| 1. |
|
|
| 2. |
|
|
| 3. |
- Glasbey, JC, et al.
(författare)
-
- 2021
-
swepub:Mat__t
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
- Chaillou, Thomas, 1985-, et al.
(författare)
-
NDUFA4L2 : Connecting metabolic signals and mitochondrial function in cardiac and skeletal muscle
- 2016
-
Ingår i: Free Radical Biology & Medicine. - : Elsevier. - 0891-5849 .- 1873-4596. ; 100:Suppl., s. S186-S186
-
Tidskriftsartikel (refereegranskat)abstract
- The nuclear-encoded mitochondrial protein NADH dehydrogenase (ubiquinone) 1 alpha subcomplex, 4-like 2 (NDUFA4L2) was recently identified. NDUFAe4L2 is shown to be induced by hypoxia via HIF1α and is thought to inhibit production of mitochondrial reactive oxygen species in fibroblasts exposed to hypoxia. Here the aim was to characterize the role of NDUFA4L2 in the mitochondria-rich tissues skeletal and cardiac muscle. We show hypoxia induced NDUFA4L2 expression in isolated muscle fibers and in cardiomyocytes with full activation after ~3-6 h in hypoxia. The half-maximal O2 level for NDUFA4L2 expression (~4.6 % of ambient O2) suggests sensitivity to changes in O2 tension that occur under physiological conditions (e.g. exercise, moderate ischemia). We identified that the NDUFA4L2 gene promoter has binding sites for transcription factors other than HIF-1α; repetitive sites for PPARα,γ and one for Nrf2. NDUFA4L2 overexpression resulted in functional effects on skeletal and cardiac muscle; e.g. it alters cellular Ca2+ signaling and the expression of Ca2+ handling genes. Further, NDUFA4L2 overexpression reduces muscle mass (~20%), leading to a decreased force production in skeletal muscle. The NDUFA4L2-induced loss of muscle mass was associated with increases in mRNA levels of e.g. MurF1, Mul1, caspase-3 and Bax. Additionally, femoral artery ligation (FAL) induced NDUFA4L2 expression, which correlates with the decreased force production eight days post-FAL in skeletal muscle. Moreover, NDUFA4L2 upregulates antioxidant gene expression and silencing NDUFA4L2 makes cardiac cells less tolerant to hypoxia/re-oxygenation. Our results suggest that NDUFA4L2 expression affects vital functions in muscle cells and at least part of this effect is mediated by a link between NDUFA4L2 and nuclear gene expression. Thus, NDUFA4L2 might act as an integrator of the nutritional, environmental and functional status in muscle cells.
|
|
| 9. |
|
|
| 10. |
|
|
| 11. |
- Cheng, Arthur J., et al.
(författare)
-
Post-exercise recovery of contractile function and endurance in humans and mice is accelerated by heating and slowed by cooling skeletal muscle
- 2017
-
Ingår i: Journal of Physiology. - : John Wiley & Sons. - 0022-3751 .- 1469-7793. ; 595:24, s. 7413-7426
-
Tidskriftsartikel (refereegranskat)abstract
- Key points: We investigated whether intramuscular temperature affects the acute recovery of exercise performance following fatigue-induced by endurance exercise. Mean power output was better preserved during an all-out arm-cycling exercise following a 2 h recovery period in which the upper arms were warmed to an intramuscular temperature of ˜ 38°C than when they were cooled to as low as 15°C, which suggested that recovery of exercise performance in humans is dependent on muscle temperature. Mechanisms underlying the temperature-dependent effect on recovery were studied in intact single mouse muscle fibres where we found that recovery of submaximal force and restoration of fatigue resistance was worsened by cooling (16-26°C) and improved by heating (36°C). Isolated whole mouse muscle experiments confirmed that cooling impaired muscle glycogen resynthesis. We conclude that skeletal muscle recovery from fatigue-induced by endurance exercise is impaired by cooling and improved by heating, due to changes in glycogen resynthesis rate.Manipulation of muscle temperature is believed to improve post-exercise recovery, with cooling being especially popular among athletes. However, it is unclear whether such temperature manipulations actually have positive effects. Accordingly, we studied the effect of muscle temperature on the acute recovery of force and fatigue resistance after endurance exercise. One hour of moderate-intensity arm cycling exercise in humans was followed by 2 h recovery in which the upper arms were either heated to 38°C, not treated (33°C), or cooled to ∼15°C. Fatigue resistance after the recovery period was assessed by performing 3 × 5 min