Yeast Model Uncovers Dual Roles of Mitochondria in the Action of Artemisinin

PubMed Central

Li, Wei; Mo, Weike; Shen, Dan; Sun, Libo; Wang, Juan; Lu, Shan; Gitschier, Jane M; Zhou, Bing

2005-01-01

Artemisinins, derived from the wormwood herb Artemisia annua, are the most potent antimalarial drugs currently available. Despite extensive research, the exact mode of action of artemisinins has not been established. Here we use yeast, Saccharamyces cerevisiae, to probe the core working mechanism of this class of antimalarial agents. We demonstrate that artemisinin's inhibitory effect is mediated by disrupting the normal function of mitochondria through depolarizing their membrane potential. Moreover, in a genetic study, we identify the electron transport chain as an important player in artemisinin's action: Deletion of NDE1 or NDI1, which encode mitochondrial NADH dehydrogenases, confers resistance to artemisinin, whereas overexpression of NDE1 or NDI1 dramatically increases sensitivity to artemisinin. Mutations or environmental conditions that affect electron transport also alter host's sensitivity to artemisinin. Sensitivity is partially restored when the Plasmodium falciparum NDI1 ortholog is expressed in yeast ndi1 strain. Finally, we showed that artemisinin's inhibitory effect is mediated by reactive oxygen species. Our results demonstrate that artemisinin's effect is primarily mediated through disruption of membrane potential by its interaction with the electron transport chain, resulting in dysfunctional mitochondria. We propose a dual role of mitochondria played during the action of artemisinin: the electron transport chain stimulates artemisinin's effect, most likely by activating it, and the mitochondria are subsequently damaged by the locally generated free radicals. PMID:16170412

Pharmacological Modulation of the Mitochondrial Electron Transport Chain in Paclitaxel-Induced Painful Peripheral Neuropathy.

PubMed

Griffiths, Lisa A; Flatters, Sarah J L

2015-10-01

Paclitaxel is an effective first-line chemotherapeutic with the major dose-limiting side effect of painful neuropathy. Mitochondrial dysfunction and oxidative stress have been implicated in paclitaxel-induced painful neuropathy. Here we show the effects of pharmacological modulation of mitochondrial sites that produce reactive oxygen species using systemic rotenone (complex I inhibitor) or antimycin A (complex III inhibitor) on the maintenance and development of paclitaxel-induced mechanical hypersensitivity in adult male Sprague Dawley rats. The maximally tolerated dose (5 mg/kg) of rotenone inhibited established paclitaxel-induced mechanical hypersensitivity. However, some of these inhibitory effects coincided with decreased motor coordination; 3 mg/kg rotenone also significantly attenuated established paclitaxel-induced mechanical hypersensitivity without any motor impairment. The maximally tolerated dose (.6 mg/kg) of antimycin A reversed established paclitaxel-induced mechanical hypersensitivity without any motor impairment. Seven daily doses of systemic rotenone or antimycin A were given either after paclitaxel administration or before and during paclitaxel administration. Rotenone had no significant effect on the development of paclitaxel-induced mechanical hypersensitivity. However, antimycin A significantly inhibited the development of paclitaxel-induced mechanical hypersensitivity when given before and during paclitaxel administration but had no effect when given after paclitaxel administration. These studies provide further evidence of paclitaxel-evoked mitochondrial dysfunction in vivo, suggesting that complex III activity is instrumental in paclitaxel-induced pain. This study provides further in vivo evidence that mitochondrial dysfunction is a key contributor to the development and maintenance of chemotherapy-induced painful neuropathy. This work also indicates that selective modulation of the electron transport chain can induce antinociceptive effects in a preclinical model of paclitaxel-induced pain. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

From the Cover: Arsenite Uncouples Mitochondrial Respiration and Induces a Warburg-like Effect in Caenorhabditis elegans

PubMed Central

Godebo, Tewodros R.; Bhatt, Dhaval P.; Ilkayeva, Olga R.; Maurer, Laura L.; Hirschey, Matthew D.; Meyer, Joel N.

2016-01-01

Millions of people worldwide are chronically exposed to arsenic through contaminated drinking water. Despite decades of research studying the carcinogenic potential of arsenic, the mechanisms by which arsenic causes cancer and other diseases remain poorly understood. Mitochondria appear to be an important target of arsenic toxicity. The trivalent arsenical, arsenite, can induce mitochondrial reactive oxygen species production, inhibit enzymes involved in energy metabolism, and induce aerobic glycolysis in vitro, suggesting that metabolic dysfunction may be important in arsenic-induced disease. Here, using the model organism Caenorhabditis elegans and a novel metabolic inhibition assay, we report an in vivo induction of aerobic glycolysis following arsenite exposure. Furthermore, arsenite exposure induced severe mitochondrial dysfunction, including altered pyruvate metabolism; reduced steady-state ATP levels, ATP-linked respiration and spare respiratory capacity; and increased proton leak. We also found evidence that induction of autophagy is an important protective response to arsenite exposure. Because these results demonstrate that mitochondria are an important in vivo target of arsenite toxicity, we hypothesized that deficiencies in mitochondrial electron transport chain genes, which cause mitochondrial disease in humans, would sensitize nematodes to arsenite. In agreement with this, nematodes deficient in electron transport chain complexes I, II, and III, but not ATP synthase, were sensitive to arsenite exposure, thus identifying a novel class of gene-environment interactions that warrant further investigation in the human populace. PMID:27208080

Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications

PubMed Central

Vernochet, Cecile; Damilano, Federico; Mourier, Arnaud; Bezy, Olivier; Mori, Marcelo A.; Smyth, Graham; Rosenzweig, Anthony; Larsson, Nils-Göran; Kahn, C. Ronald

2014-01-01

Mitochondrial dysfunction in adipose tissue occurs in obesity, type 2 diabetes, and some forms of lipodystrophy, but whether this dysfunction contributes to or is the result of these disorders is unknown. To investigate the physiological consequences of severe mitochondrial impairment in adipose tissue, we generated mice deficient in mitochondrial transcription factor A (TFAM) in adipocytes by using mice carrying adiponectin-Cre and TFAM floxed alleles. These adiponectin TFAM-knockout (adipo-TFAM-KO) mice had a 75–81% reduction in TFAM in the subcutaneous and intra-abdominal white adipose tissue (WAT) and interscapular brown adipose tissue (BAT), causing decreased expression and enzymatic activity of proteins in complexes I, III, and IV of the electron transport chain (ETC). This mitochondrial dysfunction led to adipocyte death and inflammation in WAT and a whitening of BAT. As a result, adipo-TFAM-KO mice were resistant to weight gain, but exhibited insulin resistance on both normal chow and high-fat diets. These lipodystrophic mice also developed hypertension, cardiac hypertrophy, and cardiac dysfunction. Thus, isolated mitochondrial dysfunction in adipose tissue can lead a syndrome of lipodystrophy with metabolic syndrome and cardiovascular complications.—Vernochet, C., Damilano, F., Mourier, A., Bezy, O., Mori, M. A., Smyth, G., Rosenzweig, A., Larsson, N.-G., Kahn, C. R. Adipose tissue mitochondrial dysfunction triggers a lipodystrophic syndrome with insulin resistance, hepatosteatosis, and cardiovascular complications. PMID:25005176

Loss of tubular creatinine secretion as the only sign of tubular proximal cell dysfunction in light chain proximal tubulopathy: A case report.

PubMed

Stehlé, Thomas; Vignon, Marguerite; Flamant, Martin; Figueres, Marie-Lucile; Rabant, Marion; Rodenas, Anita; Noël, Laure-Hélène; Arnulf, Bertrand; Vidal-Petiot, Emmanuelle

2016-06-01

Light chain proximal tubulopathy (LCPT) is a rare disease, characterized by cytoplasmic inclusions of light chain (usually kappa) immunoglobulins. Clinical presentation is usually a Fanconi syndrome. The proximal tubular dysfunction can be incomplete, and exceptional cases of LCPT without any tubular dysfunction have even been described. Here, we report a case of LCPT in which the only sign of proximal tubulopathy is the absence of secretion of creatinine, as assessed by the simultaneous measurement of renal clearance of creatinine and CrEDTA. The loss of tubular creatinine secretion as a sign of tubular proximal cell dysfunction ought to be identified in patients with light chain proximal tubulopathy as it leads to a clinically relevant underestimation of GFR by the creatinine-derived equations. The prevalence and prognostic significance of this particular proximal tubular damage in LCPT remain to be determined.

MicroRNA‑29a is involved lipid metabolism dysfunction and insulin resistance in C2C12 myotubes by targeting PPARδ.

PubMed

Wu, Peng; Wang, Qianyi; Jiang, Cuilian; Chen, Chen; Liu, Yun; Chen, Yajun; Zeng, Yu

2018-06-01

MicroRNA‑29a (miR‑29a) expression has been reported to be closely associated with skeletal muscle insulin resistance and type 2 diabetes. The present study investigated the effect of miR‑29a on palmitic acid (PA)‑induced lipid metabolism dysfunction and insulin resistance in C2C12 myotubes via overexpressing or silencing of miR‑29a expression. Mouse C2C12 myoblasts were cultured, differentiated and transfected with miR‑29a or miR‑29a inhibitor lentiviral with or without subsequent palmitic acid (PA) treatment. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) and western blot analysis were performed to assess the mRNA and protein levels of related genes, respectively. PA treatment increased the expression of miR‑29a in a time‑ and dose‑ dependent manner. miR‑29a silencing improved insulin‑induced glucose uptake and increased glucose transporter‑4 (GLUT4) transportation to the plasma membrane by upregulating its target peroxisome proliferator‑activated receptor δ (PPARδ). Furthermore, it was observed that miR‑29a regulated the expression of genes associated with lipid metabolism, including pyruvate dehydrogenase kinase isoform, mitochondrial uncoupling protein (UCP)2, UCP3, long chain specific acyl‑CoA dehydrogenase, mitochondrial and fatty acid transport protein 2. The results confirmed that silencing miR‑29a induced a decrease in glucose transport and affected lipid metabolism in PA‑treated C2C12 cells, and therefore may be involved in insulin resistance by targeting PPARδ in skeletal muscle. Therefore, the inhibition of miR‑29a may be a potential novel strategy for treating insulin resistance and type 2 diabetes.

Mitochondrial function as a therapeutic target in heart failure

PubMed Central

Brown, David A.; Perry, Justin B.; Allen, Mitchell E.; Sabbah, Hani N.; Stauffer, Brian L.; Shaikh, Saame Raza; Cleland, John G. F.; Colucci, Wilson S.; Butler, Javed; Voors, Adriaan A.; Anker, Stefan D.; Pitt, Bertram; Pieske, Burkert; Filippatos, Gerasimos; Greene, Stephen J.; Gheorghiade, Mihai

2017-01-01

Heart failure is a pressing worldwide public-health problem with millions of patients having worsening heart failure. Despite all the available therapies, the condition carries a very poor prognosis. Existing therapies provide symptomatic and clinical benefit, but do not fully address molecular abnormalities that occur in cardiomyocytes. This shortcoming is particularly important given that most patients with heart failure have viable dysfunctional myocardium, in which an improvement or normalization of function might be possible. Although the pathophysiology of heart failure is complex, mitochondrial dysfunction seems to be an important target for therapy to improve cardiac function directly. Mitochondrial abnormalities include impaired mitochondrial electron transport chain activity, increased formation of reactive oxygen species, shifted metabolic substrate utilization, aberrant mitochondrial dynamics, and altered ion homeostasis. In this Consensus Statement, insights into the mechanisms of mitochondrial dysfunction in heart failure are presented, along with an overview of emerging treatments with the potential to improve the function of the failing heart by targeting mitochondria. PMID:28004807

Inactivation of brain mitochondrial Lon protease by peroxynitrite precedes electron transport chain dysfunction.

PubMed

Stanyer, Lee; Jorgensen, Wenche; Hori, Osamu; Clark, John B; Heales, Simon J R

2008-09-01

The accumulation of oxidatively modified proteins has been shown to be a characteristic feature of many neurodegenerative disorders and its regulation requires efficient proteolytic processing. One component of the mitochondrial proteolytic system is Lon, an ATP-dependent protease that has been shown to degrade oxidatively modified aconitase in vitro and may thus play a role in defending against the accumulation of oxidized matrix proteins in mitochondria. Using an assay system that allowed us to distinguish between basal and ATP-stimulated Lon protease activity, we have shown in isolated non-synaptic rat brain mitochondria that Lon protease is highly susceptible to oxidative inactivation by peroxynitrite (ONOO(-)). This susceptibility was more pronounced with regard to ATP-stimulated activity, which was inhibited by 75% in the presence of a bolus addition of 1mM ONOO(-), whereas basal unstimulated activity was inhibited by 45%. Treatment of mitochondria with a range of peroxynitrite concentrations (10-1000 microM) revealed that a decline in Lon protease activity preceded electron transport chain (ETC) dysfunction (complex I, II-III and IV) and that ATP-stimulated activity was approximately fivefold more sensitive than basal Lon protease activity. Furthermore, supplementation of mitochondrial matrix extracts with reduced glutathione, following ONOO(-) exposure, resulted in partial restoration of basal and ATP-stimulated activity, thus suggesting possible redox regulation of this enzyme complex. Taken together these findings suggest that Lon protease may be particularly vulnerable to inactivation in conditions associated with GSH depletion and elevated oxidative stress.

Hyperammonaemia‐induced skeletal muscle mitochondrial dysfunction results in cataplerosis and oxidative stress

PubMed Central

Davuluri, Gangarao; Allawy, Allawy; Thapaliya, Samjhana; Rennison, Julie H.; Singh, Dharmvir; Kumar, Avinash; Sandlers, Yana; Van Wagoner, David R.; Flask, Chris A.; Hoppel, Charles; Kasumov, Takhar

2016-01-01

Key points Hyperammonaemia occurs in hepatic, cardiac and pulmonary diseases with increased muscle concentration of ammonia.We found that ammonia results in reduced skeletal muscle mitochondrial respiration, electron transport chain complex I dysfunction, as well as lower NAD+/NADH ratio and ATP content.During hyperammonaemia, leak of electrons from complex III results in oxidative modification of proteins and lipids.Tricarboxylic acid cycle intermediates are decreased during hyperammonaemia, and providing a cell‐permeable ester of αKG reversed the lower TCA cycle intermediate concentrations and increased ATP content.Our observations have high clinical relevance given the potential for novel approaches to reverse skeletal muscle ammonia toxicity by targeting the TCA cycle intermediates and mitochondrial ROS. Abstract Ammonia is a cytotoxic metabolite that is removed primarily by hepatic ureagenesis in humans. Hyperammonaemia occurs in advanced hepatic, cardiac and pulmonary disease, and in urea cycle enzyme deficiencies. Increased skeletal muscle ammonia uptake and metabolism are the major mechanism of non‐hepatic ammonia disposal. Non‐hepatic ammonia disposal occurs in the mitochondria via glutamate synthesis from α‐ketoglutarate resulting in cataplerosis. We show skeletal muscle mitochondrial dysfunction during hyperammonaemia in a comprehensive array of human, rodent and cellular models. ATP synthesis, oxygen consumption, generation of reactive oxygen species with oxidative stress, and tricarboxylic acid (TCA) cycle intermediates were quantified. ATP content was lower in the skeletal muscle from cirrhotic patients, hyperammonaemic portacaval anastomosis rat, and C2C12 myotubes compared to appropriate controls. Hyperammonaemia in C2C12 myotubes resulted in impaired intact cell respiration, reduced complex I/NADH oxidase activity and electron leak occurring at complex III of the electron transport chain. Consistently, lower NAD+/NADH ratio was observed during hyperammonaemia with reduced TCA cycle intermediates compared to controls. Generation of reactive oxygen species resulted in increased content of skeletal muscle carbonylated proteins and thiobarbituric acid reactive substances during hyperammonaemia. A cell‐permeable ester of α‐ketoglutarate reversed the low TCA cycle intermediates and ATP content in myotubes during hyperammonaemia. However, the mitochondrial antioxidant MitoTEMPO did not reverse the lower ATP content during hyperammonaemia. We provide for the first time evidence that skeletal muscle hyperammonaemia results in mitochondrial dysfunction and oxidative stress. Use of anaplerotic substrates to reverse ammonia‐induced mitochondrial dysfunction is a novel therapeutic approach. PMID:27558544

Galactose-depleted xyloglucan is dysfunctional and leads to dwarfism in Arabidopsis.

PubMed

Kong, Yingzhen; Peña, Maria J; Renna, Luciana; Avci, Utku; Pattathil, Sivakumar; Tuomivaara, Sami T; Li, Xuemei; Reiter, Wolf-Dieter; Brandizzi, Federica; Hahn, Michael G; Darvill, Alan G; York, William S; O'Neill, Malcolm A

2015-04-01

Xyloglucan is a polysaccharide that has important roles in the formation and function of the walls that surround growing land plant cells. Many of these plants synthesize xyloglucan that contains galactose in two different side chains (L and F), which exist in distinct molecular environments. However, little is known about the contribution of these side chains to xyloglucan function. Here, we show that Arabidopsis (Arabidopsis thaliana) mutants devoid of the F side chain galactosyltransferase MURUS3 (MUR3) form xyloglucan that lacks F side chains and contains much less galactosylated xylose than its wild-type counterpart. The galactose-depleted xyloglucan is dysfunctional, as it leads to mutants that are dwarfed with curled rosette leaves, short petioles, and short inflorescence stems. Moreover, cell wall matrix polysaccharides, including xyloglucan and pectin, are not properly secreted and instead accumulate within intracellular aggregates. Near-normal growth is restored by generating mur3 mutants that produce no detectable amounts of xyloglucan. Thus, cellular processes are affected more by the presence of the dysfunctional xyloglucan than by eliminating xyloglucan altogether. To identify structural features responsible for xyloglucan dysfunction, xyloglucan structure was modified in situ by generating mur3 mutants that lack specific xyloglucan xylosyltransferases (XXTs) or that overexpress the XYLOGLUCAN L-SIDE CHAIN GALACTOSYLTRANSFERASE2 (XLT2) gene. Normal growth was restored in the mur3-3 mutant overexpressing XLT2 and in mur3-3 xxt double mutants when the dysfunctional xyloglucan was modified by doubling the amounts of galactosylated side chains. Our study assigns a role for galactosylation in normal xyloglucan function and demonstrates that altering xyloglucan side chain structure disturbs diverse cellular and physiological processes. © 2015 American Society of Plant Biologists. All Rights Reserved.

Inhibition of mTOR Prevents ROS Production Initiated by Ethidium Bromide-Induced Mitochondrial DNA Depletion

PubMed Central

Nacarelli, Timothy; Azar, Ashley; Sell, Christian

2014-01-01

The regulation of mitochondrial mass and DNA content involves a complex interaction between mitochondrial DNA replication machinery, functional components of the electron transport chain, selective clearance of mitochondria, and nuclear gene expression. In order to gain insight into cellular responses to mitochondrial stress, we treated human diploid fibroblasts with ethidium bromide at concentrations that induced loss of mitochondrial DNA over a period of 7 days. The decrease in mitochondrial DNA was accompanied by a reduction in steady state levels of the mitochondrial DNA binding protein, TFAM, a reduction in several electron transport chain protein levels, increased mitochondrial and total cellular ROS, and activation of p38 MAPK. However, there was an increase in mitochondrial mass and voltage dependent anion channel levels. In addition, mechanistic target of rapamycin (mTOR) activity, as judged by p70S6K targets, was decreased while steady state levels of p62/SQSTM1 and Parkin were increased. Treatment of cells with rapamycin created a situation in which cells were better able to adapt to the mitochondrial dysfunction, resulting in decreased ROS and increased cell viability but did not prevent the reduction in mitochondrial DNA. These effects may be due to a more efficient flux through the electron transport chain, increased autophagy, or enhanced AKT signaling, coupled with a reduced growth rate. Together, the results suggest that mTOR activity is affected by mitochondrial stress, which may be part of the retrograde signal system required for normal mitochondrial homeostasis. PMID:25104948

Mitochondrial electron transport chain is involved in microcystin-RR induced tobacco BY-2 cells apoptosis.

PubMed

Huang, Wenmin; Li, Dunhai; Liu, Yongding

2014-09-01

Microcystin-RR (MC-RR) has been suggested to induce apoptosis in tobacco BY-2 cells through mitochondrial dysfunction including the loss of mitochondrial membrane potential (ΔΨm). To further elucidate the mechanisms involved in MC-RR induced apoptosis in tobacco BY-2 cells, we have investigated the role of mitochondrial electron transport chain (ETC) as a potential source for reactive oxygen species (ROS). Tobacco BY-2 cells after exposure to MC-RR (60mg/L) displayed apoptotic changes in association with an increased production of ROS and loss of ΔΨm. All of these adverse effects were significantly attenuated by ETC inhibitors including Rotenone (2μmol/L, complex I inhibitor) and antimycin A (0.01μmol/L, complex III inhibitor), but not by thenoyltrifluoroacetone (5μmol/L, complex II inhibitor). These results suggest that mitochondrial ETC plays a key role in mediating MC-RR induced apoptosis in tobacco BY-2 cells through an increased mitochondrial production of ROS. Copyright © 2014. Published by Elsevier B.V.

The effect of smoking cessation pharmacotherapies on pancreatic beta cell function

DOE Office of Scientific and Technical Information (OSTI.GOV)

Woynillowicz, Amanda K.; Raha, Sandeep; Nicholson, Catherine J.

The goal of our study was to evaluate whether drugs currently used for smoking cessation (i.e., nicotine replacement therapy, varenicline [a partial agonist at nicotinic acetylcholine receptors (nAChR)] and bupropion [which acts in part as a nAChR antagonist]) can affect beta cell function and determine the mechanism(s) of this effect. INS-1E cells, a rat beta cell line, were treated with nicotine, varenicline and bupropion to determine their effects on beta cell function, mitochondrial electron transport chain enzyme activity and cellular/oxidative stress. Treatment of INS-1E cells with equimolar concentrations (1 μM) of three test compounds resulted in an ablation of normalmore » glucose-stimulated insulin secretion by the cells. This disruption of normal beta cell function was associated with mitochondrial dysfunction since all three compounds tested significantly decreased the activity of mitochondrial electron transport chain enzyme activity. These results raise the possibility that the currently available smoking cessation pharmacotherapies may also have adverse effects on beta cell function and thus glycemic control in vivo. Therefore whether or not the use of nicotine replacement therapy, varenicline and bupropion can cause endocrine changes which are consistent with impaired pancreatic function warrants further investigation. -- Highlights: ► Smoking cessation drugs have the potential to disrupt beta cell function in vitro. ► The effects of nicotine, varenicline and bupropion are similar. ► The impaired beta cell function is mediated by mitochondrial dysfunction. ► If similar effects are seen in vivo, these drugs may increase the risk of diabetes.« less

[Mitochondrial and microcirculatory distress syndrome in the critical patient. Therapeutic implications].

PubMed

Navarrete, M L; Cerdeño, M C; Serra, M C; Conejero, R

2013-10-01

Mitochondrial and microcirculatory distress syndrome (MMDS) can occur during systemic inflammatory response syndrome (SIRS), and is characterized by cytopathic tissue hypoxia uncorrected by oxygen transport optimization, and associated with an acquired defect in the use of oxygen and energy production in mitochondria, leading to multiple organ dysfunction (MOD). We examine the pathogenesis of MMDS, new diagnostic methods, and recent therapeutic approaches adapted to each of the three phases in the evolution of the syndrome. In the initial phase, the aim is prevention and early reversal of mitochondrial dysfunction. Once the latter is established, the aim is to restore flow of the electron chain, mitochondrial respiration, and to avoid cellular energy collapse. Finally, in the third (resolution) stage, treatment should focus on stimulating mitochondrial biogenesis and the repair or replacement of damaged mitochondria. Copyright © 2012 Elsevier España, S.L. and SEMICYUC. All rights reserved.

A role for long-chain acyl-CoA synthetase-4 (ACSL4) in diet-induced phospholipid remodeling and obesity-associated adipocyte dysfunction

USDA-ARS?s Scientific Manuscript database

OBJECTIVE: Regulation of fatty acid (FA) metabolism is central to adipocyte dysfunction during diet-induced obesity (DIO). Long-chain acyl-CoA synthetase-4 (ACSL4) has been hypothesized to modulate the metabolic fates of polyunsaturated FA (PUFA), including arachidonic acid (AA), but the in vivo act...

Biogenesis of iron-sulfur clusters in mammalian cells: new insights and relevance to human disease

PubMed Central

Rouault, Tracey A.

2012-01-01

Iron-sulfur (Fe-S) clusters are ubiquitous cofactors composed of iron and inorganic sulfur. They are required for the function of proteins involved in a wide range of activities, including electron transport in respiratory chain complexes, regulatory sensing, photosynthesis and DNA repair. The proteins involved in the biogenesis of Fe-S clusters are evolutionarily conserved from bacteria to humans, and many insights into the process of Fe-S cluster biogenesis have come from studies of model organisms, including bacteria, fungi and plants. It is now clear that several rare and seemingly dissimilar human diseases are attributable to defects in the basic process of Fe-S cluster biogenesis. Although these diseases –which include Friedreich’s ataxia (FRDA), ISCU myopathy, a rare form of sideroblastic anemia, an encephalomyopathy caused by dysfunction of respiratory chain complex I and multiple mitochondrial dysfunctions syndrome – affect different tissues, a feature common to many of them is that mitochondrial iron overload develops as a secondary consequence of a defect in Fe-S cluster biogenesis. This Commentary outlines the basic steps of Fe-S cluster biogenesis as they have been defined in model organisms. In addition, it draws attention to refinements of the process that might be specific to the subcellular compartmentalization of Fe-S cluster biogenesis proteins in some eukaryotes, including mammals. Finally, it outlines several important unresolved questions in the field that, once addressed, should offer important clues into how mitochondrial iron homeostasis is regulated, and how dysfunction in Fe-S cluster biogenesis can contribute to disease. PMID:22382365

A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans.

PubMed

Knowlton, Wendy M; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D; Jin, Yishi

2017-01-01

The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo , we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1 . Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7 , and isp-1 , and the putative oxidoreductase rad-8 . In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1 . Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the cellular adaptations used by neurons under conditions of injury.

A Select Subset of Electron Transport Chain Genes Associated with Optic Atrophy Link Mitochondria to Axon Regeneration in Caenorhabditis elegans

PubMed Central

Knowlton, Wendy M.; Hubert, Thomas; Wu, Zilu; Chisholm, Andrew D.; Jin, Yishi

2017-01-01

The role of mitochondria within injured neurons is an area of active interest since these organelles are vital for the production of cellular energy in the form of ATP. Using mechanosensory neurons of the nematode Caenorhabditis elegans to test regeneration after neuronal injury in vivo, we surveyed genes related to mitochondrial function for effects on axon regrowth after laser axotomy. Genes involved in mitochondrial transport, calcium uptake, mitophagy, or fission and fusion were largely dispensable for axon regrowth, with the exception of eat-3/Opa1. Surprisingly, many genes encoding components of the electron transport chain were dispensable for regrowth, except for the iron-sulfur proteins gas-1, nduf-2.2, nduf-7, and isp-1, and the putative oxidoreductase rad-8. In these mutants, axonal development was essentially normal and axons responded normally to injury by forming regenerative growth cones, but were impaired in subsequent axon extension. Overexpression of nduf-2.2 or isp-1 was sufficient to enhance regrowth, suggesting that mitochondrial function is rate-limiting in axon regeneration. Moreover, loss of function in isp-1 reduced the enhanced regeneration caused by either a gain-of-function mutation in the calcium channel EGL-19 or overexpression of the MAP kinase DLK-1. While the cellular function of RAD-8 remains unclear, our genetic analyses place rad-8 in the same pathway as other electron transport genes in axon regeneration. Unexpectedly, rad-8 regrowth defects were suppressed by altered function in the ubiquinone biosynthesis gene clk-1. Furthermore, we found that inhibition of the mitochondrial unfolded protein response via deletion of atfs-1 suppressed the defective regrowth in nduf-2.2 mutants. Together, our data indicate that while axon regeneration is not significantly affected by general dysfunction of cellular respiration, it is sensitive to the proper functioning of a select subset of electron transport chain genes, or to the cellular adaptations used by neurons under conditions of injury. PMID:28539870

[F-18]Fluorodihydrorotenone: Synthesis and evaluation of a mitochondrial electron transport chain (ETC) complex I probe for PET

DOE Office of Scientific and Technical Information (OSTI.GOV)

VanBrocklin, H.F.; Enas, J.D.; Hanrahan, S.M.

1994-05-01

The mitochondrial electron transport chain (ETC) consists of five enzyme complexes (I-V) which participate in the transfer of electrons to oxygen and phosphorylation of ADP (oxidative phosphorylation). ETC dysfunction has been linked to several genetic neurological diseases as well as implicated in Parkinson`s (complex I) and Huntington`s (complex I) disease and normal aging processes. Dihydrorotenone (DHR) is a specific high affinity inhibitor of complex I. In order to develop a PET tracer for complex I, we have labeled DHR with fluorine-18. The tosylate precursor was produced in three steps from commercially available rotenone. Fluorine-18 was introduced by nucleophilic displacement ofmore » the tosylate using tetrabutyl-ammonium fluoride. Subsequent oxidation with MnO{sub 2} and HPLC purification gave the desired [{sup 18}F]fluoro-DHR. Initial biodistribution studies were carried out in {approximately}200 g male Sprague-Dawley rats. The tracer was taken up rapidly in the heart, an organ highly enriched with mitochondria, (5.5-6% injected dose (ID)/g at 30 minutes) and in the brain ({approximately}1.5% ID/g at 1 hour).« less

A mouse neurodegenerative dynein heavy chain mutation alters dynein motility and localization in Neurospora crassa.

PubMed

Sivagurunathan, Senthilkumar; Schnittker, Robert R; Nandini, Swaran; Plamann, Michael D; King, Stephen J

2012-09-01

Cytoplasmic dynein is responsible for the transport and delivery of cargoes in organisms ranging from humans to fungi. Dysfunction of dynein motor machinery due to mutations in dynein or its activating complex dynactin can result in one of several neurological diseases in mammals. The mouse Legs at odd angles (Loa) mutation in the tail domain of the dynein heavy chain has been shown to lead to progressive neurodegeneration in mice. The mechanism by which the Loa mutation affects dynein function is just beginning to be understood. In this work, we generated the dynein tail mutation observed in Loa mice into the Neurospora crassa genome and utilized cell biological and complementing biochemical approaches to characterize how that tail mutation affected dynein function. We determined that the Loa mutation exhibits several subtle defects upon dynein function in N. crassa that were not seen in mice, including alterations in dynein localization, impaired velocity of vesicle transport, and in the biochemical properties of purified motors. Our work provides new information on the role of the tail domain on dynein function and points out areas of future research that will be of interest to pursue in mammalian systems. 2012 Wiley Periodicals, Inc

A Mouse Neurodegenerative Dynein Heavy Chain Mutation Alters Dynein Motility and Localization in Neurospora crassa

PubMed Central

Sivagurunathan, Senthilkumar; Schnittker, Robert R.; Nandini, Swaran; Plamann, Michael D.; King, Stephen J.

2013-01-01

Cytoplasmic dynein is responsible for the transport and delivery of cargoes in organisms ranging from humans to fungi. Dysfunction of dynein motor machinery due to mutations in dynein or its activating complex dynactin can result in one of several neurological diseases in mammals. The mouse Legs at odd angles (Loa) mutation in the tail domain of the dynein heavy chain has been shown to lead to progressive neurodegeneration in mice. The mechanism by which the Loa mutation affects dynein function is just beginning to be understood. In this work, we generated the dynein tail mutation observed in Loa mice into the Neurospora crassa genome and utilized cell biological and complementing biochemical approaches to characterize how that tail mutation affected dynein function. We determined that the Loa mutation exhibits several subtle defects upon dynein function in N. crassa that were not seen in mice, including alterations in dynein localization, impaired velocity of vesicle transport, and in the biochemical properties of purified motors. Our work provides new information on the role of the tail domain on dynein function and points out areas of future research that will be of interest to pursue in mammalian systems. PMID:22991199

Electron transport chain dysfunction by H(2)O (2) is linked to increased reactive oxygen species production and iron mobilization by lipoperoxidation: studies using Saccharomyces cerevisiae mitochondria.

PubMed

Cortés-Rojo, Christian; Estrada-Villagómez, Mirella; Calderón-Cortés, Elizabeth; Clemente-Guerrero, Mónica; Mejía-Zepeda, Ricardo; Boldogh, Istvan; Saavedra-Molina, Alfredo

2011-04-01

The mitochondrial electron transport chain (ETC) contains thiol groups (-SH) which are reversibly oxidized to modulate ETC function during H(2)O(2) overproduction. Since deleterious effects of H(2)O(2) are not limited to -SH oxidation, due to the formation of other H(2)O(2)-derived species, some processes like lipoperoxidation could enhance the effects of H(2)O(2) over ETC enzymes, disrupt their modulation by -SH oxidation and increase superoxide production. To verify this hypothesis, we tested the effects of H(2)O(2) on ETC activities, superoxide production and iron mobilization in mitochondria from lipoperoxidation-resistant native yeast and lipoperoxidation-sensitized yeast. Only complex III activity from lipoperoxidation-sensitive mitochondria exhibited a higher susceptibility to H(2)O(2) and increased superoxide production. The recovery of ETC activity by the thiol reductanct β-mercaptoethanol (BME) was also altered at complex III, and a role was attributed to lipoperoxidation, the latter being also responsible for iron release. A hypothetical model linking lipoperoxidation, increased complex III damage, superoxide production and iron release is given.

Propofol induces a metabolic switch to glycolysis and cell death in a mitochondrial electron transport chain-dependent manner.

PubMed

Sumi, Chisato; Okamoto, Akihisa; Tanaka, Hiromasa; Nishi, Kenichiro; Kusunoki, Munenori; Shoji, Tomohiro; Uba, Takeo; Matsuo, Yoshiyuki; Adachi, Takehiko; Hayashi, Jun-Ichi; Takenaga, Keizo; Hirota, Kiichi

2018-01-01

The intravenous anesthetic propofol (2,6-diisopropylphenol) has been used for the induction and maintenance of anesthesia and sedation in critical patient care. However, the rare but severe complication propofol infusion syndrome (PRIS) can occur, especially in patients receiving high doses of propofol for prolonged periods. In vivo and in vitro evidence suggests that the propofol toxicity is related to the impaired mitochondrial function. However, underlying molecular mechanisms remain unknown. Therefore, we investigated effects of propofol on cell metabolism and death using a series of established cell lines of various origins, including neurons, myocytes, and trans-mitochondrial cybrids, with defined mitochondrial DNA deficits. We demonstrated that supraclinical concentrations of propofol in not less than 50 μM disturbed the mitochondrial function and induced a metabolic switch, from oxidative phosphorylation to glycolysis, by targeting mitochondrial complexes I, II and III. This disturbance in mitochondrial electron transport caused the generation of reactive oxygen species, resulting in apoptosis. We also found that a predisposition to mitochondrial dysfunction, caused by a genetic mutation or pharmacological suppression of the electron transport chain by biguanides such as metformin and phenformin, promoted propofol-induced caspase activation and cell death induced by clinical relevant concentrations of propofol in not more than 25 μM. With further experiments with appropriate in vivo model, it is possible that the processes to constitute the molecular basis of PRIS are identified.

Control of mitochondrial biogenesis and function by the ubiquitin-proteasome system.

PubMed

Bragoszewski, Piotr; Turek, Michal; Chacinska, Agnieszka

2017-04-01

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin-proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level. © 2017 The Authors.

Control of mitochondrial biogenesis and function by the ubiquitin–proteasome system

PubMed Central

Bragoszewski, Piotr; Turek, Michal

2017-01-01

Mitochondria are pivotal organelles in eukaryotic cells. The complex proteome of mitochondria comprises proteins that are encoded by nuclear and mitochondrial genomes. The biogenesis of mitochondrial proteins requires their transport in an unfolded state with a high risk of misfolding. The mislocalization of mitochondrial proteins is deleterious to the cell. The electron transport chain in mitochondria is a source of reactive oxygen species that damage proteins. Mitochondrial dysfunction is linked to many pathological conditions and, together with the loss of cellular protein homeostasis (proteostasis), are hallmarks of ageing and ageing-related degeneration diseases. The pathogenesis of neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, has been associated with mitochondrial and proteostasis failure. Thus, mitochondrial proteins require sophisticated surveillance mechanisms. Although mitochondria form a proteasome-exclusive compartment, multiple lines of evidence indicate a crucial role for the cytosolic ubiquitin–proteasome system (UPS) in the quality control of mitochondrial proteins. The proteasome affects mitochondrial proteins at stages of their biogenesis and maturity. The effects of the UPS go beyond the removal of damaged proteins and include the adjustment of mitochondrial proteome composition, the regulation of organelle dynamics and the protection of cellular homeostasis against mitochondrial failure. In turn, mitochondrial activity and mitochondrial dysfunction adjust the activity of the UPS, with implications at the cellular level. PMID:28446709

The molecular genetic basis of mitochondrial malfunction in bladder tissue following outlet obstruction.

PubMed

Levin, Robert M; Hudson, Alan P

2004-08-01

Bladder dysfunction following partial outlet obstruction is a frequent consequence of benign prostatic hyperplasia and an increasingly common problem given the aging of the general population. Recent studies from this and other groups have begun to elucidate the molecular bases for the well described physiological malfunctions that characterize this clinical entity. We summarized and synthesized that information. Using modern methods of molecular genetics, including real-time polymerase chain reaction, real-time reverse transcriptase-polymerase chain reaction and others, as well as traditional experimental techniques such as electron microscopy we and others examined the transcriptional profile, morphology, etc of bladder smooth muscle mitochondria in experimental models of outlet obstruction. Data from many studies have demonstrated that aberrant gene expression in the mitochondrial and mitochondria related nuclear genetic systems underlies the loss of compliance and other attributes of bladder dysfunction following outlet obstruction. Such aberrant transcriptional characteristics engender loss of function in the electron transport and oxidative phosphorylation systems. Morphological studies of mitochondria in the animal model systems support this conclusion. In large part the loss of function in bladder smooth muscle following outlet obstruction results from the attenuation of mitochondrial energy production. In this article we reviewed and synthesized all available experimental observations relevant to this problem and we suggest future lines of inquiry that should prove fruitful in developing new strategies to treat the condition.

Reversal of mitochondrial dysfunction by coenzyme Q10 supplement improves endothelial function in patients with ischaemic left ventricular systolic dysfunction: a randomized controlled trial.

