The Projectile Spectator Detector (PSD) of the CBM experiment at the future FAIR facility is a compensating lead-scintillator calorimeter designed to measure the energy distribution of the forward ...going projectile nucleons and nuclei fragments (reaction spectators) produced close to the beam rapidity. The detector performance for the centrality and reaction plane determination is reviewed based on Monte-Carlo simulations of gold-gold collisions by means of four different heavy-ion event generators. The PSD energy resolution and the linearity of the response measured at CERN PS for the PSD supermodule consisting of 9 modules are presented. Predictions of the calorimeter radiation conditions at CBM and response measurement of one PSD module equipped with neutron irradiated MPPCs used for the light read out are discussed.
Cardiac tamponade is a rare but serious emergency condition in the pediatric population. As treatment, a pericardial drain is often placed to evacuate the fluid. We present a case of a 4-year-old ...girl with cardiac tamponade secondary to renal failure. After the tamponade resolved, she suffered cardiovascular collapse upon attempted drain withdrawal. This case highlights an unusual cause for cardiovascular collapse, which occurred on blind removal of a pericardial drain.
The Projectile Spectator Detector (PSD) is a subsystem of the CBM experiment at the future FAIR facility designed to determine centrality and reaction plane orientation in the heavy-ion collisions. ...It will be done by measurement of the energy distribution of the heavy nucleons and nuclei fragments emitted close to the beam rapidity in forward direction. For the anticipated beam energies of FAIR SIS100 and SIS300 accelerators, different event generators (iQMD, UrQMD, DCM-QGSM, LA-QGSM and HSD) were used for the study of directed and elliptic proton flow in Au+Au collisions. Produced particles were transported with the GEANT4 Monte-Carlo using the CBM detector geometry. Performance of the reaction plane determination is shown for different PSD setups to demonstrate effects of the detector granularity and magnetic field. Simulation results are compared with the FOPI, AGS E877, E895 and STAR experimental data.
Dynamin-related protein 1 (Drp1) is the key regulator of mitochondrial fission. We and others have reported excessive Drp1 activity in skeletal muscle from both animals and humans with insulin ...resistance, which is strongly correlated to impaired skeletal muscle insulin sensitivity. To examine whether Drp1 directly regulates skeletal muscle insulin sensitivity and whole-body glucose homeostasis, we generated tamoxifen-inducible skeletal muscle-specific heterozygous Drp1 partial knockout mice (mDrp1+/-) . Male mDrp1+/- and wildtype (WT) mice were fed with either a high-fat diet (HFD) or low-fat diet (LFD) for four weeks, received tamoxifen injections for five consecutive days, and remained on their respective diet for another four weeks. Improvements in whole-body glucose tolerance and insulin sensitivity were observed in HFD-fed mDrp1+/- mice (P<0.05) , but not in LFD-fed mDrp1+/- mice, when compared to their respective WT controls. Further, HFD-induced impairment in skeletal muscle insulin-stimulated Akt Ser473 phosphorylation (P<0.05) was mitigated in HFD-fed mDrp1+/- mice. In contrast, insulin-stimulated Akt Ser473 phosphorylation was reduced in LFD-fed mDrp1+/- mice compared to LFD-fed WT mice (P<0.05) . mDrp1+/- mice exhibited more fused and interconnected mitochondrial networks in skeletal muscle than WT mice. The examination of mitochondrial function revealed no change in mitochondrial respiration but reductions in mitochondrial Complex I and II and pyruvate dehydrogenase derived H2O2 production in HFD-fed mDrp1+/- mice compared to HFD-fed WT mice (P<0.05) .
In conclusion, our data suggest that partial knockout of skeletal muscle Drp1 improves skeletal muscle insulin sensitivity and whole-body glucose homeostasis in diet-induced insulin-resistant mice but not in normal control mice. These improvements are, at least in part, due to reduced mitochondrial-derived H2O2 production.
Disclosure
B.A.Kugler: None. N.Lin: None. P.D.Nguyen: None. A.Ali: None. A.Sesay: None. B.Kalemba: None. H.Sesaki: None. K.Zou: None.