sessions of all-out arm cycling at physiological temperature for all conditions (i.e. not heated or cooled). Power output during the all-out exercise was better maintained when muscles were heated during recovery, whereas cooling had the opposite effect. Mechanisms underlying the temperature-dependent effect on recovery were tested in mouse intact single muscle fibres, which were exposed to ∼12 min of glycogen-depleting fatiguing stimulation (350 ms tetani given at 10 s interval until force decreased to 30% of the starting force). Fibres were subsequently exposed to the same fatiguing stimulation protocol after 1-2 h of recovery at 16-36°C. Recovery of submaximal force (30 Hz), the tetanic myoplasmic free [Ca2+] (measured with the fluorescent indicator indo-1), and fatigue resistance were all impaired by cooling (16-26°C) and improved by heating (36°C). In addition, glycogen resynthesis was faster at 36°C than 26°C in whole flexor digitorum brevis muscles. We conclude that recovery from exhaustive endurance exercise is accelerated by raising and slowed by lowering muscle temperature.
|
|
| 12. |
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
- Lanner, JT, et al.
(författare)
-
The role of Ca2+ influx for insulin-mediated glucose uptake in skeletal muscle
- 2006
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 55:7, s. 2077-2083
-
Tidskriftsartikel (refereegranskat)abstract
- The involvement of Ca2+ in insulin-mediated glucose uptake is uncertain. We measured Ca2+ influx (as Mn2+ quenching or Ba2+ influx) and 2-deoxyglucose (2-DG) uptake in single muscle fibers isolated from limbs of adult mice; 2-DG uptake was also measured in isolated whole muscles. Exposure to insulin increased the Ca2+ influx in single muscle cells. Ca2+ influx in the presence of insulin was decreased by 2-aminoethoxydiphenyl borate (2-APB) and increased by the membrane-permeable diacylglycerol analog 1-oleyl-2-acetyl-sn-glycerol (OAG), agents frequently used to block and activate, respectively, nonselective cation channels. Maneuvers that decreased Ca2+ influx in the presence of insulin also decreased 2-DG uptake, whereas increased Ca2+ influx was associated with increased insulin-mediated glucose uptake in isolated single cells and whole muscles from both normal and insulin-resistant obese ob/ob mice. 2-APB and OAG affected neither basal nor hypoxia- or contraction-mediated 2-DG uptake. 2-APB did not inhibit the insulin-mediated activation of protein kinase B or extracellular signal–related kinase 1/2 in whole muscles. In conclusion, alterations in Ca2+ influx specifically modulate insulin-mediated glucose uptake in both normal and insulin-resistant skeletal muscle. Moreover, the present results indicate that Ca2+ acts late in the insulin signaling pathway, for instance, in the GLUT4 translocation to the plasma membrane.
|
|
| 16. |
|
|
| 17. |
|
|
| 18. |
|
|
| 19. |
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
- Biechele, S, et al.
(författare)
-
Porcn-dependent Wnt signaling is not required prior to mouse gastrulation
- 2013
-
Ingår i: Development (Cambridge, England). - : The Company of Biologists. - 1477-9129 .- 0950-1991. ; 140:14, s. 2961-2971
-
Tidskriftsartikel (refereegranskat)abstract
- In mice and humans the X-chromosomal porcupine homolog (Porcn) gene is required for the acylation and secretion of all 19 Wnt ligands and thus represents a bottleneck for all Wnt signaling. We have generated a mouse line carrying a floxed allele for Porcn and used zygotic, oocyte-specific and visceral endoderm-specific deletions to investigate embryonic and extra-embryonic requirements for Wnt ligand secretion. We show that there is no requirement for Porcn-dependent secretion of Wnt ligands during preimplantation development of the mouse embryo. Porcn-dependent Wnts are first required for the initiation of gastrulation, where Porcn function is required in the epiblast but not the visceral endoderm. Heterozygous female embryos, which are mutant in both trophoblast and visceral endoderm due to imprinted X chromosome inactivation, complete gastrulation but display chorio-allantoic fusion defects similar to Wnt7b mutants. Our studies highlight the importance of Wnt3 and Wnt7b for embryonic and placental development but suggest that endogenous Porcn-dependent Wnt secretion does not play an essential role in either implantation or blastocyst lineage specification.
|
|
| 24. |
- Bizzarri, N, et al.