PubMed

Dai, Yuk-Ling; Luk, Ting-Hin; Yiu, Kai-Hang; Wang, Mei; Yip, Pandora M C; Lee, Stephen W L; Li, Sheung-Wai; Tam, Sidney; Fong, Bonnie; Lau, Chu-Pak; Siu, Chung-Wah; Tse, Hung-Fat

2011-06-01

Coronary artery disease (CAD) is associated with endothelial dysfunction and mitochondrial dysfunction (MD). The aim of this study was to investigate whether co-enzyme Q10 (CoQ) supplementation, which is an obligatory coenzyme in the mitochondrial respiratory transport chain, can reverse MD and improve endothelial function in patients with ischaemic left ventricular systolic dysfunction (LVSD). We performed a randomized, double-blind, placebo-controlled trial to determine the effects of CoQ supplement (300 mg/day, n=28) vs. placebo (controls, n=28) for 8 weeks on brachial flow-mediated dilation (FMD) in patients with ischaemic LVSD(left ventricular ejection fraction <45%). Mitochondrial function was determined by plasma lactate/pyruvate ratio (LP ratio). After 8 weeks, CoQ-treated patients had significant increases in plasma CoQ concentration (treatment effect 2.20 μg/mL, P<0.001) and FMD (treatment effect 1.51%, P=0.03); and decrease in LP ratio (treatment effect -2.46, P=0.03) compared with controls. However, CoQ treatment did not alter nitroglycerin-mediated dilation, blood pressure, blood levels of fasting glucose, haemoglobin A1c, lipid profile, high-sensitivity C-reactive protein and oxidative stress as determined by serum superoxide dismutase and 8-isoprostane (all P>0.05). Furthermore, the reduction in LP ratio significantly correlated with improvement in FMD (r=-0.29, P=0.047). In patients with ischaemic LVSD, 8 weeks supplement of CoQ improved mitochondrial function and FMD; and the improvement of FMD correlated with the change in mitochondrial function, suggesting that CoQ improved endothelial function via reversal of mitochondrial dysfunction in patients with ischaemic LVSD. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

Is antioxidant potential of the mitochondrial targeted ubiquinone derivative MitoQ conserved in cells lacking mtDNA?

PubMed

Lu, Chao; Zhang, Dawei; Whiteman, Matthew; Armstrong, Jeffrey S

2008-03-01

MitoQ has been developed as a mitochondrial targeted antioxidant for diseases associated with oxidative stress. Here we show that MitoQ blocks the generation of reactive oxygen species (ROS) and mitochondrial protein thiol oxidation, and preserves mitochondrial function and ultrastructure after glutathione (GSH) depletion. Furthermore, the antioxidant effect of MitoQ is conserved in cells lacking mitochondrial DNA, indicating that its antioxidant properties do not depend on a functional electron transport chain (ETC). Our results elucidate the antioxidant mechanism of MitoQ and suggest that it may be a useful therapeutic for disorders associated with a dysfunctional ETC and increased ROS production.

The chemoprotection of a blueberry anthocyanin extract against the acrylamide-induced oxidative stress in mitochondria: unequivocal evidence in mice liver.

PubMed

Zhao, Mengyao; Wang, Pengpu; Zhu, Yuchen; Liu, Xin; Hu, Xiaosong; Chen, Fang

2015-09-01

Acrylamide (AA) is one of the most important contaminants occurring in heated food products. Accumulating evidence indicates that AA-induced toxicity is associated with oxidative stress and long-term exposure to AA induced mitochondria collapse and finally leads to apoptosis. Whereas anthocyanins are natural antioxidants and have a strong ability to reduce oxidative damage in vivo. This study investigates the protection of a blueberry anthocyanin extract (BAE) against AA-induced mitochondrial oxidative stress in mice models. The activities of electron transport chain complexes, oxidative status, and the structure and function of mitochondria were measured. Results showed that pretreatment with BAE markedly inhibited reactive oxygen species (ROS) formation, and prevented the successive events associated with the mitochondrial damage and dysfunction, including recovered activities of electron transport chain, ATPase and superoxide dismutase, ameliorated depolarization of mitochondrial membrane potential and membrane lipid peroxidation, reduced release of cytochrome c and protection of mitochondria against swelling. In a word, mitochondria are a key target at the organelle level for the protective effect of BAE against AA toxicity. These results will be helpful to provide new clues for a better understanding of the AA toxicity intervention mechanism and for exploring effective dietary constituents for intervention of AA toxicity.

Mitochondrial Bioenergetics and Dysfunction in Failing Heart.

PubMed

Sheeran, Freya L; Pepe, Salvatore

2017-01-01

Energy insufficiency has been recognized as a key feature of systolic heart failure. Although mitochondria have long been known to sustain myocardial work energy supply, the capacity to therapeutically target mitochondrial bioenergetics dysfunction is hampered by a complex interplay of multiple perturbations that progressively compound causing myocardial failure and collapse. Compared to non-failing human donor hearts, activity rates of complexes I and IV, nicotinamide nucleotide transhydrogenase (NADPH-transhydrogenase, Nnt) and the Krebs cycle enzymes isocitrate dehydrogenase, malate dehydrogenase and aconitase are markedly decreased in end-stage heart failure. Diminished REDOX capacity with lower total glutathione and coenzyme Q 10 levels are also a feature of chronic left ventricular failure. Decreased enzyme activities in part relate to abundant and highly specific oxidative, nitrosylative, and hyperacetylation modifications. In this brief review we highlight that energy deficiency in end-stage failing human left ventricle predominantly involves concomitantly impaired activities of key electron transport chain and Krebs cycle enzymes rather than altered expression of respective genes or proteins. Augmented oxidative modification of these enzyme subunit structures, and the formation of highly reactive secondary metabolites, implicates dysfunction due to diminished capacity for management of mitochondrial reactive oxygen species, which contribute further to progressive decreases in bioenergetic capacity and contractile function in human heart failure.

Enhanced Respiratory Chain Supercomplex Formation in Response to Exercise in Human Skeletal Muscle.

PubMed

Greggio, Chiara; Jha, Pooja; Kulkarni, Sameer S; Lagarrigue, Sylviane; Broskey, Nicholas T; Boutant, Marie; Wang, Xu; Conde Alonso, Sonia; Ofori, Emmanuel; Auwerx, Johan; Cantó, Carles; Amati, Francesca

2017-02-07

Mitochondrial dysfunction is a hallmark of multiple metabolic complications. Physical activity is known to increase mitochondrial content in skeletal muscle, counteracting age-related decline in muscle function and protecting against metabolic and cardiovascular complications. Here, we investigated the effect of 4 months of exercise training on skeletal muscle mitochondria electron transport chain complexes and supercomplexes in 26 healthy, sedentary older adults. Exercise differentially modulated respiratory complexes. Complex I was the most upregulated complex and not stoichiometrically associated to the other complexes. In contrast to the other complexes, complex I was almost exclusively found assembled in supercomplexes in muscle mitochondria. Overall, supercomplex content was increased after exercise. In particular, complexes I, III, and IV were redistributed to supercomplexes in the form of I+III 2 +IV. Taken together, our results provide the first evidence that exercise affects the stoichiometry of supercomplex formation in humans and thus reveal a novel adaptive mechanism for increased energy demand. Copyright © 2017 Elsevier Inc. All rights reserved.

Metformin inhibits Branched Chain Amino Acid (BCAA) derived ketoacidosis and promotes metabolic homeostasis in MSUD.

PubMed

S Sonnet, Davis; N O'Leary, Monique; A Gutierrez, Mark; M Nguyen, Steven; Mateen, Samiha; Hsu, Yuehmei; P Mitchell, Kylie; J Lopez, Antonio; Vockley, Jerry; K Kennedy, Brian; Ramanathan, Arvind

2016-07-04

Maple Syrup Urine Disease (MSUD) is an inherited disorder caused by the dysfunction in the branched chain keto-acid dehydrogenase (BCKDH) enzyme. This leads to buildup of branched-chain keto-acids (BCKA) and branched-chain amino acids (BCAA) in body fluids (e.g. keto-isocaproic acid from the BCAA leucine), leading to numerous clinical features including a less understood skeletal muscle dysfunction in patients. KIC is an inhibitor of mitochondrial function at disease relevant concentrations. A murine model of intermediate MSUD (iMSUD) shows significant skeletal muscle dysfunction as by judged decreased muscle fiber diameter. MSUD is an orphan disease with a need for novel drug interventions. Here using a 96-well plate (liquid chromatography- mass spectrometry (LC-MS) based drug-screening platform we show that Metformin, a widely used anti-diabetic drug, reduces levels of KIC in patient-derived fibroblasts by 20-50%. This Metformin-mediated effect was conserved in vivo; Metformin-treatment significantly reduced levels of KIC in the muscle (by 69%) and serum (by 56%) isolated from iMSUD mice, and restored levels of mitochondrial metabolites (e.g. AMP and other TCA). The drug also decreased the expression of mitochondrial branched chain amino transferase (BCAT) which produces KIC in skeletal muscle. This suggests that Metformin can restore skeletal muscle homeostasis in MSUD by decreasing mitochondrial KIC production.

Relationship Between Mitochondrial Electron Transport Chain Dysfunction, Development, and Life Extension in Caenorhabditis elegans

PubMed Central

Johnson, Thomas E

2007-01-01

Prior studies have shown that disruption of mitochondrial electron transport chain (ETC) function in the nematode Caenorhabditis elegans can result in life extension. Counter to these findings, many mutations that disrupt ETC function in humans are known to be pathologically life-shortening. In this study, we have undertaken the first formal investigation of the role of partial mitochondrial ETC inhibition and its contribution to the life-extension phenotype of C. elegans. We have developed a novel RNA interference (RNAi) dilution strategy to incrementally reduce the expression level of five genes encoding mitochondrial proteins in C. elegans: atp-3, nuo-2, isp-1, cco-1, and frataxin (frh-1). We observed that each RNAi treatment led to marked alterations in multiple ETC components. Using this dilution technique, we observed a consistent, three-phase lifespan response to increasingly greater inhibition by RNAi: at low levels of inhibition, there was no response, then as inhibition increased, lifespan responded by monotonically lengthening. Finally, at the highest levels of RNAi inhibition, lifespan began to shorten. Indirect measurements of whole-animal oxidative stress showed no correlation with life extension. Instead, larval development, fertility, and adult size all became coordinately affected at the same point at which lifespan began to increase. We show that a specific signal, initiated during the L3/L4 larval stage of development, is sufficient for initiating mitochondrial dysfunction–dependent life extension in C. elegans. This stage of development is characterized by the last somatic cell divisions normally undertaken by C. elegans and also by massive mitochondrial DNA expansion. The coordinate effects of mitochondrial dysfunction on several cell cycle–dependent phenotypes, coupled with recent findings directly linking cell cycle progression with mitochondrial activity in C. elegans, lead us to propose that cell cycle checkpoint control plays a key role in specifying longevity of mitochondrial mutants. PMID:17914900

Alterations in mitochondrial DNA copy number and the activities of electron transport chain complexes and pyruvate dehydrogenase in the frontal cortex from subjects with autism

PubMed Central

Gu, F; Chauhan, V; Kaur, K; Brown, W T; LaFauci, G; Wegiel, J; Chauhan, A

2013-01-01

Autism is a neurodevelopmental disorder associated with social deficits and behavioral abnormalities. Recent evidence suggests that mitochondrial dysfunction and oxidative stress may contribute to the etiology of autism. This is the first study to compare the activities of mitochondrial electron transport chain (ETC) complexes (I–V) and pyruvate dehydrogenase (PDH), as well as mitochondrial DNA (mtDNA) copy number in the frontal cortex tissues from autistic and age-matched control subjects. The activities of complexes I, V and PDH were most affected in autism (n=14) being significantly reduced by 31%, 36% and 35%, respectively. When 99% confidence interval (CI) of control group was taken as a reference range, impaired activities of complexes I, III and V were observed in 43%, 29% and 43% of autistic subjects, respectively. Reduced activities of all five ETC complexes were observed in 14% of autistic cases, and the activities of multiple complexes were decreased in 29% of autistic subjects. These results suggest that defects in complexes I and III (sites of mitochondrial free radical generation) and complex V (adenosine triphosphate synthase) are more prevalent in autism. PDH activity was also reduced in 57% of autistic subjects. The ratios of mtDNA of three mitochondrial genes ND1, ND4 and Cyt B (that encode for subunits of complexes I and III) to nuclear DNA were significantly increased in autism, suggesting a higher mtDNA copy number in autism. Compared with the 95% CI of the control group, 44% of autistic children showed higher copy numbers of all three mitochondrial genes examined. Furthermore, ND4 and Cyt B deletions were observed in 44% and 33% of autistic children, respectively. This study indicates that autism is associated with mitochondrial dysfunction in the brain. PMID:24002085

S-52, a novel nootropic compound, protects against β-amyloid induced neuronal injury by attenuating mitochondrial dysfunction.

PubMed

Gao, Xin; Zheng, Chun Yan; Qin, Guo Wei; Tang, Xi Can; Zhang, Hai Yan

2012-10-01

Accumulating evidence suggests that β-amyloid (Aβ)-induced oxidative DNA damage and mitochondrial dysfunction may initiate and contribute to the progression of Alzheimer's disease (AD). This study evaluated the neuroprotective effects of S-52, a novel nootropic compound, on Aβ-induced mitochondrial failure. In an established paradigm of moderate cellular injury induced by Aβ, S-52 was observed to attenuate the toxicity of Aβ to energy metabolism, mitochondrial membrane structure, and key enzymes in the electron transport chain and tricarboxylic acid cycle. In addition, S-52 also effectively inhibited reactive oxygen species accumulation dose dependently not only in Aβ-harmed cells but also in unharmed, normal cells. The role of S-52 as a scavenger of free radicals is involved in the antioxidative effect of this compound. The beneficial effects on mitochondria and oxidative stress extend the neuroprotective effects of S-52. The present study provides crucial information for better understanding the beneficial profiles of this compound and discovering novel potential drug candidates for AD therapy. Copyright © 2012 Wiley Periodicals, Inc.

Integrated Immunomodulatory Mechanisms through which Long-Chain n-3 Polyunsaturated Fatty Acids Attenuate Obese Adipose Tissue Dysfunction

PubMed Central

Liddle, Danyelle M.; Wellings, Hannah R.; Power, Krista A.; Robinson, Lindsay E.; Monk, Jennifer M.

2017-01-01

Obesity is a global health concern with rising prevalence that increases the risk of developing other chronic diseases. A causal link connecting overnutrition, the development of obesity and obesity-associated co-morbidities is visceral adipose tissue (AT) dysfunction, characterized by changes in the cellularity of various immune cell populations, altered production of inflammatory adipokines that sustain a chronic state of low-grade inflammation and, ultimately, dysregulated AT metabolic function. Therefore, dietary intervention strategies aimed to halt the progression of obese AT dysfunction through any of the aforementioned processes represent an important active area of research. In this connection, fish oil-derived dietary long-chain n-3 polyunsaturated fatty acids (PUFA) in the form of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) have been demonstrated to attenuate obese AT dysfunction through multiple mechanisms, ultimately affecting AT immune cellularity and function, adipokine production, and metabolic signaling pathways, all of which will be discussed herein. PMID:29186929

Garlic activates SIRT-3 to prevent cardiac oxidative stress and mitochondrial dysfunction in diabetes.

PubMed

Sultana, Md Razia; Bagul, Pankaj K; Katare, Parameshwar B; Anwar Mohammed, Soheb; Padiya, Raju; Banerjee, Sanjay K

2016-11-01

Cardiac complications are major contributor in the mortality of diabetic people. Mitochondrial dysfunctioning is a crucial contributor for the cardiac complications in diabetes, and SIRT-3 remains the major mitochondrial deacetylase. We hypothesized whether garlic has any role on SIRT-3 to prevent mitochondrial dysfunction in diabetic heart. Rats with developed hyperglycemia after STZ injection were divided into two groups; diabetic (Dia) and diabetic+garlic (Dia+Garl). Garlic was administered at a dose of 250mg/kg/day, orally for four weeks. An additional group was maintained to evaluate the effect of raw garlic administration on control rat heart. We have observed altered functioning of cardiac mitochondrial enzymes involved in metabolic pathways, and increased levels of cardiac ROS with decreased activity of catalase and SOD in diabetic rats. Cardiac mRNA expression of TFAM, PGC-1α, and CO1 was also altered in diabetes. In addition, reduced levels of electron transport chain complexes that observed in Dia group were normalized with garlic administration. This indicates the presence of increased oxidative stress with mitochondrial dysfunctioning in diabetic heart. We have observed reduced activity of SIRT3 and increased acetylation of MnSOD. Silencing SIRT-3 in cells also revealed the same. However, administration of garlic improved the SIRT-3 and MnSOD activity, by deacetylating MnSOD. Increased SOD activity was correlated with reduced levels of ROS in garlic-administered rat hearts. Collectively, our results provide an insight into garlic's protection to T1DM heart through activation of SIRT3-MnSOD pathway. Copyright © 2016 Elsevier Inc. All rights reserved.

Lysosomal membrane permeabilization: Carbon nanohorn-induced reactive oxygen species generation and toxicity by this neglected mechanism

DOE Office of Scientific and Technical Information (OSTI.GOV)

Yang, Mei, E-mail: happy_deercn@163.com; Zhang, Minfang; Tahara, Yoshio

2014-10-01

Understanding the molecular mechanisms responsible for the cytotoxic effects of carbon nanomaterials is important for their future biomedical applications. Carbon nanotubular materials induce the generation of reactive oxygen species (ROS), which causes cell death; however, the exact details of this process are still unclear. Here, we identify a mechanism of ROS generation that is involved in the apoptosis of RAW264.7 macrophages caused by excess uptake of carbon nanohorns (CNHs), a typical type of carbon nanotubule. CNH accumulated in the lysosomes, where they induced lysosomal membrane permeabilization (LMP) and the subsequent release of lysosomal proteases, such as cathepsins, which in turnmore » caused mitochondrial dysfunction and triggered the generation of ROS in the mitochondria. The nicotinamide adenine dinucleotide phosphate oxidase was not directly involved in CNH-related ROS production, and the ROS generation cannot be regulated by mitochondrial electron transport chain. ROS fed back to amplify the mitochondrial dysfunction, leading to the subsequent activation of caspases and cell apoptosis. Carbon nanotubules commonly accumulate in the lysosomes after internalization in cells; however, lysosomal dysfunction has not attracted much attention in toxicity studies of these materials. These results suggest that LMP, a neglected mechanism, may be the primary reason for carbon nanotubule toxicity. - Highlights: • We clarify an apoptotic mechanism of RAW264.7 cells caused by carbon nanohorns. • In the meantime, the mechanism of CNH-induced ROS generation is identified. • LMP is the initial factor of CNH-induced ROS generation and cell death. • Cathepsins work as mediators that connect LMP and mitochondrial dysfunction.« less

Magnolol protects osteoblastic MC3T3-E1 cells against antimycin A-induced cytotoxicity through activation of mitochondrial function.

PubMed

Choi, Eun Mi

2012-06-01

Antimycin A treatment of cells blocks the mitochondrial electron transport chain and leads to elevated ROS generation. In the present study, we investigated the protective effects of magnolol, a hydroxylated biphenyl compound isolated from Magnolia officinalis, on antimycin A-induced toxicity in osteoblastic MC3T3-E1 cells. Osteoblastic MC3T3-E1 cells were pre-incubated with magnolol before treatment with antimycin A. Cell viability and mineralization of osteoblasts were assessed by MTT assay and Alizarin Red staining, respectively. Mitochondrial dysfunction in cells was measured by mitochondrial membrane potential (MMP), complex IV activity, and ATP level. The cellular antioxidant effect of magnolol in osteoblastic MC3T3-E1 cells was assessed by measuring cardiolipin oxidation, mitochondrial superoxide levels, and nitrotyrosine content. Phosphorylated cAMP-response element-binding protein (CREB ) was evaluated using ELISA assay. Pretreatment with magnolol prior to antimycin A exposure significantly reduced antimycin A-induced osteoblast dysfunction by preventing MMP dissipation, ATP loss, and CREB inactivation. Magnolol also reduced cardiolipin peroxidation, mitochondrial superoxide, and nitrotyrosine production induced by antimycin A. These results suggest that magnolol has a protective effect against antimycin A-induced cell damage by its antioxidant effects and the attenuation of mitochondrial dysfunction. All these data indicate that magnolol may reduce or prevent osteoblast degeneration in osteoporosis or other degenerative disorders.

Adaptive Evolution under Extreme Genetic Drift in Oxidatively Stressed Caenorhabditis elegans

PubMed Central

Christy, Stephen F; Wernick, Riana I; Lue, Michael J; Velasco, Griselda; Howe, Dana K; Denver, Dee R

2017-01-01

Abstract A mutation-accumulation (MA) experiment with Caenorhabditis elegans nematodes was conducted in which replicate, independently evolving lines were initiated from a low-fitness mitochondrial electron transport chain mutant, gas-1. The original intent of the study was to assess the effect of electron transport chain dysfunction involving elevated reactive oxygen species production on patterns of spontaneous germline mutation. In contrast to results of standard MA experiments, gas-1 MA lines evolved slightly higher mean fitness alongside reduced among-line genetic variance compared with their ancestor. Likewise, the gas-1 MA lines experienced partial recovery to wildtype reactive oxygen species levels. Whole-genome sequencing and analysis revealed that the molecular spectrum but not the overall rate of nuclear DNA mutation differed from wildtype patterns. Further analysis revealed an enrichment of mutations in loci that occur in a gas-1-centric region of the C. elegans interactome, and could be classified into a small number of functional-genomic categories. Characterization of a backcrossed four-mutation set isolated from one gas-1 MA line revealed this combination to be beneficial on both gas-1 mutant and wildtype genetic backgrounds. Our combined results suggest that selection favoring beneficial mutations can be powerful even under unfavorable population genetic conditions, and agree with fitness landscape theory predicting an inverse relationship between population fitness and the likelihood of adaptation. PMID:29069345

Prognostic value of depressed midwall systolic function in cardiac light-chain amyloidosis.

PubMed

Perlini, Stefano; Salinaro, Francesco; Musca, Francesco; Mussinelli, Roberta; Boldrini, Michele; Raimondi, Ambra; Milani, Paolo; Foli, Andrea; Cappelli, Francesco; Perfetto, Federico; Palladini, Giovanni; Rapezzi, Claudio; Merlini, Giampaolo

2014-05-01

Cardiac amyloidosis represents an archetypal form of restrictive heart disease, characterized by profound diastolic dysfunction. As ejection fraction is preserved until the late stage of the disease, the majority of patients do fulfill the definition of diastolic heart failure, that is, heart failure with preserved ejection fraction (HFpEF). In another clinical model of HFpEF, that is, pressure-overload hypertrophy, depressed midwall fractional shortening (mFS) has been shown to be a powerful prognostic factor. To assess the potential prognostic role of mFS in cardiac light-chain amyloidosis with preserved ejection fraction, we enrolled 221 consecutive untreated patients, in whom a first diagnosis of cardiac light-chain amyloidosis was concluded between 2008 and 2010. HFpEF was present in 181 patients. Patients in whom cardiac involvement was excluded served as controls (n = 121). Prognosis was assessed after a median follow-up of 561 days. When compared with light-chain amyloidosis patients without myocardial involvement, cardiac light-chain amyloidosis was characterized by increased wall thickness (P <0.001), reduced end-diastolic left ventricular volumes (P <0.001), and diastolic dysfunction (P <0.001). In patients with preserved ejection fraction, mFS was markedly depressed [10.6% (8.7-13.5) vs. 17.8% (15.9-19.5) P <0.001]. At multivariable analysis, mFS, troponin I, and NT-pro-brain natriuretic peptide were the only significant prognostic determinants (P <0.001), whereas other indices of diastolic (E/E' ratio, transmitral and pulmonary vein flow velocities) and systolic function (tissue Doppler systolic indices, ejection fraction), or the presence/absence of congestive heart failure did not enter the model. In cardiac light-chain amyloidosis with normal ejection fraction, depressed circumferential mFS, a marker of myocardial contractile dysfunction, is a powerful predictor of survival.

Impact of nitrophenols on the photosynthetic electron transport chain and ATP content in Nostoc muscorum and Chlorella vulgaris.

PubMed

Umamaheswari, A; Venkateswarlu, K

2004-06-01

Concentration-dependent inhibition of the photosynthetic electron transport chain (photosystem I (PS I), photosystem II (PS II) and whole chain reaction) and ATP content was observed in Nostoc muscorum and Chlorella vulgaris grown with o-nitrophenol, m-nitrophenol, or 2,4-dinitrophenol. Although the extents of inhibition of the photosynthetic electron transport chain in both organisms were similar, PS II was more sensitive than PS I and whole chain reaction to the nitrophenols. Depletion of the ATP pool was noted in nitrophenol-grown cultures, probably as a consequence of nearly complete inhibition of the photosynthetic electron transport chain.

Effect of structural modification of α-aminoxy peptides on their intestinal absorption and transport mechanism.

PubMed

Ma, Bin; Zha, Huiyan; Li, Na; Yang, Dan; Lin, Ge

2011-08-01

A representative α-aminoxy peptide 1 has been demonstrated to have a potential for the treatment of human diseases associated with Cl(-) channel dysfunctions. However, its poor intestinal absorption was determined. The purpose of this study was to delineate the transport mechanism responsible for its poor absorption and also to prepare peptide analogues by structural modifications of 1 at its isobutyl side chains without changing the α-aminoxy core for retaining biological activity to improve the intestinal absorption. The poor intestinal absorption of 1 was proved to be due to the P-glycoprotein (P-gp) mediated efflux transport in Caco-2 cell monolayer, intestinal segments in Ussing chamber and rat single pass intestinal perfusion models. Four analogues with propionic acid (2), butanamine (3), methyl (4) and hydroxymethyl side chains (5) were synthesized and tested using the same models. Except for the permeability of 2, the absorbable permeability of the modified peptides in Caco-2 cell monolayer and their intestinal absorption in rats were significantly improved to 7-fold (3), 4-fold (4), 11-fold (5) and 36-fold (2), 42-fold (3), 55-fold (4), 102-fold (5), respectively, compared with 1 (P(app), 0.034 ± 0.003 × 10(-6) cm/s; P(blood), 1.61 ± 0.807 × 10(-6) cm/s). More interestingly, the structural modification remarkably altered transport mechanism of the peptides, leading to the conversion of the active transport via P-gp mediation (1, 2), to MRP mediation (3), MRP plus BCRP mediation (4) or a passive diffusion (5). Furthermore, P-gp mediated efflux transport of 1 and 2 was demonstrated to not alter the P-gp expression, while 1 but not 2 exhibited uncompetitive inhibitory effect on P-gp ATPase. The results demonstrated that intestinal absorption and transport mechanism of the α-aminoxy peptides varied significantly with different structures, and their absorption can be dramatically improved by structural modifications, which allow us to further design and prepare better α-aminoxy peptide candidates with appropriate pharmacokinetic fates, including intestinal absorption, for potential clinical use.

Protective effects of dietary avocado oil on impaired electron transport chain function and exacerbated oxidative stress in liver mitochondria from diabetic rats.

PubMed

Ortiz-Avila, Omar; Gallegos-Corona, Marco Alonso; Sánchez-Briones, Luis Alberto; Calderón-Cortés, Elizabeth; Montoya-Pérez, Rocío; Rodriguez-Orozco, Alain R; Campos-García, Jesús; Saavedra-Molina, Alfredo; Mejía-Zepeda, Ricardo; Cortés-Rojo, Christian

2015-08-01

Electron transport chain (ETC) dysfunction, excessive ROS generation and lipid peroxidation are hallmarks of mitochondrial injury in the diabetic liver, with these alterations also playing a role in the development of non-alcoholic fatty liver disease (NAFLD). Enhanced mitochondrial sensitivity to lipid peroxidation during diabetes has been also associated to augmented content of C22:6 in membrane phospholipids. Thus, we aimed to test whether avocado oil, a rich source of C18:1 and antioxidants, attenuates the deleterious effects of diabetes on oxidative status of liver mitochondria by decreasing unsaturation of acyl chains of membrane lipids and/or by improving ETC functionality and decreasing ROS generation. Streptozocin-induced diabetes elicited a noticeable increase in the content of C22:6, leading to augmented mitochondrial peroxidizability index and higher levels of lipid peroxidation. Mitochondrial respiration and complex I activity were impaired in diabetic rats with a concomitant increase in ROS generation using a complex I substrate. This was associated to a more oxidized state of glutathione, All these alterations were prevented by avocado oil except by the changes in mitochondrial fatty acid composition. Avocado oil did not prevented hyperglycemia and polyphagia although did normalized hyperlipidemia. Neither diabetes nor avocado oil induced steatosis. These results suggest that avocado oil improves mitochondrial ETC function by attenuating the deleterious effects of oxidative stress in the liver of diabetic rats independently of a hypoglycemic effect or by modifying the fatty acid composition of mitochondrial membranes. These findings might have also significant implications in the progression of NAFLD in experimental models of steatosis.

Transport of spin qubits with donor chains under realistic experimental conditions

NASA Astrophysics Data System (ADS)

Mohiyaddin, Fahd A.; Kalra, Rachpon; Laucht, Arne; Rahman, Rajib; Klimeck, Gerhard; Morello, Andrea

2016-07-01

The ability to transport quantum information across some distance can facilitate the design and operation of a quantum processor. One-dimensional spin chains provide a compact platform to realize scalable spin transport for a solid-state quantum computer. Here, we model odd-sized donor chains in silicon under a range of experimental nonidealities, including variability of donor position within the chain. We show that the tolerance against donor placement inaccuracies is greatly improved by operating the spin chain in a mode where the electrons are confined at the Si-SiO2 interface. We then estimate the required time scales and exchange couplings, and the level of noise that can be tolerated to achieve high-fidelity transport. We also propose a protocol to calibrate and initialize the chain, thereby providing a complete guideline for realizing a functional donor chain and utilizing it for spin transport.

Transport of spin qubits with donor chains under realistic experimental conditions

DOE PAGES

Mohiyaddin, Fahd A.; Kalra, Rachpon; Laucht, Arne; ...

2016-07-25

The ability to transport quantum information across some distance can facilitate the design and operation of a quantum processor. One-dimensional spin chains provide a compact platform to realize scalable spin transport for a solid-state quantum computer. Here, we model odd-sized donor chains in silicon under a range of experimental nonidealities, including variability of donor position within the chain. We show that the tolerance against donor placement inaccuracies is greatly improved by operating the spin chain in a mode where the electrons are confined at the Si-SiO 2 interface. We then estimate the required time scales and exchange couplings, and themore » level of noise that can be tolerated to achieve high-fidelity transport. As a result, we also propose a protocol to calibrate and initialize the chain, thereby providing a complete guideline for realizing a functional donor chain and utilizing it for spin transport.« less

Defective branched chain amino acid catabolism contributes to cardiac dysfunction and remodeling following myocardial infarction.

PubMed

Wang, Wei; Zhang, Fuyang; Xia, Yunlong; Zhao, Shihao; Yan, Wenjun; Wang, Helin; Lee, Yan; Li, Congye; Zhang, Ling; Lian, Kun; Gao, Erhe; Cheng, Hexiang; Tao, Ling

2016-11-01

Cardiac metabolic remodeling is a central event during heart failure (HF) development following myocardial infarction (MI). It is well known that myocardial glucose and fatty acid dysmetabolism contribute to post-MI cardiac dysfunction and remodeling. However, the role of amino acid metabolism in post-MI HF remains elusive. Branched chain amino acids (BCAAs) are an important group of essential amino acids and function as crucial nutrient signaling in mammalian animals. The present study aimed to determine the role of cardiac BCAA metabolism in post-MI HF progression. Utilizing coronary artery ligation-induced murine MI models, we found that myocardial BCAA catabolism was significantly impaired in response to permanent MI, therefore leading to an obvious elevation of myocardial BCAA abundance. In MI-operated mice, oral BCAA administration further increased cardiac BCAA levels, activated the mammalian target of rapamycin (mTOR) signaling, and exacerbated cardiac dysfunction and remodeling. These data demonstrate that BCAAs act as a direct contributor to post-MI cardiac pathologies. Furthermore, these BCAA-mediated deleterious effects were improved by rapamycin cotreatment, revealing an indispensable role of mTOR in BCAA-mediated adverse effects on cardiac function/structure post-MI. Of note, pharmacological inhibition of branched chain ketoacid dehydrogenase kinase (BDK), a negative regulator of myocardial BCAA catabolism, significantly improved cardiac BCAA catabolic disorders, reduced myocardial BCAA levels, and ameliorated post-MI cardiac dysfunction and remodeling. In conclusion, our data provide the evidence that impaired cardiac BCAA catabolism directly contributes to post-MI cardiac dysfunction and remodeling. Moreover, improving cardiac BCAA catabolic defects may be a promising therapeutic strategy against post-MI HF. Copyright © 2016 the American Physiological Society.

Loss of Mitochondrial Function Impairs Lysosomes.

PubMed

Demers-Lamarche, Julie; Guillebaud, Gérald; Tlili, Mouna; Todkar, Kiran; Bélanger, Noémie; Grondin, Martine; Nguyen, Angela P; Michel, Jennifer; Germain, Marc

2016-05-06

Alterations in mitochondrial function, as observed in neurodegenerative diseases, lead to disrupted energy metabolism and production of damaging reactive oxygen species. Here, we demonstrate that mitochondrial dysfunction also disrupts the structure and function of lysosomes, the main degradation and recycling organelle. Specifically, inhibition of mitochondrial function, following deletion of the mitochondrial protein AIF, OPA1, or PINK1, as well as chemical inhibition of the electron transport chain, impaired lysosomal activity and caused the appearance of large lysosomal vacuoles. Importantly, our results show that lysosomal impairment is dependent on reactive oxygen species. Given that alterations in both mitochondrial function and lysosomal activity are key features of neurodegenerative diseases, this work provides important insights into the etiology of neurodegenerative diseases. © 2016 by The American Society for Biochemistry and Molecular Biology, Inc.

A traffic signal for heterodimeric amino acid transporters to transfer from the ER to the Golgi.

PubMed

Ganapathy, Vadivel

2009-01-15

Heterodimeric amino acid transporters represent a unique class of transport systems that consist of a light chain that serves as the 'transporter proper' and a heavy chain that is necessary for targeting the complex to the plasma membrane. The currently prevailing paradigm assigns no role for the light chains in the cellular processing of these transporters. In this issue of the Biochemical Journal, Sakamoto et al. provide evidence contrary to this paradigm. Their studies with the rBAT -b(0,+)AT (related to b(0,+) amino acid transporter-b(0,+)-type amino acid transporter) heterodimeric amino acid transporter show that the C-terminus of the light chain b(0,+)AT contains a sequence motif that serves as the traffic signal for the transfer of the heterodimeric complex from the endoplasmic reticulum to the Golgi. This is a novel function for the light chain in addition to its already established role as the subunit responsible for the transport activity. These new findings also seem to be applicable to other heterodimeric amino acid transporters as well.

Investigation of Mitochondrial Dysfunction by Sequential Microplate-Based Respiration Measurements from Intact and Permeabilized Neurons

PubMed Central

Clerc, Pascaline; Polster, Brian M.

2012-01-01

Mitochondrial dysfunction is a component of many neurodegenerative conditions. Measurement of oxygen consumption from intact neurons enables evaluation of mitochondrial bioenergetics under conditions that are more physiologically realistic compared to isolated mitochondria. However, mechanistic analysis of mitochondrial function in cells is complicated by changing energy demands and lack of substrate control. Here we describe a technique for sequentially measuring respiration from intact and saponin-permeabilized cortical neurons on single microplates. This technique allows control of substrates to individual electron transport chain complexes following permeabilization, as well as side-by-side comparisons to intact cells. To illustrate the utility of the technique, we demonstrate that inhibition of respiration by the drug KB-R7943 in intact neurons is relieved by delivery of the complex II substrate succinate, but not by complex I substrates, via acute saponin permeabilization. In contrast, methyl succinate, a putative cell permeable complex II substrate, failed to rescue respiration in intact neurons and was a poor complex II substrate in permeabilized cells. Sequential measurements of intact and permeabilized cell respiration should be particularly useful for evaluating indirect mitochondrial toxicity due to drugs or cellular signaling events which cannot be readily studied using isolated mitochondria. PMID:22496810

The Role of Mitochondrial Dysfunction in Psychiatric Disease

ERIC Educational Resources Information Center

Scaglia, Fernando

2010-01-01

Mitochondrial respiratory chain disorders are a group of genetically and clinically heterogeneous disorders caused by the biochemical complexity of mitochondrial respiration and the fact that two genomes, one mitochondrial and one nuclear, encode the components of the respiratory chain. These disorders can manifest at birth or present later in…

Tryptamine-gallic acid hybrid prevents non-steroidal anti-inflammatory drug-induced gastropathy: correction of mitochondrial dysfunction and inhibition of apoptosis in gastric mucosal cells.

PubMed

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

2012-01-27

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O(2)(·-)) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled ((99m)Tc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy.

Impaired Lysosomal Function Underlies Monoclonal Light Chain–Associated Renal Fanconi Syndrome

PubMed Central

Luciani, Alessandro; Sirac, Christophe; Terryn, Sara; Javaugue, Vincent; Prange, Jenny Ann; Bender, Sébastien; Bonaud, Amélie; Cogné, Michel; Aucouturier, Pierre; Ronco, Pierre

2016-01-01

Monoclonal gammopathies are frequently complicated by kidney lesions that increase the disease morbidity and mortality. In particular, abnormal Ig free light chains (LCs) may accumulate within epithelial cells, causing proximal tubule (PT) dysfunction and renal Fanconi syndrome (RFS). To investigate the mechanisms linking LC accumulation and PT dysfunction, we used transgenic mice overexpressing human control or RFS-associated κLCs (RFS-κLCs) and primary cultures of mouse PT cells exposed to low doses of corresponding human κLCs (25 μg/ml). Before the onset of renal failure, mice overexpressing RFS-κLCs showed PT dysfunction related to loss of apical transporters and receptors and increased PT cell proliferation rates associated with lysosomal accumulation of κLCs. Exposure of PT cells to RFS-κLCs resulted in κLC accumulation within enlarged and dysfunctional lysosomes, alteration of cellular dynamics, defective proteolysis and hydrolase maturation, and impaired lysosomal acidification. These changes were specific to the RFS-κLC variable (V) sequence, because they did not occur with control LCs or the same RFS-κLC carrying a single substitution (Ala30→Ser) in the V domain. The lysosomal alterations induced by RFS-κLCs were reflected in increased cell proliferation, decreased apical expression of endocytic receptors, and defective endocytosis. These results reveal that specific κLCs accumulate within lysosomes, altering lysosome dynamics and proteolytic function through defective acidification, thereby causing dedifferentiation and loss of reabsorptive capacity of PT cells. The characterization of these early events, which are similar to those encountered in congenital lysosomal disorders, provides a basis for the reported differential LC toxicity and new perspectives on LC-induced RFS. PMID:26614382

Age-related endothelial dysfunction in human skeletal muscle feed arteries: the role of free radicals derived from mitochondria in the vasculature.

PubMed

Park, S-Y; Kwon, O S; Andtbacka, R H I; Hyngstrom, J R; Reese, V; Murphy, M P; Richardson, R S

2018-01-01

This study sought to determine the role of free radicals derived from mitochondria in the vasculature in the recognized age-related endothelial dysfunction of human skeletal muscle feed arteries (SMFAs). A total of 44 SMFAs were studied with and without acute exposure to the mitochondria-targeted antioxidant MitoQ and nitric oxide synthase (NOS) blockade. The relative abundance of proteins from the electron transport chain, phosphorylated (p-) to endothelial (e) NOS ratio, manganese superoxide dismutase (MnSOD) and the mitochondria-derived superoxide (O2-) levels were assessed in SMFA. Endothelium-dependent and endothelium-independent SMFA vasodilation was assessed in response to flow-induced shear stress, acetylcholine (ACh) and sodium nitroprusside (SNP). MitoQ restored endothelium-dependent vasodilation in the old to that of the young when stimulated by both flow (young: 68 ± 5; old: 25 ± 7; old + MitoQ 65 ± 9%) and ACh (young: 97 ± 4; old: 59 ± 10; old + MitoQ: 98 ± 5%), but did not alter the initially uncompromised, endothelium-independent vasodilation (SNP). Compared to the young, MitoQ in the old diminished the initially elevated mitochondria-derived O2- levels and appeared to attenuate the breakdown of MnSOD. Furthermore, MitoQ increased the ratio of p-eNOS to NOS and the restoration of endothelium-dependent vasodilation in the old by MitoQ was ablated by NOS blockade. This study demonstrated that MitoQ reverses age-related vascular dysfunction by what appears to be an NO-dependent mechanism in human SMFAs. These findings suggest that mitochondria-targeted antioxidants may have utility in terms of counteracting the attenuated blood flow and vascular dysfunction associated with advancing age. © 2017 Scandinavian Physiological Society. Published by John Wiley & Sons Ltd.