Funding
National Institutes of Health (R15DK131512) Diabetes Action Research and Education Foundation Grant (#505)
Dynamin‐related protein 1 (Drp1) is a key regulator of mitochondrial fission. Excessive Drp1‐mediated mitochondrial fission in skeletal muscle from humans with severe obesity is associated with ...impaired insulin action. However, it remains unclear whether specific inhibition of Drp1 in skeletal muscle cells alleviates insulin resistance in obesity. Therefore, this study aims to determine the direct role of Drp1 on regulating insulin action in human skeletal muscle cells derived from humans with severe obesity. Human skeletal muscle cells from six lean, insulin‐sensitive (LN, BMI = 22.7 ± 1.2 kg/m2,HOMA‐IR = 1.9 ± 0.4) and six severely obese, insulin‐resistant (OB, BMI = 47.3 ± 2.8 kg/m2, HOMA‐IR = 3.4 ± 0.4) subjects were pooled together, respectively. At 90% confluency, myoblasts were transfected using polyethyleneimine with a Drp1 shRNA (shDrp1) or scramble shRNA constructs (shCtrl). After 48 h, the medium was replaced with differentiation media with puromycin. On day 7 of differentiation, the mitochondrial network, reactive oxygen species (ROS), insulin signaling, glucose uptake, and protein markers of mitochondrial dynamics and mitochondrial content were assessed. RNA sequencing was also performed on OB‐shCtrl and OB‐shDrp1 myotubes. Differentially regulated genes were identified, and a gene set enrichment was used to determine pathway modulations. Drp1 protein expression was reduced in OB‐shDrp1 myotubes compared to LN‐shCtrl and OB‐shCtrl (72% and 78%, respectively, P<0.05). OB‐shCtrl myotubes exhibited fragmented mitochondrial networks with an increase in the number of non‐networked individual mitochondria compared to the LN‐shCtrl (P<0.05). The loss of Drp1 in OB‐shDrp1 myotubes restored the mitochondrial network structure with the reduced number of non‐networked mitochondria compared to OB‐shCtrl (P<0.05), and is not different from LN‐shCtrl. There were no differences in protein expression of markers of mitochondrial dynamics and content. Regarding insulin action, insulin‐stimulated Akt Ser473 phosphorylation and glucose uptake (over basal condition) were both reduced in OB‐shCtrl myotubes compared to LN‐shCtrl (P<0.05). Importantly, OB‐shDrp1 myotubes significantly increased insulin‐stimulated Akt Ser473 phosphorylation and glucose uptake compared to OB‐shCtrl (P<0.05). In addition, ROS was elevated in OB‐shCtrl myotubes when compared to LN‐shCtrl (P<0.05) but was reduced in OB‐shDrp1 myotubes (P<0.05). Lastly, the loss of Drp1 revealed an upregulation in genes responsible for fatty acid oxidation and downregulation in genes for glycolysis in OB‐shDrp1 myotubes compared to OB‐shCtrl. These results demonstrate that the loss of Drp1 improves mitochondrial morphology and enhances insulin action, which may, at least partially, be due to reduced ROS production and improved fat oxidation in skeletal muscle cells from humans with severe obesity. Our data suggest that Drp1 may serve as an important regulator of skeletal muscle insulin action.
Mitochondrial quality control processes are essential in governing mitochondrial integrity and function. The purpose of the study was to examine the effects of 10 weeks of high-intensity interval ...training (HIIT) on the regulatory protein machinery of skeletal muscle mitochondrial quality control and whole-body glucose homeostasis in diet-induced obese mice. Male C57BL/6 mice were assigned to low-fat diet (LFD) or high-fat diet (HFD) group. After 10 weeks, HFD-fed mice were divided into sedentary and HIIT (HFD + HIIT) groups for another 10 weeks (
= 9/group). Graded exercise test, glucose and insulin tolerance tests, mitochondrial respiration, and protein markers of mitochondrial quality control processes were determined. HFD-fed mice exhibited lower ADP-stimulated mitochondrial respiration (
< 0.05). However, 10 weeks of HIIT prevented this impairment (
< 0.05). Importantly, the ratio of Drp1(Ser
) over Drp1(Ser
) phosphorylation, an indicator of mitochondrial fission, was significantly higher in HFD-fed mice (
< 0.05), but such increase was attenuated in HFD-HIIT compared to HFD (-35.7%,
< 0.05). Regarding autophagy, skeletal muscle p62 content was lower in the HFD group than the LFD group (-35.1%,
< 0.05); however, such reduction was disappeared in the HFD + HIIT group. In addition, LC3B II/I ratio was higher in the HFD group than the LFD group (15.5%,
< 0.05) but was ameliorated in the HFD + HIIT group (-29.9%,
< 0.05). Overall, our study demonstrated that 10 weeks of HIIT was effective in improving skeletal muscle mitochondrial respiration and the regulatory protein machinery of mitochondrial quality control in diet-induced obese mice through the alterations of mitochondrial fission protein Drp1 phosphorylations and p62/LC3B-mediated regulatory machinery of autophagy.