(författare)
-
Quality of training in cervical cancer radical surgery: a survey from the European Network of Young Gynaecologic Oncologists (ENYGO)
- 2022
-
Ingår i: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. - : BMJ. - 1525-1438. ; 32:4, s. 494-501
-
Tidskriftsartikel (refereegranskat)abstract
- The European Society of Gynaecological Oncology (ESGO) and partners are committed to improving the training for gynecologic oncology fellows. The aim of this survey was to assess the type and level of training in cervical cancer surgery and to investigate whether the Laparoscopic Approach to Cervical Cancer (LACC) trial results impacted training in radical surgery for gynecologic oncology fellows.MethodsIn June 2020, a 47-question electronic survey was shared with European Network of Young Gynaecologic Oncologists (ENYGO) members. Specialist fellows in obstetrics and gynecology, and gynecologic oncology, from high- and low-volume centers, who started training between January 1, 2017 and January 1, 2020 or started before January 1, 2017 but finished their training at least 6 months after the LACC trial publication (October 2018), were included.Results81 of 125 (64.8%) respondents were included. The median time from the start of the fellowship to completion of the survey was 28 months (range 6–48). 56 (69.1%) respondents were still fellows-in-training. 6 of 56 (10.7%) and 14 of 25 (56.0%) respondents who were still in training and completed the fellowship, respectively, performed ≥10 radical hysterectomies during their training. Fellows trained in an ESGO accredited center had a higher chance to perform sentinel lymph node biopsy (60.4% vs 30.3%; p=0.027). There was no difference in the mean number of radical hysterectomies performed by fellows during fellowship before and after the LACC trial publication (8±12.0 vs 7±8.4, respectively; p=0.46). A significant reduction in number of minimally invasive radical hysterectomies was noted when comparing the period before and after the LACC trial (38.5% vs 13.8%, respectively; p<0.001).ConclusionExposure to radical surgery for cervical cancer among gynecologic oncology fellows is low. Centralization of cervical cancer cases to high-volume centers may provide an increase in fellows’ exposure to radical procedures. The LACC trial publication was associated with a decrease in minimally invasive radical hysterectomies performed by fellows.
|
|
| 25. |
|
|
| 26. |
- Blackwood, Sarah J, et al.
(författare)
-
Role of nitration in control of phosphorylase and glycogenolysis in mouse skeletal muscle.
- 2021
-
Ingår i: American Journal of Physiology. Endocrinology and Metabolism. - : American Physiological Society. - 0193-1849 .- 1522-1555. ; 320:4, s. E691-E701
-
Tidskriftsartikel (refereegranskat)abstract
- Phosphorylase is one of the most carefully studied proteins in history, but knowledge of its regulation during intense muscle contraction is incomplete. Tyrosine nitration of purified preparations of skeletal muscle phosphorylase results in inactivation of the enzyme and this is prevented by antioxidants. Whether an altered redox state affects phosphorylase activity and glycogenolysis in contracting muscle is not known. Here, we investigate the role of redox state in control of phosphorylase and glycogenolysis in isolated mouse fast-twitch (extensor digitorum longus, EDL) and slow-twitch (soleus) muscle preparations during repeated contractions. Exposure of crude muscle extracts to H2O2 had little effect on phosphorylase activity. However, exposure of extracts to peroxynitrite (ONOO-), a nitrating/oxidizing agent, resulted in complete inactivation of phosphorylase (half maximal inhibition at ~200 µM ONOO-), which was fully reversed by the presence of an ONOO-scavanger, dithiothreitol (DTT). Incubation of isolated muscles with ONOO- resulted in nitration of phosphorylase and marked inhibition of glycogenolysis during repeated contractions. ONOO- also resulted in large decreases in high-energy phosphates (ATP and phosphocreatine) in the rested state and following repeated contractions. These metabolic changes were associated with decreased force production during repeated contractions (to ~60% of control). In contrast, repeated contractions did not result in nitration of phosphorylase, nor did DTT or the general antioxidant N-acetylcysteine alter glycogenolysis during repeated contractions. These findings demonstrate that ONOO- inhibits phosphorylase and glycogenolysis in living muscle under extreme conditions. However, nitration does not play a significant role in control of phosphorylase and glycogenolysis during repeated contractions.