Effect of reproductive ageing on pregnant mouse uterus and cervix

PubMed Central

Patel, Rima; Moffatt, James D.; Mourmoura, Evangelia; Demaison, Luc; Seed, Paul T.; Poston, Lucilla

2017-01-01

Key points Older pregnant women have a greater risk of operative delivery, still birth and post‐term induction.This suggests that maternal age can influence the timing of birth and processes of parturition.We have found that increasing maternal age in C57BL/6J mice is associated with prolongation of gestation and length of labour.Older pregnant mice also had delayed progesterone withdrawal and impaired myometrial function.Uterine ageing and labour dysfunction should be investigated further in older primigravid women. Abstract Advanced maternal age (≥35 years) is associated with increased rates of operative delivery, stillbirth and post‐term labour induction. The physiological causes remain uncertain, although impaired myometrial function has been implicated. To investigate the hypothesis that maternal age directly influences successful parturition, we assessed the timing of birth and fetal outcome in pregnant C57BL/6J mice at 3 months (young) and 5 months (intermediate) vs. 8 months (older) of age using infrared video recording. Serum progesterone profiles, myometrium and cervix function, and mitochondrial electron transport chain complex enzymatic activities were also examined. Older pregnant mice had a longer mean gestation and labour duration (P < 0.001), as well as reduced litter size (P < 0.01) vs. 3‐month‐old mice. Older mice did not exhibit the same decline in serum progesterone concentrations as younger mice. Cervical tissues from older mice were more distensible than younger mice (P < 0.05). Oxytocin receptor and connexin‐43 mRNA expression were reduced in the myometrium from 8‐month‐old vs. 3‐month‐old mice (P < 0.05 and P < 0.01 respectively) in tandem with more frequent but shorter duration spontaneous myometrial contractions (P < 0.05) and an attenuated contractile response to oxytocin. Myometrial mitochondrial copy number was reduced in older mice, although there were no age‐induced changes to the enzymatic activities of the mitochondrial electron transport chain complexes. In conclusion, 8‐month‐old mice provide a useful model of reproductive ageing. The present study has identified potential causes of labour dysfunction amenable to investigation in older primigravid women. PMID:28083928

Assessment of mitochondrial electron transport chain function in a primary astrocyte cell model of hyperhomocystinaemia.

PubMed

Turkes, Fiona; Murphy, Elaine; Land, John; Demiray, Berna; Duberley, Kate; Briddon, Antony; Hargreaves, Iain

2013-07-01

Elevated plasma homocysteine (Hcy) has been detected in patients with various neurodegenerative conditions. Studies on neurones and cerebral tissue have revealed that hyperhomocystinaemia may inhibit mitochondrial electron transport chain (ETC) enzyme activity resulting in neuronal morbidity. As astrocytes convey a protective and supportive role towards neurones, we postulated that Hcy-induced astrocytic ETC inhibition may contribute to neurological dysfunction. In order to investigate this hypothesis, we established a cellular model of hyperhomocystinaemia using primary rat astrocytes. Which were incubated were incubated with 200 µM, 500 µM Hcy and the Hcy metabolite, thiolactone (10 µM). Following 96 h of incubation with 200 µM and 500 µM Hcy, an approximate two-fold (1.11 nmol/mg) and three-fold (1.45 nmol/mg) increase in mitochondrial levels of Hcy, respectively, were detected compared to control levels (0.54 nmol/mg). However, on exposure to Hcy (200 or 500 µM) and Hcy-thiolactone (10 µM), the activities of astrocytic ETC complex I, II-III and IV were found to be comparable to control levels. In addition, the extracellular lactate:pyruvate ratio and the intracellular glutathione status of primary rat astrocytes were not significantly different between Hcy (200 or 500 µM) treated and controls. In conclusion, the results of this study suggest that Hcy induced impairment of astrocytic ETC function may not contribute to the pathophysiology of hyperhomocystinaemia.

Light Chain Amyloid Fibrils Cause Metabolic Dysfunction in Human Cardiomyocytes

DOE PAGES

McWilliams-Koeppen, Helen P.; Foster, James S.; Hackenbrack, Nicole; ...

2015-09-22

Light chain (AL) amyloidosis is the most common form of systemic amyloid disease, and cardiomyopathy is a dire consequence, resulting in an extremely poor prognosis. AL is characterized by the production of monoclonal free light chains that deposit as amyloid fibrils principally in the heart, liver, and kidneys causing organ dysfunction. We have studied the effects of amyloid fibrils, produced from recombinant λ6 light chain variable domains, on metabolic activity of human cardiomyocytes. The data indicate that fibrils at 0.1 μM, but not monomer, significantly decrease the enzymatic activity of cellular NAD(P)H-dependent oxidoreductase, without causing significant cell death. The presencemore » of amyloid fibrils did not affect ATP levels; however, oxygen consumption was increased and reactive oxygen species were detected. Confocal fluorescence microscopy showed that fibrils bound to and remained at the cell surface with little fibril internalization. Ultimately, these data indicate that AL amyloid fibrils severely impair cardiomyocyte metabolism in a dose dependent manner. These data suggest that effective therapeutic intervention for these patients should include methods for removing potentially toxic amyloid fibrils.« less

Augmenting Transport versus Increasing Cold Storage to Improve Vaccine Supply Chains

PubMed Central

Haidari, Leila A.; Connor, Diana L.; Wateska, Angela R.; Brown, Shawn T.; Mueller, Leslie E.; Norman, Bryan A.; Schmitz, Michelle M.; Paul, Proma; Rajgopal, Jayant; Welling, Joel S.; Leonard, Jim; Chen, Sheng-I; Lee, Bruce Y.

2013-01-01

Background When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment. Methods This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015. Results Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled. Conclusions When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce stationary storage needs. PMID:23717590

Augmenting transport versus increasing cold storage to improve vaccine supply chains.

PubMed

Haidari, Leila A; Connor, Diana L; Wateska, Angela R; Brown, Shawn T; Mueller, Leslie E; Norman, Bryan A; Schmitz, Michelle M; Paul, Proma; Rajgopal, Jayant; Welling, Joel S; Leonard, Jim; Chen, Sheng-I; Lee, Bruce Y

2013-01-01

When addressing the urgent task of improving vaccine supply chains, especially to accommodate the introduction of new vaccines, there is often a heavy emphasis on stationary storage. Currently, donations to vaccine supply chains occur largely in the form of storage equipment. This study utilized a HERMES-generated detailed, dynamic, discrete event simulation model of the Niger vaccine supply chain to compare the impacts on vaccine availability of adding stationary cold storage versus transport capacity at different levels and to determine whether adding stationary storage capacity alone would be enough to relieve potential bottlenecks when pneumococcal and rotavirus vaccines are introduced by 2015. Relieving regional level storage bottlenecks increased vaccine availability (by 4%) more than relieving storage bottlenecks at the district (1% increase), central (no change), and clinic (no change) levels alone. Increasing transport frequency (or capacity) yielded far greater gains (e.g., 15% increase in vaccine availability when doubling transport frequency to the district level and 18% when tripling). In fact, relieving all stationary storage constraints could only increase vaccine availability by 11%, whereas doubling the transport frequency throughout the system led to a 26% increase and tripling the frequency led to a 30% increase. Increasing transport frequency also reduced the amount of stationary storage space needed in the supply chain. The supply chain required an additional 61,269L of storage to relieve constraints with the current transport frequency, 55,255L with transport frequency doubled, and 51,791L with transport frequency tripled. When evaluating vaccine supply chains, it is important to understand the interplay between stationary storage and transport. The HERMES-generated dynamic simulation model showed how augmenting transport can result in greater gains than only augmenting stationary storage and can reduce stationary storage needs.

Neurodegenerative disease and iron storage in the brain.

PubMed

Thomas, Madhavi; Jankovic, Joseph

2004-08-01

Iron is very important for normal regulation of various metabolic pathways. Neurons store iron in the form of ferrous ion or neuromelanin. In specific disorders the axonal transport of iron is impaired, leading to iron deposition which in the presence of reactive oxygen species results in neurodegeneration. Recent developments in genetics, including the finding of mutations in the pantothenate kinase gene and ferritin light chain gene, have demonstrated a direct relationship between the presence of a mutation in the iron-regulatory pathways and iron deposition in the brain resulting in neurodegeneration. These two disorders now add to our understanding of the mechanism of disease due to dysfunction of iron-regulatory pathways. In addition to these disorders there may be several other mutations of iron-regulatory genes or related genes that are yet to be found. The animal models of disease have also added value to this area. In this review we provide a summary of recent developments in the field of movement disorders with abnormalities in iron transport, and the current evidence in neurodegenerative disorders such as Parkinson's disease.

Mitochondrial dysfunction in obesity.

PubMed

de Mello, Aline Haas; Costa, Ana Beatriz; Engel, Jéssica Della Giustina; Rezin, Gislaine Tezza

2018-01-01

Obesity leads to various changes in the body. Among them, the existing inflammatory process may lead to an increase in the production of reactive oxygen species (ROS) and cause oxidative stress. Oxidative stress, in turn, can trigger mitochondrial changes, which is called mitochondrial dysfunction. Moreover, excess nutrients supply (as it commonly is the case with obesity) can overwhelm the Krebs cycle and the mitochondrial respiratory chain, causing a mitochondrial dysfunction, and lead to a higher ROS formation. This increase in ROS production by the respiratory chain may also cause oxidative stress, which may exacerbate the inflammatory process in obesity. All these intracellular changes can lead to cellular apoptosis. These processes have been described in obesity as occurring mainly in peripheral tissues. However, some studies have already shown that obesity is also associated with changes in the central nervous system (CNS), with alterations in the blood-brain barrier (BBB) and in cerebral structures such as hypothalamus and hippocampus. In this sense, this review presents a general view about mitochondrial dysfunction in obesity, including related alterations, such as inflammation, oxidative stress, and apoptosis, and focusing on the whole organism, covering alterations in peripheral tissues, BBB, and CNS. Copyright © 2017 Elsevier Inc. All rights reserved.

l-Carnitine and heart disease.

PubMed

Wang, Zhong-Yu; Liu, Ying-Yi; Liu, Guo-Hui; Lu, Hai-Bin; Mao, Cui-Ying

2018-02-01

Cardiovascular disease (CVD) is a key cause of deaths worldwide, comprising 15-17% of healthcare expenditure in developed countries. Current records estimate an annual global average of 30 million cardiac dysfunction cases, with a predicted escalation by two-three folds for the next 20-30years. Although β-blockers and angiotensin-converting-enzymes are commonly prescribed to control CVD risk, hepatotoxicity and hematological changes are frequent adverse events associated with these drugs. Search for alternatives identified endogenous cofactor l-carnitine, which is capable of promoting mitochondrial β-oxidation towards a balanced cardiac energy metabolism. l-Carnitine facilitates transport of long-chain fatty acids into the mitochondrial matrix, triggering cardioprotective effects through reduced oxidative stress, inflammation and necrosis of cardiac myocytes. Additionally, l-carnitine regulates calcium influx, endothelial integrity, intracellular enzyme release and membrane phospholipid content for sustained cellular homeostasis. Carnitine depletion, characterized by reduced expression of "organic cation transporter-2" gene, is a metabolic and autosomal recessive disorder that also frequently associates with CVD. Hence, exogenous carnitine administration through dietary and intravenous routes serves as a suitable protective strategy against ventricular dysfunction, ischemia-reperfusion injury, cardiac arrhythmia and toxic myocardial injury that prominently mark CVD. Additionally, carnitine reduces hypertension, hyperlipidemia, diabetic ketoacidosis, hyperglycemia, insulin-dependent diabetes mellitus, insulin resistance, obesity, etc. that enhance cardiovascular pathology. These favorable effects of l-carnitine have been evident in infants, juvenile, young, adult and aged patients of sudden and chronic heart failure as well. This review describes the mechanism of action, metabolism and pharmacokinetics of l-carnitine. It specifically emphasizes upon the beneficial role of l-carnitine in cardiomyopathy. Copyright © 2017 Elsevier Inc. All rights reserved.

Ferritin light-chain subunits: key elements for the electron transfer across the protein cage.

PubMed

Carmona, Unai; Li, Le; Zhang, Lianbing; Knez, Mato

2014-12-18

The first specific functionality of the light-chain (L-chain) subunit of the universal iron storage protein ferritin was identified. The electrons released during iron-oxidation were transported across the ferritin cage specifically through the L-chains and the inverted electron transport through the L-chains also accelerated the demineralization of ferritin.

Electron transport chains in organohalide-respiring bacteria and bioremediation implications.

PubMed

Wang, Shanquan; Qiu, Lan; Liu, Xiaowei; Xu, Guofang; Siegert, Michael; Lu, Qihong; Juneau, Philippe; Yu, Ling; Liang, Dawei; He, Zhili; Qiu, Rongliang

In situ remediation employing organohalide-respiring bacteria represents a promising solution for cleanup of persistent organohalide pollutants. The organohalide-respiring bacteria conserve energy by utilizing H 2 or organic compounds as electron donors and organohalides as electron acceptors. Reductive dehalogenase (RDase), a terminal reductase of the electron transport chain in organohalide-respiring bacteria, is the key enzyme that catalyzes halogen removal. Accumulating experimental evidence thus far suggests that there are distinct models for respiratory electron transfer in organohalide-respirers of different lineages, e.g., Dehalococcoides, Dehalobacter, Desulfitobacterium and Sulfurospirillum. In this review, to connect the knowledge in organohalide-respiratory electron transport chains to bioremediation applications, we first comprehensively review molecular components and their organization, together with energetics of the organohalide-respiratory electron transport chains, as well as recent elucidation of intramolecular electron shuttling and halogen elimination mechanisms of RDases. We then highlight the implications of organohalide-respiratory electron transport chains in stimulated bioremediation. In addition, major challenges and further developments toward understanding the organohalide-respiratory electron transport chains and their bioremediation applications are identified and discussed. Copyright © 2018 Elsevier Inc. All rights reserved.

Glucose Modulates Respiratory Complex I Activity in Response to Acute Mitochondrial Dysfunction

PubMed Central

Cannino, Giuseppe; El-Khoury, Riyad; Pirinen, Marja; Hutz, Bettina; Rustin, Pierre; Jacobs, Howard T.; Dufour, Eric

2012-01-01

Proper coordination between glycolysis and respiration is essential, yet the regulatory mechanisms involved in sensing respiratory chain defects and modifying mitochondrial functions accordingly are unclear. To investigate the nature of this regulation, we introduced respiratory bypass enzymes into cultured human (HEK293T) cells and studied mitochondrial responses to respiratory chain inhibition. In the absence of respiratory chain inhibitors, the expression of alternative respiratory enzymes did not detectably alter cell physiology or mitochondrial function. However, in permeabilized cells NDI1 (alternative NADH dehydrogenase) bypassed complex I inhibition, whereas alternative oxidase (AOX) bypassed complex III or IV inhibition. In contrast, in intact cells the effects of the AOX bypass were suppressed by growth on glucose, whereas those produced by NDI1 were unaffected. Moreover, NDI1 abolished the glucose suppression of AOX-driven respiration, implicating complex I as the target of this regulation. Rapid Complex I down-regulation was partly released upon prolonged respiratory inhibition, suggesting that it provides an “emergency shutdown” system to regulate metabolism in response to dysfunctions of the oxidative phosphorylation. This system was independent of HIF1, mitochondrial superoxide, or ATP synthase regulation. Our findings reveal a novel pathway for adaptation to mitochondrial dysfunction and could provide new opportunities for combatting diseases. PMID:23007390

Malfunctioning of the iron-sulfur cluster assembly machinery in Saccharomyces cerevisiae produces oxidative stress via an iron-dependent mechanism, causing dysfunction in respiratory complexes.

PubMed

Gomez, Mauricio; Pérez-Gallardo, Rocío V; Sánchez, Luis A; Díaz-Pérez, Alma L; Cortés-Rojo, Christian; Meza Carmen, Victor; Saavedra-Molina, Alfredo; Lara-Romero, Javier; Jiménez-Sandoval, Sergio; Rodríguez, Francisco; Rodríguez-Zavala, José S; Campos-García, Jesús

2014-01-01

Biogenesis and recycling of iron-sulfur (Fe-S) clusters play important roles in the iron homeostasis mechanisms involved in mitochondrial function. In Saccharomyces cerevisiae, the Fe-S clusters are assembled into apoproteins by the iron-sulfur cluster machinery (ISC). The aim of the present study was to determine the effects of ISC gene deletion and consequent iron release under oxidative stress conditions on mitochondrial functionality in S. cerevisiae. Reactive oxygen species (ROS) generation, caused by H2O2, menadione, or ethanol, was associated with a loss of iron homeostasis and exacerbated by ISC system dysfunction. ISC mutants showed increased free Fe2+ content, exacerbated by ROS-inducers, causing an increase in ROS, which was decreased by the addition of an iron chelator. Our study suggests that the increment in free Fe2+ associated with ROS generation may have originated from mitochondria, probably Fe-S cluster proteins, under both normal and oxidative stress conditions, suggesting that Fe-S cluster anabolism is affected. Raman spectroscopy analysis and immunoblotting indicated that in mitochondria from SSQ1 and ISA1 mutants, the content of [Fe-S] centers was decreased, as was formation of Rieske protein-dependent supercomplex III2IV2, but this was not observed in the iron-deficient ATX1 and MRS4 mutants. In addition, the activity of complexes II and IV from the electron transport chain (ETC) was impaired or totally abolished in SSQ1 and ISA1 mutants. These results confirm that the ISC system plays important roles in iron homeostasis, ROS stress, and in assembly of supercomplexes III2IV2 and III2IV1, thus affecting the functionality of the respiratory chain.

Only adding stationary storage to vaccine supply chains may create and worsen transport bottlenecks.

PubMed

Haidari, Leila A; Connor, Diana L; Wateska, Angela R; Brown, Shawn T; Mueller, Leslie E; Norman, Bryan A; Schmitz, Michelle M; Paul, Proma; Rajgopal, Jayant; Welling, Joel S; Leonard, Jim; Claypool, Erin G; Weng, Yu-Ting; Chen, Sheng-I; Lee, Bruce Y

2013-01-01

Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints.

Only Adding Stationary Storage to Vaccine Supply Chains May Create and Worsen Transport Bottlenecks

PubMed Central

Haidari, Leila A.; Connor, Diana L.; Wateska, Angela R.; Brown, Shawn T.; Mueller, Leslie E.; Norman, Bryan A.; Schmitz, Michelle M.; Paul, Proma; Rajgopal, Jayant; Welling, Joel S.; Leonard, Jim; Claypool, Erin G.; Weng, Yu-Ting; Chen, Sheng-I; Lee, Bruce Y.

2015-01-01

Although vaccine supply chains in many countries require additional stationary storage and transport capacity to meet current and future needs, international donors tend to donate stationary storage devices far more often than transport equipment. To investigate the impact of only adding stationary storage equipment on the capacity requirements of transport devices and vehicles, we used HERMES (Highly Extensible Resource for Modeling Supply Chains) to construct a discrete event simulation model of the Niger vaccine supply chain. We measured the transport capacity requirement for each mode of transport used in the Niger vaccine cold chain, both before and after adding cold rooms and refrigerators to relieve all stationary storage constraints in the system. With the addition of necessary stationary storage, the average transport capacity requirement increased from 88% to 144% for cold trucks, from 101% to 197% for pickup trucks, and from 366% to 420% for vaccine carriers. Therefore, adding stationary storage alone may worsen or create new transport bottlenecks as more vaccines flow through the system, preventing many vaccines from reaching their target populations. Dynamic modeling can reveal such relationships between stationary storage capacity and transport constraints. PMID:23903398

A Metabolic Signature of Mitochondrial Dysfunction Revealed through a Monogenic Form of Leigh Syndrome

PubMed

Thompson Legault, Julie; Strittmatter, Laura; Tardif, Jessica; Sharma, Rohit; Tremblay-Vaillancourt, Vanessa; Aubut, Chantale; Boucher, Gabrielle; Clish, Clary B; Cyr, Denis; Daneault, Caroline; Waters, Paula J; Vachon, Luc; Morin, Charles; Laprise, Catherine; Rioux, John D; Mootha, Vamsi K; Des Rosiers, Christine

2015-11-03

A decline in mitochondrial respiration represents the root cause of a large number of inborn errors of metabolism. It is also associated with common age-associated diseases and the aging process. To gain insight into the systemic, biochemical consequences of respiratory chain dysfunction, we performed a case-control, prospective metabolic profiling study in a genetically homogenous cohort of patients with Leigh syndrome French Canadian variant, a mitochondrial respiratory chain disease due to loss-of-function mutations in LRPPRC. We discovered 45 plasma and urinary analytes discriminating patients from controls, including classic markers of mitochondrial metabolic dysfunction (lactate and acylcarnitines), as well as unexpected markers of cardiometabolic risk (insulin and adiponectin), amino acid catabolism linked to NADH status (α-hydroxybutyrate), and NAD(+) biosynthesis (kynurenine and 3-hydroxyanthranilic acid). Our study identifies systemic, metabolic pathway derangements that can lie downstream of primary mitochondrial lesions, with implications for understanding how the organelle contributes to rare and common diseases. Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia.

PubMed

Moos, Walter H; Maneta, Eleni; Pinkert, Carl A; Irwin, Michael H; Hoffman, Michelle E; Faller, Douglas V; Steliou, Kosta

2016-03-01

Neuropsychiatric disorders are a heterogeneous group of conditions that often share underlying mitochondrial dysfunction and biological pathways implicated in their pathogenesis, progression, and treatment. To date, these disorders have proven notoriously resistant to molecular-targeted therapies, and clinical options are relegated to interventional types, which do not address the core symptoms of the disease. In this review, we discuss emerging epigenetic-driven approaches using novel acylcarnitine esters (carnitinoids) that act on master regulators of antioxidant and cytoprotective genes and mitophagic pathways. These carnitinoids are actively transported, mitochondria-localizing, biomimetic coenzyme A surrogates of short-chain fatty acids, which inhibit histone deacetylase and may reinvigorate synaptic plasticity and protect against neuronal damage. We outline these neuroprotective effects in the context of treatment of neuropsychiatric disorders such as autism spectrum disorder and schizophrenia. © 2016 Wiley Periodicals, Inc.

Cold-Chain Adaptability During Introduction of Inactivated Polio Vaccine in Bangladesh, 2015.

PubMed

Billah, Mallick M; Zaman, K; Estivariz, Concepcion F; Snider, Cynthia J; Anand, Abhijeet; Hampton, Lee M; Bari, Tajul I A; Russell, Kevin L; Chai, Shua J

2017-07-01

Introduction of inactivated polio vaccine creates challenges in maintaining the cold chain for vaccine storage and distribution. We evaluated the cold chain in 23 health facilities and 36 outreach vaccination sessions in 8 districts and cities of Bangladesh, using purposive sampling during August-October 2015. We interviewed immunization and cold-chain staff, assessed equipment, and recorded temperatures during vaccine storage and transportation. All health facilities had functioning refrigerators, and 96% had freezers. Temperature monitors were observed in all refrigerators and freezers but in only 14 of 66 vaccine transporters (21%). Recorders detected temperatures >8°C for >60 minutes in 5 of 23 refrigerators (22%), 3 of 6 cold boxes (50%) transporting vaccines from national to subnational depots, and 8 of 48 vaccine carriers (17%) used in outreach vaccination sites. Temperatures <2°C were detected in 4 of 19 cold boxes (21%) transporting vaccine from subnational depots to health facilities and 14 of 48 vaccine carriers (29%). Bangladesh has substantial cold-chain storage and transportation capacity after inactivated polio vaccine introduction, but temperature fluctuations during vaccine transport could cause vaccine potency loss that could go undetected. Bangladesh and other countries should strive to ensure consistent and sufficient cold-chain storage and monitor the cold chain during vaccine transportation at all levels. © The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.

Using Adobe Flash Animations of Electron Transport Chain to Teach and Learn Biochemistry

ERIC Educational Resources Information Center

Teplá, Milada; Klímová, Helena

2015-01-01

Teaching the subject of the electron transport chain is one of the most challenging aspects of the chemistry curriculum at the high school level. This article presents an educational program called "Electron Transport Chain" which consists of 14 visual animations including a biochemistry quiz. The program was created in the Adobe Flash…

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mohiyaddin, Fahd A.; Kalra, Rachpon; Laucht, Arne

The ability to transport quantum information across some distance can facilitate the design and operation of a quantum processor. One-dimensional spin chains provide a compact platform to realize scalable spin transport for a solid-state quantum computer. Here, we model odd-sized donor chains in silicon under a range of experimental nonidealities, including variability of donor position within the chain. We show that the tolerance against donor placement inaccuracies is greatly improved by operating the spin chain in a mode where the electrons are confined at the Si-SiO 2 interface. We then estimate the required time scales and exchange couplings, and themore » level of noise that can be tolerated to achieve high-fidelity transport. As a result, we also propose a protocol to calibrate and initialize the chain, thereby providing a complete guideline for realizing a functional donor chain and utilizing it for spin transport.« less

Beyond Ussing's chambers: contemporary thoughts on integration of transepithelial transport

PubMed Central

Herrmann, Jeremy R.

2016-01-01

In the mid-20th century, Hans Ussing developed a chamber that allowed for the simultaneous measurement of current and labeled probe flux across epithelia. Using frog skin as a model, Ussing used his results to propose mechanisms of transcellular Na+ and K+ transport across apical (exterior/luminal) and basolateral (interior) membranes that is essentially unchanged today. Others took advantage of Ussing's chambers to study mucosal tissues, including bladder and intestines. It quickly became clear that, in some tissues, passive paracellular flux, i.e., across the tight junction, was an important component of overall transepithelial transport. Subsequent work demonstrated that activation of the apical Na+-glucose cotransporter SGLT1 regulated paracellular permeability such that intestinal paracellular transport could coordinate with and amplify transcellular transport. Intermediates in this process include activation of p38 MAPK, the apical Na+/H+ exchanger NHE3, and myosin light chain kinase (MLCK). Investigators then focused on these processes in disease. They found that TNF induces barrier dysfunction via MLCK activation and downstream caveolin-1-dependent endocytosis of the tight junction protein occludin. TNF also inhibited NHE3, and both barrier loss and PKCα-dependent NHE3 inhibition were required for TNF-induced acute diarrhea, emphasizing the interplay between transcellular and paracellular transport. Finally, studies using immune-mediated inflammatory bowel disease models showed that mice lacking epithelial MLCK were initially protected, but became ill as epithelial damage progressed and provided a tight junction-independent means of barrier loss. None of these advances would have been possible without the insights provided by Ussing and others using Ussing's ingenious, and still useful, chambers. PMID:26702131

Moderate exercise ameliorates dysregulated hippocampal glycometabolism and memory function in a rat model of type 2 diabetes.

PubMed

Shima, Takeru; Matsui, Takashi; Jesmin, Subrina; Okamoto, Masahiro; Soya, Mariko; Inoue, Koshiro; Liu, Yu-Fan; Torres-Aleman, Ignacio; McEwen, Bruce S; Soya, Hideaki

2017-03-01

Type 2 diabetes is likely to be an independent risk factor for hippocampal-based memory dysfunction, although this complication has yet to be investigated in detail. As dysregulated glycometabolism in peripheral tissues is a key symptom of type 2 diabetes, it is hypothesised that diabetes-mediated memory dysfunction is also caused by hippocampal glycometabolic dysfunction. If so, such dysfunction should also be ameliorated with moderate exercise by normalising hippocampal glycometabolism, since 4 weeks of moderate exercise enhances memory function and local hippocampal glycogen levels in normal animals. The hippocampal glycometabolism in OLETF rats (model of human type 2 diabetes) was assessed and, subsequently, the effects of exercise on memory function and hippocampal glycometabolism were investigated. OLETF rats, which have memory dysfunction, exhibited higher levels of glycogen in the hippocampus than did control rats, and breakdown of hippocampal glycogen with a single bout of exercise remained unimpaired. However, OLETF rats expressed lower levels of hippocampal monocarboxylate transporter 2 (MCT2, a transporter for lactate to neurons). Four weeks of moderate exercise improved spatial memory accompanied by further increase in hippocampal glycogen levels and restoration of MCT2 expression independent of neurotrophic factor and clinical symptoms in OLETF rats. Our findings are the first to describe detailed profiles of glycometabolism in the type 2 diabetic hippocampus and to show that 4 weeks of moderate exercise improves memory dysfunction in type 2 diabetes via amelioration of dysregulated hippocampal glycometabolism. Dysregulated hippocampal lactate-transport-related glycometabolism is a possible aetiology of type-2-diabetes-mediated memory dysfunction.

The Parkinsonian mimetic, 6-OHDA, impairs axonal transport in dopaminergic axons

PubMed Central

2014-01-01

6-hydroxydopamine (6-OHDA) is one of the most commonly used toxins for modeling degeneration of dopaminergic (DA) neurons in Parkinson's disease. 6-OHDA also causes axonal degeneration, a process that appears to precede the death of DA neurons. To understand the processes involved in 6-OHDA-mediated axonal degeneration, a microdevice designed to isolate axons fluidically from cell bodies was used in conjunction with green fluorescent protein (GFP)-labeled DA neurons. Results showed that 6-OHDA quickly induced mitochondrial transport dysfunction in both DA and non-DA axons. This appeared to be a general effect on transport function since 6-OHDA also disrupted transport of synaptophysin-tagged vesicles. The effects of 6-OHDA on mitochondrial transport were blocked by the addition of the SOD1-mimetic, Mn(III)tetrakis(4-benzoic acid)porphyrin chloride (MnTBAP), as well as the anti-oxidant N-acetyl-cysteine (NAC) suggesting that free radical species played a role in this process. Temporally, microtubule disruption and autophagy occurred after transport dysfunction yet before DA cell death following 6-OHDA treatment. The results from the study suggest that ROS-mediated transport dysfunction occurs early and plays a significant role in inducing axonal degeneration in response to 6-OHDA treatment. PMID:24885281

Kinetic chain contributions to elbow function and dysfunction in sports.

PubMed

Ben Kibler, W; Sciascia, Aaron

2004-10-01

The elbow functions in throwing and other athletic activities as a link in the kinetic chain of force development, regulation, and transfer. Efficient function, with maximal performance and minimal injury risk, requires optimum activation of all the link in the kinetic chain. Injury is often associated with alterations in force production or regulation capabilities in links that may be distant to the site of injury. Evaluation of injured athletes should include screening examinations for these areas, and treatment and conditioning should also include these areas.

Skeletal muscle mitochondrial health and spinal cord injury.

PubMed

O'Brien, Laura C; Gorgey, Ashraf S

2016-10-18

Mitochondria are the main source of cellular energy production and are dynamic organelles that undergo biogenesis, remodeling, and degradation. Mitochondrial dysfunction is observed in a number of disease states including acute and chronic central or peripheral nervous system injury by traumatic brain injury, spinal cord injury (SCI), and neurodegenerative disease as well as in metabolic disturbances such as insulin resistance, type II diabetes and obesity. Mitochondrial dysfunction is most commonly observed in high energy requiring tissues like the brain and skeletal muscle. In persons with chronic SCI, changes to skeletal muscle may include remarkable atrophy and conversion of muscle fiber type from oxidative to fast glycolytic, combined with increased infiltration of intramuscular adipose tissue. These changes contribute to a proinflammatory environment, glucose intolerance and insulin resistance. The loss of metabolically active muscle combined with inactivity predisposes individuals with SCI to type II diabetes and obesity. The contribution of skeletal muscle mitochondrial density and electron transport chain activity to the development of the aforementioned comorbidities following SCI is unclear. A better understanding of the mechanisms involved in skeletal muscle mitochondrial dynamics is imperative to designing and testing effective treatments for this growing population. The current editorial will review ways to study mitochondrial function and the importance of improving skeletal muscle mitochondrial health in clinical populations with a special focus on chronic SCI.

Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration

PubMed Central

Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

2010-01-01

Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS. PMID:20123860

Loss of thymidine kinase 2 alters neuronal bioenergetics and leads to neurodegeneration.

PubMed

Bartesaghi, Stefano; Betts-Henderson, Joanne; Cain, Kelvin; Dinsdale, David; Zhou, Xiaoshan; Karlsson, Anna; Salomoni, Paolo; Nicotera, Pierluigi

2010-05-01

Mutations of thymidine kinase 2 (TK2), an essential component of the mitochondrial nucleotide salvage pathway, can give rise to mitochondrial DNA (mtDNA) depletion syndromes (MDS). These clinically heterogeneous disorders are characterized by severe reduction in mtDNA copy number in affected tissues and are associated with progressive myopathy, hepatopathy and/or encephalopathy, depending in part on the underlying nuclear genetic defect. Mutations of TK2 have previously been associated with an isolated myopathic form of MDS (OMIM 609560). However, more recently, neurological phenotypes have been demonstrated in patients carrying TK2 mutations, thus suggesting that loss of TK2 results in neuronal dysfunction. Here, we directly address the role of TK2 in neuronal homeostasis using a knockout mouse model. We demonstrate that in vivo loss of TK2 activity leads to a severe ataxic phenotype, accompanied by reduced mtDNA copy number and decreased steady-state levels of electron transport chain proteins in the brain. In TK2-deficient cerebellar neurons, these abnormalities are associated with impaired mitochondrial bioenergetic function, aberrant mitochondrial ultrastructure and degeneration of selected neuronal types. Overall, our findings demonstrate that TK2 deficiency leads to neuronal dysfunction in vivo, and have important implications for understanding the mechanisms of neurological impairment in MDS.

Mitochondrial dysfunction in myocardium obtained from clinically normal dogs, clinically normal anesthetized dogs, and dogs with dilated cardiomyopathy.

PubMed

Sleeper, Meg M; Rosato, Bradley P; Bansal, Seema; Avadhani, Narayan G

2012-11-01

To compare mitochondrial complex I and complex IV activity in myocardial mitochondria of clinically normal dogs, clinically normal dogs exposed to inhalation anesthesia, and dogs affected with dilated cardiomyopathy. Myocardial samples obtained from 21 euthanized dogs (6 clinically normal [control] dogs, 5 clinically normal dogs subjected to inhalation anesthesia with isoflurane prior to euthanasia, 5 dogs with juvenile-onset dilated cardiomyopathy, and 5 dogs with adult-onset dilated cardiomyopathy). Activity of mitochondrial complex I and complex IV was assayed spectrophotometrically in isolated mitochondria from left ventricular tissue obtained from the 4 groups of dogs. Activity of complex I and complex IV was significantly decreased in anesthetized dogs, compared with activities in the control dogs and dogs with juvenile-onset or adult-onset dilated cardiomyopathy. Inhalation anesthesia disrupted the electron transport chain in the dogs, which potentially led to an outburst of reactive oxygen species that caused mitochondrial dysfunction. Inhalation anesthesia depressed mitochondrial function in dogs, similar to results reported in other species. This effect is important to consider when anesthetizing animals with myocardial disease and suggested that antioxidant treatments may be beneficial in some animals. Additionally, this effect should be considered when designing studies in which mitochondrial enzyme activity will be measured. Additional studies that include a larger number of animals are warranted.

Electron transport chains of lactic acid bacteria - walking on crutches is part of their lifestyle

PubMed Central

Brooijmans, Rob; Hugenholtz, Jeroen

2009-01-01

A variety of lactic acid bacteria contain rudimentary electron transport chains that can be reconstituted by the addition of heme and menaquinone to the growth medium. These activated electron transport chains lead to higher biomass production and increased robustness, which is beneficial for industrial applications, but a major concern when dealing with pathogenic lactic acid bacteria. PMID:20948651

Tryptamine-Gallic Acid Hybrid Prevents Non-steroidal Anti-inflammatory Drug-induced Gastropathy

PubMed Central

Pal, Chinmay; Bindu, Samik; Dey, Sumanta; Alam, Athar; Goyal, Manish; Iqbal, Mohd. Shameel; Sarkar, Souvik; Kumar, Rahul; Halder, Kamal Krishna; Debnath, Mita Chatterjee; Adhikari, Susanta; Bandyopadhyay, Uday

2012-01-01

We have investigated the gastroprotective effect of SEGA (3a), a newly synthesized tryptamine-gallic acid hybrid molecule against non-steroidal anti-inflammatory drug (NSAID)-induced gastropathy with mechanistic details. SEGA (3a) prevents indomethacin (NSAID)-induced mitochondrial oxidative stress (MOS) and dysfunctions in gastric mucosal cells, which play a pathogenic role in inducing gastropathy. SEGA (3a) offers this mitoprotective effect by scavenging of mitochondrial superoxide anion (O2˙̄) and intramitochondrial free iron released as a result of MOS. SEGA (3a) in vivo blocks indomethacin-mediated MOS, as is evident from the inhibition of indomethacin-induced mitochondrial protein carbonyl formation, lipid peroxidation, and thiol depletion. SEGA (3a) corrects indomethacin-mediated mitochondrial dysfunction in vivo by restoring defective electron transport chain function, collapse of transmembrane potential, and loss of dehydrogenase activity. SEGA (3a) not only corrects mitochondrial dysfunction but also inhibits the activation of the mitochondrial pathway of apoptosis by indomethacin. SEGA (3a) inhibits indomethacin-induced down-regulation of bcl-2 and up-regulation of bax genes in gastric mucosa. SEGA (3a) also inhibits indometacin-induced activation of caspase-9 and caspase-3 in gastric mucosa. Besides the gastroprotective effect against NSAID, SEGA (3a) also expedites the healing of already damaged gastric mucosa. Radiolabeled (99mTc-labeled SEGA (3a)) tracer studies confirm that SEGA (3a) enters into mitochondria of gastric mucosal cell in vivo, and it is quite stable in serum. Thus, SEGA (3a) bears an immense potential to be a novel gastroprotective agent against NSAID-induced gastropathy. PMID:22157011

Loss of protohaem IX farnesyltransferase in mature dentate granule cells impairs short-term facilitation at mossy fibre to CA3 pyramidal cell synapses.

