Nutrient excess and altered mitochondrial proteome and function contribute to neurodegeneration in diabetes

Diabetic neuropathy is a major complication of diabetes that results in the progressive deterioration of the sensory nervous system. Mitochondrial dysfunction has been proposed to play an important role in the pathogenesis of the neurodegeneration observed in diabetic neuropathy. Our recent work has shown that mitochondrial dysfunction occurs in dorsal root ganglia (DRG) sensory neurons in streptozotocin (STZ) induced diabetic rodents. In neurons, the nutrient excess associated with prolonged diabetes may trigger a switching off of AMP kinase (AMPK) and/or silent information regulator T1 (SIRT1) signaling leading to impaired peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α expression/activity and diminished mitochondrial activity. This review briefly summarizes the alterations of mitochondrial function and proteome in sensory neurons of STZ-diabetic rodents. We also discuss the possible involvement of AMPK/SIRT/PGC-1α pathway in other diabetic models and different tissues affected by diabetes

Genomic Characterisation of a Multiple Drug Resistant IncHI2 ST4 Plasmid in Escherichia coli ST744 in Australia.

Antibiotic resistance genes (ARGs) including those from the blaCTX-M family and mcr-1 that encode resistance to extended spectrum β-lactams and colistin, respectively, have been linked with IncHI2 plasmids isolated from swine production facilities globally but not in IncHI2 plasmids from Australia. Here we describe the first complete sequence of a multiple drug resistance Australian IncHI2-ST4 plasmid, pTZ41_1P, from a commensal E. coli from a healthy piglet. pTZ41_1P carries genes conferring resistance to heavy-metals (copper, silver, tellurium and arsenic), β-lactams, aminoglycosides and sulphonamides. The ARGs reside within a complex resistance locus (CRL) that shows considerable sequence identity to a CRL in pSDE_SvHI2, an IncHI2:ST3 plasmid from an enterotoxigenic E. coli with serotype O157:H19 of porcine origin that caused substantial losses to swine production operations in Australia in 2007. pTZ41_1P is closely related to IncHI2 plasmids found in E. coli and Salmonella enterica from porcine, avian and human sources in Europe and China but it does not carry genes encoding resistance to clinically-important antibiotics. We identified regions of IncHI2 plasmids that contribute to the genetic plasticity of this group of plasmids and highlight how they may readily acquire new resistance gene cargo. Genomic surveillance should be improved to monitor IncHI2 plasmids

Long-term reduction of jaundice in gunn rats by nonviral liver-targeted delivery of sleeping beauty transposon

Asialoglycoprotein receptor (ASGPR)-mediated endocytosis has been used to target genes to hepatocytes in vivo. However, the level and duration of transgene expression have been low because of lysosomal translocation and degradation of the DNA and lack of its integration into the host genome. In this study we packaged the DNA of interest in proteoliposomes containing the fusogenic galactose-terminated F-glycoprotein of the Sendai virus (FPL) for targeted delivery to hepatocytes. After the FPL binds to ASGPR on the hepatocyte surface, fusogenic activity of the F-protein delivers the DNA into the cytosol, bypassing the endosomal pathway. For transgene integration we designed plasmids containing one transcription unit expressing the Sleeping Beauty transposase (SB) and another expressing human uridinediphosphoglucuronate glucuronosyltransferase-1A1 (pSB-hUGT1A1). The latter was flanked by inverted/direct repeats that are substrates of SB. In cell culture, FPL-mediated delivery of the E. coli β-galactosidase gene (LacZ) resulted in transduction of ASGPR-positive cells (rat hepatocytes or Hepa1 cell line), but not of ASGPR-negative 293 cells. Intravenous injection of the FPL-entrapped pSB-hUGT1A1 (4-8 μg/day, 1-4 doses) into UGT1A1-deficient hyperbilirubinemic Gunn rats (model of Crigler-Najjar syndrome type 1) resulted in hUGT1A1 expression in 5%-10% of hepatocytes, but not in other cell types. Serum bilirubin levels declined by 30% ± 4% in 2 weeks and remained at that level throughout the 7-month study duration. With histidine containing FPL, serum bilirubin was reduced by 40% ± 5%, and bilirubin glucuronides were excreted into bile. No antibodies were detectable in the recipient rats against the F-protein or human UGT1A1. Conclusion: FPL is an efficient hepatocyte-targeted gene delivery platform in vivo that warrants further exploration toward clinical application