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
- Cheng, A, et al.
(författare)
-
Increased fatigue resistance and preserved specific force in intact single muscle fibres from the SOD1G93A mouse model of ALS
- 2017
-
Ingår i: Acta Physiologica. - : Wiley-Blackwell. - 1748-1708 .- 1748-1716. ; 219:S710, s. 17-17
-
Tidskriftsartikel (refereegranskat)abstract
- Introduction: Amyotrophic lateral sclerosis (ALS) is a motor neurone disease characterized by degeneration and loss of motor neurones, leading to severe muscle weakness and paralysis. Although motor neurone degeneration is already a well-characterized symptom that contributes to muscle weakness in the SOD1G93A mouse model of ALS, the purpose of the current study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles of SOD1G93A mice.Methods: Experiments were performed on whole muscles and mechanically dissected intact single fibres from the flexor digitorum brevis (FDB) muscle of SOD1G93A mice at three age groups of 50, 125 and 150 days of age (P50, P125 and P150). Myoplasmic free [Ca2+] ([Ca2+]i) was measured using the fluorescent indicator, indo-1.Results: Motor neurone loss and decreased force were evident in whole FDB muscles of P125–150 mice. In the intact single muscle fibres however, specific force, tetanic [Ca2+]iand resting [Ca2+]i were similar in single FDB fibres from symptomatic P125–150 SOD1G93A and age-matched wild-type littermates. The most intriguing finding was a markedly greater fatigue resistance in single fibres from P125–150 SOD1G93A vs. wild-type mice, which was not present in asymptomatic young P50 SOD1G93A mice. No shift in fibre-type distribution was observed in whole FDB muscles to explain the increased fatigue resistance of single fibres from P125–150 SOD1G93A mice.Conclusion: These results support the hypothesis that muscle weakness in ALS is not attributed to intrinsicdefects in skeletal muscle fibre force generation.
|
|
| 31. |
|
|
| 32. |
- Cheng, Arthur J., et al.
(författare)
-
Intact single muscle fibres from SOD1(G93A) amyotrophic lateral sclerosis mice display preserved specific force, fatigue resistance and training-like adaptations
- 2019
-
Ingår i: Journal of Physiology. - : Cambridge University Press. - 0022-3751 .- 1469-7793. ; 597:12, s. 3133-3146
-
Tidskriftsartikel (refereegranskat)abstract
- Key points:How defects in muscle contractile function contribute to weakness in amyotrophic lateral sclerosis (ALS) were systematically investigated.Weakness in whole muscles from late stage SOD1G93A mice was explained by muscle atrophy as seen by reduced mass and maximal force.On the other hand, surviving single muscle fibres in late stage SOD1G93A have preserved intracellular Ca2+ handling, normal force-generating capacity and increased fatigue resistance.These intriguing findings provide a substrate for therapeutic interventions to potentiate muscular capacity and delay the progression of the ALS phenotype.Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by degeneration and loss of motor neurons, leading to severe muscle weakness and paralysis. The SOD1G93A mouse model of ALS displays motor neuron degeneration and a phenotype consistent with human ALS. The purpose of this study was to determine whether muscle weakness in ALS can be attributed to impaired intrinsic force generation in skeletal muscles. In the current study, motor neuron loss and decreased force were evident in whole flexor digitorum brevis (FDB) muscles of mice in the late stage of disease (125–150 days of age). However, in intact single muscle fibres, specific force, tetanic myoplasmic free [Ca2+] ([Ca2+]i), and resting [Ca2+]i remained unchanged with disease. Fibre-type distribution was maintained in late-stage SOD1G93A FDB muscles, but remaining muscle fibres displayed greater fatigue resistance compared to control and showed increased expression of myoglobin and mitochondrial respiratory chain proteins that are important determinants of fatigue resistance. Expression of genes central to both mitochondrial biogenesis and muscle atrophy where increased, suggesting that atrophic and compensatory adaptive signalling occurs simultaneously within the muscle tissue. These results support the hypothesis that muscle weakness in SOD1G93A is primarily attributed to neuromuscular degeneration and not intrinsic muscle fibre defects. In fact, surviving muscle fibres displayed maintained adaptive capacity with an exercise training-like phenotype, which suggests that compensatory mechanisms are activated that can function to delay disease progression.