PubMed

Booker, Sam A; Campbell, Graham R; Mysiak, Karolina S; Brophy, Peter J; Kind, Peter C; Mahad, Don J; Wyllie, David J A

2017-03-15

Neurodegenerative disorders can exhibit dysfunctional mitochondrial respiratory chain complex IV activity. Conditional deletion of cytochrome c oxidase, the terminal enzyme in the respiratory electron transport chain of mitochondria, from hippocampal dentate granule cells in mice does not affect low-frequency dentate to CA3 glutamatergic synaptic transmission. High-frequency dentate to CA3 glutamatergic synaptic transmission and feedforward inhibition are significantly attenuated in cytochrome c oxidase-deficient mice. Intact presynaptic mitochondrial function is critical for the short-term dynamics of mossy fibre to CA3 synaptic function. Neurodegenerative disorders are characterized by peripheral and central symptoms including cognitive impairments which have been associated with reduced mitochondrial function, in particular mitochondrial respiratory chain complex IV or cytochrome c oxidase activity. In the present study we conditionally removed a key component of complex IV, protohaem IX farnesyltransferase encoded by the COX10 gene, in granule cells of the adult dentate gyrus. Utilizing whole-cell patch-clamp recordings from morphologically identified CA3 pyramidal cells from control and complex IV-deficient mice, we found that reduced mitochondrial function did not result in overt deficits in basal glutamatergic synaptic transmission at the mossy-fibre synapse because the amplitude, input-output relationship and 50 ms paired-pulse facilitation were unchanged following COX10 removal from dentate granule cells. However, trains of stimuli given at high frequency (> 20 Hz) resulted in dramatic reductions in short-term facilitation and, at the highest frequencies (> 50 Hz), also reduced paired-pulse facilitation, suggesting a requirement for adequate mitochondrial function to maintain glutamate release during physiologically relevant activity patterns. Interestingly, local inhibition was reduced, suggesting the effect observed was not restricted to synapses with CA3 pyramidal cells via large mossy-fibre boutons, but rather to all synapses formed by dentate granule cells. Therefore, presynaptic mitochondrial function is critical for the short-term dynamics of synapse function, which may contribute to the cognitive deficits observed in pathological mitochondrial dysfunction. © 2017 The Authors. The Journal of Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.

EFFECTS OF THE ORGANOCHLORINE PESTICIDE METHOXYCHLOR ON DOPAMINE METABOLITES AND TRANSPORTERS IN THE MOUSE BRAIN

PubMed Central

Schuh, Rosemary A.; Richardson, Jason R.; Gupta, Rupesh K.; Flaws, Jodi A.; Fiskum, Gary

2009-01-01

Pesticide exposure has been suggested as an increased risk factor in developing Parkinson’s disease (PD). While the molecular mechanism underlying this association is not clear, several studies have demonstrated a role for mitochondrial dysfunction and oxidative damage in PD. Although data on specific pesticides associated with PD are often lacking, several lines of evidence point to the potential involvement of the organochlorine class of pesticides. Previously, we have found that the organochlorine pesticide methoxychlor (mxc) causes mitochondrial dysfunction and oxidative stress in isolated mitochondria. Here, we sought to determine whether mxc-induced mitochondrial dysfunction results in oxidative damage and dysfunction of the dopamine system. Adult female CD1 mice were dosed with either vehicle (sesame oil) or mxc (16, 32, or 64 mg/kg/day) for 20 consecutive days. Following treatment, we observed a dose-related increase in protein carbonyl levels in non-synaptic mitochondria, indicating oxidative modification of mitochondrial proteins which may lead to mitochondrial dysfunction. Mxc exposure also caused a dose-related decrease in striatal levels of dopamine (16–31%), which were accompanied by decreased levels of the dopamine transporter (DAT; 35–48%) and the vesicular monoamine transporter 2 (VMAT2; 21–44%). Because mitochondrial dysfunction, oxidative damage, and decreased levels of DAT and VMAT2 are found in PD patients, our data suggests that mxc should be investigated as a possible candidate involved in the association of pesticides with increased risk for PD, particularly in highly-exposed populations. PMID:19459224

Endocrine manifestations related to inherited metabolic diseases in adults

PubMed Central

2012-01-01

Most inborn errors of metabolism (IEM) are recessive, genetically transmitted diseases and are classified into 3 main groups according to their mechanisms: cellular intoxication, energy deficiency, and defects of complex molecules. They can be associated with endocrine manifestations, which may be complications from a previously diagnosed IEM of childhood onset. More rarely, endocrinopathies can signal an IEM in adulthood, which should be suspected when an endocrine disorder is associated with multisystemic involvement (neurological, muscular, hepatic features, etc.). IEM can affect all glands, but diabetes mellitus, thyroid dysfunction and hypogonadism are the most frequent disorders. A single IEM can present with multiple endocrine dysfunctions, especially those involving energy deficiency (respiratory chain defects), and metal (hemochromatosis) and storage disorders (cystinosis). Non-autoimmune diabetes mellitus, thyroid dysfunction and/or goiter and sometimes hypoparathyroidism should steer the diagnosis towards a respiratory chain defect. Hypogonadotropic hypogonadism is frequent in haemochromatosis (often associated with diabetes), whereas primary hypogonadism is reported in Alström disease and cystinosis (both associated with diabetes, the latter also with thyroid dysfunction) and galactosemia. Hypogonadism is also frequent in X-linked adrenoleukodystrophy (with adrenal failure), congenital disorders of glycosylation, and Fabry and glycogen storage diseases (along with thyroid dysfunction in the first 3 and diabetes in the last). This is a new and growing field and is not yet very well recognized in adulthood despite its consequences on growth, bone metabolism and fertility. For this reason, physicians managing adult patients should be aware of these diagnoses. PMID:22284844

The Impact of Implementing a Demand Forecasting System into a Low-Income Country’s Supply Chain

PubMed Central

Mueller, Leslie E.; Haidari, Leila A.; Wateska, Angela R.; Phillips, Roslyn J.; Schmitz, Michelle M.; Connor, Diana L.; Norman, Bryan A.; Brown, Shawn T.; Welling, Joel S.; Lee, Bruce Y.

2016-01-01

OBJECTIVE To evaluate the potential impact and value of applications (e.g., ordering levels, storage capacity, transportation capacity, distribution frequency) of data from demand forecasting systems implemented in a lower-income country’s vaccine supply chain with different levels of population change to urban areas. MATERIALS AND METHODS Using our software, HERMES, we generated a detailed discrete event simulation model of Niger’s entire vaccine supply chain, including every refrigerator, freezer, transport, personnel, vaccine, cost, and location. We represented the introduction of a demand forecasting system to adjust vaccine ordering that could be implemented with increasing delivery frequencies and/or additions of cold chain equipment (storage and/or transportation) across the supply chain during varying degrees of population movement. RESULTS Implementing demand forecasting system with increased storage and transport frequency increased the number of successfully administered vaccine doses and lowered the logistics cost per dose up to 34%. Implementing demand forecasting system without storage/transport increases actually decreased vaccine availability in certain circumstances. DISCUSSION The potential maximum gains of a demand forecasting system may only be realized if the system is implemented to both augment the supply chain cold storage and transportation. Implementation may have some impact but, in certain circumstances, may hurt delivery. Therefore, implementation of demand forecasting systems with additional storage and transport may be the better approach. Significant decreases in the logistics cost per dose with more administered vaccines support investment in these forecasting systems. CONCLUSION Demand forecasting systems have the potential to greatly improve vaccine demand fulfillment, and decrease logistics cost/dose when implemented with storage and transportation increases direct vaccines. Simulation modeling can demonstrate the potential health and economic benefits of supply chain improvements. PMID:27219341

The impact of implementing a demand forecasting system into a low-income country's supply chain.

PubMed

Mueller, Leslie E; Haidari, Leila A; Wateska, Angela R; Phillips, Roslyn J; Schmitz, Michelle M; Connor, Diana L; Norman, Bryan A; Brown, Shawn T; Welling, Joel S; Lee, Bruce Y

2016-07-12

To evaluate the potential impact and value of applications (e.g. adjusting ordering levels, storage capacity, transportation capacity, distribution frequency) of data from demand forecasting systems implemented in a lower-income country's vaccine supply chain with different levels of population change to urban areas. Using our software, HERMES, we generated a detailed discrete event simulation model of Niger's entire vaccine supply chain, including every refrigerator, freezer, transport, personnel, vaccine, cost, and location. We represented the introduction of a demand forecasting system to adjust vaccine ordering that could be implemented with increasing delivery frequencies and/or additions of cold chain equipment (storage and/or transportation) across the supply chain during varying degrees of population movement. Implementing demand forecasting system with increased storage and transport frequency increased the number of successfully administered vaccine doses and lowered the logistics cost per dose up to 34%. Implementing demand forecasting system without storage/transport increases actually decreased vaccine availability in certain circumstances. The potential maximum gains of a demand forecasting system may only be realized if the system is implemented to both augment the supply chain cold storage and transportation. Implementation may have some impact but, in certain circumstances, may hurt delivery. Therefore, implementation of demand forecasting systems with additional storage and transport may be the better approach. Significant decreases in the logistics cost per dose with more administered vaccines support investment in these forecasting systems. Demand forecasting systems have the potential to greatly improve vaccine demand fulfilment, and decrease logistics cost/dose when implemented with storage and transportation increases. Simulation modeling can demonstrate the potential health and economic benefits of supply chain improvements. Copyright © 2016 Elsevier Ltd. All rights reserved.

Branched-chain amino acids and brain function.

PubMed

Fernstrom, John D

2005-06-01

Branched-chain amino acids (BCAAs) influence brain function by modifying large, neutral amino acid (LNAA) transport at the blood-brain barrier. Transport is shared by several LNAAs, notably the BCAAs and the aromatic amino acids (ArAAs), and is competitive. Consequently, when plasma BCAA concentrations rise, which can occur in response to food ingestion or BCAA administration, or with the onset of certain metabolic diseases (e.g., uncontrolled diabetes), brain BCAA concentrations rise, and ArAA concentrations decline. Such effects occur acutely and chronically. Such reductions in brain ArAA concentrations have functional consequences: biochemically, they reduce the synthesis and the release of neurotransmitters derived from ArAAs, notably serotonin (from tryptophan) and catecholamines (from tyrosine and phenylalanine). The functional effects of such neurochemical changes include altered hormonal function, blood pressure, and affective state. Although the BCAAs thus have biochemical and functional effects in the brain, few attempts have been made to characterize time-course or dose-response relations for such effects. And, no studies have attempted to identify levels of BCAA intake that might produce adverse effects on the brain. The only "model" of very high BCAA exposure is a very rare genetic disorder, maple syrup urine disease, a feature of which is substantial brain dysfunction but that probably cannot serve as a useful model for excessive BCAA intake by normal individuals. Given the known biochemical and functional effects of the BCAAs, it should be a straightforward exercise to design studies to assess dose-response relations for biochemical and functional effects and, in this context, to explore for adverse effect thresholds.

Research on Coordination of Fresh Produce Supply Chain in Big Market Sales Environment

PubMed Central

Su, Juning; Liu, Chenguang

2014-01-01

In this paper, we propose two decision models for decentralized and centralized fresh produce supply chains with stochastic supply and demand and controllable transportation time. The optimal order quantity and the optimal transportation time in these two supply chain systems are derived. To improve profits in a decentralized supply chain, based on analyzing the risk taken by each participant in the supply chain, we design a set of contracts which can coordinate this type of fresh produce supply chain with stochastic supply and stochastic demand, and controllable transportation time as well. We also obtain a value range of contract parameters that can increase profits of all participants in the decentralized supply chain. The expected profits of the decentralized setting and the centralized setting are compared with respect to given numerical examples. Furthermore, the sensitivity analyses of the deterioration rate factor and the freshness factor are performed. The results of numerical examples show that the transportation time is shorter, the order quantity is smaller, the total profit of whole supply chain is less, and the possibility of cooperation between supplier and retailer is higher for the fresh produce which is more perishable and its quality decays more quickly. PMID:24764770

Research on coordination of fresh produce supply chain in big market sales environment.

PubMed

Su, Juning; Wu, Jiebing; Liu, Chenguang

2014-01-01

In this paper, we propose two decision models for decentralized and centralized fresh produce supply chains with stochastic supply and demand and controllable transportation time. The optimal order quantity and the optimal transportation time in these two supply chain systems are derived. To improve profits in a decentralized supply chain, based on analyzing the risk taken by each participant in the supply chain, we design a set of contracts which can coordinate this type of fresh produce supply chain with stochastic supply and stochastic demand, and controllable transportation time as well. We also obtain a value range of contract parameters that can increase profits of all participants in the decentralized supply chain. The expected profits of the decentralized setting and the centralized setting are compared with respect to given numerical examples. Furthermore, the sensitivity analyses of the deterioration rate factor and the freshness factor are performed. The results of numerical examples show that the transportation time is shorter, the order quantity is smaller, the total profit of whole supply chain is less, and the possibility of cooperation between supplier and retailer is higher for the fresh produce which is more perishable and its quality decays more quickly.

In female rat heart mitochondria, oophorectomy results in loss of oxidative phosphorylation.

PubMed

Pavón, Natalia; Cabrera-Orefice, Alfredo; Gallardo-Pérez, Juan Carlos; Uribe-Alvarez, Cristina; Rivero-Segura, Nadia A; Vazquez-Martínez, Edgar Ricardo; Cerbón, Marco; Martínez-Abundis, Eduardo; Torres-Narvaez, Juan Carlos; Martínez-Memije, Raúl; Roldán-Gómez, Francisco-Javier; Uribe-Carvajal, Salvador

2017-02-01

Oophorectomy in adult rats affected cardiac mitochondrial function. Progression of mitochondrial alterations was assessed at one, two and three months after surgery: at one month, very slight changes were observed, which increased at two and three months. Gradual effects included decrease in the rates of oxygen consumption and in respiratory uncoupling in the presence of complex I substrates, as well as compromised Ca 2+ buffering ability. Malondialdehyde concentration increased, whereas the ROS-detoxifying enzyme Mn 2+ superoxide dismutase (MnSOD) and aconitase lost activity. In the mitochondrial respiratory chain, the concentration and activity of complex I and complex IV decreased. Among other mitochondrial enzymes and transporters, adenine nucleotide carrier and glutaminase decreased. 2-Oxoglutarate dehydrogenase and pyruvate dehydrogenase also decreased. Data strongly suggest that in the female rat heart, estrogen depletion leads to progressive, severe mitochondrial dysfunction. © 2017 Society for Endocrinology.

Prediction of FAD binding sites in electron transport proteins according to efficient radial basis function networks and significant amino acid pairs.

PubMed

Le, Nguyen-Quoc-Khanh; Ou, Yu-Yen

2016-07-30

Cellular respiration is a catabolic pathway for producing adenosine triphosphate (ATP) and is the most efficient process through which cells harvest energy from consumed food. When cells undergo cellular respiration, they require a pathway to keep and transfer electrons (i.e., the electron transport chain). Due to oxidation-reduction reactions, the electron transport chain produces a transmembrane proton electrochemical gradient. In case protons flow back through this membrane, this mechanical energy is converted into chemical energy by ATP synthase. The convert process is involved in producing ATP which provides energy in a lot of cellular processes. In the electron transport chain process, flavin adenine dinucleotide (FAD) is one of the most vital molecules for carrying and transferring electrons. Therefore, predicting FAD binding sites in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. We used an independent data set to evaluate the performance of the proposed method, which had an accuracy of 69.84 %. We compared the performance of the proposed method in analyzing two newly discovered electron transport protein sequences with that of the general FAD binding predictor presented by Mishra and Raghava and determined that the accuracy of the proposed method improved by 9-45 % and its Matthew's correlation coefficient was 0.14-0.5. Furthermore, the proposed method enabled reducing the number of false positives significantly and can provide useful information for biologists. We developed a method that is based on PSSM profiles and SAAPs for identifying FAD binding sites in newly discovered electron transport protein sequences. This approach achieved a significant improvement after we added SAAPs to PSSM features to analyze FAD binding proteins in the electron transport chain. The proposed method can serve as an effective tool for predicting FAD binding sites in electron transport proteins and can help biologists understand the functions of the electron transport chain, particularly those of FAD binding sites. We also developed a web server which identifies FAD binding sites in electron transporters available for academics.

Matrix Metalloproteinases and their Tissue Inhibitors in Cardiac Amyloidosis: Relationship to Structural, Functional Myocardial Changes and to Light Chain Amyloid Deposition

PubMed Central

Biolo, Andreia; Ramamurthy, Sujata; Connors, Lawreen H.; O'Hara, Carl J.; Meier-Ewert, Hans K.; Hoo, Pamela T. Soo; Sawyer, Douglas B.; Seldin, David S.; Sam, Flora

2009-01-01

Background Cardiac amyloidosis is characterized by amyloid infiltration resulting in extracellular matrix (ECM) disruption. Amyloid cardiomyopathy due to immunoglobulin light chain protein (AL-CMP) deposition, has an accelerated clinical course and a worse prognosis compared to non-light chain cardiac amyloidoses i.e., forms associated with wild-type or mutated transthyretin (TTR). We therefore tested the hypothesis that determinants of proteolytic activity of the ECM, the matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs), would have distinct patterns and contribute to the pathogenesis of AL-CMP vs. TTR. Methods / Results We studied 40 patients with systemic amyloidosis: 10 AL-CMP patients, 20 patients with TTR-associated forms of cardiac amyloidosis, i.e. senile systemic amyloidois (SSA, involving wild-type TTR) or mutant TTR (ATTR), and 10 patients with AL amyloidosis without cardiac involvement. Serum MMP-2 and −9, TIMP-1, −2 and −4, brain natriuretic peptide (BNP) values and echocardiography were determined. AL-CMP and SSA-ATTR groups had similar degrees of increased left ventricular wall thickness (LVWT). However, BNP, MMP-9 and TIMP-1 levels were distinctly elevated accompanied by marked diastolic dysfunction in the AL-CMP group vs. no or minimal increases in the SSA-ATTR group. BNP, MMPs and TIMPs were not correlated with the degree of LVWT but were correlated to each other and to measures of diastolic dysfunction. Immunostaining of human endomyocardial biopsies showed diffuse expression of MMP-9 and TIMP-1 in AL-CMP and limited expression in SSA or ATTR hearts. Conclusions Despite comparable LVWT with TTR-related cardiac amyloidosis, AL-CMP patients have higher BNP, MMPs and TIMPs, which correlated with diastolic dysfunction. These findings suggest a relationship between light chains and ECM proteolytic activation that may play an important role in the functional and clinical manifestations of AL-CMP, distinct from the other non-light chain cardiac amyloidoses. PMID:19808299

The electrical and thermal transport properties of hybrid zigzag graphene-BN nanoribbons

NASA Astrophysics Data System (ADS)

Gao, Song; Lu, Wei; Zheng, Guo-Hui; Jia, Yalei; Ke, San-Huang

2017-06-01

The electron and phonon transport in hybrid graphene-BN zigzag nanoribbons are investigated by the nonequilibrium Green’s function method combined with density functional theory calculations. A 100% spin-polarized electron transport in a large energy window around the Fermi level is found and this behavior is independent of the ribbon width as long as there contain 3 zigzag carbon chains. The phonon transport calculations show that the ratio of C-chain number to BN-chain number will modify the thermal conductance of the hybrid nanoribbon in a complicated manner.

Heat conduction in diatomic chains with correlated disorder

NASA Astrophysics Data System (ADS)

Savin, Alexander V.; Zolotarevskiy, Vadim; Gendelman, Oleg V.

2017-01-01

The paper considers heat transport in diatomic one-dimensional lattices, containing equal amounts of particles with different masses. Ordering of the particles in the chain is governed by single correlation parameter - the probability for two neighboring particles to have the same mass. As this parameter grows from zero to unity, the structure of the chain varies from regular staggering chain to completely random configuration, and then - to very long clusters of particles with equal masses. Therefore, this correlation parameter allows a control of typical cluster size in the chain. In order to explore different regimes of the heat transport, two interatomic potentials are considered. The first one is an infinite potential wall, corresponding to instantaneous elastic collisions between the neighboring particles. In homogeneous chains such interaction leads to an anomalous heat transport. The other one is classical Lennard-Jones interatomic potential, which leads to a normal heat transport. The simulations demonstrate that the correlated disorder of the particle arrangement does not change the convergence properties of the heat conduction coefficient, but essentially modifies its value. For the collision potential, one observes essential growth of the coefficient for fixed chain length as the limit of large homogeneous clusters is approached. The thermal transport in these models remains superdiffusive. In the Lennard-Jones chain the effect of correlation appears to be not monotonous in the limit of low temperatures. This behavior stems from the competition between formation of long clusters mentioned above, and Anderson localization close to the staggering ordered state.

The single IGF-1 partial deficiency is responsible for mitochondrial dysfunction and is restored by IGF-1 replacement therapy.

PubMed

Olleros Santos-Ruiz, M; Sádaba, M C; Martín-Estal, I; Muñoz, U; Sebal Neira, C; Castilla-Cortázar, I

2017-08-01

We previously described in cirrhosis and aging, both conditions of IGF-1 deficiency, a clear hepatic mitochondrial dysfunction with increased oxidative damage. In both conditions, the hepatic mitochondrial function was improved with low doses of IGF-1. The aim of this work was to explore if the only mere IGF-1 partial deficiency, without any exogenous insult, is responsible for hepatic mitochondrial dysfunction. Heterozygous (igf1 +/- ) mice were divided into two groups: untreated and treated mice with low doses of IGF-1. WT group was used as controls. Parameters of hepatic mitochondrial function were determined by flow cytometry, antioxidant enzyme activities were determined by spectrophotometry, and electron chain transport enzyme levels were determined by immunohistochemistry and immunofluorescence analyses. Liver expression of genes coding for proteins involved in mitochondrial protection and apoptosis was studied by microarray analysis and RT-qPCR. Hz mice showed a significant reduction in hepatic mitochondrial membrane potential (MMP) and ATPase activity, and an increase in intramitochondrial free radical production and proton leak rates, compared to controls. These parameters were normalized by IGF-1 replacement therapy. No significant differences were found between groups in oxygen consumption and antioxidant enzyme activities, except for catalase, whose activity was increased in both Hz groups. Relevant genes coding for proteins involved in mitochondrial protection and survival were altered in Hz group and were reverted to normal in Hz+IGF-1 group. The mere IGF-1 partial deficiency is per se associated with hepatic mitochondrial dysfunction sensitive to IGF-1 replacement therapy. Results in this work prove that IGF-1 is involved in hepatic mitochondrial protection, because it is able to reduce free radical production, oxidative damage and apoptosis. All these IGF-1 actions are mediated by the modulation of the expression of genes encoding citoprotective and antiapoptotic proteins. Copyright © 2017. Published by Elsevier Ltd.

Relation of Mitochondrial Oxygen Consumption in Peripheral Blood Mononuclear Cells to Vascular Function in Type 2 Diabetes Mellitus

PubMed Central

Hartman, Mor-Li; Shirihai, Orian S.; Holbrook, Monika; Xu, Guoquan; Kocherla, Marsha; Shah, Akash; Fetterman, Jessica L.; Kluge, Matthew A.; Frame, Alissa A.; Hamburg, Naomi M.; Vita, Joseph A.

2014-01-01

Recent studies have shown mitochondrial dysfunction and increased production of reactive oxygen species in peripheral blood mononuclear cells (PBMC’s) and endothelial cells from patients with diabetes mellitus. Mitochondria oxygen consumption is coupled to ATP production and also occurs in an uncoupled fashion during formation of reactive oxygen species by components of the electron transport chain and other enzymatic sites. We therefore hypothesized that diabetes would be associated with higher total and uncoupled oxygen consumption in PBMC’s that would correlate with endothelial dysfunction. We developed a method to measure oxygen consumption in freshly isolated PBMC’s and applied it to 26 patients with type 2 diabetes mellitus and 28 non-diabetic controls. Basal (192±47 vs. 161±44 pMoles/min, P=0.01), uncoupled (64±16 vs. 53±16 pMoles/min, P=0.007), and maximal (795±87 vs. 715±128 pMoles/min, P=0.01) oxygen consumption rates were higher in diabetic patients compared to controls. There were no significant correlations between oxygen consumption rates and endothelium-dependent flow-mediated dilation measured by vascular ultrasound. Non-endothelium-dependent nitroglycerin-mediated dilation was lower in diabetics (10.1±6.6 vs. 15.8±4.8%, P=0.03) and correlated with maximal oxygen consumption (R= −0.64, P=0.001). In summary, we found that diabetes mellitus is associated with a pattern of mitochondrial oxygen consumption consistent with higher production of reactive oxygen species. The correlation between oxygen consumption and nitroglycerin-mediated dilation may suggest a link between mitochondrial dysfunction and vascular smooth muscle cell dysfunction that merits further study. Finally, the described method may have utility for assessment of mitochondrial function in larger scale observational and interventional studies in humans. PMID:24558030

Use of side-chain for rational design of n-type diketopyrrolopyrrole-based conjugated polymers: what did we find out?

PubMed

Kanimozhi, Catherine; Yaacobi-Gross, Nir; Burnett, Edmund K; Briseno, Alejandro L; Anthopoulos, Thomas D; Salzner, Ulrike; Patil, Satish

2014-08-28

The primary role of substituted side chains in organic semiconductors is to increase their solubility in common organic solvents. In the recent past, many literature reports have suggested that the side chains play a critical role in molecular packing and strongly impact the charge transport properties of conjugated polymers. In this work, we have investigated the influence of side-chains on the charge transport behavior of a novel class of diketopyrrolopyrrole (DPP) based alternating copolymers. To investigate the role of side-chains, we prepared four diketopyrrolopyrrole-diketopyrrolopyrrole (DPP-DPP) conjugated polymers with varied side-chains and carried out a systematic study of thin film microstructure and charge transport properties in polymer thin-film transistors (PTFTs). Combining results obtained from grazing incidence X-ray diffraction (GIXD) and charge transport properties in PTFTs, we conclude side-chains have a strong influence on molecular packing, thin film microstructure, and the charge carrier mobility of DPP-DPP copolymers. However, the influence of side-chains on optical properties was moderate. The preferential "edge-on" packing and dominant n-channel behavior with exceptionally high field-effect electron mobility values of >1 cm(2) V(-1) s(-1) were observed by incorporating hydrophilic (triethylene glycol) and hydrophobic side-chains of alternate DPP units. In contrast, moderate electron and hole mobilities were observed by incorporation of branched hydrophobic side-chains. This work clearly demonstrates that the subtle balance between hydrophobicity and hydrophilicity induced by side-chains is a powerful strategy to alter the molecular packing and improve the ambipolar charge transport properties in DPP-DPP based conjugated polymers. Theoretical analysis supports the conclusion that the side-chains influence polymer properties through morphology changes, as there is no effect on the electronic properties in the gas phase. The exceptional electron mobility is at least partially a result of the strong intramolecular conjugation of the donor and acceptor as evidenced by the unusually wide conduction band of the polymer.

Copper Transporter ATP7A Protects Against Endothelial Dysfunction in Type 1 Diabetic Mice by Regulating Extracellular Superoxide Dismutase

PubMed Central

Sudhahar, Varadarajan; Urao, Norifumi; Oshikawa, Jin; McKinney, Ronald D.; Llanos, Roxana M.; Mercer, Julian F.B.; Ushio-Fukai, Masuko; Fukai, Tohru

2013-01-01

Oxidative stress and endothelial dysfunction contribute to vascular complication in diabetes. Extracellular superoxide dismutase (SOD3) is one of the key antioxidant enzymes that obtains copper via copper transporter ATP7A. SOD3 is secreted from vascular smooth muscles cells (VSMCs) and anchors at the endothelial surface. The role of SOD3 and ATP7A in endothelial dysfunction in type 1 diabetes mellitus (T1DM) is entirely unknown. Here we show that the specific activity of SOD3, but not SOD1, is decreased, which is associated with increased O2•− production in aortas of streptozotocin-induced and genetically induced Ins2Akita T1DM mice. Exogenous copper partially rescued SOD3 activity in isolated T1DM vessels. Functionally, acetylcholine-induced, endothelium-dependent relaxation is impaired in T1DM mesenteric arteries, which is rescued by SOD mimetic tempol or gene transfer of SOD3. Mechanistically, ATP7A expression in T1DM vessels is dramatically decreased whereas other copper transport proteins are not altered. T1DM-induced endothelial dysfunction and decrease of SOD3 activity are rescued in transgenic mice overexpressing ATP7A. Furthermore, SOD3-deficient T1DM mice or ATP7A mutant T1DM mice augment endothelial dysfunction and vascular O2•− production versus T1DM mice. These effects are in part due to hypoinsulinemia in T1DM mice, since insulin treatment, but not high glucose, increases ATP7A expression in VSMCs and restores SOD3 activity in the organoid culture of T1DM vessels. In summary, a decrease in ATP7A protein expression contributes to impaired SOD3 activity, resulting in O2•− overproduction and endothelial dysfunction in blood vessels of T1DM. Thus, restoring copper transporter function is an essential therapeutic approach for oxidant stress–dependent vascular and metabolic diseases. PMID:23884884

Beyond Ussing's chambers: contemporary thoughts on integration of transepithelial transport.

PubMed

Herrmann, Jeremy R; Turner, Jerrold R

2016-03-15

In the mid-20th century, Hans Ussing developed a chamber that allowed for the simultaneous measurement of current and labeled probe flux across epithelia. Using frog skin as a model, Ussing used his results to propose mechanisms of transcellular Na(+) and K(+) transport across apical (exterior/luminal) and basolateral (interior) membranes that is essentially unchanged today. Others took advantage of Ussing's chambers to study mucosal tissues, including bladder and intestines. It quickly became clear that, in some tissues, passive paracellular flux, i.e., across the tight junction, was an important component of overall transepithelial transport. Subsequent work demonstrated that activation of the apical Na(+)-glucose cotransporter SGLT1 regulated paracellular permeability such that intestinal paracellular transport could coordinate with and amplify transcellular transport. Intermediates in this process include activation of p38 MAPK, the apical Na(+)/H(+) exchanger NHE3, and myosin light chain kinase (MLCK). Investigators then focused on these processes in disease. They found that TNF induces barrier dysfunction via MLCK activation and downstream caveolin-1-dependent endocytosis of the tight junction protein occludin. TNF also inhibited NHE3, and both barrier loss and PKCα-dependent NHE3 inhibition were required for TNF-induced acute diarrhea, emphasizing the interplay between transcellular and paracellular transport. Finally, studies using immune-mediated inflammatory bowel disease models showed that mice lacking epithelial MLCK were initially protected, but became ill as epithelial damage progressed and provided a tight junction-independent means of barrier loss. None of these advances would have been possible without the insights provided by Ussing and others using Ussing's ingenious, and still useful, chambers. Copyright © 2016 the American Physiological Society.

Nonequilibrium generalised Langevin equation for the calculation of heat transport properties in model 1D atomic chains coupled to two 3D thermal baths.

PubMed

Ness, H; Stella, L; Lorenz, C D; Kantorovich, L

2017-04-28

We use a generalised Langevin equation scheme to study the thermal transport of low dimensional systems. In this approach, the central classical region is connected to two realistic thermal baths kept at two different temperatures [H. Ness et al., Phys. Rev. B 93, 174303 (2016)]. We consider model Al systems, i.e., one-dimensional atomic chains connected to three-dimensional baths. The thermal transport properties are studied as a function of the chain length N and the temperature difference ΔT between the baths. We calculate the transport properties both in the linear response regime and in the non-linear regime. Two different laws are obtained for the linear conductance versus the length of the chains. For large temperatures (T≳500 K) and temperature differences (ΔT≳500 K), the chains, with N>18 atoms, present a diffusive transport regime with the presence of a temperature gradient across the system. For lower temperatures (T≲500 K) and temperature differences (ΔT≲400 K), a regime similar to the ballistic regime is observed. Such a ballistic-like regime is also obtained for shorter chains (N≤15). Our detailed analysis suggests that the behaviour at higher temperatures and temperature differences is mainly due to anharmonic effects within the long chains.

Using Adobe Flash animations of electron transport chain to teach and learn biochemistry.

PubMed

Teplá, Milada; Klímová, Helena

2015-01-01

Teaching the subject of the electron transport chain is one of the most challenging aspects of the chemistry curriculum at the high school level. This article presents an educational program called "Electron Transport Chain" which consists of 14 visual animations including a biochemistry quiz. The program was created in the Adobe Flash CS3 Professional animation program and is designed for high school chemistry students. Our goal is to develop educational materials that facilitate the comprehension of this complex subject through dynamic animations which show the course of the electron transport chain and simultaneously explain its nature. We record the process of the electron transport chain, including connections with oxidative phosphorylation, in such a way as to minimize the occurrence of discrepancies in interpretation. The educational program was evaluated in high schools through the administration of a questionnaire, which contained 12 opened-ended items and which required participants to evaluate the graphics of the animations, chemical content, student preferences, and its suitability for high school biochemistry teaching. © 2015 The International Union of Biochemistry and Molecular Biology.

Interface-facilitated energy transport in coupled Frenkel-Kontorova chains

NASA Astrophysics Data System (ADS)

Su, Rui-Xia; Yuan, Zong-Qiang; Wang, Jun; Zheng, Zhi-Gang

2016-04-01

The role of interface couplings on the energy transport of two coupled Frenkel-Kontorova (FK) chains is explored through numerical simulations. In general, it is expected that the interface couplings result in the suppression of heat conduction through the coupled system due to the additional interface phonon-phonon scattering. In the present paper, it is found that the thermal conductivity increases with increasing intensity of interface interactions for weak inter-chain couplings, whereas the heat conduction is suppressed by the interface interaction in the case of strong inter-chain couplings. Based on the phonon spectral energy density method, we demonstrate that the enhancement of energy transport results from the excited phonon modes (in addition to the intrinsic phonon modes), while the strong interface phonon-phonon scattering results in the suppressed energy transport.

DOS cones along atomic chains

NASA Astrophysics Data System (ADS)

Kwapiński, Tomasz

2017-03-01

The electron transport properties of a linear atomic chain are studied theoretically within the tight-binding Hamiltonian and the Green’s function method. Variations of the local density of states (DOS) along the chain are investigated. They are crucial in scanning tunnelling experiments and give important insight into the electron transport mechanism and charge distribution inside chains. It is found that depending on the chain parity the local DOS at the Fermi level can form cone-like structures (DOS cones) along the chain. The general condition for the local DOS oscillations is obtained and the linear behaviour of the local density function is confirmed analytically. DOS cones are characterized by a linear decay towards the chain which is in contrast to the propagation properties of charge density waves, end states and Friedel oscillations in one-dimensional systems. We find that DOS cones can appear due to non-resonant electron transport, the spin-orbit scattering or for chains fabricated on a substrate with localized electrons. It is also shown that for imperfect chains (e.g. with a reduced coupling strength between two neighboring sites) a diamond-like structure of the local DOS along the chain appears.

NITROTYROSINATION OF A TUBULIN INDUCES EPITHELIAL BARRIER DYSFUNCTION

EPA Science Inventory

Nitrotyrosination of a-Tubulin Induces Epithelial Transport Dysfunction. Yuh-Chin Huang, Lisa Dailey, Wen-Li Zhang and Ilona Jaspers. ORD, Environmental Protection Agency and CEMLB, University of North Carolina

a-Tubulin undergoes a cyclic removal and readdition of tyrosin...

Hydrogen peroxide scavenger, catalase, alleviates ion transport dysfunction in murine colitis.

PubMed

Barrett, Kim E; McCole, Declan F

2016-11-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H 2 O 2 ) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhoea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H 2 O 2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H 2 O 2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H 2 O. Mice were administered either pegylated catalase or saline at day -1, 0 and +1 of DSS treatment. Ion transport responses to the Ca 2+ -dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic I sc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na + -K + -2Cl - cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhoea. © 2016 John Wiley & Sons Australia, Ltd.

The Hydrogen Peroxide Scavenger, Catalase, Alleviates Ion Transport Dysfunction in Murine Colitis

PubMed Central

Barrett, Kim E.; McCole, Declan F.

2016-01-01

Reactive oxygen species (ROS) such as hydrogen peroxide (H2O2) contribute to epithelial damage and ion transport dysfunction (key events in inflammatory diarrhea) in inflammatory bowel disease (IBD). The aim of this study was to identify if H2O2 mediates suppression of colonic ion transport function in the murine dextran sulfate sodium (DSS) colitis model by using the H2O2 degrading enzyme, catalase. Colitis was induced by administering DSS (4%) in drinking water for 5 days followed by 3 days on normal H2O. Mice were administered either pegylated-catalase or saline at day −1, 0 and +1 of DSS treatment. Ion transport responses to the Ca2+-dependent agonist, carbachol (CCh), or the cAMP-dependent agonist, forskolin, were measured across distal colonic mucosa mounted in Ussing chambers. Parameters of DSS-induced inflammation (loss in body weight, decreased colon length, altered stool consistency), were only partially alleviated by catalase while histology was only minimally improved. However, catalase significantly reversed the DSS-induced reduction in baseline ion transport as well as colonic Isc responses to CCh. However, ion transport responses to forskolin were not significantly restored. Catalase also reduced activation of ERK MAP kinase in the setting of colitis, and increased expression of the Na+-K+-2Cl− cotransporter, NKCC1, consistent with restoration of ion transport function. Ex vivo treatment of inflamed colonic mucosae with catalase also partially restored ion transport function. Therefore, catalase partially prevents, and rescues, the loss of ion transport properties in DSS colitis even in the setting of unresolved tissue inflammation. These findings indicate a prominent role for ROS in ion transport dysfunction in colitis and may suggest novel strategies for the treatment of inflammatory diarrhea. PMID:27543846

Microemulsions containing long-chain oil ethyl oleate improve the oral bioavailability of piroxicam by increasing drug solubility and lymphatic transportation simultaneously.

PubMed

Xing, Qiao; Song, Jia; You, Xiuhua; Xu, Dongling; Wang, Kexin; Song, Jiaqi; Guo, Qin; Li, Pengyu; Wu, Chuanbin; Hu, Haiyan

2016-09-25

Drug solubility and lymphatic transport enhancements are two main pathways to improve drug oral bioavailability for microemulsions. However, it is not easy to have both achieved simultaneously because excipients used for improving lymphatic transport were usually insufficient in forming microemulsions and solubilizing drugs. Our research is to explore whether ethyl oleate, an oil effective in developing microemulsions with desired solubilizing capability, could increase bioavailability to a higher extent by enhancing lymphatic transport. As a long-chain oil, ethyl oleate won larger microemulsion area than short-chain tributyrin and medium-chain GTCC. In contrast, long-chain soybean oil failed to prepare microemulsions. The solubility of piroxicam in ethyl oleate microemulsions (ME-C) increased by about 30 times than in water. ME-C also won significantly higher AUC0-t compared with tributyrin microemulsions (ME-A) and GTCC microemulsions (ME-B). Oral bioavailability in ME-C decreased by 38% after lymphatic transport was blocked by cycloheximide, severer than those in ME-A and ME-B (8% and 34%). These results suggest that improving lymphatic transport and solubility simultaneously might be a novel strategy to increase drug oral bioavailability to a higher extent than increasing solubility only. Ethyl oleate is a preferred oil candidate due to its integrated advantages of high solubilizing capability, large microemulsion area and effective lymphatic transport. Copyright © 2016 Elsevier B.V. All rights reserved.

Anomalous charge transport in conjugated polymers reveals underlying mechanisms of trapping and percolation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Mollinger, Sonya A.; Salleo, Alberto; Spakowitz, Andrew J.

