of the invaluable work done by Imaging Scientists on a global scale.
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