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
- Fahlstedt, M., et al.
(författare)
-
How Efficient are the Rotational Impact Tests in ECE R22.06 Motorcycle Helmet Test Standard to Decrease the Rotational-Induced Brain Injuries?
- 2022
-
Ingår i: Conference proceedings International Research Council on the Biomechanics of Injury, IRCOBI. - : International Research Council on the Biomechanics of Injury. ; , s. 912-923
-
Konferensbidrag (refereegranskat)abstract
- Head injuries are among the most common injuries in motorcycle accidents, where the helmet is the main protection. Until recently, the test standards have only evaluated protection against linear impacts. Evaluating protection against rotational impacts has been recently introduced. The objective of this study was to evaluate how current motorcycle helmets perform in ECE R22.06 rotational impact tests. The rotational impact tests were performed on three helmet models and the linear impact tests were performed on one helmet model. All the helmets passed the rotational impact tests. The maximum value for the experimental tests was 4.5 krad/s2 for PRA and 0.48 for BrIC compared to the threshold values of 10.4 krad/s2 and 0.78. In the linear impact tests five out of twenty-two impact tests failed the threshold for peak linear acceleration or head injury criterion. The results from this study suggest that motorcycle helmets will be more optimised towards reducing linear-induced injuries and not rotational-induced injuries in the newly introduced test standard ECE R22.06. This is not responding to the protection requirements when evaluating the accident statistics, which shows that rotational-induced injuries are as common or even more common than linear-induced injuries in helmeted motorcycle accidents.
|
|
| 37. |
- Faiss, R, et al.
(författare)
-
Elevated Temperature Accelerates Recovery of Mouse and Human Skeletal Muscle Following Fatigue
- 2015
-
Ingår i: Abstract Book for the 20th Annual <em>ECSS</em> Congress.
-
Konferensbidrag (refereegranskat)abstract
- IntroductionThis study was designed to determine whether elevated muscle temperature allows muscles to recover their force or power more rapidly following fatigueMethodsIntact single fibers from mouse flexor digitorum brevis muscle were fatigued at 31˚C (70-Hz 350-ms tetani once every 10s until initial force decreased to 30%). During a subsequent 2-hr recovery period, the fibers were perfused in Tyrode solution at either 31°C (physiological temperature) or 36°C and isometric force and cytoplasmic free [Ca2+] ([Ca2+]i) were measured during 30-Hz tetani evoked periodically. In addition, seven human subjects performed fatiguing arm exercise consisting of 3 x 5min maximal effort arm cycling at 100 rpm followed by 4 x 15 min at an intensity of 50% of VO2peak. Then followed 2hr of recovery during which both arms were either heated or not heated at 5˚C above physiological temperatures using arm cuffs continuously perfused with temperature-regulated water; the order of heating vs. not heating was randomized between two visits. Intramuscular temperature was recorded with probes inserted 1.5 cm into the lateral head of the triceps brachii muscle. During the recovery period, subjects consumed 1.0 g/hr/kg body weight carbohydrates to support glycogen repletion. After recovery, the subjects repeated the 3 x 5 min time trials to evaluate the effect of the recovery intervention.ResultsRecovery from fatigue in mouse single fibers was dependent on muscle glycogen restoration since fibers perfused with glucose-free Tyrode did not recover contractile force (P<0.05). After 30 min of recovery, the tetanic [Ca2+]i was 107±10% and 92 ± 8% and the corresponding forces were 69±15% vs.49±14% of the initial values for the heated and non-heated muscles, respectively. In seven human subjects, 2h of muscle heating also appeared to improve muscle recovery, leading to higher mean power output in the post-recovery arm cycling time trial than without muscle heating.DiscussionElevating muscle temperature by 5°C above physiological temperature accelerates recovery in mouse muscle in-vitro and in human skeletal muscle in-vivo and this appears to depend on faster muscle glycogen resynthesis following fatigue.