While transport in conjugated polymers has many similarities to that in crystalline inorganic materials, several key differences reveal the unique relationship between the morphology of polymer films and the charge mobility. We develop a model that directly incorporates the molecular properties of the polymer film and correctly predicts these unique transport features. At low degree of polymerization, the increase of the mobility with the polymer chain length reveals trapping at chain ends, and saturation of the mobility at high degree of polymerization results from conformational traps within the chains. Similarly, the inverse field dependence of the mobility reveals that transportmore » on single polymer chains is characterized by the ability of the charge to navigate around kinks and loops in the chain. Lastly, these insights emphasize the connection between the polymer conformations and the transport and thereby offer a route to designing improved device morphologies through molecular design and materials processing.« less

Anomalous charge transport in conjugated polymers reveals underlying mechanisms of trapping and percolation

DOE PAGES

Mollinger, Sonya A.; Salleo, Alberto; Spakowitz, Andrew J.

2016-11-10

While transport in conjugated polymers has many similarities to that in crystalline inorganic materials, several key differences reveal the unique relationship between the morphology of polymer films and the charge mobility. We develop a model that directly incorporates the molecular properties of the polymer film and correctly predicts these unique transport features. At low degree of polymerization, the increase of the mobility with the polymer chain length reveals trapping at chain ends, and saturation of the mobility at high degree of polymerization results from conformational traps within the chains. Similarly, the inverse field dependence of the mobility reveals that transportmore » on single polymer chains is characterized by the ability of the charge to navigate around kinks and loops in the chain. Lastly, these insights emphasize the connection between the polymer conformations and the transport and thereby offer a route to designing improved device morphologies through molecular design and materials processing.« less

Aldehydic load and aldehyde dehydrogenase 2 profile during the progression of post-myocardial infarction cardiomyopathy: benefits of Alda-1

PubMed Central

Gomes, Katia M.S.; Bechara, Luiz R.G.; Lima, Vanessa M.; Ribeiro, Márcio A.C.; Campos, Juliane C.; Dourado, Paulo M.; Kowaltowski, Alicia J.; Mochly-Rosen, Daria; Ferreira, Julio C.B.

2015-01-01

Background/Objectives We previously demonstrated that reducing cardiac aldehydic load by aldehyde dehydrogenase 2 (ALDH2), a mitochondrial enzyme responsible for metabolizing the major lipid peroxidation product, protects against acute ischemia/reperfusion injury and chronic heart failure. However, time-dependent changes in ALDH2 profile, aldehydic load and mitochondrial bioenergetics during progression of post-myocardial infarction (post-MI) cardiomyopathy is unknown and should be established to determine the optimal time window for drug treatment. Methods Here we characterized cardiac ALDH2 activity and expression, lipid peroxidation, 4-hydroxy-2-nonenal (4-HNE) adduct formation, glutathione pool and mitochondrial energy metabolism and H2O2 release during the 4 weeks after permanent left anterior descending (LAD) coronary artery occlusion in rats. Results We observed a sustained disruption of cardiac mitochondrial function during the progression of post-MI cardiomyopathy, characterized by >50% reduced mitochondrial respiratory control ratios and up to 2 fold increase in H2O2 release. Mitochondrial dysfunction was accompanied by accumulation of cardiac and circulating lipid peroxides and 4-HNE protein adducts and down-regulation of electron transport chain complexes I and V. Moreover, increased aldehydic load was associated with a 90% reduction in cardiac ALDH2 activity and increased glutathione pool. Further supporting an ALDH2 mechanism, sustained Alda-1 treatment (starting 24hrs after permanent LAD occlusion surgery) prevented aldehydic overload, mitochondrial dysfunction and improved ventricular function in post-MI cardiomyopathy rats. Conclusion Taken together, our findings demonstrate a disrupted mitochondrial metabolism along with an insufficient cardiac ALDH2-mediated aldehyde clearance during the progression of ventricular dysfunction, suggesting a potential therapeutic value of ALDH2 activators during the progression of post-myocardial infarction cardiomyopathy. PMID:25464432

Sirtuin signaling controls mitochondrial function in glycogen storage disease type Ia.

PubMed

Cho, Jun-Ho; Kim, Goo-Young; Mansfield, Brian C; Chou, Janice Y

2018-05-08

Glycogen storage disease type Ia (GSD-Ia) deficient in glucose-6-phosphatase-α (G6Pase-α) is a metabolic disorder characterized by impaired glucose homeostasis and a long-term complication of hepatocellular adenoma/carcinoma (HCA/HCC). Mitochondrial dysfunction has been implicated in GSD-Ia but the underlying mechanism and its contribution to HCA/HCC development remain unclear. We have shown that hepatic G6Pase-α deficiency leads to downregulation of sirtuin 1 (SIRT1) signaling that underlies defective hepatic autophagy in GSD-Ia. SIRT1 is a NAD + -dependent deacetylase that can deacetylate and activate peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α), a master regulator of mitochondrial integrity, biogenesis, and function. We hypothesized that downregulation of hepatic SIRT1 signaling in G6Pase-α-deficient livers impairs PGC-1α activity, leading to mitochondrial dysfunction. Here we show that the G6Pase-α-deficient livers display defective PGC-1α signaling, reduced numbers of functional mitochondria, and impaired oxidative phosphorylation. Overexpression of hepatic SIRT1 restores PGC-1α activity, normalizes the expression of electron transport chain components, and increases mitochondrial complex IV activity. We have previously shown that restoration of hepatic G6Pase-α expression normalized SIRT1 signaling. We now show that restoration of hepatic G6Pase-α expression also restores PGC-1α activity and mitochondrial function. Finally, we show that HCA/HCC lesions found in G6Pase-α-deficient livers contain marked mitochondrial and oxidative DNA damage. Taken together, our study shows that downregulation of hepatic SIRT1/PGC-1α signaling underlies mitochondrial dysfunction and that oxidative DNA damage incurred by damaged mitochondria may contribute to HCA/HCC development in GSD-Ia.

Mitochondrial dysfunction in H9c2 cells during ischemia and amelioration with Tribulus terrestris L.

PubMed

Reshma, P L; Sainu, Neethu S; Mathew, Anil K; Raghu, K G

2016-05-01

The present study investigates the protective effect of partially characterized Tribulus terrestris L. fruit methanol extract against mitochondrial dysfunction in cell based (H9c2) myocardial ischemia model. To induce ischemia, the cells were maintained in an ischemic buffer (composition in mM -137 NaCl, 12 KCl, 0.5 MgCl2, 0.9 CaCl2, 20 HEPES, 20 2-deoxy-d-glucose, pH-6.2) at 37°C with 0.1% O2, 5% CO2, and 95% N2 in a hypoxia incubator for 1h. Cells were pretreated with various concentrations of T. terrestris L. fruit methanol extract (10 and 25μg/ml) and Cyclosporin A (1μM) for 24h prior to the induction of ischemia. Different parameters like lactate dehydrogenase release, total antioxidant capacity, glutathione content and antioxidant enzymes were investigated. Studies were conducted on mitochondria by analyzing alterations in mitochondrial membrane potential, integrity, and dynamics (fission and fusion proteins - Mfn1, Mfn2, OPA1, Drp1 and Fis1). Various biochemical processes in mitochondria like activity of electron transport chain (ETC) complexes, oxygen consumption and ATP production was measured. Ischemia for 1h caused a significant (p≤0.05) increase in LDH leakage, decrease in antioxidant activity and caused mitochondrial dysfunction. T. terrestris L. fruit methanol extract pretreatment was found effective in safeguarding mitochondria via its antioxidant potential, mediated through various bioactives. HPLC of T. terrestris L. fruit methanol extract revealed the presence of ferulic acid, phloridzin and diosgenin. T. terrestris L. fruit ameliorate ischemic insult in H9c2 cells by safeguarding mitochondrial function. This validates the use of T. terrestris L. against heart disorders. Copyright © 2016 Elsevier Inc. All rights reserved.

TiO2 nanoparticles cause mitochondrial dysfunction, activate inflammatory responses, and attenuate phagocytosis in macrophages: A proteomic and metabolomic insight.

PubMed

Chen, Qun; Wang, Ningning; Zhu, Mingjiang; Lu, Jianhong; Zhong, Huiqin; Xue, Xinli; Guo, Shuoyuan; Li, Min; Wei, Xinben; Tao, Yongzhen; Yin, Huiyong

2018-05-01

Titanium dioxide nanoparticles (TiO 2 NPs) are widely used in food and cosmetics but the health impact of human exposure remains poorly defined. Emerging evidence suggests that TiO 2 NPs may elicit immune responses by acting on macrophages. Our proteomic study showed that treatment of macrophages with TiO 2 NPs led to significant re-organization of cell membrane and activation of inflammation. These observations were further corroborated with transmission electron microscopy (TEM) experiments, which demonstrated that TiO 2 NPs were trapped inside of multi-vesicular bodies (MVB) through endocytotic pathways. TiO 2 NP caused significant mitochondrial dysfunction by increasing levels of mitochondrial reactive oxygen species (ROS), decreasing ATP generation, and decreasing metabolic flux in tricarboxylic acid (TCA) cycle from 13 C-labelled glutamine using GC-MS-based metabolic flux analysis. Further lipidomic analysis showed that TiO 2 NPs significantly decreased levels of cardiolipins, an important class of mitochondrial phospholipids for maintaining proper function of electron transport chains. Furthermore, TiO 2 NP exposure activates inflammatory responses by increasing mRNA levels of TNF-α, iNOS, and COX-2. Consistently, our targeted metabolomic analysis showed significantly increased production of COX-2 metabolites including PGD 2 , PGE 2 , and 15d-PGJ 2 . In addition, TiO 2 NP also caused significant attenuation of phagocytotic function of macrophages. In summary, our studies utilizing multiple powerful omic techniques suggest that human exposure of TiO 2 NPs may have profound impact on macrophage function through activating inflammatory responses and causing mitochondrial dysfunction without physical presence in mitochondria. Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.

Mitochondrial pharmacology: electron transport chain bypass as strategies to treat mitochondrial dysfunction.

PubMed

Atamna, Hani; Mackey, Jeanette; Dhahbi, Joseph M

2012-01-01

Mitochondrial dysfunction (primary or secondary) is detrimental to intermediary metabolism. Therapeutic strategies to treat/prevent mitochondrial dysfunction could be valuable for managing metabolic and age-related disorders. Here, we review strategies proposed to treat mitochondrial impairment. We then concentrate on redox-active agents, with mild-redox potential, who shuttle electrons among specific cytosolic or mitochondrial redox-centers. We propose that specific redox agents with mild redox potential (-0.1 V; 0.1 V) improve mitochondrial function because they can readily donate or accept electrons in biological systems, thus they enhance metabolic activity and prevent reactive oxygen species (ROS) production. These agents are likely to lack toxic effects because they lack the risk of inhibiting electron transfer in redox centers. This is different from redox agents with strong negative (-0.4 V; -0.2 V) or positive (0.2 V; 0.4 V) redox potentials who alter the redox status of redox-centers (i.e., become permanently reduced or oxidized). This view has been demonstrated by testing the effect of several redox active agents on cellular senescence. Methylene blue (MB, redox potential ≅10 mV) appears to readily cycle between the oxidized and reduced forms using specific mitochondrial and cytosolic redox centers. MB is most effective in delaying cell senescence and enhancing mitochondrial function in vivo and in vitro. Mild-redox agents can alter the biochemical activity of specific mitochondrial components, which then in response alters the expression of nuclear and mitochondrial genes. We present the concept of mitochondrial electron-carrier bypass as a potential result of mild-redox agents, a method to prevent ROS production, improve mitochondrial function, and delay cellular aging. Thus, mild-redox agents may prevent/delay mitochondria-driven disorders. Copyright © 2012 International Union of Biochemistry and Molecular Biology, Inc.

Respiratory chain inhibition: one more feature to propose MPTP intoxication as a Leigh syndrome model.

PubMed

Da Costa, Barbara; Dumon, Elodie; Le Moigno, Laurence; Bodard, Sylvie; Castelnau, Pierre; Letellier, Thierry; Rocher, Christophe

2016-10-01

1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) intoxicated mice have been widely used to model the loss of dopaminergic neurons. As this treatment leads to basal ganglia degeneration, it was proposed that MPTP mice could be used as a model of Leigh syndrome. However, this mitochondrial pathology is biochemically characterized by a respiratory chain dysfunction. To determine if MPTP can affect in vivo mitochondria function, we measured the activities of mitochondrial respiratory chain complexes in several tissues. Our results show that MPTP affects mainly mitochondrial respiratory chain complex IV, as found in Leigh Syndrome, confirming that acute MPTP intoxicated mice are a good model of Leigh Syndrome.

Room-temperature ballistic energy transport in molecules with repeating units

DOE Office of Scientific and Technical Information (OSTI.GOV)

Rubtsova, Natalia I.; Nyby, Clara M.; Zhang, Hong

2015-06-07

In materials, energy can propagate by means of two limiting regimes: diffusive and ballistic. Ballistic energy transport can be fast and efficient and often occurs with a constant speed. Using two-dimensional infrared spectroscopy methods, we discovered ballistic energy transport via individual polyethylene chains with a remarkably high speed of 1440 m/s and the mean free path length of 14.6 Å in solution at room temperature. Whereas the transport via the chains occurs ballistically, the mechanism switches to diffusive with the effective transport speed of 130 m/s at the end-groups attached to the chains. A unifying model of the transport inmore » molecules is presented with clear time separation and additivity among the transport along oligomeric fragments, which occurs ballistically, and the transport within the disordered fragments, occurring diffusively. The results open new avenues for making novel elements for molecular electronics, including ultrafast energy transporters, controlled chemical reactors, and sub-wavelength quantum nanoseparators.« less

Cost Effective Measures to Reduce CO2 Emissions in the Air Freight Sector

NASA Technical Reports Server (NTRS)

Blinge, Magnus

2003-01-01

This paper presents cost effective measures to reduce CO2 emissions in the air freight sector. One door-to-door transport chain is studied in detail from a Scandinavian city to a city in southern Europe. The transport chain was selected by a group of representatives from the air freight sector in order to encompass general characteristics within the sector. Three different ways of shipping air cargo are studied, i.e., by air freighter, as belly freight (in passenger aircrafts) and trucking. CO2 emissions are calculated for each part of the transport chain and its relative importance towards the total amount CO2 emitted during the whole transport chain is shown. It is confirmed that the most CO2 emitting part of the transport chain is the actual flight and that it is in the take-off and climbing phases that most fuel are burned. It is also known that the technical development of aircraft implies a reduction in fuel consumption for each new generation of aircraft. Thus, the aircraft manufacturers have an important role in this development. Having confirmed these observations, this paper focuses on other factors that significantly affects the fuel consumption. Analyzed factors are, e.g., optimization of speed and altitude, traffic management, congestion on and around the airfields, tankering, "latest acceptance time" for goods and improving the load factor. The different factors relative contribution to the total emission levels for the transport chain has been estimated.

Regional myocardial extraction of a radioiodinated branched chain fatty acid during right ventricular pressure overload due to acute pulmonary hypertension

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hurford, W.; Lowenstein, E.; Zapol, W.

1985-05-01

To determine whether branched chain fatty acid extraction is reduced during right ventricular (RV) dysfunction due to acute pulmonary artery hypertension, studies were done in 6 anesthetized dogs. Regional branched chain fatty acid extraction was measured by comparing the myocardial uptake of I-125 labeled 15-(p-(iodophenyl))-3-methylpentadecanoic acid (I-PDA) to myocardial blood flow. Acute pulmonary hypertension was induced by incremental intravenous injection of 100 micron diameter glass beads into six pentobarbital anesthetized, mechanically ventilated dogs. Myocardial blood flow was measured by radiolabeled microspheres both under baseline conditions and during pulmonary hypertension. Mean RV pressure rose from 12 +- 2 (mean +- SEM)more » to 30 +-3mmHg resulting in a 225 +- 16% increase in RV stroke work. RV ejection fraction, as assessed by gated blood pool scans fell from 39 +- 2 to 18 +- 2%. Left ventricular (LV) pressures, stroke work and ejection fraction were unchanged. Myocardial blood flow increased 132 + 59% in the RV free wall and 67 +- 22% in the RV septum. LV blood flow was unchanged. Despite increased RV work and myocardial blood flow, no differences were noted in the branched chain fatty acid extraction ratios among LV or RV free walls or septum. The authors conclude that early RV dysfunction associated with pulmonary artery hypertension is not due to inadequate myocardial blood flow or branched chain fatty acid extraction.« less

Function of fusion regulatory proteins (FRPs) in immune cells and virus-infected cells.

PubMed

Tsurudome, M; Ito, Y

2000-01-01

Two molecules that regulate cell fusion have been identified and designated fusion regulatory protein-1 (FRP-1) and FRP-2. FRP-1 is a complex composed of a glycosylated heavy chain and a nonglycosylated light chain that are disulfide linked. FRP-1 heavy chain is identical to 4F2/CD98 heavy chain, whereas FRP-2 is identical to integrin alpha3 subunit. The FRP-1 heavy chain is a multifunctional molecule: that is, fusion regulator, amino acid transporter, integrin regulator, comitogenic factor, Na+-Ca2+ exchanger, oncogenic protein, and so on. Several aspects of the structure and function of the FRP-1 system are reviewed: fusion regulatory molecular mechanisms, cross-talk between the FRP-1 and integrin, the FRP-1 system as amino acid transporter, and FRP-1-mediated T-cell activation. The FRP-1 system is involved in virus-mediated cell fusion and multinucleated giant cell formation of blood monocytes. Monoclonal antibodies against human FRP-1 heavy chain induce polykaryocytes that have properties as osteoclasts. Multiple steps participate in molecular mechanisms regulating cell fusion. The FRP-1 heavy chain supports amino acid transport activity and the FRP-1 light chains have recently been cloned as amino acid transporters that require association with the heavy chain to exhibit their activity. Novel pathways for monocyte-dependent regulation of T-cell activation have recently been found that are mediated by the FRP-1 system. In conclusion, the FRP-1 molecules are essential factors for basic cellular functions.

Approaching Intra- and Interchain Charge Transport of Conjugated Polymers Facilely by Topochemical Polymerized Single Crystals.

PubMed

Yao, Yifan; Dong, Huanli; Liu, Feng; Russell, Thomas P; Hu, Wenping

2017-08-01

Charge transport of small molecules is measured well with scanning tunneling microscopy, conducting atomic force microscopy, break junction, nanopore, and covalently bridging gaps. However, the manipulation and measurement of polymer chains remain a long-standing fundamental issue in conjugated polymers and full of challenge since conjugated polymers are naturally disordered materials. Here, a fundamental breakthrough in generating high-quality conjugated-polymer nanocrystals with extended conjugation and exceptionally high degrees of order using a surface-supported topochemical polymerization method is demonstrated. In the crystal the conjugated-polymer chains are extended along the long axis of the crystal with the side chains perpendicular to the long axis. Devices with conducting channels along the polymer chains show efficient charge transport, nearly two orders of magnitude greater than the interchain charge transport along the π-π stacking direction. This is the first example to clarify intra- and interchain charge transport based on an individual single crystal of conjugated polymers, and demonstrate the importance of intrachain charge transport in plastic electronics. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Transcription factors CEP-1/p53 and CEH-23 collaborate with AAK-2/AMPK to modulate longevity in Caenorhabditis elegans.

PubMed

Chang, Hsin-Wen; Pisano, Steve; Chaturbedi, Amaresh; Chen, Jennifer; Gordon, Sarah; Baruah, Aiswarya; Lee, Siu Sylvia

2017-08-01

A decline in mitochondrial electron transport chain (ETC) function has long been implicated in aging and various diseases. Recently, moderate mitochondrial ETC dysfunction has been found to prolong lifespan in diverse organisms, suggesting a conserved and complex role of mitochondria in longevity determination. Several nuclear transcription factors have been demonstrated to mediate the lifespan extension effect associated with partial impairment of the ETC, suggesting that compensatory transcriptional response to be crucial. In this study, we showed that the transcription factors CEP-1/p53 and CEH-23 act through a similar mechanism to modulate longevity in response to defective ETC in Caenorhabditis elegans. Genomewide gene expression profiling comparison revealed a new link between these two transcription factors and AAK-2/AMP kinase (AMPK) signaling. Further functional analyses suggested that CEP-1/p53 and CEH-23 act downstream of AAK-2/AMPK signaling and CRTC-1 transcriptional coactivator to promote stress resistance and lifespan. As AAK-2, CEP-1, and CEH-23 are all highly conserved, our findings likely provide important insights for understanding the organismal adaptive response to mitochondrial dysfunction in diverse organisms and will be relevant to aging and pathologies with a mitochondrial etiology in human. © 2017 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.

Mitochondrial dysfunction and lipid peroxidation in rat frontal cortex by chronic NMDA administration can be partially prevented by lithium treatment.

PubMed

Kim, Helena K; Isaacs-Trepanier, Cameron; Elmi, Nika; Rapoport, Stanley I; Andreazza, Ana C

2016-05-01

Chronic N-methyl-d-aspartate (NMDA) administration to rats may be a model to investigate excitotoxicity mediated by glutamatergic hyperactivity, and lithium has been reported to be neuroprotective. We hypothesized that glutamatergic hyperactivity in chronic NMDA injected rats would cause mitochondrial dysfunction and lipid peroxidation in the brain, and that chronic lithium treatment would ameliorate some of these NMDA-induced alterations. Rats treated with lithium for 6 weeks were injected i.p. 25 mg/kg NMDA on a daily basis for the last 21 days of lithium treatment. Brain was removed and frontal cortex was analyzed. Chronic NMDA decreased brain levels of mitochondrial complex I and III, and increased levels of the lipid oxidation products, 8-isoprostane and 4-hydroxynonenal, compared with non-NMDA injected rats. Lithium treatment prevented the NMDA-induced increments in 8-isoprostane and 4-hydroxynonenal. Our findings suggest that increased chronic activation of NMDA receptors can induce alterations in electron transport chain complexes I and III and in lipid peroxidation in brain. The NMDA-induced changes may contribute to glutamate-mediated excitotoxicity, which plays a role in brain diseases such as bipolar disorder. Lithium treatment prevented changes in 8-isoprostane and 4-hydroxynonenal, which may contribute to lithium's reported neuroprotective effect and efficacy in bipolar disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mitochondrial multifaceted dysfunction in schizophrenia; complex I as a possible pathological target.

PubMed

Ben-Shachar, Dorit

2017-09-01

Mitochondria are key players in various essential cellular processes beyond being the main energy supplier of the cell. Accordingly, they are involved in neuronal synaptic transmission, neuronal growth and sprouting and consequently neuronal plasticity and connectivity. In addition, mitochondria participate in the modulation of gene transcription and inflammation as well in physiological responses in health and disease. Schizophrenia is currently regarded as a neurodevelopmental disorder associated with impaired immune system, aberrant neuronal differentiation and abnormalities in various neurotransmitter systems mainly the dopaminergic, glutaminergic and GABAergic. Ample evidence has been accumulated over the last decade indicating a multifaceted dysfunction of mitochondria in schizophrenia. Indeed, mitochondrial deficit can be of relevance for the majority of the pathologies observed in this disease. In the present article, we overview specific deficits of the mitochondria in schizophrenia, with a focus on the first complex (complex I) of the mitochondrial electron transport chain (ETC). We argue that complex I, being a major factor in the regulation of mitochondrial ETC, is a possible key modulator of various functions of the mitochondria. We review biochemical, molecular, cellular and functional evidence for mitochondrial impairments and their possible convergence to impact in-vitro neuronal differentiation efficiency in schizophrenia. Mitochondrial function in schizophrenia may advance our knowledge of the disease pathophysiology and open the road for new treatment targets for the benefit of the patients. Copyright © 2016 Elsevier B.V. All rights reserved.

Phloretin ameliorates arsenic trioxide induced mitochondrial dysfunction in H9c2 cardiomyoblasts mediated via alterations in membrane permeability and ETC complexes.

PubMed

Vineetha, Vadavanath Prabhakaran; Soumya, Rema Sreenivasan; Raghu, Kozhiparambil Gopalan

2015-05-05

Arsenic trioxide (ATO), though a very effective drug for the treatment of acute promyelocytic leukemia, leads to cardiotoxicity. As mitochondria are the center of attention of cardiac cell׳s general metabolic status, it is primarily important to see the interaction of ATO with mitochondria. Studies related exclusively to the alterations in mitochondria and its associated functions caused by ATO are very limited. The present investigation aims to explore the effect of ATO on various components of electron transport chain, oxygen consumption, ATP production, mitochondrial superoxide generation, transmembrane potential, permeability pore opening, calcium homeostasis and apoptosis. Attempts were also made to see the efficacy of phloretin, a potent antioxidant flavonoid found majorly in apple peel on cardiotoxicity. The H9c2 cells exposed to ATO (5µM) exhibited increased oxidative stress with reduced innate antioxidant status, mitochondrial dysfunctions and apoptosis. It increased the intracellular calcium content, caused alterations in the activity of transcription factor Nrf2, xanthine oxidase, aconitase and caspase 3 compared to the control group. Phloretin at 2.5 and 5µM concentrations were able to protect the cells from ATO toxicity via protecting mitochondria through its antioxidant potential. The present investigation based on mitochondria reveals the probability of cardioprotective potential of phloretin for the cancer patients on ATO chemotherapy. Copyright © 2015 Elsevier B.V. All rights reserved.

Mitochondrial Modulation by Epigallocatechin 3-Gallate Ameliorates Cisplatin Induced Renal Injury through Decreasing Oxidative/Nitrative Stress, Inflammation and NF-kB in Mice

PubMed Central

Wang, Xueping; Wang, Ping; Fu, Guanghou; Meng, Hongzhou; Wang, Yimin; Jin, Baiye

2015-01-01

Cancer chemotherapy drug cisplatin is known for its nephrotoxicity. The aim of this study is to investigate whether Epigallocatechin 3-Gallate (EGCG) can reduce cisplatin mediated side effect in kidney and to understand its mechanism of protection against tissue injury. We used a well-established 3-day cisplatin induced nephrotoxicity mice model where EGCG were administered. EGCG is a major active compound in Green Tea and have strong anti-oxidant and anti-inflammatory properties. EGCG protected against cisplatin induced renal dysfunction as measured by serum creatinine and blood urea nitrogen (BUN). EGCG improved cisplatin induced kidney structural damages such as tubular dilatation, cast formation, granulovaculoar degeneration and tubular cell necrosis as evident by PAS staining. Cisplatin induced kidney specific mitochondrial oxidative stress, impaired activities of mitochondrial electron transport chain enzyme complexes, impaired anti-oxidant defense enzyme activities such as glutathione peroxidase (GPX) and manganese superoxide dismutase (MnSOD) in mitochondria, inflammation (tumor necrosis factor α and interleukin 1β), increased accumulation of NF-κB in nuclear fraction, p53 induction, and apoptotic cell death (caspase 3 activity and DNA fragmentation). Treatment of mice with EGCG markedly attenuated cisplatin induced mitochondrial oxidative/nitrative stress, mitochondrial damages to electron transport chain activities and antioxidant defense enzyme activities in mitochondria. These mitochondrial modulations by EGCG led to protection mechanism against cisplatin induced inflammation and apoptotic cell death in mice kidney. As a result, EGCG improved renal function in cisplatin mediated kidney damage. In addition to that, EGCG attenuated cisplatin induced apoptotic cell death and mitochondrial reactive oxygen species (ROS) generation in human kidney tubular cell line HK-2. Thus, our data suggest that EGCG may represent new promising adjunct candidate for cisplatin. PMID:25875356

Human microvascular dysfunction and apoptotic injury induced by AL amyloidosis light chain proteins.

PubMed

Migrino, Raymond Q; Truran, Seth; Gutterman, David D; Franco, Daniel A; Bright, Megan; Schlundt, Brittany; Timmons, Mitchell; Motta, Angelica; Phillips, Shane A; Hari, Parameswaran

2011-12-01

Light chain amyloidosis (AL) involves overproduction of amyloidogenic light chain proteins (LC) leading to heart failure, yet the mechanisms underlying tissue toxicity remain unknown. We hypothesized that LC induces endothelial dysfunction in non-AL human microvasculature and apoptotic injury in human coronary artery endothelial cells (HCAECs). Adipose arterioles (n = 34, 50 ± 3 yr) and atrial coronary arterioles (n = 19, 68 ± 2 yr) from non-AL subjects were cannulated. Adipose arteriole dilator responses to acetylcholine/papaverine were measured at baseline and 1 h exposure to LC (20 μg/ml) from biopsy-proven AL subjects (57 ± 11 yr) without and with antioxidant cotreatment. Coronary arteriole dilation to bradykinin/papaverine was measured post-LC exposure. HCAECs were exposed to 1 or 24 h of LC. LC reduced dilation to acetylcholine (10(-4) M: 41.6 ± 7 vs. 85.8 ± 2.2% control, P < 0.001) and papaverine (81.4 ± 4.6 vs. 94.8 ± 1.3% control, P < 0.01) in adipose arterioles and to bradykinin (10(-6) M: 68.6 ± 6.2 vs. 90.9 ± 1.6% control, P < 0.001) but not papaverine in coronary arterioles. There was an increase in superoxide and peroxynitrite in arterioles treated with LC. Adipose arteriole dilation was restored by cotreatment with polyethylene glycol-superoxide dismutase and tetrahydrobiopterin but only partially restored by mitoquinone (mitochondria-targeted antioxidant) and gp91ds-tat (NADPH oxidase inhibitor). HCAECs exposed to LC showed reduced NO and increased superoxide, peroxynitrite, annexin-V, and propidium iodide compared with control. Brief exposure to physiological amounts of LC induced endothelial dysfunction in human adipose and coronary arterioles and increased apoptotic injury in coronary artery endothelial cells likely as a result of oxidative stress, reduced NO bioavailability, and peroxynitrite production. Microvascular dysfunction and injury is a novel mechanism underlying AL pathobiology and is a potential target for therapy.

Characterizing the tradeoffs and costs associated with transportation congestion in supply chains.

DOT National Transportation Integrated Search

2010-01-21

We consider distribution and location-planning models for supply chains that explicitly : account for traffic congestion effects. The majority of facility location and transportation : planning models in the operations research literature consider fa...

Three cases of congenital dysfibrinogenemia in unrelated Chinese families: heterozygous missense mutation in fibrinogen alpha chain Argl6His

PubMed Central

Luo, Meiling; Deng, Donghong; Xiang, Liqun; Cheng, Peng; Liao, Lin; Deng, Xuelian; Yan, Jie; Lin, Faquan

2016-01-01

Abstract Congenital dysfibrinogenemia (CD) is a qualitative fibrinogen disorder caused by an abnormal fibrinogen molecule structure, leading to dysfunctional blood coagulation. This study describes 3 cases of dysfibrinogenemia identified in the unrelated Chinese pedigrees. Routine coagulation screening tests were performed on the probands and their families. The antigens and functionality of fibrinogen was measured using an immunoturbidimetry assay and the Clauss method, respectively. To identify the genetic mutation responsible for these dysfibrinogens, genomic DNA extracted from the blood was analyzed using PCR amplification and direct sequencing. The presence of the mutant chains was determined using matrix-assisted laser desorption/ionization time of flight (MALDI-TOF) mass spectroscopy. Purified plasma fibrinogen of 3 probands was analyzed using SDS–PAGE, fibrinogen clottability, fibrin polymerization, fibrinopeptide release, and scanning electron microscopy (SEM). The 3 probands had a long thrombin time. Levels of functional fibrinogen were found to be very low, while the fibrinogen antigen was within the normal range. DNA sequencing revealed a heterozygous Arg16His substitution in the fibrinogen Aα chain (FGA). The mutant chains were found to be expressed using MALDI-TOF mass spectroscopy. SDS–PAGE did not reveal any difference in the molecular weights of 3 polypeptide chains between normal and abnormal fibrinogens. Fibrinogen clottability showed a slower fibrin clot formation than the healthy control. Fibrin polymerization, after addition of thrombin, showed a prolonged lag phase and decreased final turbidity. The kinetics of fibrinopeptides release revealed a decreased amount of the released fibrinopeptide A. SEM of the patient's fibrin clot was found to be abnormal. Results indicate that the 3 probands with dysfibrinogenemia were caused by mutations of Aα chain Arg16His. Mutation of this fibrinogen induced dysfunction of plasma fibrinogen. PMID:27684817

Top-Down Targeted Proteomics Reveals Decrease in Myosin Regulatory Light-Chain Phosphorylation That Contributes to Sarcopenic Muscle Dysfunction.

PubMed

Gregorich, Zachery R; Peng, Ying; Cai, Wenxuan; Jin, Yutong; Wei, Liming; Chen, Albert J; McKiernan, Susan H; Aiken, Judd M; Moss, Richard L; Diffee, Gary M; Ge, Ying

2016-08-05

Sarcopenia, the loss of skeletal muscle mass and function with advancing age, is a significant cause of disability and loss of independence in the elderly and thus, represents a formidable challenge for the aging population. Nevertheless, the molecular mechanism(s) underlying sarcopenia-associated muscle dysfunction remain poorly understood. In this study, we employed an integrated approach combining top-down targeted proteomics with mechanical measurements to dissect the molecular mechanism(s) in age-related muscle dysfunction. Top-down targeted proteomic analysis uncovered a progressive age-related decline in the phosphorylation of myosin regulatory light chain (RLC), a critical protein involved in the modulation of muscle contractility, in the skeletal muscle of aging rats. Top-down tandem mass spectrometry analysis identified a previously unreported bis-phosphorylated proteoform of fast skeletal RLC and localized the sites of decreasing phosphorylation to Ser14/15. Of these sites, Ser14 phosphorylation represents a previously unidentified site of phosphorylation in RLC from fast-twitch skeletal muscle. Subsequent mechanical analysis of single fast-twitch fibers isolated from the muscles of rats of different ages revealed that the observed decline in RLC phosphorylation can account for age-related decreases in the contractile properties of sarcopenic fast-twitch muscles. These results strongly support a role for decreasing RLC phosphorylation in sarcopenia-associated muscle dysfunction and suggest that therapeutic modulation of RLC phosphorylation may represent a new avenue for the treatment of sarcopenia.

First Principles Study for Proton Transport and Diffusion Behavior in Hydrous Hexagonal WO3

NASA Astrophysics Data System (ADS)

Liu, Chi-Ping; Zhou, Fei; Ozolins, Vidvuds; QPAM Team

2013-03-01

Proton transport is of great importance in biological species and energy storage and conversion systems. Previous studies have shown fast proton conduction in liquids and polymers but seldom in inorganic materials. In this work, first principles density functional theory (DFT) reveals that the formation of hydronium and water chains inside the hexagonal channels plays the key roles for the anomalously fast proton transport, by following modified Grotthuss mechanism. Our DFT study shows the detailed microscopic proton diffusion mechanism along the channel in hydrous WO3 with 50% water composition, which is proper for water chain formation. The water chain in the channel serves as a possible diffusion media for hydronium (H3O +) . With the continuous formation and cleavage of hydrogen bonds in the channel, the hydronium diffuses by hydrogen bonds exchange between water molecules. This mechanism is very similar with Grotthuss relay mechanism for proton transport in liquid. The possible proton diffusion were studied for hydronium is either far away from the water chain bond defect or next to H2O defect at the end of water chain. The diffusion barriers for both conditions are around 150 meV to 200 meV, and water defects reorganization in the chain is the rate-limited step for proton diffusion. These small diffusion barriers could explain the fast 1-D proton transport in hydrous WO3 channel. Further studies about fast proton transport in other inorganic materials could be an important topic in not only biochemistry but also clean energy applications like fuel cell applications.

Agile Transportation for the 21st Century Objectives for the Defense Transportation System

DTIC Science & Technology

2002-06-01

Strategic Distribution Management Initiative (SDMI) are key supply-chain initiatives in RML. Will the objectives of AT2000 improve or hinder these supply-chain initiatives? This question provides the impetus for this research paper.

Parvalbumin-positive interneurons of the prefrontal cortex support working memory and cognitive flexibility

PubMed Central

Murray, Andrew J.; Woloszynowska-Fraser, Marta U.; Ansel-Bollepalli, Laura; Cole, Katy L. H.; Foggetti, Angelica; Crouch, Barry; Riedel, Gernot; Wulff, Peer

2015-01-01

Dysfunction of parvalbumin (PV)-positive GABAergic interneurons (PVIs) within the prefrontal cortex (PFC) has been implicated in schizophrenia pathology. It is however unclear, how impaired signaling of these neurons may contribute to PFC dysfunction. To identify how PVIs contribute to PFC-dependent behaviors we inactivated PVIs in the PFC in mice using region- and cell-type-selective expression of tetanus toxin light chain (TeLC) and compared the functional consequences of this manipulation with non-cell-type-selective perturbations of the same circuitry. By sampling for behavioral alterations that map onto distinct symptom categories in schizophrenia, we show that dysfunction of PVI signaling in the PFC specifically produces deficits in the cognitive domain, but does not give rise to PFC-dependent correlates of negative or positive symptoms. Our results suggest that distinct aspects of the complex symptomatology of PFC dysfunction in schizophrenia can be attributed to specific prefrontal circuit elements. PMID:26608841

Diminished superoxide generation is associated with respiratory chain dysfunction and changes in the mitochondrial proteome of sensory neurons from diabetic rats.

PubMed

Akude, Eli; Zherebitskaya, Elena; Chowdhury, Subir K Roy; Smith, Darrell R; Dobrowsky, Rick T; Fernyhough, Paul

2011-01-01

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. 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). 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. 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.

Facile Fabrication of Hierarchically Thermoresponsive Binary Polymer Pattern for Controlled Cell Adhesion.

PubMed

Hou, Jianwen; Cui, Lele; Chen, Runhai; Xu, Xiaodong; Chen, Jiayue; Yin, Ligang; Liu, Jingchuan; Shi, Qiang; Yin, Jinghua

2018-03-01

A versatile platform allowing capture and detection of normal and dysfunctional cells on the same patterned surface is important for accessing the cellular mechanism, developing diagnostic assays, and implementing therapy. Here, an original and effective method for fabricating binary polymer brushes pattern is developed for controlled cell adhesion. The binary polymer brushes pattern, composed of poly(N-isopropylacrylamide) (PNIPAAm) and poly[poly(ethylene glycol) methyl ether methacrylate] (POEGMA) chains, is simply obtained via a combination of surface-initiated photopolymerization and surface-activated free radical polymerization. This method is unique in that it does not utilize any protecting groups or procedures of backfilling with immobilized initiator. It is demonstrated that the precise and well-defined binary polymer patterns with high resolution are fabricated using this facile method. PNIPAAm chains capture and release cells by thermoresponsiveness, while POEGMA chains possess high capability to capture dysfunctional cells specifically, inducing a switch of normal red blood cells (RBCs) arrays to hemolytic RBCs arrays on the pattern with temperature. This novel platform composed of binary polymer brush pattern is smart and versatile, which opens up pathways to potential applications as microsensors, biochips, and bioassays. © 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

The Impact of Supply Chain Business Processes on Competitive Advantage and Organizational Performance

DTIC Science & Technology

2012-03-22

Manager, Vice President (VP) Distribution & Fulfillment, Transportation Manager, VP of Supply Chain Management, Production Manager, Director of...Logistics/ Transportation /Distribution (75%), and Supply/Purchasing/Procurement (25%) were identified as functions that best describe the respondents...manufacturing industry (50%), one respondent represented the wholesale trade (12.5%), the retail trade (12.5%), and the transportation and warehousing

The Agr quorum-sensing system regulates fibronectin binding but not hemolysis in the absence of a functional electron transport chain.