Search for long lived heaviest nuclei beyond the valley of stability

The existence of long lived superheavy nuclei (SHN) is controlled mainly by spontaneous fission and $\alpha$-decay processes. According to microscopic nuclear theory, spherical shell effects at Z=114, 120, 126 and N=184 provide the extra stability to such SHN to have long enough lifetime to be observed. To investigate whether the so-called "stability island" could really exist around the above Z, N values, the $\alpha$-decay half lives along with the spontaneous fission and $\beta$-decay half lives of such nuclei are studied. The $\alpha$-decay half lives of SHN with Z=102-120 are calculated in a quantum tunneling model with DDM3Y effective nuclear interaction using $Q_\alpha$ values from three different mass formulae prescribed by Koura, Uno, Tachibana, Yamada (KUTY), Myers, Swiatecki (MS) and Muntian, Hofmann, Patyk, Sobiczewski (MMM). Calculation of spontaneous fission (SF) half lives for the same SHN are carried out using a phenomenological formula and compared with SF half lives predicted by Smolanczuk {\it et al}. Possible source of discrepancy between the calculated $\alpha$-decay half lives of some nuclei and the experimental data of GSI, JINR-FLNR, RIKEN are discussed. In the region of Z=106-108 with N$\sim$ 160-164, the $\beta$-stable SHN $^{268}_{106}Sg_{162}$ is predicted to have highest $\alpha$-decay half life ($T_\alpha \sim 3.2hrs$) using $Q_\alpha$ value from MMM. Interestingly, it is much greater than the recently measured $T_\alpha$ ($\sim 22s$) of deformed doubly magic $^{270}_{108}Hs_{162}$ nucleus. A few fission-survived long-lived SHN which are either $\beta$-stable or having large $\beta$-decay half lives are predicted to exist near $^{294}110_{184}$, $^{293}110_{183}$, $^{296}112_{184}$ and $^{298}114_{184}$. These nuclei might decay predominantly through $\alpha$-particle emission.Comment: 14 pages, 6 figures, 1 tabl

Origin of Ferroelectricity in Orthorhombic LuFeO3_3

We demonstrate that small but finite ferroelectric polarization ($\sim$0.01 $\mu$C/cm$^2$) emerges in orthorhombic LuFeO$_3$ ($Pnma$) at $T_N$ ($\sim$600 K) because of commensurate (k = 0) and collinear magnetic structure. The synchrotron x-ray and neutron diffraction data suggest that the polarization could originate from enhanced bond covalency together with subtle contribution from lattice. The theoretical calculations indicate enhancement of bond covalency as well as the possibility of structural transition to the polar $Pna2_1$ phase below $T_N$. The $Pna2_1$ phase, in fact, is found to be energetically favorable below $T_N$ in orthorhombic LuFeO$_3$ ($albeit$ with very small energy difference) than in isostructural and nonferroelectric LaFeO$_3$ or NdFeO$_3$. Application of electric field induces finite piezostriction in LuFeO$_3$ via electrostriction resulting in clear domain contrast images in piezoresponse force microscopy.Comment: 12 pages, 8 figure

First and second-order dust-ion-acoustic rogue waves in non-thermal plasma

A nonlinear Schr\"{o}dinger equation (NLSE) has been derived by employing reductive perturbation method for investigating the modulational instability of dust-ion-acoustic waves (DIAWs) in a four-component plasma having stationary negatively charged dust grains, inertial warm ions, and inertialess non-thermal electrons and positrons. It is observed that under consideration, the plasma system supports both modulationally stable and unstable domains, which are determined by the sign of the dispersive and nonlinear coefficients of NLSE, of the DIAWs. It is also found that the nonlinearity as well as the height and width of the first and second-order rogue waves increases with the non-thermality of electron and positron. The relevancy of our present investigation to the observations in space plasmas is pinpointed.Comment: 5 pages, 5 figure

