THE ROLE OF ACYL-COA SYNTHETASE-MEDIATED FATTY ACID METABOLISM IN METABOLIC MYOPATHY AND ATHEROSCLEROSIS

Long chain acyl-CoA synthetases (ACSLs), and very long chain acyl-CoA synthetases (ACSVLs) which are also known as fatty acid transporters (FATPs), initiate long chain fatty acid (LCFA) oxidation through activation of LCFA by thiol-esterification. Impaired fatty acid oxidation (FAO) can cause metabolic myopathy; however, the underlying mechanisms by which FAO impairment contributes to the pathogenesis of myopathy remain obscure. Compared to control mice (Acsl1flox/flox), Acsl1M-/- mice had 3.4- and 1.5-fold higher plasma creatine kinase (CK) and aspartate aminotransferase (AST) activities, suggesting muscle damage. Gastrocnemius from Acsl1M-/- mice showed central nuclei, a marker of muscle regeneration. The expression of caspase-3 protein exclusively in Acsl1M-/- muscle suggested muscle regeneration. After endurance exercise, compared to control mice, the rate of new protein synthesis was 2.1-fold higher, and the phosphorylation of pS6K was 2.5-fold higher in glycolytic muscle from Acsl1M-/- mice. These results suggested an increased need to resynthesize protein that had been degraded to supply amino acids for fuel. Additionally, loss of ACSL1 promoted an increase in mitochondrial biogenesis while impairing mitochondrial structure in gastrocnemius. FATP1 is necessary to maintain the oxidative and anti-inflammatory phenotype in macrophages. Macrophages play multifaceted roles in atherogenesis, but the effect of macrophage substrate metabolism in atherogenesis is unclear. To test the hypothesis that FATP1 limits macrophage-mediated inflammation during atherogenesis, bone marrow collected from Fatp1+/+ or Fatp1-/- mice was transplanted into Ldlr-/- mice, and chimeric mice were fed a Western-Diet for 12 weeks. Compared to Fatp1+/+Ldlr-/- mice, Fatp1-/-Ldlr-/- mice exhibit larger lesions and evidence of elevated oxidative stress and inflammation in the atherosclerotic plaque without systemic alterations in plasma cholesterols, suggesting that the effect is localized to the cells of the vessel microenvironment. This dissertation shows that two of the acyl-CoA synthetases are essential for maintaining normal skeletal muscle and macrophage fatty acid (FA) metabolism. Lack of ACSL1 led to an enhanced drain on amino acids by enhancing protein synthesis after exercise and increased mitochondrial biogenesis with disordered mitochondrial structure, which was partially responsible for the myopathy in Acsl1M-/- mice. FATP1-directed FA metabolism in macrophages limits atherogenesis; hence FATP1 may be a viable target to reprogram macrophages metabolically.Doctor of Philosoph

The Role of Macrophage GLUT1-Mediated Glucose Metabolism in Atherosclerosis

Macrophages play a key role in the pathogenesis of atherosclerosis. We recently created a novel murine model with GLUT1 specifically deleted from monocyte/macrophages. Preliminary results from our lab suggest that macrophages lacking GLUT1 reduce the pro-inflammatory response. We therefore hypothesized that macrophages with GLUT1 deletion will have reduced pro-inflammatory activation during atherogenesis, which will reduce formation of atherosclerosis in a mouse model lacking the LDL receptor (Ldlr-/-). We transplanted bone marrow from Glut1fl/fl or Glut1MΦ-/- mice into Ldlr-/- mice and fed mice a Western Diet (WD) for 12 weeks. Glut1MΦ-/- Ldlr-/- mice exhibited significantly less plasma total cholesterol and LDL cholesterol compared to Glut1fl/fl Ldlr-/- mice. Additionally, our results demonstrated that mice with macrophages lacking GLUT1 displayed more and larger necrotic cores in atherosclerotic lesions compared to floxed transplanted controls. These results suggest that macrophage glucose metabolism mediates systemic cholesterol metabolism, and atherogenesis. Importantly, the maintenance of atherosclerotic lesion stability may be regulated by macrophage glucose metabolism-dependent mechanisms.Master of Scienc

Poly[[chloridodimethanol(μ3-pyridine-2,3-dicarboxyl­ato)europium(III)] methanol monosolvate]

The asymmetric unit of the title compound, {[Eu(C7H3NO4)Cl(CH3OH)2]·CH3OH}n, contains one EuIII ion, one pyridine 2,3-dicarboxylate dianion (PDC), two CH3OH mol­ecules coordinating to the metal atom, one coordinating chloride and one lattice occluded CH3OH mol­ecule. In the crystal, each PDC anion coordinates to three adjacent EuIII ions by the pyridine N and O atoms of the carboxyl­ate groups. The EuIII cation is eightfold coordinated by four carboxyl­ate O atoms, one pyridine N atom, two MeOH and one chloride anion in the form of a distorted polyhedron. Extended coordination of the PDC ligand lead to the formation of a two-dimensional coordination polymer parallel to (10-1)

Spin Seebeck effect at low temperatures in the nominally paramagnetic insulating state of vanadium dioxide