PubMed

Pader, Vera; James, Ellen H; Painter, Kimberley L; Wigneshweraraj, Sivaramesh; Edwards, Andrew M

2014-10-01

Staphylococcus aureus is responsible for numerous chronic and recurrent infections, which are frequently associated with the emergence of small-colony variants (SCVs) that lack a functional electron transport chain. SCVs exhibit enhanced expression of fibronectin-binding protein (FnBP) and greatly reduced hemolysin production, although the basis for this is unclear. One hypothesis is that these phenotypes are a consequence of the reduced Agr activity of SCVs, while an alternative is that the lack of a functional electron transport chain and the resulting reduction in ATP production are responsible. Disruption of the electron transport chain of S. aureus genetically (hemB and menD) or chemically, using 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), inhibited both growth and Agr activity and conferred an SCV phenotype. Supplementation of the culture medium with synthetic autoinducing peptide (sAIP) significantly increased Agr expression in both hemB mutant strains and S. aureus grown with HQNO and significantly reduced staphylococcal adhesion to fibronectin. However, sAIP did not promote hemolysin expression in hemB mutant strains or S. aureus grown with HQNO. Therefore, while Agr regulates fibronectin binding in SCVs, it cannot promote hemolysin production in the absence of a functional electron transport chain. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

The Agr Quorum-Sensing System Regulates Fibronectin Binding but Not Hemolysis in the Absence of a Functional Electron Transport Chain

PubMed Central

Pader, Vera; James, Ellen H.; Painter, Kimberley L.; Wigneshweraraj, Sivaramesh

2014-01-01

Staphylococcus aureus is responsible for numerous chronic and recurrent infections, which are frequently associated with the emergence of small-colony variants (SCVs) that lack a functional electron transport chain. SCVs exhibit enhanced expression of fibronectin-binding protein (FnBP) and greatly reduced hemolysin production, although the basis for this is unclear. One hypothesis is that these phenotypes are a consequence of the reduced Agr activity of SCVs, while an alternative is that the lack of a functional electron transport chain and the resulting reduction in ATP production are responsible. Disruption of the electron transport chain of S. aureus genetically (hemB and menD) or chemically, using 2-n-heptyl-4-hydroxyquinoline N-oxide (HQNO), inhibited both growth and Agr activity and conferred an SCV phenotype. Supplementation of the culture medium with synthetic autoinducing peptide (sAIP) significantly increased Agr expression in both hemB mutant strains and S. aureus grown with HQNO and significantly reduced staphylococcal adhesion to fibronectin. However, sAIP did not promote hemolysin expression in hemB mutant strains or S. aureus grown with HQNO. Therefore, while Agr regulates fibronectin binding in SCVs, it cannot promote hemolysin production in the absence of a functional electron transport chain. PMID:25092909

The Enigma of the Respiratory Chain Supercomplex.

PubMed

Milenkovic, Dusanka; Blaza, James N; Larsson, Nils-Göran; Hirst, Judy

2017-04-04

Respiratory chain dysfunction plays an important role in human disease and aging. It is now well established that the individual respiratory complexes can be organized into supercomplexes, and structures for these macromolecular assemblies, determined by electron cryo-microscopy, have been described recently. Nevertheless, the reason why supercomplexes exist remains an enigma. The widely held view that they enhance catalysis by channeling substrates is challenged by both structural and biophysical information. Here, we evaluate and discuss data and hypotheses on the structures, roles, and assembly of respiratory-chain supercomplexes and propose a future research agenda to address unanswered questions. Copyright © 2017. Published by Elsevier Inc.

p53/CEP-1 Increases or Decreases Lifespan, Depending on Level of Mitochondrial Bioenergetic Stress

PubMed Central

Ventura, Natascia; Rea, Shane L.; Schiavi, Alfonso; Torgovnick, Alessandro; Testi, Roberto; Johnson, Thomas E.

2009-01-01

SUMMARY Mitochondrial pathologies underlie a number of life-shortening diseases in humans. In the nematode Caenorhabditis elegans, severely reduced expression of mitochondrial proteins involved in electron transport chain-mediated energy production also leads to pathological phenotypes, including arrested development and/or shorter life; in sharp contrast, mild suppression of these same proteins extends lifespan. Here we show that the C. elegans p53 ortholog cep-1 mediates these opposite effects. We find that cep-1 is required to extend longevity in response to mild suppression of several bioenergetically relevant mitochondrial proteins, including frataxin - the protein defective in patients with Friedreich’s Ataxia. Importantly we show that cep-1 also mediates both the developmental arrest and life shortening induced by severe mitochondrial stress. Our findings support an evolutionarily conserved function for p53 in modulating organismal responses to mitochondrial dysfunction and suggest that metabolic checkpoint responses may play a role in longevity control and in human mitochondrial-associated diseases. PMID:19416129

Bioavailability enhancement of coenzyme Q10: an extensive review of patents.

PubMed

Beg, Sarwar; Javed, Shamama; Kohli, Kanchan

2010-11-01

Coenzyme Q10 (CoQ10) is a major antioxidant principle found in human body which plays a vital role in maintaining several biochemical pathways of body. It acts as a potential mediator in transferring electrons in oxidoreductive reactions of electron transport chain. Chemically, it is a basic quinone containing moiety having a large and high molecular weight structure. Deficiency of this in body leads to several potential disorders like dysfunctions in cellular energetics, neurological degeneration, higher oxidative stress induced damage, breast cancer etc. The high molecular weight and lipophilicity of CoQ10 makes it poorly water soluble and consequently leads to low systemic availability. Several advancements have been made to enhance the bioavailability of CoQ10 using various approaches like size reduction, solubility enhancement (by solid dispersion, prodrug, complexation, ionization) and use of novel drug carriers such as liposomes, microspheres, nanoparticles, nanoemulsions and self-emulsifying system. The primary objective of the present review is to assemble patents representing the various approaches used for enhancement of CoQ10 bioavailability.

DNA Damage Related Crosstalk Between the Nucleus and Mitochondria

PubMed Central

Saki, Mohammad; Prakash, Aishwarya

2017-01-01

The electron transport chain is the primary pathway by which a cell generates energy in the form of ATP. Byproducts of this process produce reactive oxygen species that can cause damage to mitochondrial DNA. If not properly repaired, the accumulation of DNA damage can lead to mitochondrial dysfunction linked to several human disorders including neurodegenerative diseases and cancer. Mitochondria are able to combat oxidative DNA damage via repair mechanisms that are analogous to those found in the nucleus. Of the repair pathways currently reported in the mitochondria, the base excision repair pathway is the most comprehensively described. Proteins that are involved with the maintenance of mtDNA are encoded by nuclear genes and translocate to the mitochondria making signaling between the nucleus and mitochondria imperative. In this review, we discuss the current understanding of mitochondrial DNA repair mechanisms and also highlight the sensors and signaling pathways that mediate crosstalk between the nucleus and mitochondria in the event of mitochondrial stress. PMID:27915046

Chain conformations dictate multiscale charge transport phenomena in disordered semiconducting polymers

PubMed Central

Noriega, Rodrigo; Salleo, Alberto; Spakowitz, Andrew J.

2013-01-01

Existing models for the electronic properties of conjugated polymers do not capture the spatial arrangement of the disordered macromolecular chains over which charge transport occurs. Here, we present an analytical and computational description in which the morphology of individual polymer chains is dictated by well-known statistical models and the electronic coupling between units is determined using Marcus theory. The multiscale transport of charges in these materials (high mobility at short length scales, low mobility at long length scales) is naturally described with our framework. Additionally, the dependence of mobility with electric field and temperature is explained in terms of conformational variability and spatial correlation. Our model offers a predictive approach to connecting processing conditions with transport behavior. PMID:24062459

Chain conformations dictate multiscale charge transport phenomena in disordered semiconducting polymers.

PubMed

Noriega, Rodrigo; Salleo, Alberto; Spakowitz, Andrew J

2013-10-08

Existing models for the electronic properties of conjugated polymers do not capture the spatial arrangement of the disordered macromolecular chains over which charge transport occurs. Here, we present an analytical and computational description in which the morphology of individual polymer chains is dictated by well-known statistical models and the electronic coupling between units is determined using Marcus theory. The multiscale transport of charges in these materials (high mobility at short length scales, low mobility at long length scales) is naturally described with our framework. Additionally, the dependence of mobility with electric field and temperature is explained in terms of conformational variability and spatial correlation. Our model offers a predictive approach to connecting processing conditions with transport behavior.

A decision support system for transportation infrastructure and supply chain system planning.

DOT National Transportation Integrated Search

2013-07-01

This project makes the results (models and methodology) of the research and development efforts on freight movement modeling (FMM) and supply chain design carried out by faculty at OSU and OU available to transportation and logistics professionals. A...

Copper accumulation and transport in a marine food chain composed of Platymonas subcordiformis, brachionus plicatilis and Penaeus monodon

NASA Astrophysics Data System (ADS)

Cai, A.-Gen; Chen, Wei-Qi; Li, Wen-Quan

1997-09-01

Accumulation, transport and toxicity of Cu in the food chain consisting of Platymonas subcordiformis, Brachionus plicatilis and Penaeus monodon were studied. Effects of Cu on the growth of organisms in the food chain were investigated and the inhibiting effect concentration (EC50) of Cu was then determined according to the dynamics of the relative number of cells or total individuals of organisms, expressed in percentages with reference to the controlled system, under different culture conditions. On the basis of the variations in accumulation and percentages of accumulation of Cu in the biological phase, the relationship between the accumulation of Cu in organisms and its toxicity was analyzed and the main approach for determining the transport of Cu in the food chain was then discussed.

Systems pharmacology modeling of drug‐induced hyperbilirubinemia: Differentiating hepatotoxicity and inhibition of enzymes/transporters

PubMed Central

Battista, C; Woodhead, JL; Stahl, SH; Mettetal, JT; Watkins, PB; Siler, SQ; Howell, BA

2017-01-01

Elevations in serum bilirubin during drug treatment may indicate global liver dysfunction and a high risk of liver failure. However, drugs also can increase serum bilirubin in the absence of hepatic injury by inhibiting specific enzymes/transporters. We constructed a mechanistic model of bilirubin disposition based on known functional polymorphisms in bilirubin metabolism/transport. Using physiologically based pharmacokinetic (PBPK) model‐predicted drug exposure and enzyme/transporter inhibition constants determined in vitro, our model correctly predicted indinavir‐mediated hyperbilirubinemia in humans and rats. Nelfinavir was predicted not to cause hyperbilirubinemia, consistent with clinical observations. We next examined a new drug candidate that caused both elevations in serum bilirubin and biochemical evidence of liver injury in rats. Simulations suggest that bilirubin elevation primarily resulted from inhibition of transporters rather than global liver dysfunction. We conclude that mechanistic modeling of bilirubin can help elucidate underlying mechanisms of drug‐induced hyperbilirubinemia, and thereby distinguish benign from clinically important elevations in serum bilirubin. PMID:28074467

Transport properties for carbon chain sandwiched between heteroatom-doped carbon nanotubes with different doping sites

DOE Office of Scientific and Technical Information (OSTI.GOV)

Liu, Wenjiang; Guizhou University of Finance and Economics, Guiyang 550025; Deng, Xiaoqing, E-mail: xq-deng@163.com, E-mail: caish@mail.gufe.edu.cn

The First-principles calculation is used to investigate the transport properties of a carbon chain connected with N-and/or B-doped caped carbon nanotube acting as electrodes. The I-V curves of the carbon chain are affected by the N/B doping sites, and rectifying behavior can be obtained distinctly when the carbon chain is just connected onto two doping atom sites (N- chain-B), and a weak rectification occurs when N (B) doping at other sites. Interestingly, the spin-filtering effects exist in the junction when it is doped at other sites, undoped system, or N-terminal carbon chains. However, no this behavior is found in N-chain-Bmore » and B-chain-B systems. The analysis on the transmission spectra, PDOS, LDOS, spin density, and the electron transmission pathways give an insight into the observed results for the system.« less

The ABC transporter Rv1272c of Mycobacterium tuberculosis enhances the import of long-chain fatty acids in Escherichia coli.

PubMed

Martin, Audrey; Daniel, Jaiyanth

2018-02-05

Mycobacterium tuberculosis (Mtb), which causes tuberculosis, is capable of accumulating triacylglycerol (TAG) by utilizing fatty acids from host cells. ATP-binding cassette (ABC) transporters are involved in transport processes in all organisms. Among the classical ABC transporters in Mtb none have been implicated in fatty acid import. Since the transport of fatty acids from the host cell is important for dormancy-associated TAG synthesis in the pathogen, mycobacterial ABC transporter(s) could potentially be involved in this process. Based on sequence identities with a bacterial ABC transporter that mediates fatty acid import for TAG synthesis, we identified Rv1272c, a hitherto uncharacterized ABC-transporter in Mtb that also shows sequence identities with a plant ABC transporter involved in fatty acid transport. We expressed Rv1272c in E. coli and show that it enhances the import of radiolabeled fatty acids. We also show that Rv1272c causes a significant increase in the metabolic incorporation of radiolabeled long-chain fatty acids into cardiolipin, a tetra-acylated phospholipid, and phosphatidylglycerol in E. coli. This is the first report on the function of Rv1272c showing that it displays a long-chain fatty acid transport function. Copyright © 2018 Elsevier Inc. All rights reserved.

[Carrier-mediated Transport of Cationic Drugs across the Blood-Tissue Barrier].

PubMed

Kubo, Yoshiyuki

2015-01-01

Studies of neurological dysfunction have revealed the neuroprotective effect of several cationic drugs, suggesting their usefulness in the treatment of neurological diseases. In the brain and retina, blood-tissue barriers such as blood-brain barrier (BBB) and blood-retinal barrier (BRB) are formed to restrict nonspecific solute transport between the circulating blood and neural tissues. Therefore study of cationic drug transport at these barriers is essential to achieve systemic delivery of neuroprotective agents into the neural tissues. In the retina, severe diseases such as diabetic retinopathy and macular degeneration can cause neurological dysfunction that dramatically affects patients' QOL. The BRB is formed by retinal capillary endothelial cells (inner BRB) and retinal pigment epithelial cells (outer BRB). Blood-to-retina transport of cationic drugs was investigated at the inner BRB, which is known to nourish two thirds of the retina. Blood-to-retinal transport of verapamil suggested that the barrier function of the BRB differs from that of the BBB. Moreover, carrier-mediated transport of verapamil and pyrilamine revealed the involvement of novel organic cation transporters at the inner BRB. The identified transport systems for cationic drugs are sensitive to several cationic neuroprotective and anti-angiogenic agents such as clonidine and propranolol, and the involvement of novel transporters was also suggested in their blood-to-retina transport across the inner BRB.

Mitochondrial modulators in experimental Huntington's disease: reversal of mitochondrial dysfunctions and cognitive deficits.

PubMed

Mehrotra, Arpit; Kanwal, Abhinav; Banerjee, Sanjay Kumar; Sandhir, Rajat

2015-06-01

Huntington's disease (HD) is a chronic neurodegenerative condition involving impaired mitochondrial functions. The present study evaluates the therapeutic potential of combined administration of mitochondrial modulators: alpha-lipoic acid and acetyl-l-carnitine on mitochondrial dysfunctions in 3-NP-induced HD. Our results reveal 3-NP administration resulted in compromise of mitochondrial functions in terms of: (1) impaired activity of mitochondrial respiratory chain enzymes, altered cytochrome levels, reduced histochemical staining of complex-II and IV, reduced in-gel activity of complex-I to V, and reduced mRNA expression of respiratory chain complexes; (2) enhanced mitochondrial oxidative stress indicated by increased malondialdehyde, protein carbonyls, reactive oxygen species and nitrite levels, along with decreased Mn-superoxide dismutase and catalase activity; (3) mitochondrial structural changes measured by mitochondrial swelling, reduced mitochondrial membrane potential and ultra-structure changes; (4) increased cytosolic cytochrome c levels, caspase-3 and -9 activity along with altered expression of apoptotic proteins (AIF, Bim, Bad, and Bax); and (5) impaired cognitive functions assessed using Morris water maze and Y-maze. Combination of mitochondrial modulators (alpha-lipoic acid + acetyl-l-carnitine) on the other hand ameliorated 3-NP-induced mitochondrial dysfunctions, oxidative stress, histologic alterations, and behavioral deficits, suggesting their therapeutic efficacy in the management of HD. Copyright © 2015 Elsevier Inc. All rights reserved.

The tunnel magnetoresistance in chains of quantum dots weakly coupled to external leads.

PubMed

Weymann, Ireneusz

2010-01-13

We analyze numerically the spin-dependent transport through coherent chains of three coupled quantum dots weakly connected to external magnetic leads. In particular, using the diagrammatic technique on the Keldysh contour, we calculate the conductance, shot noise and tunnel magnetoresistance (TMR) in the sequential and cotunneling regimes. We show that transport characteristics greatly depend on the strength of the interdot Coulomb correlations, which determines the spatial distribution of the electron wavefunction in the chain. When the correlations are relatively strong, depending on the transport regime, we find both negative TMR as well as TMR enhanced above the Julliere value, accompanied with negative differential conductance (NDC) and super-Poissonian shot noise. This nontrivial behavior of tunnel magnetoresistance is associated with selection rules that govern tunneling processes and various high-spin states of the chain that are relevant for transport. For weak interdot correlations, on the other hand, the TMR is always positive and not larger than the Julliere TMR, although super-Poissonian shot noise and NDC can still be observed.

Baicalin Ameliorates Experimental Liver Cholestasis in Mice by Modulation of Oxidative Stress, Inflammation, and NRF2 Transcription Factor

PubMed Central

Feng, Xiaowen; Zhang, Feng; Xie, Haiyang

2017-01-01

Experimental cholestatic liver fibrosis was performed by bile duct ligation (BDL) in mice, and significant liver injury was observed in 15 days. Administration of baicalin in mice significantly ameliorates liver fibrosis. Experimental cholestatic liver fibrosis was associated with induced gene expression of fibrotic markers such as collagen I, fibronectin, alpha smooth muscle actin (SMA), and connective tissue growth factor (CTGF); increased inflammatory cytokines (TNFα, MIP1α, IL1β, and MIP2); increased oxidative stress and reactive oxygen species- (ROS-) inducing enzymes (NOX2 and iNOS); dysfunctional mitochondrial electron chain complexes; and apoptotic/necrotic cell death markers (DNA fragmentation, caspase 3 activity, and PARP activity). Baicalin administration on alternate day reduced fibrosis along with profibrotic gene expression, proinflammatory cytokines, oxidative stress, and cell death whereas improving the function of mitochondrial electron transport chain. We observed baicalin enhanced NRF2 activation by nuclear translocation and induced its target genes HO-1 and GCLM, thus enhancing antioxidant defense. Interplay of oxidative stress/inflammation and NRF2 were key players for baicalin-mediated protection. Stellate cell activation is crucial for initiation of fibrosis. Baicalin alleviated stellate cell activation and modulated TIMP1, SMA, collagen 1, and fibronectin in vitro. This study indicates that baicalin might be beneficial for reducing inflammation and fibrosis in liver injury models. PMID:28757911

Application studies of RFID technology in the process of coal logistics transport

NASA Astrophysics Data System (ADS)

Qiao, Bingqin; Chang, Xiaoming; Hao, Meiyan; Kong, Dejin

2012-04-01

For quality control problems in coal transport, RFID technology has been proposed to be applied to coal transportation process. The whole process RFID traceability system from coal production to consumption has been designed and coal supply chain logistics tracking system integration platform has been built, to form the coal supply chain traceability and transport tracking system and providing more and more transparent tracking and monitoring of coal quality information for consumers of coal. Currently direct transport and combined transport are the main forms of coal transportation in China. The means of transport are cars, trains and ships. In the booming networking environment of RFID technology, the RFID technology will be applied to coal logistics and provide opportunity for the coal transportation tracking in the process transportation.

Correlation between morphology, electron band structure, and resistivity of Pb atomic chains on the Si(5 5 3)-Au surface

NASA Astrophysics Data System (ADS)

Jałochowski, M.; Kwapiński, T.; Łukasik, P.; Nita, P.; Kopciuszyński, M.

2016-07-01

Structural and electron transport properties of multiple Pb atomic chains fabricated on the Si(5 5 3)-Au surface are investigated using scanning tunneling spectroscopy, reflection high electron energy diffraction, angular resolved photoemission electron spectroscopy and in situ electrical resistance. The study shows that Pb atomic chains growth modulates the electron band structure of pristine Si(5 5 3)-Au surface and hence changes its sheet resistivity. Strong correlation between chains morphology, electron band structure and electron transport properties is found. To explain experimental findings a theoretical tight-binding model of multiple atomic chains interacting on effective substrate is proposed.

Loss of macrophage fatty acid oxidation does not potentiate systemic metabolic dysfunction

PubMed Central

Gonzalez-Hurtado, Elsie; Lee, Jieun; Choi, Joseph; Selen Alpergin, Ebru S.; Collins, Samuel L.; Horton, Maureen R.

2017-01-01

Fatty acid oxidation in macrophages has been suggested to play a causative role in high-fat diet-induced metabolic dysfunction, particularly in the etiology of adipose-driven insulin resistance. To understand the contribution of macrophage fatty acid oxidation directly to metabolic dysfunction in high-fat diet-induced obesity, we generated mice with a myeloid-specific knockout of carnitine palmitoyltransferase II (CPT2 Mϕ-KO), an obligate step in mitochondrial long-chain fatty acid oxidation. While fatty acid oxidation was clearly induced upon IL-4 stimulation, fatty acid oxidation-deficient CPT2 Mϕ-KO bone marrow-derived macrophages displayed canonical markers of M2 polarization following IL-4 stimulation in vitro. In addition, loss of macrophage fatty acid oxidation in vivo did not alter the progression of high-fat diet-induced obesity, inflammation, macrophage polarization, oxidative stress, or glucose intolerance. These data suggest that although IL-4-stimulated alternatively activated macrophages upregulate fatty acid oxidation, fatty acid oxidation is dispensable for macrophage polarization and high-fat diet-induced metabolic dysfunction. Macrophage fatty acid oxidation likely plays a correlative, rather than causative, role in systemic metabolic dysfunction. PMID:28223293

Unraveling Biochemical Pathways Affected by Mitochondrial Dysfunctions Using Metabolomic Approaches

PubMed Central

Demine, Stéphane; Reddy, Nagabushana; Renard, Patricia; Raes, Martine; Arnould, Thierry

2014-01-01

Mitochondrial dysfunction(s) (MDs) can be defined as alterations in the mitochondria, including mitochondrial uncoupling, mitochondrial depolarization, inhibition of the mitochondrial respiratory chain, mitochondrial network fragmentation, mitochondrial or nuclear DNA mutations and the mitochondrial accumulation of protein aggregates. All these MDs are known to alter the capacity of ATP production and are observed in several pathological states/diseases, including cancer, obesity, muscle and neurological disorders. The induction of MDs can also alter the secretion of several metabolites, reactive oxygen species production and modify several cell-signalling pathways to resolve the mitochondrial dysfunction or ultimately trigger cell death. Many metabolites, such as fatty acids and derived compounds, could be secreted into the blood stream by cells suffering from mitochondrial alterations. In this review, we summarize how a mitochondrial uncoupling can modify metabolites, the signalling pathways and transcription factors involved in this process. We describe how to identify the causes or consequences of mitochondrial dysfunction using metabolomics (liquid and gas chromatography associated with mass spectrometry analysis, NMR spectroscopy) in the obesity and insulin resistance thematic. PMID:25257998

76 FR 38614 - Transportation Infrastructure/Multimodal Products and Services Trade Mission to Doha, Qatar, and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-07-01

...- modal freight and intelligent supply chain management, provides significant business opportunities in... technologies, supply chain systems and strategies; mass transportation systems; advanced vehicle technologies... opportunities for U.S. engineers, program management firms, and manufacturers to contribute to the creation of...

76 FR 32953 - Transportation Infrastructure/Multimodal Products and Services Trade Mission to Doha, Qatar, and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-06-07

... new systems, particularly those related to multimodal freight and intelligent supply chain management... technologies, supply chain systems and strategies; mass transportation systems; advanced vehicle technologies... country. There are excellent opportunities for U.S. engineers, program management firms, and manufacturers...

Nanoliposomes protect against AL amyloid light chain protein-induced endothelial injury.

PubMed

Truran, Seth; Weissig, Volkmar; Ramirez-Alvarado, Marina; Franco, Daniel A; Burciu, Camelia; Georges, Joseph; Murarka, Shishir; Okoth, Winter A; Schwab, Sara; Hari, Parameswaran; Migrino, Raymond Q

2014-03-01

A newly-recognized pathogenic mechanism underlying light chain amyloidosis (AL) involves endothelial dysfunction and cell injury caused by misfolded light chain proteins (LC). Nanoliposomes (NL) are artificial phospholipid vesicles that could attach to misfolded proteins and reduce tissue injury. To test whether co-treatment with NL reduces LC-induced endothelial dysfunction and cell death. Abdominal subcutaneous adipose arterioles from 14 non-AL subjects were cannulated; dilator response to acetylcholine and papaverine were measured at baseline and following 1-hour exposure to LC (20 µg/mL, 2 purified from AL subjects' urine, 1 from human recombinant LC [AL-09]) ± NL (phosphatidylcholine/cholesterol/phosphatidic acid 70/25/5 molar ratio) or NL alone. Human aortic artery endothelial cells (HAEC) were exposed to Oregon Green-labeled LC ± NL for 24 hours and intracellular LC and apoptosis (Hoechst stain) were measured. Circular dichroism spectroscopy was performed on AL-09 LC ± NL to follow changes in secondary structure and protein thermal stability. LC caused impaired dilation to acetylcholine that was restored by NL (control - 94.0 ± 1.8%, LC - 65.0 ± 7.1%, LC + NL - 95.3 ± 1.8%, p ≤ 0.001 LC versus control or LC + NL). NL protection was inhibited by L-NG-nitroarginine methyl ester. NL increased the beta sheet structure of LC, reduced endothelial cell internalization of LC and protected against LC-induced endothelial cell death. LC induced human adipose arteriole endothelial dysfunction and endothelial cell death, which were reversed by co-treatment with NL. This protection may partly be due to enhancing LC protein structure and reducing LC internalization. Nanoliposomes represent a promising new class of agents to ameliorate tissue injury from protein misfolding diseases such as AL.

Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis by inhibiting the activation of nuclear factor-kappa B

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cheng, Jian; Zhang, Lin; Dai, Weiqi

Aim: This study aimed to investigate the effect and underlying mechanism of ghrelin on intestinal barrier dysfunction in dextran sulfate sodium (DSS)-induced colitis. Methods and results: Acute colitis was induced in C57BL/6J mice by administering 2.5% DSS. Saline or 25, 125, 250 μg/kg ghrelin was administrated intraperitoneally (IP) to mice 1 day before colitis induction and on days 4, 5, and 6 after DSS administration. IP injection of a ghrelin receptor antagonist, [D-lys{sup 3}]-GHRP-6, was performed immediately prior to ghrelin injection. Ghrelin (125 or 250 μg/kg) could reduce the disease activity index, histological score, and myeloperoxidase activities in experimental colitis, and alsomore » prevented shortening of the colon. Ghrelin could prevent the reduction of transepithelial electrical resistance and tight junction expression, and bolstered tight junction structural integrity and regulated cytokine secretion. Ultimately, ghrelin inhibited nuclear factor kappa B (NF-κB), inhibitory κB-α, myosin light chain kinase, and phosphorylated myosin light chain 2 activation. Conclusions: Ghrelin prevented the breakdown of intestinal barrier function in DSS-induced colitis. The protective effects of ghrelin on intestinal barrier function were mediated by its receptor GHSR-1a. The inhibition of NF-κB activation might be part of the mechanism underlying the effects of ghrelin that protect against barrier dysfunction. - Highlights: • Ghrelin ameliorates intestinal barrier dysfunction in experimental colitis. • The effect of ghrelin is mediated by GHSR-1a. • Inhibition of NF-κB activation.« less

Lipid Emulsions Containing Medium Chain Triacylglycerols Blunt Bradykinin-Induced Endothelium-Dependent Relaxation in Porcine Coronary Artery Rings.

PubMed

Amissi, Said; Boisramé-Helms, Julie; Burban, Mélanie; Rashid, Sherzad K; León-González, Antonio J; Auger, Cyril; Toti, Florence; Meziani, Ferhat; Schini-Kerth, Valérie B

2017-03-01

Lipid emulsions for parenteral nutrition are used to provide calories and essential fatty acids for patients. They have been associated with hypertriglyceridemia, hypercholesterolemia, and metabolic stress, which may promote the development of endothelial dysfunction in patients. The aim of the present study was to determine whether five different industrial lipid emulsions may affect the endothelial function of coronary arteries. Porcine coronary artery rings were incubated with lipid emulsions 0.5, 1, or 2% (v/v) for 30 min before the determination of vascular reactivity in organ chambers and the level of oxidative stress using electron paramagnetic resonance. Incubation of coronary artery rings with either Lipidem ® , Medialipid ® containing long- and medium-chain triacylglycerols (LCT/MCT), or SMOFlipid ® containing LCT, MCT, omega-9, and -3, significantly reduced the bradykinin-induced endothelium-dependent relaxation, affecting both the nitric oxide (NO) and endothelium-dependent hyperpolarization (EDH) components, whereas, Intralipid ® containing LCT (soybean oil) and ClinOleic ® containing LCT (soybean and olive oil) did not have such an effect. The endothelial dysfunction induced by Lipidem ® was significantly improved by indomethacin, a cyclooxygenase (COX) inhibitor, inhibitors of oxidative stress (N-acetylcysteine, superoxide dismutase, catalase) and transition metal chelating agents (neocuproine, tetrathiomolybdate, deferoxamine and L-histidine). Lipidem ® significantly increased the arterial level of oxidative stress. The present findings indicate that lipid emulsions containing LCT/MCT induce endothelial dysfunction in coronary artery rings by blunting both NO- and EDH-mediated relaxations. The Lipidem ® -induced endothelial dysfunction is associated with increased vascular oxidative stress and the formation of COX-derived vasoconstrictor prostanoids.

Land transportation model for supply chain manufacturing industries

NASA Astrophysics Data System (ADS)

Kurniawan, Fajar

2017-12-01

Supply chain is a system that integrates production, inventory, distribution and information processes for increasing productivity and minimize costs. Transportation is an important part of the supply chain system, especially for supporting the material distribution process, work in process products and final products. In fact, Jakarta as the distribution center of manufacturing industries for the industrial area. Transportation system has a large influences on the implementation of supply chain process efficiency. The main problem faced in Jakarta is traffic jam that will affect on the time of distribution. Based on the system dynamic model, there are several scenarios that can provide solutions to minimize timing of distribution that will effect on the cost such as the construction of ports approaching industrial areas other than Tanjung Priok, widening road facilities, development of railways system, and the development of distribution center.

Oxidative Stress in HIV Infection and Alcohol Use: Role of Redox Signals in Modulation of Lipid Rafts and ATP-Binding Cassette Transporters.

PubMed

Thangavel, Samikkannu; Mulet, Carmen T; Atluri, Venkata S R; Agudelo, Marisela; Rosenberg, Rhonda; Devieux, Jessy G; Nair, Madhavan P N

2018-02-01

Human immunodeficiency virus (HIV) infection induces oxidative stress and alcohol use accelerates disease progression, subsequently causing immune dysfunction. However, HIV and alcohol impact on lipid rafts-mediated immune dysfunction remains unknown. In this study, we investigate the modulation by which oxidative stress induces reactive oxygen species (ROS) affecting redox expression, lipid rafts caveiloin-1, ATP-binding cassette (ABC) transporters, and transcriptional sterol regulatory element-binding protein (SREBP) gene and protein modification and how these mechanisms are associated with arachidonic acid (AA) metabolites in HIV positive alcohol users, and how they escalate immune dysfunction. In both alcohol using HIV-positive human subjects and in vitro studies of alcohol with HIV-1 gp120 protein in peripheral blood mononuclear cells, increased ROS production significantly affected redox expression in glutathione synthetase (GSS), super oxide dismutase (SOD), and glutathione peroxidase (GPx), and subsequently impacted lipid rafts Cav-1, ABC transporters ABCA1, ABCG1, ABCB1, and ABCG4, and SREBP transcription. The increased level of rate-limiting enzyme 3-hydroxy-3-methylglutaryl HMG-CoA reductase (HMGCR), subsequently, inhibited 7-dehydrocholesterol reductase (DHCR-7). Moreover, the expression of cyclooxygenase-2 (COX-2) and lipoxygenase-5 (5-LOX) mRNA and protein modification tentatively increased the levels of prostaglandin E2 synthases (PGE 2 ) in plasma when compared with either HIV or alcohol alone. This article suggests for the first time that the redox inhibition affects lipid rafts, ABC-transporter, and SREBP transcription and modulates AA metabolites, serving as an important intermediate signaling network during immune cell dysfunction in HIV-positive alcohol users. These findings indicate that HIV infection induces oxidative stress and redox inhibition, affecting lipid rafts and ABC transports, subsequently upregulating AA metabolites and leading to immune toxicity, and further exacerbation with alcohol use. Antioxid. Redox Signal. 28, 324-337.

Neurometabolic mechanisms for memory enhancement and neuroprotection of methylene blue

PubMed Central

Rojas, Julio C.; Bruchey, Aleksandra K.; Gonzalez-Lima, F.

2011-01-01

This paper provides the first review of the memory-enhancing and neuroprotective metabolic mechanisms of action of methylene blue in vivo. These mechanisms have important implications as a new neurobiological approach to improve normal memory and to treat memory impairment and neurodegeneration associated with mitochondrial dysfunction. Methylene blue’s action is unique because its neurobiological effects are not determined by regular drug-receptor interactions or drug-response paradigms. Methylene blue shows a hormetic dose-response, with opposite effects at low and high doses. At low doses, methylene blue is an electron cycler in the mitochondrial electron transport chain, with unparalleled antioxidant and cell respiration-enhancing properties that affect the function of the nervous system in a versatile manner. A major role of the respiratory enzyme cytochrome oxidase on the memory-enhancing effects of methylene blue is supported by available data. The memory-enhancing effects have been associated with improvement of memory consolidation in a network-specific and use-dependent fashion. In addition, low doses of methylene blue have also been used for neuroprotection against mitochondrial dysfunction in humans and experimental models of disease. The unique auto-oxidizing property of methylene blue and its pleiotropic effects on a number of tissue oxidases explain its potent neuroprotective effects at low doses. The evidence reviewed supports a mechanistic role of low-dose methylene blue as a promising and safe intervention for improving memory and for the treatment of acute and chronic conditions characterized by increased oxidative stress, neurodegeneration and memory impairment. PMID:22067440

MELAS syndrome: Clinical manifestations, pathogenesis, and treatment options.

PubMed

El-Hattab, Ayman W; Adesina, Adekunle M; Jones, Jeremy; Scaglia, Fernando

2015-01-01

Mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS) syndrome is one of the most frequent maternally inherited mitochondrial disorders. MELAS syndrome is a multi-organ disease with broad manifestations including stroke-like episodes, dementia, epilepsy, lactic acidemia, myopathy, recurrent headaches, hearing impairment, diabetes, and short stature. The most common mutation associated with MELAS syndrome is the m.3243A>G mutation in the MT-TL1 gene encoding the mitochondrial tRNA(Leu(UUR)). The m.3243A>G mutation results in impaired mitochondrial translation and protein synthesis including the mitochondrial electron transport chain complex subunits leading to impaired mitochondrial energy production. The inability of dysfunctional mitochondria to generate sufficient energy to meet the needs of various organs results in the multi-organ dysfunction observed in MELAS syndrome. Energy deficiency can also stimulate mitochondrial proliferation in the smooth muscle and endothelial cells of small blood vessels leading to angiopathy and impaired blood perfusion in the microvasculature of several organs. These events will contribute to the complications observed in MELAS syndrome particularly the stroke-like episodes. In addition, nitric oxide deficiency occurs in MELAS syndrome and can contribute to its complications. There is no specific consensus approach for treating MELAS syndrome. Management is largely symptomatic and should involve a multidisciplinary team. Unblinded studies showed that l-arginine therapy improves stroke-like episode symptoms and decreases the frequency and severity of these episodes. Additionally, carnitine and coenzyme Q10 are commonly used in MELAS syndrome without proven efficacy. Copyright © 2015 Elsevier Inc. All rights reserved.

Cardiovascular Mitochondrial Dysfunction Induced by Cocaine: Biomarkers and Possible Beneficial Effects of Modulators of Oxidative Stress.

PubMed

Graziani, Manuela; Sarti, Paolo; Arese, Marzia; Magnifico, Maria Chiara; Badiani, Aldo; Saso, Luciano

2017-01-01

Cocaine abuse has long been known to cause morbidity and mortality due to its cardiovascular toxic effects. The pathogenesis of the cardiovascular toxicity of cocaine use has been largely reviewed, and the most recent data indicate a fundamental role of oxidative stress in cocaine-induced cardiovascular toxicity, indicating that mitochondrial dysfunction is involved in the mechanisms of oxidative stress. The comprehension of the mechanisms involving mitochondrial dysfunction could help in selecting the most appropriate mitochondria injury biological marker, such as superoxide dismutase-2 activity and glutathionylated hemoglobin. The potential use of modulators of oxidative stress (mitoubiquinone, the short-chain quinone idebenone, and allopurinol) in the treatment of cocaine cardiotoxic effects is also suggested to promote further investigations on these potential mitochondria-targeted antioxidant strategies.

Measuring and Managing Army Supply Chain Risk: A Quantitative Approach by Item Number and Commercial Entity Code

DTIC Science & Technology

2015-01-01

services to the end user across the modes of transport .” As such, the supply chain “may include vendors, manufacturing facilities, logistics providers...sharing them with a group, before ranking each. For more information, see Van De Ven and Delbecq, 1974. 12 “When working through the vulnerability...are cost-effective (Kiser and Cantrell, 2006), avoiding higher production and transportation costs. Figure 2.5 outlines two prevalent supply chain

Hand-arm vibration in tropical rain forestry workers.

PubMed

Futatsuka, M; Inaoka, T; Ohtsuka, R; Sakurai, T; Moji, K; Igarashi, T

1995-01-01

Working conditions and health hazards including vibration syndrome related to forestry work using chain-saws were studied in Papua New Guinea and Indonesia. The subjects comprised 291 workers including 97 chain-saw operators. The health examination consisted of peripheral circulatory and sensory tests in the upper extremities. The vibration spectrum measured at the handle of the chain-saw indicated that these acceleration levels would lead to a moderately high risk of hand-arm vibration syndrome (HAVS). The peripheral circulatory function tests revealed dysfunction after more than five years vibration exposure. However, in general, the results of the function tests and subjective complaints showed fewer health problems compared to those of Japanese forestry workers. The reason of such differences of vibration effects seem to be the following: (1) warmer climate (more than 25 degrees C throughout the year), (2) young workers and short work experience. (3) short time vibration exposures on working days in the natural forests, (4) seasonal changes in logging work (5) healthy workers effects. Thus, we found no clear evidence that the workers of our study suffered from HAVS. A principal component analysis was applied. The factor score of the components of the reactive dynamics of peripheral circulation differed significantly after more than five years' exposure. On the other hand, we cannot deny the possibility that subclinical dysfunction of peripheral circulation may be caused by chain-saw operation in the tropics in future. Further investigations on the HAVS among forestry workers in the tropic environment are needed.