|
|
| 38. |
- Fauconnier, J, et al.
(författare)
-
Effects of palmitate on Ca(2+) handling in adult control and ob/ob cardiomyocytes: impact of mitochondrial reactive oxygen species
- 2007
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 56:4, s. 1136-1142
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity and insulin resistance are associated with enhanced fatty acid utilization, which may play a central role in diabetic cardiomyopathy. We now assess the effect of the saturated fatty acid palmitate (1.2 mmol/l) on Ca2+ handling, cell shortening, and mitochondrial production of reactive oxygen species (ROS) in freshly isolated ventricular cardiomyocytes from normal (wild-type) and obese, insulin-resistant ob/ob mice. Cardiomyocytes were electrically stimulated at 1 Hz, and the signal of fluorescent indicators was measured with confocal microscopy. Palmitate decreased the amplitude of cytosolic Ca2+ transients (measured with fluo-3), the sarcoplasmic reticulum Ca2+ load, and cell shortening by ∼20% in wild-type cardiomyocytes; these decreases were prevented by the general antioxidant N-acetylcysteine. In contrast, palmitate accelerated Ca2+ transients and increased cell shortening in ob/ob cardiomyocytes. Application of palmitate rapidly dissipated the mitochondrial membrane potential (measured with tetra-methyl rhodamine-ethyl ester) and increased the mitochondrial ROS production (measured with MitoSOX Red) in wild-type but not in ob/ob cardiomyocytes. In conclusion, increased saturated fatty acid levels impair cellular Ca2+ handling and contraction in a ROS-dependent manner in normal cardiomyocytes. Conversely, high fatty acid levels may be vital to sustain cardiac Ca2+ handling and contraction in obesity and insulin-resistant conditions.
|
|
| 39. |
- Fauconnier, J, et al.
(författare)
-
Insulin and inositol 1,4,5-trisphosphate trigger abnormal cytosolic Ca2+ transients and reveal mitochondrial Ca2+ handling defects in cardiomyocytes of ob/ob mice
- 2005
-
Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 54:8, s. 2375-2381
-
Tidskriftsartikel (refereegranskat)abstract
- Obesity, insulin resistance, and type 2 diabetes are leading causes of heart failure, and defective cellular Ca2+ handling seems to be a fundamental problem in diabetes. Therefore, we studied the effect of insulin on Ca2+ homeostasis in normal, freshly isolated mouse ventricular cardiomyocytes and whether Ca2+ handling was changed in an animal model of obesity and type 2 diabetes, ob/ob mice. Electrically evoked Ca2+ transients were smaller and slower in ob/ob compared with wild-type cardiomyocytes. Application of insulin (6 or 60 nmol/l) increased the amplitude of Ca2+ transients in wild-type cells by ∼30%, whereas it broadened the transients and triggered extra Ca2+ transients in ob/ob cells. The effects of insulin in ob/ob cells could be reproduced by application of a membrane-permeant inositol trisphosphate (IP3) analog and blocked by a frequently used IP3 receptor inhibitor, 2-aminoethoxydiphenyl borate. In ob/ob cardiomyocytes, insulin increased the IP3 concentration and mitochondrial Ca2+ handling was impaired. In conclusion, we propose a model where insulin increases IP3 in ob/ob cardiomyocytes, which prolongs the electrically evoked Ca2+ release. This, together with an impaired mitochondrial Ca2+ handling, results in insulin-mediated extra Ca2+ transients in ob/ob cardiomyocytes that may predispose for arrhythmias in vivo.
|
|
| 40. |
|
|
| 41. |
|
|
| 42. |
- Fernandez-Alonso, R, et al.