Diminished Superoxide Generation Is Associated With Respiratory Chain Dysfunction and Changes in the Mitochondrial Proteome of Sensory Neurons From Diabetic Rats

Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.OBJECTIVE Impairments in mitochondrial function have been proposed to play a role in the etiology of diabetic sensory neuropathy. We tested the hypothesis that mitochondrial dysfunction in axons of sensory neurons in type 1 diabetes is due to abnormal activity of the respiratory chain and an altered mitochondrial proteome. RESEARCH DESIGN AND METHODS Proteomic analysis using stable isotope labeling with amino acids in cell culture (SILAC) determined expression of proteins in mitochondria from dorsal root ganglia (DRG) of control, 22-week-old streptozotocin (STZ)-diabetic rats, and diabetic rats treated with insulin. Rates of oxygen consumption and complex activities in mitochondria from DRG were measured. Fluorescence imaging of axons of cultured sensory neurons determined the effect of diabetes on mitochondrial polarization status, oxidative stress, and mitochondrial matrix-specific reactive oxygen species (ROS). RESULTS Proteins associated with mitochondrial dysfunction, oxidative phosphorylation, ubiquinone biosynthesis, and the citric acid cycle were downregulated in diabetic samples. For example, cytochrome c oxidase subunit IV (COX IV; a complex IV protein) and NADH dehydrogenase Fe-S protein 3 (NDUFS3; a complex I protein) were reduced by 29 and 36% (P < 0.05), respectively, in diabetes and confirmed previous Western blot studies. Respiration and mitochondrial complex activity was significantly decreased by 15 to 32% compared with control. The axons of diabetic neurons exhibited oxidative stress and depolarized mitochondria, an aberrant adaption to oligomycin-induced mitochondrial membrane hyperpolarization, but reduced levels of intramitochondrial superoxide compared with control. CONCLUSIONS Abnormal mitochondrial function correlated with a downregulation of mitochondrial proteins, with components of the respiratory chain targeted in lumbar DRG in diabetes. The reduced activity of the respiratory chain was associated with diminished superoxide generation within the mitochondrial matrix and did not contribute to oxidative stress in axons of diabetic neurons. Alternative pathways involving polyol pathway activity appear to contribute to raised ROS in axons of diabetic neurons under high glucose concentration.This work was supported by grants from the Juvenile Diabetes Research Foundation (#1-2008-280) and the National Institutes of Health to R.T.D. (grants NS-054847 and DK-073594). E.A. was supported by a grant from the National Science and Engineering Research Council (#3311686-06) to P.F. and subsequently by a postgraduate scholarship from the Manitoba Health Research Council. S.K.R.C. and E.Z. were supported by grants to P.F. from the Canadian Institutes for Health Research (#MOP-84214) and the Juvenile Diabetes Research Foundation (#1-2008-193). D.R.S. was supported by a grant to P.F. from the Manitoba Health Research Council. This work was also funded by the St. Boniface General Hospital and Research Foundation

Self-organising comprehensive handover strategy for multi-tier LTE-advanced heterogeneous networks

Long term evolution (LTE)-advanced was introduced as real fourth generation (4G) with its new features and additional functions, satisfying the growing demands of quality and network coverage for the network operators' subscribers. The term muti-tier has also been recently used with respect to the heterogeneity of the network by applying the various subnetwork cooperative systems and functionalities with self-organising capabilities. Using indoor short-range low-power cellular base stations, for example, femtocells, in cooperation with existing long-range macrocells are considered as the key technical challenge of this multi-tier configuration. Furthermore, shortage of network spectrum is a major concern for network operators which forces them to spend additional attentions to overcome the degradation in performance and quality of services in 4G HetNets. This study investigates handover between the different layers of a heterogeneous LTE-advanced system, as a critical attribute to plan the best way of interactive coordination within the network for the proposed HetNet. The proposed comprehensive handover algorithm takes multiple factors in both handover sensing and decision stages, based on signal power reception, resource availability and handover optimisation, as well as prioritisation among macro and femto stations, to obtain maximum signal quality while avoiding unnecessary handovers