The Electron Transport Chain: An Interactive Simulation

ERIC Educational Resources Information Center

Romero, Chris; Choun, James

2014-01-01

This activity provides students an interactive demonstration of the electron transport chain and chemiosmosis during aerobic respiration. Students use simple, everyday objects as hydrogen ions and electrons and play the roles of the various proteins embedded in the inner mitochondrial membrane to show how this specific process in cellular…

Phosphorylated ubiquitin chain is the genuine Parkin receptor

PubMed Central

Okatsu, Kei; Koyano, Fumika; Kimura, Mayumi; Kosako, Hidetaka; Saeki, Yasushi

2015-01-01

PINK1 selectively recruits Parkin to depolarized mitochondria for quarantine and removal of damaged mitochondria via ubiquitylation. Dysfunction of this process predisposes development of familial recessive Parkinson’s disease. Although various models for the recruitment process have been proposed, none of them adequately explain the accumulated data, and thus the molecular basis for PINK1 recruitment of Parkin remains to be fully elucidated. In this study, we show that a linear ubiquitin chain of phosphomimetic tetra-ubiquitin(S65D) recruits Parkin to energized mitochondria in the absence of PINK1, whereas a wild-type tetra-ubiquitin chain does not. Under more physiologically relevant conditions, a lysosomal phosphorylated polyubiquitin chain recruited phosphomimetic Parkin to the lysosome. A cellular ubiquitin replacement system confirmed that ubiquitin phosphorylation is indeed essential for Parkin translocation. Furthermore, physical interactions between phosphomimetic Parkin and phosphorylated polyubiquitin chain were detected by immunoprecipitation from cells and in vitro reconstitution using recombinant proteins. We thus propose that the phosphorylated ubiquitin chain functions as the genuine Parkin receptor for recruitment to depolarized mitochondria. PMID:25847540

CypD(-/-) hearts have altered levels of proteins involved in Krebs cycle, branch chain amino acid degradation and pyruvate metabolism.

PubMed

Menazza, Sara; Wong, Renee; Nguyen, Tiffany; Wang, Guanghui; Gucek, Marjan; Murphy, Elizabeth

2013-03-01

Cyclophilin D (CypD) is a mitochondrial chaperone that has been shown to regulate the mitochondrial permeability transition pore (MPTP). MPTP opening is a major determinant of mitochondrial dysfunction and cardiomyocyte death during ischemia/reperfusion (I/R) injury. Mice lacking CypD have been widely used to study regulation of the MPTP, and it has been shown recently that genetic depletion of CypD correlates with elevated levels of mitochondrial Ca(2+). The present study aimed to characterize the metabolic changes in CypD(-/-) hearts. Initially, we used a proteomics approach to examine protein changes in CypD(-/-) mice. Using pathway analysis, we found that CypD(-/-) hearts have alterations in branched chain amino acid metabolism, pyruvate metabolism and the Krebs cycle. We tested whether these metabolic changes were due to inhibition of electron transfer from these metabolic pathways into the electron transport chain. As we found decreased levels of succinate dehydrogenase and electron transfer flavoprotein in the proteomics analysis, we examined whether activities of these enzymes might be altered. However, we found no alterations in their activities. The proteomics study also showed a 23% decrease in carnitine-palmitoyltransferase 1 (CPT1), which prompted us to perform a metabolomics analysis. Consistent with the decrease in CPT1, we found a significant decrease in C4/Ci4, C5-OH/C3-DC, C12:1, C14:1, C16:1, and C20:3 acyl carnitines in hearts from CypD(-/-) mice. In summary, CypD(-/-) hearts exhibit changes in many metabolic pathways and caution should be used when interpreting results from these mice as due solely to inhibition of the MPTP. Published by Elsevier Ltd.

The targeted anti-oxidant MitoQ causes mitochondrial swelling and depolarization in kidney tissue.

PubMed

Gottwald, Esther M; Duss, Michael; Bugarski, Milica; Haenni, Dominik; Schuh, Claus D; Landau, Ehud M; Hall, Andrew M

2018-04-01

Kidney proximal tubules (PTs) contain a high density of mitochondria, which are required to generate ATP to power solute transport. Mitochondrial dysfunction is implicated in the pathogenesis of numerous kidney diseases. Damaged mitochondria are thought to produce excess reactive oxygen species (ROS), which can lead to oxidative stress and activation of cell death pathways. MitoQ is a mitochondrial targeted anti-oxidant that has shown promise in preclinical models of renal diseases. However, recent studies in nonkidney cells have suggested that MitoQ might also have adverse effects. Here, using a live imaging approach, and both in vitro and ex vivo models, we show that MitoQ induces rapid swelling and depolarization of mitochondria in PT cells, but these effects were not observed with SS-31, another targeted anti-oxidant. MitoQ consists of a lipophilic cation (Tetraphenylphosphonium [TPP]) joined to an anti-oxidant component (quinone) by a 10-carbon alkyl chain, which is thought to insert into the inner mitochondrial membrane (IMM). We found that mitochondrial swelling and depolarization was also induced by dodecyltriphenylphosphomium (DTPP), which consists of TPP and the alkyl chain, but not by TPP alone. Surprisingly, MitoQ-induced mitochondrial swelling occurred in the absence of a decrease in oxygen consumption rate. We also found that DTPP directly increased the permeability of artificial liposomes with a cardiolipin content similar to that of the IMM. In summary, MitoQ causes mitochondrial swelling and depolarization in PT cells by a mechanism unrelated to anti-oxidant activity, most likely because of increased IMM permeability due to insertion of the alkyl chain. © 2018 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

Simultaneous evaluation of substrate-dependent oxygen consumption rates and mitochondrial membrane potential by TMRM and safranin in cortical mitochondria.

PubMed

Chowdhury, Subir Roy; Djordjevic, Jelena; Albensi, Benedict C; Fernyhough, Paul

2015-12-08

Mitochondrial membrane potential (mtMP) is critical for maintaining the physiological function of the respiratory chain to generate ATP. The present study characterized the inter-relationship between mtMP, using safranin and tetramethyl rhodamine methyl ester (TMRM), and mitochondrial respiratory activity and established a protocol for functional analysis of mitochondrial bioenergetics in a multi-sensor system. Coupled respiration was decreased by 27 and 30-35% in the presence of TMRM and safranin respectively. Maximal respiration was higher than coupled with Complex I- and II-linked substrates in the presence of both dyes. Safranin showed decreased maximal respiration at a higher concentration of carbonyl cyanide-4-(trifluoromethoxy)phenylhydrazone (FCCP) compared with TMRM. FCCP titration revealed that maximal respiration in the presence of glutamate and malate was not sustainable at higher FCCP concentrations as compared with pyruvate and malate. Oxygen consumption rate (OCR) and mtMP in response to mitochondrial substrates were higher in isolated mitochondria compared with tissue homogenates. Safranin exhibited higher sensitivity to changes in mtMP than TMRM. This multi-sensor system measured mitochondrial parameters in the brain of transgenic mice that model Alzheimer's disease (AD), because mitochondrial dysfunction is believed to be a primary event in the pathogenesis of AD. The coupled and maximal respiration of electron transport chain were decreased in the cortex of AD mice along with the mtMP compared with age-matched controls. Overall, these data demonstrate that safranin and TMRM are suitable for the simultaneous evaluation of mtMP and respiratory chain activity using isolated mitochondria and tissue homogenate. However, certain care should be taken concerning the selection of appropriate substrates and dyes for specific experimental circumstances. © 2016 Authors.

Identifying the molecular functions of electron transport proteins using radial basis function networks and biochemical properties.

PubMed

Le, Nguyen-Quoc-Khanh; Nguyen, Trinh-Trung-Duong; Ou, Yu-Yen

2017-05-01

The electron transport proteins have an important role in storing and transferring electrons in cellular respiration, which is the most proficient process through which cells gather energy from consumed food. According to the molecular functions, the electron transport chain components could be formed with five complexes with several different electron carriers and functions. Therefore, identifying the molecular functions in the electron transport chain is vital for helping biologists understand the electron transport chain process and energy production in cells. This work includes two phases for discriminating electron transport proteins from transport proteins and classifying categories of five complexes in electron transport proteins. In the first phase, the performances from PSSM with AAIndex feature set were successful in identifying electron transport proteins in transport proteins with achieved sensitivity of 73.2%, specificity of 94.1%, and accuracy of 91.3%, with MCC of 0.64 for independent data set. With the second phase, our method can approach a precise model for identifying of five complexes with different molecular functions in electron transport proteins. The PSSM with AAIndex properties in five complexes achieved MCC of 0.51, 0.47, 0.42, 0.74, and 1.00 for independent data set, respectively. We suggest that our study could be a power model for determining new proteins that belongs into which molecular function of electron transport proteins. Copyright © 2017 Elsevier Inc. All rights reserved.

Effect of molecular asymmetry on the charge transport physics of high mobility n-type molecular semiconductors investigated by scanning Kelvin probe microscopy.

PubMed

Hu, Yuanyuan; Berdunov, Nikolai; Di, Chong-an; Nandhakumar, Iris; Zhang, Fengjiao; Gao, Xike; Zhu, Daoben; Sirringhaus, Henning

2014-07-22

We have investigated the influence of the symmetry of the side chain substituents in high-mobility, solution processable n-type molecular semiconductors on the performance of organic field-effect transistors (OFETs). We compare two molecules with the same conjugated core, but either symmetric or asymmetric side chain substituents, and investigate the transport properties and thin film growth mode using scanning Kelvin probe microscopy (SKPM) and atomic force microscopy (AFM). We find that asymmetric side chains can induce a favorable two-dimensional growth mode with a bilayer structure, which enables ultrathin films with a single bilayer to exhibit excellent transport properties, while the symmetric molecules adopt an unfavorable three-dimensional growth mode in which transport in the first monolayer at the interface is severely hindered by high-resistance grain boundaries.

Regulation of Mitochondrial Function and Glutamatergic System Are the Target of Guanosine Effect in Traumatic Brain Injury.

PubMed

Dobrachinski, Fernando; da Rosa Gerbatin, Rogério; Sartori, Gláubia; Ferreira Marques, Naiani; Zemolin, Ana Paula; Almeida Silva, Luiz Fernando; Franco, Jeferson Luis; Freire Royes, Luiz Fernando; Rechia Fighera, Michele; Antunes Soares, Félix Alexandre

2017-04-01

Traumatic brain injury (TBI) is a highly complex multi-factorial disorder. Experimental trauma involves primary and secondary injury cascades that underlie delayed neuronal dysfunction and death. Mitochondrial dysfunction and glutamatergic excitotoxicity are the hallmark mechanisms of damage. Accordingly, a successful pharmacological intervention requires a multi-faceted approach. Guanosine (GUO) is known for its neuromodulator effects in various models of brain pathology, specifically those that involve the glutamatergic system. The aim of the study was to investigate the GUO effects against mitochondrial damage in hippocampus and cortex of rats subjected to TBI, as well as the relationship of this effect with the glutamatergic system. Adult male Wistar rats were subjected to a unilateral moderate fluid percussion brain injury (FPI) and treated 15 min later with GUO (7.5 mg/kg) or vehicle (saline 0.9%). Analyses were performed in hippocampus and cortex 3 h post-trauma and revealed significant mitochondrial dysfunction, characterized by a disrupted membrane potential, unbalanced redox system, decreased mitochondrial viability, and complex I inhibition. Further, disruption of Ca 2+ homeostasis and increased mitochondrial swelling was also noted. Our results showed that mitochondrial dysfunction contributed to decreased glutamate uptake and levels of glial glutamate transporters (glutamate transporter 1 and glutamate aspartate transporter), which leads to excitotoxicity. GUO treatment ameliorated mitochondrial damage and glutamatergic dyshomeostasis. Thus, GUO might provide a new efficacious strategy for the treatment acute physiological alterations secondary to TBI.

Opportunities and Challenges in the Design and Analysis of Biomass Supply Chains.

PubMed

Lautala, Pasi T; Hilliard, Michael R; Webb, Erin; Busch, Ingrid; Richard Hess, J; Roni, Mohammad S; Hilbert, Jorge; Handler, Robert M; Bittencourt, Roger; Valente, Amir; Laitinen, Tuuli

2015-12-01

The biomass supply chain is one of the most critical elements of large-scale bioenergy production and in many cases a key barrier for procuring initial funding for new developments on specific energy crops. Most productions rely on complex transforming chains linked to feed and food markets. The term 'supply chain' covers various aspects from cultivation and harvesting of the biomass, to treatment, transportation, and storage. After energy conversion, the product must be delivered to final consumption, whether it is in the form of electricity, heat, or more tangible products, such as pellets and biofuels. Effective supply chains are of utmost importance for bioenergy production, as biomass tends to possess challenging seasonal production cycles and low mass, energy and bulk densities. Additionally, the demand for final products is often also dispersed, further complicating the supply chain. The goal of this paper is to introduce key components of biomass supply chains, examples of related modeling applications, and if/how they address aspects related to environmental metrics and management. The paper will introduce a concept of integrated supply systems for sustainable biomass trade and the factors influencing the bioenergy supply chain landscape, including models that can be used to investigate the factors. The paper will also cover various aspects of transportation logistics, ranging from alternative modal and multi-modal alternatives to introduction of support tools for transportation analysis. Finally gaps and challenges in supply chain research are identified and used to outline research recommendations for the future direction in this area of study.

Opportunities and Challenges in the Design and Analysis of Biomass Supply Chains

NASA Astrophysics Data System (ADS)

Lautala, Pasi T.; Hilliard, Michael R.; Webb, Erin; Busch, Ingrid; Richard Hess, J.; Roni, Mohammad S.; Hilbert, Jorge; Handler, Robert M.; Bittencourt, Roger; Valente, Amir; Laitinen, Tuuli

2015-12-01

The biomass supply chain is one of the most critical elements of large-scale bioenergy production and in many cases a key barrier for procuring initial funding for new developments on specific energy crops. Most productions rely on complex transforming chains linked to feed and food markets. The term `supply chain' covers various aspects from cultivation and harvesting of the biomass, to treatment, transportation, and storage. After energy conversion, the product must be delivered to final consumption, whether it is in the form of electricity, heat, or more tangible products, such as pellets and biofuels. Effective supply chains are of utmost importance for bioenergy production, as biomass tends to possess challenging seasonal production cycles and low mass, energy and bulk densities. Additionally, the demand for final products is often also dispersed, further complicating the supply chain. The goal of this paper is to introduce key components of biomass supply chains, examples of related modeling applications, and if/how they address aspects related to environmental metrics and management. The paper will introduce a concept of integrated supply systems for sustainable biomass trade and the factors influencing the bioenergy supply chain landscape, including models that can be used to investigate the factors. The paper will also cover various aspects of transportation logistics, ranging from alternative modal and multi-modal alternatives to introduction of support tools for transportation analysis. Finally gaps and challenges in supply chain research are identified and used to outline research recommendations for the future direction in this area of study.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease.

PubMed

German, Christopher L; Baladi, Michelle G; McFadden, Lisa M; Hanson, Glen R; Fleckenstein, Annette E

2015-10-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson's disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein-protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.

Regulation of the Dopamine and Vesicular Monoamine Transporters: Pharmacological Targets and Implications for Disease

PubMed Central

German, Christopher L.; Baladi, Michelle G.; McFadden, Lisa M.; Hanson, Glen R.

2015-01-01

Dopamine (DA) plays a well recognized role in a variety of physiologic functions such as movement, cognition, mood, and reward. Consequently, many human disorders are due, in part, to dysfunctional dopaminergic systems, including Parkinson’s disease, attention deficit hyperactivity disorder, and substance abuse. Drugs that modify the DA system are clinically effective in treating symptoms of these diseases or are involved in their manifestation, implicating DA in their etiology. DA signaling and distribution are primarily modulated by the DA transporter (DAT) and by vesicular monoamine transporter (VMAT)-2, which transport DA into presynaptic terminals and synaptic vesicles, respectively. These transporters are regulated by complex processes such as phosphorylation, protein–protein interactions, and changes in intracellular localization. This review provides an overview of 1) the current understanding of DAT and VMAT2 neurobiology, including discussion of studies ranging from those conducted in vitro to those involving human subjects; 2) the role of these transporters in disease and how these transporters are affected by disease; and 3) and how selected drugs alter the function and expression of these transporters. Understanding the regulatory processes and the pathologic consequences of DAT and VMAT2 dysfunction underlies the evolution of therapeutic development for the treatment of DA-related disorders. PMID:26408528

Microwave emulations and tight-binding calculations of transport in polyacetylene

NASA Astrophysics Data System (ADS)

Stegmann, Thomas; Franco-Villafañe, John A.; Ortiz, Yenni P.; Kuhl, Ulrich; Mortessagne, Fabrice; Seligman, Thomas H.

2017-01-01

A novel approach to investigate the electron transport of cis- and trans-polyacetylene chains in the single-electron approximation is presented by using microwave emulation measurements and tight-binding calculations. In the emulation we take into account the different electronic couplings due to the double bonds leading to coupled dimer chains. The relative coupling constants are adjusted by DFT calculations. For sufficiently long chains a transport band gap is observed if the double bonds are present, whereas for identical couplings no band gap opens. The band gap can be observed also in relatively short chains, if additional edge atoms are absent, which cause strong resonance peaks within the band gap. The experimental results are in agreement with our tight-binding calculations using the nonequilibrium Green's function method. The tight-binding calculations show that it is crucial to include third nearest neighbor couplings to obtain the gap in the cis-polyacetylene.

Putative inflammatory effects of saturated fatty acids: Experimental confounders and context-specificity

USDA-ARS?s Scientific Manuscript database

Based primarily on cell culture experiments, long-chain saturated fatty acids (SFAs) are thought to promote inflammation and contribute to metabolic dysfunction through toll-like receptor activation. This, in turn, has been implicated in contributing to chronic low-grade inflammation associated with...

Chronic HIV-1 Infection Induces B-Cell Dysfunction That Is Incompletely Resolved by Long-Term Antiretroviral Therapy.

PubMed

Abudulai, Laila N; Fernandez, Sonia; Corscadden, Karli; Hunter, Michael; Kirkham, Lea-Ann S; Post, Jeffrey J; French, Martyn A

2016-04-01

To determine the effect of long-term antiretroviral therapy (ART) on HIV-1-induced B-cell dysfunction. Comparative study of ART-naive and ART-treated HIV-infected patients with non-HIV controls. B-cell dysfunction was examined in patients with HIV-1 infection (n = 30) who had received ART for a median time of 9.25 years (range: 1.3-21.7) by assessing proportions of CD21 B cells (a marker of B-cell exhaustion) and proportions of tumor necrosis factor-related apoptosis-inducing ligand or B and T lymphocyte attenuator B cells, and serum levels of immunoglobulin free light chains (markers of B-cell hyperactivation). The association of these markers with serum levels of IgG1 and IgG2, and production of IgG antibodies after vaccination with pneumococcal polysaccharides were also examined. ART-naive patients with HIV (n = 20) and controls (n = 20) were also assessed for comparison. ART-treated patients had increased proportions of CD21 and tumor necrosis factor-related apoptosis-inducing ligand B cells and, furthermore, although proportions of B and T lymphocyte attenuator B cells were not significantly different from controls, they correlated negatively with CD21 B cells. Proportions of CD21 B cells also correlated negatively with current CD4 T-cell counts. In ART-naive patients with HIV, free light chains correlated with CD21 B cells and IgG1, but not IgG2. Serum IgG2:IgG1 ratios were substantially lower than normal in patients with HIV and did not resolve on ART. In ART-treated patients, IgG antibody responses to pneumococcal polysaccharides after vaccination were not associated with markers of B-cell dysfunction. B-cell dysfunction persists in patients with HIV receiving long-term ART. The causes and consequences of this require further investigation.

Short- and medium-chain fatty acids enhance the cell surface expression and transport capacity of the bile salt export pump (BSEP/ABCB11).

PubMed

Kato, Takuya; Hayashi, Hisamitsu; Sugiyama, Yuichi

2010-09-01

The reduced expression of the bile salt export pump (BSEP/ABCB11) at the canalicular membrane is associated with cholestasis-induced hepatotoxicity due to the accumulation of bile acids in hepatocytes. We previously reported that 4-phenylbutyrate (4PBA), an approved drug for urea cycle disorders, is a promising agent for intrahepatic cholestasis because it increases both the cell surface expression and the transport capacity of BSEP. In the present study, we searched for effective compounds other than 4PBA by focusing on short- and medium-chain fatty acids, which have similar characteristics to 4PBA such as their low-molecular-weight and a carboxyl group. In transcellular transport studies using Madin-Darby canine kidney (MDCK) II cells, all short- and medium-chain fatty acids tested except for formate, acetate, and hexanoic acid showed more potent effects on wild type (WT) BSEP-mediated [3H]taurocholate transport than did 4PBA. The increase in WT BSEP transport with butyrate and octanoic acid treatment correlated with an increase in its expression at the cell surface. Two PFIC2-type variants, E297G and D482G BSEP, were similarly affected with both compounds treatment. The prolonged half-life of cell surface-resident WT BSEP was responsible for this increased octanoic acid-stimulated transport, but not for that of butyrate. In conclusion, short- and medium-chain fatty acids have potent effects on the increase in WT and PFIC2-type BSEP-mediated transport in MDCK II cells. Although both short- and medium-chain fatty acids enhance the transport capacity of WT and PFIC2-type BSEP by inducing those expressions at the cell surface, the underlying mechanism seems to differ between fatty acids. 2010 Elsevier B.V. All rights reserved.

Bias-dependent oscillatory electron transport of monatomic sulfur chains

NASA Astrophysics Data System (ADS)

Yu, Jing-Xin; Cheng, Yan; Sanvito, Stefano; Chen, Xiang-Rong

2012-03-01

The bias-dependent oscillatory electron transport of monatomic sulfur chains sandwiched between gold electrodes is investigated with density functional theory and non-equilibrium Green's function method. At zero bias, in contrast to the typical odd-even oscillations observed in most metallic chains, we find that the conductance oscillates with a period of four atoms. However, as the bias voltage is increased the current displays a two-atom periodicity. This emerges gradually, first for the longer chains and then, at voltages larger than 0.7 V, for lengths. The oscillatory behaviors are analyzed by the density of states and the energy-dependent and bias-dependent transmission coefficients.

Optimal dephasing for ballistic energy transfer in disordered linear chains

NASA Astrophysics Data System (ADS)

Zhang, Yang; Celardo, G. Luca; Borgonovi, Fausto; Kaplan, Lev

2017-11-01

We study the interplay between dephasing, disorder, and coupling to a sink on transport efficiency in a one-dimensional chain of finite length N , and in particular the beneficial or detrimental effect of dephasing on transport. The excitation moves along the chain by coherent nearest-neighbor hopping Ω , under the action of static disorder W and dephasing γ . The last site is coupled to an external acceptor system (sink), where the excitation can be trapped with a rate Γtrap. While it is known that dephasing can help transport in the localized regime, here we show that dephasing can enhance energy transfer even in the ballistic regime. Specifically, in the localized regime we recover previous results, where the optimal dephasing is independent of the chain length and proportional to W or W2/Ω . In the ballistic regime, the optimal dephasing decreases as 1 /N or 1 /√{N } , respectively, for weak and moderate static disorder. When focusing on the excitation starting at the beginning of the chain, dephasing can help excitation transfer only above a critical value of disorder Wcr, which strongly depends on the sink coupling strength Γtrap. Analytic solutions are obtained for short chains.

Endothelial dysfunction as a predictor of cardiovascular disease in type 1 diabetes

PubMed Central

Bertoluci, Marcello C; Cé, Gislaine V; da Silva, Antônio MV; Wainstein, Marco V; Boff, Winston; Puñales, Marcia

2015-01-01

Macro and microvascular disease are the main cause of morbi-mortality in type 1 diabetes (T1DM). Although there is a clear association between endothelial dysfunction and atherosclerosis in type 2 diabetes, a cause-effect relationship is less clear in T1DM. Although endothelial dysfunction (ED) precedes atherosclerosis, it is not clear weather, in recent onset T1DM, it may progress to clinical macrovascular disease. Moreover, endothelial dysfunction may either be reversed spontaneously or in response to intensive glycemic control, long-term exercise training and use of statins. Acute, long-term and post-prandial hyperglycemia as well as duration of diabetes and microalbuminuria are all conditions associated with ED in T1DM. The pathogenesis of endothelial dysfunction is closely related to oxidative-stress. NAD(P)H oxidase over activity induces excessive superoxide production inside the mitochondrial oxidative chain of endothelial cells, thus reducing nitric oxide bioavailability and resulting in peroxynitrite formation, a potent oxidant agent. Moreover, oxidative stress also uncouples endothelial nitric oxide synthase, which becomes dysfunctional, inducing formation of superoxide. Other important mechanisms are the activation of both the polyol and protein kinase C pathways as well as the presence of advanced glycation end-products. Future studies are needed to evaluate the potential clinical applicability of endothelial dysfunction as a marker for early vascular complications in T1DM. PMID:26069717

ETMB-RBF: discrimination of metal-binding sites in electron transporters based on RBF networks with PSSM profiles and significant amino acid pairs.

PubMed

Ou, Yu-Yen; Chen, Shu-An; Wu, Sheng-Cheng

2013-01-01

Cellular respiration is the process by which cells obtain energy from glucose and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation-reduction reactions. In these oxidation-reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain. We propose a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins. We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Compared with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88. We have developed a novel approach based on PSSM profiles and significant amino acid pairs for identifying metal-binding sites from electron transport proteins. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins.

ETMB-RBF: Discrimination of Metal-Binding Sites in Electron Transporters Based on RBF Networks with PSSM Profiles and Significant Amino Acid Pairs

PubMed Central

Ou, Yu-Yen; Chen, Shu-An; Wu, Sheng-Cheng

2013-01-01

Background Cellular respiration is the process by which cells obtain energy from glucose and is a very important biological process in living cell. As cells do cellular respiration, they need a pathway to store and transport electrons, the electron transport chain. The function of the electron transport chain is to produce a trans-membrane proton electrochemical gradient as a result of oxidation–reduction reactions. In these oxidation–reduction reactions in electron transport chains, metal ions play very important role as electron donor and acceptor. For example, Fe ions are in complex I and complex II, and Cu ions are in complex IV. Therefore, to identify metal-binding sites in electron transporters is an important issue in helping biologists better understand the workings of the electron transport chain. Methods We propose a method based on Position Specific Scoring Matrix (PSSM) profiles and significant amino acid pairs to identify metal-binding residues in electron transport proteins. Results We have selected a non-redundant set of 55 metal-binding electron transport proteins as our dataset. The proposed method can predict metal-binding sites in electron transport proteins with an average 10-fold cross-validation accuracy of 93.2% and 93.1% for metal-binding cysteine and histidine, respectively. Compared with the general metal-binding predictor from A. Passerini et al., the proposed method can improve over 9% of sensitivity, and 14% specificity on the independent dataset in identifying metal-binding cysteines. The proposed method can also improve almost 76% sensitivity with same specificity in metal-binding histidine, and MCC is also improved from 0.28 to 0.88. Conclusions We have developed a novel approach based on PSSM profiles and significant amino acid pairs for identifying metal-binding sites from electron transport proteins. The proposed approach achieved a significant improvement with independent test set of metal-binding electron transport proteins. PMID:23405059

ONR Far East Scientific Information Bulletin

DTIC Science & Technology

1990-09-01

In bone, grafting onto a polymer chain, inter- continuous processes, such as reactive extru- chain reactions, formation of interpenetrat- sion and...reaction kinetics, rheology, and side- and end-chain grafting , homopolymer transport phenomena occurring during REX. chain coupling, polymer...the Grafting reactions yield block or graft coupling species becomes a part of the chain, copolymers. Polyethylene, polypropylene, or by

Effect of plasma membrane fluidity on serotonin transport by endothelial cells

DOE Office of Scientific and Technical Information (OSTI.GOV)

Block, E.R.; Edwards, D.

1987-11-01

To evaluate the effect of plasma membrane fluidity of lung endothelial cells on serotonin transport, porcine pulmonary artery endothelial cells were incubated for 3 h with either 0.1 mM cholesterol hemisuccinate, 0.1 mM cis-vaccenic acid, or vehicle (control), after which plasma membrane fluidity and serotinin transport were measured. Fluorescence spectroscopy was used to measure fluidity in the plasma membrane. Serotonin uptake was calculated from the disappearance of ({sup 14}C)-serotonin from the culture medium. Cholesterol decreased fluidity in the subpolar head group and central and midacyl side-chain regions of the plasma membrane and decreased serotonin transport, whereas cis-vaccenic acid increased fluiditymore » in the central and midacyl side-chain regions of the plasma membrane and also increased serotonin transport. Cis-vaccenic acid had no effect of fluidity in the subpolar head group region of the plasma membrane. These results provide evidence that the physical state of the central and midacyl chains within the pulmonary artery endothelial cell plasma membrane lipid bilayer modulates transmembrane transport of serotonin by these cells.« less

Molecule-assisted ferromagnetic atomic chain formation

NASA Astrophysics Data System (ADS)

Kumar, Manohar; Sethu, Kiran Kumar Vidya; van Ruitenbeek, Jan M.

2015-06-01

One dimensional systems strongly enhance the quantum character of electron transport. Such systems can be realized in 5 d transition metals Au, Pt, and Ir, in the form of suspended monatomic chains between bulk leads. Atomic chains between ferromagnetic leads would open up many perspectives in the context of spin-dependent transport and spintronics, but the evidence suggests that for pure metals only the mentioned three 5 d metals are susceptible to chain formation. It has been argued that the stability of atomic chains made up from ferromagnetic metals is compromised by the same exchange interaction that produces the local moments. Here we demonstrate that magnetic atomic chains can be induced to form in break junctions under the influence of light molecules. Explicitly, we find deuterium assisted chain formation in the 3 d ferromagnetic transition metals Fe and Ni. Chain lengths up to eight atoms are formed upon stretching the ferromagnetic atomic contact in deuterium atmosphere at cryogenic temperatures. From differential conductance spectra vibronic states of D2 can be identified, confirming the presence of deuterium in the atomic chains. Shot noise spectroscopy indicates the presence of weakly spin polarized transmission channels.

Peptide amphiphile nanofiber hydrogel delivery of sonic hedgehog protein to the cavernous nerve to promote regeneration and prevent erectile dysfunction.

PubMed

Choe, Shawn; Bond, Christopher W; Harrington, Daniel A; Stupp, Samuel I; McVary, Kevin T; Podlasek, Carol A

2017-01-01

Erectile dysfunction (ED) has high impact on quality of life in prostatectomy, diabetic and aging patients. An underlying mechanism is cavernous nerve (CN) injury, which causes ED in up to 80% of prostatectomy patients. We examine how sonic hedgehog (SHH) treatment with innovative peptide amphiphile nanofiber hydrogels (PA), promotes CN regeneration after injury. SHH and its receptors patched (PTCH1) and smoothened (SMO) are localized in PG neurons and glia. SMO undergoes anterograde transport to signal to downstream targets. With crush injury, PG neurons degenerate and undergo apoptosis. SHH protein decreases, SMO localization changes to the neuronal cell surface, and anterograde transport stops. With SHH treatment SHH is taken up at the injury site and undergoes retrograde transport to PG neurons, allowing SMO transport to occur, and neurons remain intact. SHH treatment prevents neuronal degeneration, maintains neuronal, glial and downstream target signaling, and is significant as a regenerative therapy. Published by Elsevier Inc.

Preparing Texas' freight transportation system for 2055.

DOT National Transportation Integrated Search

2017-04-01

Efficient, reliable, and safe freight transportation is critical to the economic prosperity of any region. An efficient multimodal and intermodal transportation system reduces transportation and supply chain transaction costs and increases connectivi...

Non-local electron transport through normal and topological ladder-like atomic systems

NASA Astrophysics Data System (ADS)

Kurzyna, Marcin; Kwapiński, Tomasz

2018-05-01

We propose a locally protected ladder-like atomic system (nanoconductor) on a substrate that is insensitive to external perturbations. The system corresponds to coupled atomic chains fabricated on different surfaces. Electron transport properties of such conductors are studied theoretically using the model tight-binding Su-Schriffer-Hegger (SSH) Hamiltonian and Green's function formalism. We have found that the conductance of the system is almost insensitive to single adatoms and oscillates as a function of the side chain length with very large periods. Non-local character of the electron transport was observed also for topological SSH chains where nontrivial end states survive in the presence of disturbances as well as for different substrates. We have found that the careful inspection of the density of states or charge waves can provide the information about the atom energy levels and hopping amplitudes. Moreover, the ladder-like geometry allows one to distinguish between normal and topological zero-energy states. It is important that topological chains do not reveal Friedel oscillations which are observed in non-topological chains.

Quantitative PCR Analysis of Laryngeal Muscle Fiber Types

ERIC Educational Resources Information Center

Van Daele, Douglas J.

2010-01-01

Voice and swallowing dysfunction as a result of recurrent laryngeal nerve paralysis can be improved with vocal fold injections or laryngeal framework surgery. However, denervation atrophy can cause late-term clinical failure. A major determinant of skeletal muscle physiology is myosin heavy chain (MyHC) expression, and previous protein analyses…

An environmental assessment of food supply chains: a case study on dessert apples.

PubMed

Jones, Andy

2002-10-01

The contemporary food system provides consumers with convenience, extensive choice, and the year-round availability of fresh produce. In this paper these achievements are recognized within the context of the associated environmental impacts. While many analyses have considered the energy and material efficiency of various options for food production and packaging, very few studies have investigated the environmental impacts of the transport components of food supply chains. This is surprising, given that the global sourcing of food produce, centralized distribution systems, and shopping by car have become prevalent in recent decades and have contributed to an increase in the distance between producer and consumer or "food miles." In a case study the transport energy consumption is calculated for all possible ways in which dessert apples can be supplied to the UK consumer. The aim is to assess the environmental performance of the predominant fresh produce supply chains and to investigate claims that localized systems are more environmentally efficient. The main criteria used to compare the environmental efficiency in alternative food supply chains are the transport-related fossil-fuel energy consumption and associated carbon dioxide emissions. Analysis of the empirical data shows that transportation is now responsible for a considerable fraction of the total energy consumption in the life cycle of fresh apples, and in most cases exceeds the energy consumed in commercial apple cultivation. By developing local production and marketing systems for fresh products, transport demand can be reduced and many of the environmental impacts associated with existing supply chains can be avoided. The results of the study are then discussed in relation to the wider issues of transport policy, international trade, food security, and product-related environmental information for consumers.

Ammonia mediates cortical hemichannel dysfunction in rodent models of chronic liver disease

PubMed Central

Hadjihambi, Anna; De Chiara, Francesco; Hosford, Patrick S.; Habtetion, Abeba; Karagiannis, Anastassios; Davies, Nathan

2017-01-01

The pathogenesis of hepatic encephalopathy (HE) in cirrhosis is multifactorial and ammonia is thought to play a key role. Astroglial dysfunction is known to be present in HE. Astrocytes are extensively connected by gap junctions formed of connexins, which also exist as functional hemichannels allowing exchange of molecules between the cytoplasm and the extracellular milieu. The astrocyte‐neuron lactate shuttle hypothesis suggests that neuronal activity is fueled (at least in part) by lactate provided by neighboring astrocytes. We hypothesized that in HE, astroglial dysfunction could impair metabolic communication between astrocytes and neurons. In this study, we determined whether hyperammonemia leads to hemichannel dysfunction and impairs lactate transport in the cerebral cortex using rat models of HE (bile duct ligation [BDL] and induced hyperammonemia) and also evaluated the effect of ammonia‐lowering treatment (ornithine phenylacetate [OP]). Plasma ammonia concentration in BDL rats was significantly reduced by OP treatment. Biosensor recordings demonstrated that HE is associated with a significant reduction in both tonic and hypoxia‐induced lactate release in the cerebral cortex, which was normalized by OP treatment. Cortical dye loading experiments revealed hemichannel dysfunction in HE with improvement following OP treatment, while the expression of key connexins was unaffected. Conclusion: The results of the present study demonstrate that HE is associated with central nervous system hemichannel dysfunction, with ammonia playing a key role. The data provide evidence of a potential neuronal energy deficit due to impaired hemichannel‐mediated lactate transport between astrocytes and neurons as a possible mechanism underlying pathogenesis of HE. (Hepatology 2017;65:1306‐1318) PMID:28066916

Social stress in mice induces voiding dysfunction and bladder wall remodeling

PubMed Central

Chang, Andy; Butler, Stephan; Sliwoski, Joanna; Valentino, Rita; Canning, Douglas

2009-01-01

Several studies have anecdotally reported the occurrence of altered urinary voiding patterns in rodents exposed to social stress. A recent study characterized the urodynamic and central changes in a rat model of social defeat. Here, we describe a similar voiding phenotype induced in mice by social stress and in addition we describe potential molecular mechanisms underlying the resulting bladder wall remodeling. The mechanism leading to the altered voiding habits and underlying bladder phenotype may be relevant to the human syndrome of dysfunctional voiding which is thought to have a psychological component. To better characterize and investigate social stress-induced bladder wall hypertrophy, FVB mice (6 wk old) were randomized to either social stress or control manipulation. The stress involved repeated cycles of a 1-h direct exposure to a larger aggressive C57Bl6 breeder mouse followed by a 23-h period of barrier separation over 4 wk. Social stress resulted in altered urinary voiding patterns suggestive of urinary retention and increased bladder mass. In vivo cystometry revealed an increased volume at micturition with no change in the voiding pressure. Examination of these bladders revealed increased nuclear expression of the transcription factors MEF-2 and NFAT, as well as increased expression of the myosin heavy chain B isoform mRNA. BrdU uptake was increased within the urothelium and lamina propria layers in the social stress group. We conclude that social stress induces urinary retention that ultimately leads to shifts in transcription factors, alterations in myosin heavy chain isoform expression, and increases in DNA synthesis that mediate bladder wall remodeling. Social stress-induced bladder dysfunction in rodents may provide insight into the underlying mechanisms and potential treatment of dysfunctional voiding in humans. PMID:19587139

Ecstasy produces left ventricular dysfunction and oxidative stress in rats

PubMed Central

Shenouda, Sylvia K.; Lord, Kevin C.; McIlwain, Elizabeth; Lucchesi, Pamela A.; Varner, Kurt J.