(författare)
-
Phosphoproteomics identifies a bimodal EPHA2 receptor switch that promotes embryonic stem cell differentiation
- 2020
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1, s. 1357-
-
Tidskriftsartikel (refereegranskat)abstract
- Embryonic Stem Cell (ESC) differentiation requires complex cell signalling network dynamics, although the key molecular events remain poorly understood. Here, we use phosphoproteomics to identify an FGF4-mediated phosphorylation switch centred upon the key Ephrin receptor EPHA2 in differentiating ESCs. We show that EPHA2 maintains pluripotency and restrains commitment by antagonising ERK1/2 signalling. Upon ESC differentiation, FGF4 utilises a bimodal strategy to disable EPHA2, which is accompanied by transcriptional induction of EFN ligands. Mechanistically, FGF4-ERK1/2-RSK signalling inhibits EPHA2 via Ser/Thr phosphorylation, whilst FGF4-ERK1/2 disrupts a core pluripotency transcriptional circuit required for Epha2 gene expression. This system also operates in mouse and human embryos, where EPHA receptors are enriched in pluripotent cells whilst surrounding lineage-specified trophectoderm expresses EFNA ligands. Our data provide insight into function and regulation of EPH-EFN signalling in ESCs, and suggest that segregated EPH-EFN expression coordinates cell fate with compartmentalisation during early embryonic development.
|
|
| 43. |
- Ferreira, Duarte M. S., et al.
(författare)
-
LIM and cysteine-rich domains 1 (LMCD1) regulates skeletal muscle hypertrophy, calcium handling, and force
- 2019
-
Ingår i: Skeletal Muscle. - : BioMed Central. - 2044-5040. ; 9:1
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Skeletal muscle mass and strength are crucial determinants of health. Muscle mass loss is associated with weakness, fatigue, and insulin resistance. In fact, it is predicted that controlling muscle atrophy can reduce morbidity and mortality associated with diseases such as cancer cachexia and sarcopenia.Methods: We analyzed gene expression data from muscle of mice or human patients with diverse muscle pathologies and identified LMCD1 as a gene strongly associated with skeletal muscle function. We transiently expressed or silenced LMCD1 in mouse gastrocnemius muscle or in mouse primary muscle cells and determined muscle/cell size, targeted gene expression, kinase activity with kinase arrays, protein immunoblotting, and protein synthesis levels. To evaluate force, calcium handling, and fatigue, we transduced the flexor digitorum brevis muscle with a LMCD1-expressing adenovirus and measured specific force and sarcoplasmic reticulum Ca2+ release in individual fibers. Finally, to explore the relationship between LMCD1 and calcineurin, we ectopically expressed Lmcd1 in the gastrocnemius muscle and treated those mice with cyclosporine A (calcineurin inhibitor). In addition, we used a luciferase reporter construct containing the myoregulin gene promoter to confirm the role of a LMCD1-calcineurin-myoregulin axis in skeletal muscle mass control and calcium handling.Results: Here, we identify LIM and cysteine-rich domains 1 (LMCD1) as a positive regulator of muscle mass, that increases muscle protein synthesis and fiber size. LMCD1 expression in vivo was sufficient to increase specific force with lower requirement for calcium handling and to reduce muscle fatigue. Conversely, silencing LMCD1 expression impairs calcium handling and force, and induces muscle fatigue without overt atrophy. The actions of LMCD1 were dependent on calcineurin, as its inhibition using cyclosporine A reverted the observed hypertrophic phenotype. Finally, we determined that LMCD1 represses the expression of myoregulin, a known negative regulator of muscle performance. Interestingly, we observed that skeletal muscle LMCD1 expression is reduced in patients with skeletal muscle disease.Conclusions: Our gain- and loss-of-function studies show that LMCD1 controls protein synthesis, muscle fiber size, specific force, Ca2+ handling, and fatigue resistance. This work uncovers a novel role for LMCD1 in the regulation of skeletal muscle mass and function with potential therapeutic implications.
|
|
| 44. |
- Gaba, F, et al.