High versus low aerobic capacity significantly impacts the risk for metabolic diseases. Rats selectively bred for high or low intrinsic aerobic capacity differently modify hepatic bile acid ...metabolism in response to high-fat diets (HFDs). Here we tested if a bile acid sequestrant would alter hepatic and whole body metabolism differently in rats with high and low aerobic capacity fed a 1-wk HFD. Male rats (8 mo of age) that were artificially selected to be high (HCR) and low-capacity runners (LCR) with divergent intrinsic aerobic capacities were transitioned from a low-fat diet (LFD, 10% fat) to an HFD (45% fat) with or without a bile acid sequestrant (BA-Seq, 2% cholestyramine resin) for 7 days while maintained in an indirect calorimetry system. HFD + BA-Seq increased fecal excretion of lipids and bile acids and prevented weight and fat mass gain in both strains. Interestingly, HCR rats had increased adaptability to enhance fecal bile acid and lipid loss, resulting in more significant energy loss than their LCR counterpart. In addition, BA-Seq induced a greater expression of hepatic CYP7A1 gene expression, the rate-limiting enzyme of bile acid synthesis in HCR rats both on HFD and HFD + BA-Seq diets. HCR displayed a more significant reduction of RQ in response to HFD than LCR, but HFD + BA-Seq lowered RQ in both groups compared with HFD alone, demonstrating a pronounced impact on metabolic flexibility. In conclusion, BA-Seq provides uniform metabolic benefits for metabolic flexibility and adiposity, but rats with higher aerobic capacity display adaptability for hepatic bile acid metabolism.
The administration of bile acid sequestrant (BA-Seq) has uniform metabolic benefits in terms of metabolic flexibility and adiposity in rats with high and low aerobic capacity. However, rats with higher aerobic capacity demonstrate greater adaptability in hepatic bile acid metabolism, resulting in increased fecal bile acid and lipid loss, as well as enhanced fecal energy loss.
Experiments with
6,8
He,
9
Li +
28
Si,
59
Co, and
181
Ta reactions in the energy range of
6,8
He and
9
Li beams 6–36
A
MeV have been preformed. Prompt neutrons and gamma radiation were registered by ...a 12‑detector gamma spectrometer. The values of the total reaction cross sections and the multiplicity distributions for the emission of γ-quanta and neutrons were calculated taking into account the distributions over the number of triggered detectors.
Healthy mitochondrial networks are maintained via balanced integration of mitochondrial quality control processes (biogenesis, fusion, fission, and mitophagy). The purpose of this study was to ...investigate the effects of severe obesity and type 2 diabetes (T2D) on mitochondrial network morphology and expression of proteins regulating mitochondrial quality control processes in cultured human myotubes. Primary human skeletal muscle cells were isolated from biopsies from lean, severely obese nondiabetic individuals and severely obese type 2 diabetic individuals (n = 8–9/group) and were differentiated to myotubes. Mitochondrial network morphology was determined in live cells via confocal microscopy and protein markers of mitochondrial quality control were measured by immunoblotting. Myotubes from severely obese nondiabetic and type 2 diabetic humans exhibited fragmented mitochondrial networks (P < 0.05). Mitochondrial fission protein Drp1 (Ser
616
) phosphorylation was higher in myotubes from severely obese nondiabetic humans when compared with the lean controls (P < 0.05), while mitophagy protein Parkin expression was lower in myotubes from severely obese individuals with T2D in comparison to the other groups (P < 0.05). These data suggest that regulatory proteins in mitochondrial quality control processes, specifically mitochondrial fission protein Drp1 (Ser
616
) phosphorylation and mitophagy protein Parkin, are intrinsically dysregulated at cellular level in skeletal muscle from severely obese nondiabetic and type 2 diabetic humans, respectively. These differentially expressed mitochondrial quality control proteins may play a role in mitochondrial fragmentation evident in skeletal muscle from severely obese and type 2 diabetic humans.
Novelty
Mitochondrial network morphology and mitochondrial quality control proteins are intrinsically dysregulated in skeletal muscle cells from severely obese humans with or without T2D.
The cross-sections of relativistic deuteron reactions on natural copper were studied in detail by means of activation method. The copper foils were irradiated during experiments with the model ...spallation targets in the Joint Institute for Nuclear Research. The irradiation of activation samples was performed by beams in the energy range from 1 to 8GeV. Residual nuclides were measured by the gamma spectrometry. While the EXFOR database contains sets of data for relativistic proton reactions, data for deuteron reactions in this energy range are almost missing. Lack of such experimental cross-section values prevents the use of copper foils from beam integral monitoring. For this reason our experiments focused on their measurement and completely new data were obtained in the energy region where no experimental data have been available so far. The copper monitors with their low sensitivity to fast neutrons will contribute to improvement of the beam integral determination during accelerator-driven system studies.
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