The low temperature monoclinic, insulating phase of vanadium dioxide is ordinarily considered nonmagnetic, with dimerized vanadium atoms forming spin singlets, though paramagnetic response is seen at low temperatures. We find a nonlocal spin Seebeck signal in VO2 films that appears below 30 K and which increases with decreasing temperature. The spin Seebeck response has a non-hysteretic dependence on in-plane external magnetic field. This paramagnetic spin Seebeck response is discussed in terms of prior findings on paramagnetic spin Seebeck effects and expected magnetic excitations of the monoclinic ground state.Comment: 11 pages, 3 figures, + 11 pages and 10 figures of supplemental materia

The challenges of measuring spin Seebeck noise

Just as electronic shot noise results from the granularity of charge and the statistical variation in the arrival times of carriers in driven conductors, there are predictions for fundamental noise in magnon currents due to angular momentum being carried by discrete excitations. The advent of the inverse spin Hall effect as a transduction mechanism to convert spin current into charge current raises the prospect of experimental investigations of such magnon shot noise. Spin Seebeck effect measurements have demonstrated the electrical detection of thermally driven magnon currents and have been suggested as an avenue for accessing spin current fluctuations. We report measurements of spin Seebeck structures made from yttrium iron garnet on gadolinium gallium garnet. While these measurements do show an increase in measured noise in the presence of a magnetic field at low temperatures, the dependence on field orientation suggests an alternative origin for this signal. We describe theoretical predictions for the expected magnitude of magnon shot noise, highlighting ambiguities that exist. Analysis in terms of the sample geometry dependence of the known inverse spin Hall transduction of spin currents into charge currents implies that magnon shot noise detection through this approach is strongly suppressed. Implications for future attempts to measure magnon shot noise are discussed.Comment: 20 pages, 3 figures, + 7 pages/6 figures of supplementary materia

Maternal ambient air pollution exposure with spatial-temporal variations and preterm birth risk assessment during 2013-2017 in Zhejiang Province, China.

Preterm birth (PTB) can give rise to significant neonatal morbidity and mortality, as well as children's long-term health defects. Many studies have illustrated the associations between ambient air pollution exposure during gestational periods and PTB risks, but most of them only focused on one single air pollutant, such as PM2.5. In this population-based environmental-epidemiology study, we recruited 6275 pregnant mothers in Zhejiang Province, China, and evaluated their gestational exposures to various air pollutants during 2013-2017. Time-to-event logistic regressions were performed to estimate risk associations after adjusting all confounders, and Quasi-AQI model and PCA-GLM analysis were applied to resolve the collinearity issues in multi-pollutant regression models. It was found that gestational exposure to ambient air pollutants was significantly associated with the occurrence of PTB, and SO2 was the largest contributor with a proportion of 29.4%. Three new variables, prime factor (a combination of PM2.5, PM10, SO2, and NO2), carbon factor (CO), and ozone factor (O3), were generated by PCA integration, contributing 63.4%, 17.1%, and 19.5% to PTB risks, respectively. The first and third trimester was the most crucial exposure window, suggesting the pregnant mothers better to avoid severe air pollution exposures during these sensitive periods

Emulsion Electrospinning of Polytetrafluoroethylene (PTFE) Nanofibrous Membranes for High-Performance Triboelectric Nanogenerators

Electrospinning is a simple, versatile technique for fabricating fibrous nanomaterials with the desirable features of extremely high porosities and large surface areas. Using emulsion electrospinning, polytetrafluoro­ethylene/polyethene oxide (PTFE/PEO) membranes were fabricated, followed by a sintering process to obtain pure PTFE fibrous membranes, which were further utilized against a polyamide 6 (PA6) membrane for vertical contact-mode triboelectric nanogenerators (TENGs). Electrostatic force microscopy (EFM) measurements of the sintered electrospun PTFE membranes revealed the presence of both positive and negative surface charges owing to the transfer of positive charge from PEO which was further corroborated by FTIR measurements. To enhance the ensuing triboelectric surface charge, a facile negative charge-injection process was carried out onto the electrospun (ES) PTFE subsequently. The fabricated TENG gave a stabilized peak-to-peak open-circuit voltage (<i>V</i>_oc) of up to ∼900 V, a short-circuit current density (<i>J</i>_sc) of ∼20 mA m^–2, and a corresponding charge density of ∼149 μC m^–2, which are ∼12, 14, and 11 times higher than the corresponding values prior to the ion-injection treatment. This increase in the surface charge density is caused by the inversion of positive surface charges with the simultaneous increase in the negative surface charge on the PTFE surface, which was confirmed by using EFM measurements. The negative charge injection led to an enhanced power output density of ∼9 W m^–2 with high stability as confirmed from the continuous operation of the ion-injected PTFE/PA6 TENG for 30 000 operation cycles, without any significant reduction in the output. The work thus introduces a relatively simple, cost-effective, and environmentally friendly technique for fabricating fibrous fluoropolymer polymer membranes with high thermal/chemical resistance in TENG field and a direct ion-injection method which is able to dramatically improve the surface negative charge density of the PTFE fibrous membranes