(författare)
-
Impact of SARS-CoV-2 on training and mental well-being of surgical gynecological oncology trainees
- 2021
-
Ingår i: International journal of gynecological cancer : official journal of the International Gynecological Cancer Society. - : BMJ. - 1525-1438. ; 31:9, s. 1268-1277
-
Tidskriftsartikel (refereegranskat)abstract
- The SARS-CoV-2 global pandemic has caused a crisis disrupting health systems worldwide. While efforts are being made to determine the extent of the disruption, the impact on gynecological oncology trainees/training has not been explored. We conducted an international survey of the impact of SARS-CoV-2 on clinical practice, medical education, and mental well-being of surgical gynecological oncology trainees.MethodsIn our cross-sectional study, a customized web-based survey was circulated to surgical gynecological oncology trainees from national/international organizations from May to November 2020. Validated questionnaires assessed mental well-being. The Wilcoxon rank-sum test and Fisher’s exact test were used to analyse differences in means and proportions. Multiple linear regression was used to evaluate the effect of variables on psychological/mental well-being outcomes. Outcomes included clinical practice, medical education, anxiety and depression, distress, and mental well-being.ResultsA total of 127 trainees from 34 countries responded. Of these, 52% (66/127) were from countries with national training programs (UK/USA/Netherlands/Canada/Australia) and 48% (61/127) from countries with no national training programs. Altogether, 28% (35/125) had suspected/confirmed COVID-19, 28% (35/125) experienced a fall in household income, 20% (18/90) were self-isolated from households, 45% (57/126) had to re-use personal protective equipment, and 22% (28/126) purchased their own. In total, 32.3% (41/127) of trainees (16.6% (11/66) from countries with a national training program vs 49.1% (30/61) from countries with no national training program, p=0.02) perceived they would require additional time to complete their training fellowship. The additional training time anticipated did not differ between trainees from countries with or without national training programs (p=0.11) or trainees at the beginning or end of their fellowship (p=0.12). Surgical exposure was reduced for 50% of trainees. Departmental teaching continued throughout the pandemic for 69% (87/126) of trainees, although at reduced frequency for 16.1% (14/87), and virtually for 88.5% (77/87). Trainees reporting adequate pastoral support (defined as allocation of a dedicated mentor/access to occupational health support services) had better mental well-being with lower levels of anxiety/depression (p=0.02) and distress (p<0.001). Trainees from countries with a national training program experienced higher levels of distress (p=0.01). Mean (SD) pre-pandemic mental well-being scores were significantly higher than post-pandemic scores (8.3 (1.6) vs 7 (1.8); p<0.01).ConclusionSARS-CoV-2 has negatively impacted the surgical training, household income, and psychological/mental well-being of surgical gynecological oncology trainees. The overall clinical impact was worse for trainees in countries with no national training program than for those in countries with a national training program, although national training program trainees reported greater distress. COVID-19 sickness increased anxiety/depression. The recovery phase must focus on improving mental well-being and addressing lost training opportunities.
|
|
| 45. |
|
|
| 46. |
- Gelali, E, et al.
(författare)
-
iFISH is a publically available resource enabling versatile DNA FISH to study genome architecture
- 2019
-
Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 10:1, s. 1636-
-
Tidskriftsartikel (refereegranskat)abstract
- DNA fluorescence in situ hybridization (DNA FISH) is a powerful method to study chromosomal organization in single cells. At present, there is a lack of free resources of DNA FISH probes and probe design tools which can be readily applied. Here, we describe iFISH, an open-source repository currently comprising 380 DNA FISH probes targeting multiple loci on the human autosomes and chromosome X, as well as a genome-wide database of optimally designed oligonucleotides and a freely accessible web interface (http://ifish4u.org) that can be used to design DNA FISH probes. We individually validate 153 probes and take advantage of our probe repository to quantify the extent of intermingling between multiple heterologous chromosome pairs, showing a much higher extent of intermingling in human embryonic stem cells compared to fibroblasts. In conclusion, iFISH is a versatile and expandable resource, which can greatly facilitate the use of DNA FISH in research and diagnostics.
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
|
|