2008-01-01

Aims Our aim was to determine whether the repeated, binge administration of 3,4-methylenedioxymethamphetamine (ecstasy; MDMA) produces structural and/or functional changes in the myocardium that are associated with oxidative stress. Methods and results Echocardiography and pressure–volume conductance catheters were used to assess left ventricular (LV) structure and function in rats subjected to four ecstasy binges (9 mg/kg i.v. for 4 days, separated by a 10 day drug-free period). Hearts from treated and control rats were used for either biochemical and proteomic analysis or the isolation of adult LV myocytes. After the fourth binge, treated hearts showed eccentric LV dilation and diastolic dysfunction. Systolic function was not altered in vivo; however, the magnitude of the contractile responses to electrical stimulation was significantly smaller in myocytes from rats treated in vivo with ecstasy compared with myocytes from control rats. The magnitude of the peak increase in intracellular calcium (measured by Fura-2) was also significantly smaller in myocytes from ecstasy-treated vs. control rats. The relaxation kinetics of the intracellular calcium transients were significantly longer in myocytes from ecstasy-treated rats. Ecstasy significantly increased nitrotyrosine content in the left ventricle. Proteomic analysis revealed increased nitration of contractile proteins (troponin-T, tropomyosin alpha-1 chain, myosin light polypeptide, and myosin regulatory light chain), mitochondrial proteins (Ub-cytochrome-c reductase and ATP synthase), and sarcoplasmic reticulum calcium ATPase. Conclusion The repeated binge administration of ecstasy produces eccentric LV dilation and dysfunction that is accompanied by oxidative stress. These functional responses may result from the redox modification of proteins involved in excitation-contraction coupling and/or mitochondrial energy production. Together, these results indicate that ecstasy has the potential to produce serious cardiac toxicity and ventricular dysfunction. PMID:18495670

Persistent neurochemical and behavioral abnormalities in adulthood despite early iron supplementation for perinatal iron deficiency anemia in rats⋆

PubMed Central

Felt, Barbara T.; Beard, John L.; Schallert, Timothy; Shao, Jie; Aldridge, J. Wayne; Connor, James R.; Georgieff, Michael K.; Lozoff, Betsy

2006-01-01

Background Iron deficiency anemia (IDA) has been associated with altered cognitive, motor, and social-emotional outcomes in human infants. We recently reported that rats with chronic perinatal IDA, had altered regional brain iron, monoamines, and sensorimotor skill emergence during early development. Objective To examine the long-term consequences of chronic perinatal IDA on behavior, brain iron and monoamine systems after dietary iron treatment in rats. Methods Sixty dams were randomly assigned to iron-sufficient (CN) or low-iron (EID) diets during gestation and lactation. Thereafter, all offspring were fed the iron-sufficient diet, assessed for hematology and behavior after weaning and into adulthood and for brain measures as adults (regional brain iron, monoamines, dopamine and serotonin transporters, and dopamine receptor). Behavioral assessments included sensorimotor function, general activity, response to novelty, spatial alternation, and spatial water maze performance. Results Hematology and growth were similar for EID and CN rats by postnatal day 35. In adulthood, EID thalamic iron content was lower. Monoamines, dopamine transporter, and dopamine receptor concentrations did not differ from CN. EID serotonin transporter concentration was reduced in striatum and related regions. EID rats had persisting sensorimotor deficits (delayed vibrissae-evoked forelimb placing, longer sticker removal time, and more imperfect grooming chains), were more hesitant in novel settings, and had poorer spatial water maze performance than CN. General activity and spatial alternation were similar for EID and CN. Conclusion Rats that had chronic perinatal IDA showed behavioral impairments that suggest persistent striatal dopamine and hippocampal dysfunction despite normalization of hematology, growth and most brain measures. PMID:16713640

Compounds having aromatic rings and side-chain amide-functionality and a method for transporting monovalent anions across biological membranes using the same

DOEpatents

Davis, Jeffery T [College Park, MD; Sidorov, Vladimir [Richmond, VA; Kotch, Frank W [New Phila., PA

2008-04-08

A compound containing at least two aromatic rings covalently bonded together, with each aromatic ring containing at least one oxyacetamide-based side chain, the compound being capable of forming a chloride ion channel across a lipid bilayer, and transporting chloride ion across the lipid bilayer.

Learning How the Electron Transport Chain Works: Independent and Interactive Effects of Instructional Strategies and Learners' Characteristics

ERIC Educational Resources Information Center

Darabi, Aubteen; Arrastia-Lloyd, Meagan C.; Nelson, David W.; Liang, Xinya; Farrell, Jennifer

2015-01-01

In order to develop an expert-like mental model of complex systems, causal reasoning is essential. This study examines the differences between forward and backward instructional strategies in terms of efficiency, students' learning and progression of their mental models of the electronic transport chain in an undergraduate metabolism course…

A big-data model for multi-modal public transportation with application to macroscopic control and optimisation

NASA Astrophysics Data System (ADS)

Faizrahnemoon, Mahsa; Schlote, Arieh; Maggi, Lorenzo; Crisostomi, Emanuele; Shorten, Robert

2015-11-01

This paper describes a Markov-chain-based approach to modelling multi-modal transportation networks. An advantage of the model is the ability to accommodate complex dynamics and handle huge amounts of data. The transition matrix of the Markov chain is built and the model is validated using the data extracted from a traffic simulator. A realistic test-case using multi-modal data from the city of London is given to further support the ability of the proposed methodology to handle big quantities of data. Then, we use the Markov chain as a control tool to improve the overall efficiency of a transportation network, and some practical examples are described to illustrate the potentials of the approach.

Mitochondria-Targeted Antioxidant Prevents Cardiac Dysfunction Induced by Tafazzin Gene Knockdown in Cardiac Myocytes

PubMed Central

He, Quan; Harris, Nicole; Ren, Jun; Han, Xianlin

2014-01-01

Tafazzin, a mitochondrial acyltransferase, plays an important role in cardiolipin side chain remodeling. Previous studies have shown that dysfunction of tafazzin reduces cardiolipin content, impairs mitochondrial function, and causes dilated cardiomyopathy in Barth syndrome. Reactive oxygen species (ROS) have been implicated in the development of cardiomyopathy and are also the obligated byproducts of mitochondria. We hypothesized that tafazzin knockdown increases ROS production from mitochondria, and a mitochondria-targeted antioxidant prevents tafazzin knockdown induced mitochondrial and cardiac dysfunction. We employed cardiac myocytes transduced with an adenovirus containing tafazzin shRNA as a model to investigate the effects of the mitochondrial antioxidant, mito-Tempo. Knocking down tafazzin decreased steady state levels of cardiolipin and increased mitochondrial ROS. Treatment of cardiac myocytes with mito-Tempo normalized tafazzin knockdown enhanced mitochondrial ROS production and cellular ATP decline. Mito-Tempo also significantly abrogated tafazzin knockdown induced cardiac hypertrophy, contractile dysfunction, and cell death. We conclude that mitochondria-targeted antioxidant prevents cardiac dysfunction induced by tafazzin gene knockdown in cardiac myocytes and suggest mito-Tempo as a potential therapeutic for Barth syndrome and other dilated cardiomyopathies resulting from mitochondrial oxidative stress. PMID:25247053

Opportunities and Challenges in the Design and Analysis of Biomass Supply Chains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Lautala, Pasi T.; Hilliard, Michael R.; Webb, Erin

The biomass supply chain is one of the most critical elements of large-scale bioenergy production and in many cases a key barrier for procuring initial funding for new developments on specific energy crops. Most productions rely on complex transforming chains linked to feed and food markets. The term 'supply chain' covers various aspects from cultivation and harvesting of the biomass, to treatment, transportation, and storage. After energy conversion, the product must be delivered to final consumption, whether it is in the form of electricity, heat, or more tangible products, such as pellets and biofuels. Effective supply chains are of utmostmore » importance for bioenergy production, as biomass tends to possess challenging seasonal production cycles and low mass, energy and bulk densities. Additionally, the demand for final products is often also dispersed, further complicating the supply chain. The goal of this paper is to introduce key components of biomass supply chains, examples of related modeling applications, and if/how they address aspects related to environmental metrics and management. The paper will introduce a concept of integrated supply systems for sustainable biomass trade and the factors influencing the bioenergy supply chain landscape, including models that can be used to investigate the factors. Our paper will also cover various aspects of transportation logistics, ranging from alternative modal and multi-modal alternatives to introduction of support tools for transportation analysis. Lastly, gaps and challenges in supply chain research are identified and used to outline research recommendations for the future direction in this area of study.« less

Opportunities and Challenges in the Design and Analysis of Biomass Supply Chains

DOE PAGES

Lautala, Pasi T.; Hilliard, Michael R.; Webb, Erin; ...

2015-06-30

The biomass supply chain is one of the most critical elements of large-scale bioenergy production and in many cases a key barrier for procuring initial funding for new developments on specific energy crops. Most productions rely on complex transforming chains linked to feed and food markets. The term 'supply chain' covers various aspects from cultivation and harvesting of the biomass, to treatment, transportation, and storage. After energy conversion, the product must be delivered to final consumption, whether it is in the form of electricity, heat, or more tangible products, such as pellets and biofuels. Effective supply chains are of utmostmore » importance for bioenergy production, as biomass tends to possess challenging seasonal production cycles and low mass, energy and bulk densities. Additionally, the demand for final products is often also dispersed, further complicating the supply chain. The goal of this paper is to introduce key components of biomass supply chains, examples of related modeling applications, and if/how they address aspects related to environmental metrics and management. The paper will introduce a concept of integrated supply systems for sustainable biomass trade and the factors influencing the bioenergy supply chain landscape, including models that can be used to investigate the factors. Our paper will also cover various aspects of transportation logistics, ranging from alternative modal and multi-modal alternatives to introduction of support tools for transportation analysis. Lastly, gaps and challenges in supply chain research are identified and used to outline research recommendations for the future direction in this area of study.« less

Downregulation of the expression of mitochondrial electron transport complex genes in autism brains.

PubMed

Anitha, Ayyappan; Nakamura, Kazuhiko; Thanseem, Ismail; Matsuzaki, Hideo; Miyachi, Taishi; Tsujii, Masatsugu; Iwata, Yasuhide; Suzuki, Katsuaki; Sugiyama, Toshiro; Mori, Norio

2013-05-01

Mitochondrial dysfunction (MtD) and abnormal brain bioenergetics have been implicated in autism, suggesting possible candidate genes in the electron transport chain (ETC). We compared the expression of 84 ETC genes in the post-mortem brains of autism patients and controls. Brain tissues from the anterior cingulate gyrus, motor cortex, and thalamus of autism patients (n = 8) and controls (n = 10) were obtained from Autism Tissue Program, USA. Quantitative real-time PCR arrays were used to quantify gene expression. We observed reduced expression of several ETC genes in autism brains compared to controls. Eleven genes of Complex I, five genes each of Complex III and Complex IV, and seven genes of Complex V showed brain region-specific reduced expression in autism. ATP5A1 (Complex V), ATP5G3 (Complex V) and NDUFA5 (Complex I) showed consistently reduced expression in all the brain regions of autism patients. Upon silencing ATP5A1, the expression of mitogen-activated protein kinase 13 (MAPK13), a p38 MAPK responsive to stress stimuli, was upregulated in HEK 293 cells. This could have been induced by oxidative stress due to impaired ATP synthesis. We report new candidate genes involved in abnormal brain bioenergetics in autism, supporting the hypothesis that mitochondria, critical for neurodevelopment, may play a role in autism. © 2012 The Authors; Brain Pathology © 2012 International Society of Neuropathology.

Tunneling conductance of amine-linked alkyl chains.

PubMed

Prodan, Emil; Car, Roberto

2008-06-01

The tunneling transport theory developed in ref 9 (Phys. Rev. B 2007, 76, 115102) is applied to molecular devices made of alkyl chains linked to gold electrodes via amine groups. Using the analytic expression of the tunneling conductance derived in our previous work, we identify the key physical quantities that characterize the conductance of these devices. By investigating the transport characteristics of three devices, containing four, six, and eight methyl groups, we extract the dependence of the tunneling conductance on the chain's length, which is an exponential decay law in agreement with recent experimental data.

Livestock transport from the perspective of the pre-slaughter logistic chain: a review.

PubMed

Miranda-de la Lama, G C; Villarroel, M; María, G A

2014-09-01

New developments in livestock transport within the pre-slaughter chain are discussed in terms of three logistic nodes: origin, stopovers and slaughterhouse. Factors as transport cost, haulier, truck specifications, micro-environment conditions, loading density, route planning, vehicle accidents and journey length are discussed as well as causes of morbidity, mortality, live weight and carcass damage. Taking into account current trends towards increased transport times, logistics stopovers and mixed transport, there is a need to develop systems of evaluation and decision-making that provide tools and protocols that can minimize the biological cost to animals, which may have been underestimated in the past. Copyright © 2014 Elsevier Ltd. All rights reserved.

Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease.

PubMed

Sunny, Nishanth E; Kalavalapalli, Srilaxmi; Bril, Fernando; Garrett, Timothy J; Nautiyal, Manisha; Mathew, Justin T; Williams, Caroline M; Cusi, Kenneth

2015-08-15

Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD.

Cross-talk between branched-chain amino acids and hepatic mitochondria is compromised in nonalcoholic fatty liver disease

PubMed Central

Kalavalapalli, Srilaxmi; Bril, Fernando; Garrett, Timothy J.; Nautiyal, Manisha; Mathew, Justin T.; Williams, Caroline M.; Cusi, Kenneth

2015-01-01

Elevated plasma branched-chain amino acids (BCAA) in the setting of insulin resistance have been relevant in predicting type 2 diabetes mellitus (T2DM) onset, but their role in the etiology of hepatic insulin resistance remains uncertain. We determined the link between BCAA and dysfunctional hepatic tricarboxylic acid (TCA) cycle, which is a central feature of hepatic insulin resistance and nonalcoholic fatty liver disease (NAFLD). Plasma metabolites under basal fasting and euglycemic hyperinsulinemic clamps (insulin stimulation) were measured in 94 human subjects with varying degrees of insulin sensitivity to identify their relationships with insulin resistance. Furthermore, the impact of elevated BCAA on hepatic TCA cycle was determined in a diet-induced mouse model of NAFLD, utilizing targeted metabolomics and nuclear magnetic resonance (NMR)-based metabolic flux analysis. Insulin stimulation revealed robust relationships between human plasma BCAA and indices of insulin resistance, indicating chronic metabolic overload from BCAA. Human plasma BCAA and long-chain acylcarnitines also showed a positive correlation, suggesting modulation of mitochondrial metabolism by BCAA. Concurrently, mice with NAFLD failed to optimally induce hepatic mTORC1, plasma ketones, and hepatic long-chain acylcarnitines, following acute elevation of plasma BCAA. Furthermore, elevated BCAA failed to induce multiple fluxes through hepatic TCA cycle in mice with NAFLD. Our data suggest that BCAA are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Impairment of BCAA-mediated upregulation of the TCA cycle could be a significant contributor to mitochondrial dysfunction in NAFLD. PMID:26058864

Metabolic pathway profiling of mitochondrial respiratory chain mutants in C. elegans

PubMed Central

MJ, Falk; Z, Zhang; Rosenjack; Nissim; E, Daikhin; Nissim; MM, Sedensky; M, Yudkoff; PG, Morgan

2008-01-01

C. elegans affords a model of primary mitochondrial dysfunction that provides insight into cellular adaptations which accompany mutations in nuclear gene that encode mitochondrial proteins. To this end, we characterized genome-wide expression profiles of C. elegans strains with mutations in nuclear-encoded subunits of respiratory chain complexes. Our goal was to detect concordant changes among clusters of genes that comprise defined metabolic pathways. Results indicate that respiratory chain mutants significantly upregulate a variety of basic cellular metabolic pathways involved in carbohydrate, amino acid, and fatty acid metabolism, as well as cellular defense pathways such as the metabolism of P450 and glutathione. To further confirm and extend expression analysis findings, quantitation of whole worm free amino acid levels was performed in C. elegans mitochondrial mutants for subunits of complexes I, II, and III. Significant differences were seen for 13 of 16 amino acid levels in complex I mutants compared with controls, as well as overarching similarities among profiles of complex I, II, and III mutants compared with controls. The specific pattern of amino acid alterations observed provides novel evidence to suggest that an increase in glutamate-linked transamination reactions caused by the failure of NAD+ dependent oxidation of ketoacids occurs in primary mitochondrial respiratory chain mutants. Recognition of consistent alterations among patterns of nuclear gene expression for multiple biochemical pathways and in quantitative amino acid profiles in a translational genetic model of mitochondrial dysfunction allows insight into the complex pathogenesis underlying primary mitochondrial disease. Such knowledge may enable the development of a metabolomic profiling diagnostic tool applicable to human mitochondrial disease. PMID:18178500

Selective downregulation of mitochondrial electron transport chain activity and increased oxidative stress in human atrial fibrillation.

PubMed

Emelyanova, Larisa; Ashary, Zain; Cosic, Milanka; Negmadjanov, Ulugbek; Ross, Gracious; Rizvi, Farhan; Olet, Susan; Kress, David; Sra, Jasbir; Tajik, A Jamil; Holmuhamedov, Ekhson L; Shi, Yang; Jahangir, Arshad

2016-07-01

Mitochondria are critical for maintaining normal cardiac function, and a deficit in mitochondrial energetics can lead to the development of the substrate that promotes atrial fibrillation (AF) and its progression. However, the link between mitochondrial dysfunction and AF in humans is still not fully defined. The aim of this study was to elucidate differences in the functional activity of mitochondrial oxidative phosphorylation (OXPHOS) complexes and oxidative stress in right atrial tissue from patients without (non-AF) and with AF (AF) who were undergoing open-heart surgery and were not significantly different for age, sex, major comorbidities, and medications. The overall functional activity of the electron transport chain (ETC), NADH:O2 oxidoreductase activity, was reduced by 30% in atrial tissue from AF compared with non-AF patients. This was predominantly due to a selective reduction in complex I (0.06 ± 0.007 vs. 0.09 ± 0.006 nmol·min(-1)·citrate synthase activity(-1), P = 0.02) and II (0.11 ± 0.012 vs. 0.16 ± 0.012 nmol·min(-1)·citrate synthase activity(-1), P = 0.003) functional activity in AF patients. Conversely, complex V activity was significantly increased in AF patients (0.21 ± 0.027 vs. 0.12 ± 0.01 nmol·min(-1)·citrate synthase activity(-1), P = 0.005). In addition, AF patients exhibited a higher oxidative stress with increased production of mitochondrial superoxide (73 ± 17 vs. 11 ± 2 arbitrary units, P = 0.03) and 4-hydroxynonenal level (77.64 ± 30.2 vs. 9.83 ± 2.83 ng·mg(-1) protein, P = 0.048). Our findings suggest that AF is associated with selective downregulation of ETC activity and increased oxidative stress that can contribute to the progression of the substrate for AF. Copyright © 2016 the American Physiological Society.

The TNF-α/NF-κB signaling pathway has a key role in methamphetamine–induced blood–brain barrier dysfunction

PubMed Central

Coelho-Santos, Vanessa; Leitão, Ricardo A; Cardoso, Filipa L; Palmela, Inês; Rito, Manuel; Barbosa, Marcos; Brito, Maria A; Fontes-Ribeiro, Carlos A; Silva, Ana P

2015-01-01

Methamphetamine (METH) is a psychostimulant that causes neurologic and psychiatric abnormalities. Recent studies have suggested that its neurotoxicity may also result from its ability to compromise the blood–brain barrier (BBB). Herein, we show that METH rapidly increased the vesicular transport across endothelial cells (ECs), followed by an increase of paracellular transport. Moreover, METH triggered the release of tumor necrosis factor-alpha (TNF-α), and the blockade of this cytokine or the inhibition of nuclear factor-kappa B (NF-κB) pathway prevented endothelial dysfunction. Since astrocytes have a crucial role in modulating BBB function, we further showed that conditioned medium obtained from astrocytes previously exposed to METH had a negative impact on barrier properties also via TNF-α/NF-κB pathway. Animal studies corroborated the in vitro results. Overall, we show that METH directly interferes with EC properties or indirectly via astrocytes through the release of TNF-α and subsequent activation of NF-κB pathway culminating in barrier dysfunction. PMID:25899299

Illustrating Business Marketing Concepts through the Value Chain Game

ERIC Educational Resources Information Center

Liao-Troth, Sara; Thomas, Stephanie P.; Webb, G. Scott

2015-01-01

The Value Chain Game is an activity that helps students to develop a holistic understanding of the processes and challenges in managing the value chain so that customer needs are met. Competing value chains work to produce and sell two products. Seasonal demand, quality defects, transportation delays, and audits offer complexities that represent…

Impaired branched-chain amino acid metabolism may underlie the nonalcoholic fatty liver disease-like pathology of neonatal testosterone-treated female rats.

PubMed

Anzai, Álvaro; Marcondes, Rodrigo R; Gonçalves, Thiago H; Carvalho, Kátia C; Simões, Manuel J; Garcia, Natália; Soares, José M; Padmanabhan, Vasantha; Baracat, Edmund C; da Silva, Ismael D C G; Maciel, Gustavo A R

2017-10-13

Polycystic ovary syndrome (PCOS) is frequently associated with non-alcoholic fatty liver disease (NAFLD), but the mechanisms involved in the development of NAFLD in PCOS are not well known. We investigated histological changes and metabolomic profile in the liver of rat models of PCOS phenotype induced by testosterone or estradiol. Two-day old female rats received sc injections of 1.25 mg testosterone propionate (Testos; n = 10), 0.5 mg estradiol benzoate (E2; n = 10), or vehicle (control group, CNT; n = 10). Animals were euthanized at 90-94 d of age and the liver was harvested for histological and metabolomic analyses. Findings showed only Testos group exhibited fatty liver morphology and higher levels of ketogenic and branched-chain amino acids (BCAA). Enrichment analysis showed effects of testosterone on BCAA degradation pathway and mitochondrial enzymes related to BCAA metabolism. Testos group also had a decreased liver fatty acid elongase 2 (ELOVL2) activity. E2 group had reduced lipid and acylcarnitine metabolites in the liver. Both groups had increased organic cation transporters (SLC22A4 and SLC16A9) activity. These findings indicate that neonatal testosterone treatment, but not estradiol, produces histological changes in female rat liver that mimic NAFLD with testosterone-treated rats showing impaired BCAA metabolism and dysfunctions in ELOVL2, SLC22A4 and SLC16A9 activity.

In vivo visualizations of drought-induced embol 35 ism spread in Vitis vinifera

USDA-ARS?s Scientific Manuscript database

Long distance water transport through plant xylem is vulnerable to hydraulic dysfunction during periods of increased tension on the xylem sap, often coinciding with drought. While the effects of local and systemic embolism on plant water transport and physiology are well documented, the spatial patt...

Hydrogen is a preferred intermediate in the energy-conserving electron transport chain of Methanosarcina barkeri.

PubMed

Kulkarni, Gargi; Kridelbaugh, Donna M; Guss, Adam M; Metcalf, William W

2009-09-15

Methanogens use an unusual energy-conserving electron transport chain that involves reduction of a limited number of electron acceptors to methane gas. Previous biochemical studies suggested that the proton-pumping F(420)H(2) dehydrogenase (Fpo) plays a crucial role in this process during growth on methanol. However, Methanosarcina barkeri Delta fpo mutants constructed in this study display no measurable phenotype on this substrate, indicating that Fpo plays a minor role, if any. In contrast, Delta frh mutants lacking the cytoplasmic F(420)-reducing hydrogenase (Frh) are severely affected in their ability to grow and make methane from methanol, and double Delta fpo/Delta frh mutants are completely unable to use this substrate. These data suggest that the preferred electron transport chain involves production of hydrogen gas in the cytoplasm, which then diffuses out of the cell, where it is reoxidized with transfer of electrons into the energy-conserving electron transport chain. This hydrogen-cycling metabolism leads directly to production of a proton motive force that can be used by the cell for ATP synthesis. Nevertheless, M. barkeri does have the flexibility to use the Fpo-dependent electron transport chain when needed, as shown by the poor growth of the Delta frh mutant. Our data suggest that the rapid enzymatic turnover of hydrogenases may allow a competitive advantage via faster growth rates in this freshwater organism. The mutant analysis also confirms the proposed role of Frh in growth on hydrogen/carbon dioxide and suggests that either Frh or Fpo is needed for aceticlastic growth of M. barkeri.

Interaction of CO with an Au monatomic chain at different strains: Electronic structure and ballistic transport

NASA Astrophysics Data System (ADS)

Sclauzero, Gabriele; Dal Corso, Andrea; Smogunov, Alexander

2012-04-01

We study the energetics, the electronic structure, and the ballistic transport of an infinite Au monatomic chain with an adsorbed CO molecule. We find that the bridge adsorption site is energetically favored with respect to the atop site, both at the equilibrium Au-Au spacing of the chain and at larger spacings. Instead, a substitutional configuration requires a very elongated Au-Au bond, well above the rupture distance of the pristine Au chain. The electronic structure properties can be described by the Blyholder model, which involves the formation of bonding/antibonding pairs of 5σ and 2π states through the hybridization between molecular levels of CO and metallic states of the chain. In the atop geometry, we find an almost vanishing conductance due to the 5σ antibonding states giving rise to a Fano-like destructive interference close to the Fermi energy. In the bridge geometry, instead, the same states are shifted to higher energies and the conductance reduction with respect to pristine Au chain is much smaller. We also examine the effects of strain on the ballistic transport, finding opposite behaviors for the atop and bridge conductances. Only the bridge geometry shows a strain dependence compatible with the experimental conductance traces.

A novel sputum transport solution eliminates cold chain and supports routine tuberculosis testing in Nepal.

PubMed

Maharjan, Bhagwan; Shrestha, Bhabana; Weirich, Alexandra; Stewart, Andrew; Kelly-Cirino, Cassandra D

2016-12-01

This preliminary study evaluated the transport reagent OMNIgene SPUTUM (OMS) in a real-world, resource-limited setting: a zonal hospital and national tuberculosis (TB) reference laboratory, Nepal. The objectives were to: (1) assess the performance of OMS for transporting sputum from peripheral sites without cold chain stabilization; and (2) compare with Nepal's standard of care (SOC) for Mycobacterium tuberculosis smear and culture diagnostics. Sixty sputa were manually split into a SOC sample (airline-couriered to the laboratory, conventional processing) and an OMS sample (OMS added at collection, no cold chain transport or processing). Smear microscopy and solid culture were performed. Transport was 0-8days. Forty-one samples (68%) were smear-positive using both methods. Of the OMS cultures, 37 (62%) were positive, 22 (36%) were negative, and one (2%) was contaminated. Corresponding SOC results were 32 (53%), 21 (35%), and seven (12%). OMS "rescued" six (i.e., missed using SOC) compared with one rescue using SOC. Of smear-positives, six SOC samples produced contaminated cultures whereas only one OMS sample was contaminated. OMS reduced culture contamination from 12% to 2%, and improved TB detection by 9%. The results suggest that OMS could perform well as a no cold chain, long-term transport solution for smear and culture testing. The findings provide a basis for larger feasibility studies. Copyright © 2016 Ministry of Health, Saudi Arabia. Published by Elsevier Ltd. All rights reserved.

Pathways of acetylcholine synthesis, transport and release as targets for treatment of adult-onset cognitive dysfunction.

PubMed

Amenta, F; Tayebati, S K

2008-01-01

Acetylcholine (ACh) is a neurotransmitter widely diffused in central, peripheral, autonomic and enteric nervous system. This paper has reviewed the main mechanisms of ACh synthesis, storage, and release. Presynaptic choline transport supports ACh production and release, and cholinergic terminals express a unique transporter critical for neurotransmitter release. Neurons cannot synthesize choline, which is ultimately derived from the diet and is delivered through the blood stream. ACh released from cholinergic synapses is hydrolyzed by acetylcholinesterase into choline and acetyl coenzyme A and almost 50% of choline derived from ACh hydrolysis is recovered by a high-affinity choline transporter. Parallel with the development of cholinergic hypothesis of geriatric memory dysfunction, cholinergic precursor loading strategy was tried for treating cognitive impairment occurring in Alzheimer's disease. Controlled clinical studies denied clinical usefulness of choline and lecithin (phosphatidylcholine), whereas for other phospholipids involved in choline biosynthetic pathways such as cytidine 5'-diphosphocholine (CDP-choline) or alpha-glyceryl-phosphorylcholine (choline alphoscerate) a modest improvement of cognitive dysfunction in adult-onset dementia disorders is documented. These inconsistencies have probably a metabolic explanation. Free choline administration increases brain choline availability but it does not increase ACh synthesis/or release. Cholinergic precursors to serve for ACh biosynthesis should be incorporate and stored into phospholipids in brain. It is probable that appropriate ACh precursors and other correlated molecules (natural or synthesized) could represent a tool for developing therapeutic strategies by revisiting and updating treatments/supplementations coming out from this therapeutic stalemate.

Transport of triplet excitons along continuous 100 nm polyfluorene chains

DOE PAGES

Xi, Liang; Bird, Matthew; Mauro, Gina; ...

2014-12-03

Triplet excitons created in poly-2,7-(9,9-dihexyl)fluorene (pF) chains with end trap groups in solution are efficiently transported to and captured by the end groups. The triplets explore the entire lengths of the chains, even for ~100 nm long chains enabling determination of the completeness of end capping. The results show that the chains continuous: they may contain transient barriers or traps, such as those from fluctuations of dihedral angles, but are free of major defects that stop motion of the triplets. Quantitative determinations are aided by the addition of a strong electron donor, TMPD, which removes absorption bands of the end-trappedmore » triplets. For chains having at least one end trap, triplet capture is quantitative on the 1 µs timescale imposed by the use of the donor. Fractions of chains having no end traps were 0.15 for pF samples with anthraquinone (AQ) end traps and 0.063 with naphthylimide (NI) end traps. These determinations agreed with measurements by NMR for short (<40 polymer repeat units (PRU)) chains, where NMR determinations are accurate. The results find no evidence for traps or barriers to transport of triplets, and places limits on the possible presence of defects as impenetrable barriers to less than one per 300 PRU. The present results present a paradigm different from the current consensus, derived from observations of singlet excitons, that conjugated chains are divided into “segments,” perhaps by some kind of defects. For the present pF chains, the segmentation either does not apply to triplet excitons or is transient so that the defects are healed or surmounted in times much shorter than 1 µs. Triplets on chains without end trap groups transfer to chains with end traps on a slower time scale. Rate constants for these bimolecular triplet transfer reactions were found to increase with the length of the accepting chain, as did rate constants for triplet transfer to the chains from small molecules like biphenyl. As a result, a second set of polyfluorenes with 2-butyloctyl side chains was found to have a much lower completeness of end capping.« less

[Oxygen-transport function of the blood and endothelial dysfunction in patients with angina pectoris and arterial hypertension].

PubMed

Iankovskaia, A V; Zinchuk, M A

2007-01-01

Parameters of oxygen-transport function of the blood and function of the endothelium were studied in 49 patients with stable angina pectoris of I and II functional class with or without concomitant 2nd degree arterial hypertension. All patients received pathogenetic therapy. Signs of endothelial dysfunction were found in group III in which endothelium dependent vasodilation (8.22 +/- 1.71%) was 73.4% (p1 < 0.001) lower than in control group and 47.2% (p3 < 0.05) lower than in patients with class I angina. In all groups baseline content of nitrates/nitrites was lower. Main parameters of acid-base balance were lowered in patients of group III evidencing for emergence of signs of metabolic acidosis and hypoxia. Lowering of hemoglobin affinity to oxygen and its rise after therapy was also revealed. Maximal lowering of this parameter (-10.2%, p2 < 0.05) reflecting shift of oxyhemoglobin dissociation curve to the right was noted in group II. Endothelium can participate in formation of these disturbances because its dysfunction is associated with deranged release of NO in various parts of vascular tree. This affects formation of various NO-derivatives of hemoglobin and oxygen transport system of the blood.

Phenotypic Screening for Friedreich Ataxia Using Random shRNA Selection.

PubMed

Cotticelli, M Grazia; Acquaviva, Fabio; Xia, Shujuan; Kaur, Avinash; Wang, Yongping; Wilson, Robert B

2015-10-01

Friedreich ataxia (FRDA) is an autosomal recessive neuro- and cardio-degenerative disorder for which there are no proven effective treatments. FRDA is caused by decreased expression and/or function of the protein frataxin. Frataxin chaperones iron in the mitochondrial matrix and regulates the iron-sulfur cluster (ISC) assembly complex. ISCs are prosthetic groups critical for the function of the Krebs cycle and the mitochondrial electron transport chain. Decreased expression of frataxin is associated with decreased ISC assembly, mitochondrial iron accumulation, and increased oxidative stress, all of which contribute to mitochondrial dysfunction. In media with beta-hydroxybutyrate (BHB) as carbon source, primary FRDA fibroblasts grow poorly and/or lose viability over several days. We screened a random, short-hairpin-RNA (shRNA)-expressing library in primary FRDA fibroblasts and identified two shRNAs that reverse the growth/viability defect in BHB media. One of these two clones increases frataxin expression in primary FRDA fibroblasts, either as a vector-expressed shRNA or as a transfected short-interfering RNA (siRNA). © 2015 Society for Laboratory Automation and Screening.

Control mechanisms in mitochondrial oxidative phosphorylation☆

PubMed Central

Hroudová, Jana; Fišar, Zdeněk

2013-01-01

Distribution and activity of mitochondria are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5’- triphosphate production is regulated by many control mechanism–firstly by oxygen, substrate level, adenosine-5’-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by “second control mechanisms,” such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, allosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5’-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria, similarly, decline of antioxidative enzyme activities (e.g. in the elderly) enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production. PMID:25206677

Control mechanisms in mitochondrial oxidative phosphorylation.

PubMed

Hroudová, Jana; Fišar, Zdeněk

2013-02-05

Distribution and activity of mitochondria are key factors in neuronal development, synaptic plasticity and axogenesis. The majority of energy sources, necessary for cellular functions, originate from oxidative phosphorylation located in the inner mitochondrial membrane. The adenosine-5'- triphosphate production is regulated by many control mechanism-firstly by oxygen, substrate level, adenosine-5'-diphosphate level, mitochondrial membrane potential, and rate of coupling and proton leak. Recently, these mechanisms have been implemented by "second control mechanisms," such as reversible phosphorylation of the tricarboxylic acid cycle enzymes and electron transport chain complexes, allosteric inhibition of cytochrome c oxidase, thyroid hormones, effects of fatty acids and uncoupling proteins. Impaired function of mitochondria is implicated in many diseases ranging from mitochondrial myopathies to bipolar disorder and schizophrenia. Mitochondrial dysfunctions are usually related to the ability of mitochondria to generate adenosine-5'-triphosphate in response to energy demands. Large amounts of reactive oxygen species are released by defective mitochondria, similarly, decline of antioxidative enzyme activities (e.g. in the elderly) enhances reactive oxygen species production. We reviewed data concerning neuroplasticity, physiology, and control of mitochondrial oxidative phosphorylation and reactive oxygen species production.

Molecular chaperones and photoreceptor function

PubMed Central

Kosmaoglou, Maria; Schwarz, Nele; Bett, John S.; Cheetham, Michael E.

2008-01-01

Molecular chaperones facilitate and regulate protein conformational change within cells. This encompasses many fundamental cellular processes: including the correct folding of nascent chains; protein transport and translocation; signal transduction and protein quality control. Chaperones are, therefore, important in several forms of human disease, including neurodegeneration. Within the retina, the highly specialized photoreceptor cell presents a fascinating paradigm to investigate the specialization of molecular chaperone function and reveals unique chaperone requirements essential to photoreceptor function. Mutations in several photoreceptor proteins lead to protein misfolding mediated neurodegeneration. The best characterized of these are mutations in the molecular light sensor, rhodopsin, which cause autosomal dominant retinitis pigmentosa. Rhodopsin biogenesis is likely to require chaperones, while rhodopsin misfolding involves molecular chaperones in quality control and the cellular response to protein aggregation. Furthermore, the specialization of components of the chaperone machinery to photoreceptor specific roles has been revealed by the identification of mutations in molecular chaperones that cause inherited retinal dysfunction and degeneration. These chaperones are involved in several important cellular pathways and further illuminate the essential and diverse roles of molecular chaperones. PMID:18490186

Functional analysis, a resilience improvement tool applied to a waste management system - application to the "household waste management chain"

NASA Astrophysics Data System (ADS)

Beraud, H.; Barroca, B.; Hubert, G.

2012-12-01

A waste management system plays a leading role in the capacity of an area to restart after flooding, as their impact on post-crisis management can be very considerable. Improving resilience, i.e. enabling it to maintain or recover acceptable operating levels after flooding is primordial. To achieve this, we must understand how the system works for bringing any potential dysfunctions to light and taking preventive measures. Functional analysis has been used for understanding the complexity of this type of system. The purpose of this article is to show the interest behind this type of method and the limits in its use for improving resilience of waste management system as well as other urban technical systems1, by means of theoretical modelling and its application on a study site. 1In a systemic vision of the city, urban technical systems combine all the user service systems that are essential for the city to operate (electricity, water supplies, transport, sewerage, etc.). These systems are generally organised in the form of networks (Coutard, 2010; CERTU, 2005).

Analysis of charge transport in gels containing polyoxometallates using methods of different sensitivity to migration.

PubMed

Caban, Karolina; Lewera, Adam; Zukowska, Grazyna Z; Kulesza, Pawel J; Stojek, Zbigniew; Jeffrey, Kenneth R

2006-08-04

Two methods have been used for examination of transport of charge in gels soaked with DMF and containing dissolved polyoxometallates. The first method is based on the analysis of both Cottrellian and steady-state currents and therefore is capable of giving the concentration of the electroactive redox centres and their transport (diffusion-type) coefficient. The second method provides the real diffusion coefficients, i.e. transport coefficients free of migrational influence, for both the substrate and the product of the electrode reaction. Several gels based on poly(methyl methacrylate), with charged (addition of 1-acrylamido-2-methyl-2-propanesulphonic acid to the polymerization mixture) and uncharged chains, have been used in the investigation. The ratio obtained for the diffusion coefficient (second method) and transport coefficient (first method) was smaller for the gels containing charged polymer chains than for the gels with uncharged chains. In part these changes could be explained by the contribution of migration to the transport of polyoxomatallates in the gels. However, the impact of the changes in the polymer-channel capacity at the electrode surface while the electrode process proceeds was also considered. These structural changes should affect differently the methods based on different time domains.

Reduction in reactive oxygen species production by mitochondria from elderly subjects with normal and impaired glucose tolerance.

PubMed

Ghosh, Sangeeta; Lertwattanarak, Raweewan; Lefort, Natalie; Molina-Carrion, Marjorie; Joya-Galeana, Joaquin; Bowen, Benjamin P; Garduno-Garcia, Jose de Jesus; Abdul-Ghani, Muhammad; Richardson, Arlan; DeFronzo, Ralph A; Mandarino, Lawrence; Van Remmen, Holly; Musi, Nicolas

2011-08-01

Aging increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes. It has been proposed that increased reactive oxygen species (ROS) generation by dysfunctional mitochondria could play a role in the pathogenesis of these metabolic abnormalities. We examined whether aging per se (in subjects with normal glucose tolerance [NGT]) impairs mitochondrial function and how this relates to ROS generation, whether older subjects with IGT have a further worsening of mitochondrial function (lower ATP production and elevated ROS generation), and whether exercise reverses age-related changes in mitochondrial function. Mitochondrial ATP and ROS production were measured in muscle from younger individuals with NGT, older individuals with NGT, and older individuals with IGT. Measurements were performed before and after 16 weeks of aerobic exercise. ATP synthesis was lower in older subjects with NGT and older subjects with IGT versus younger subjects. Notably, mitochondria from older subjects (with NGT and IGT) displayed reduced ROS production versus the younger group. ATP and ROS production were similar between older groups. Exercise increased ATP synthesis in the three groups. Mitochondrial ROS production also increased after training. Proteomic analysis revealed downregulation of several electron transport chain proteins with aging, and this was reversed by exercise. Old mitochondria from subjects with NGT and IGT display mitochondrial dysfunction as manifested by reduced ATP production but not with respect to increased ROS production. When adjusted to age, the development of IGT in elderly individuals does not involve changes in mitochondrial ATP and ROS production. Lastly, exercise reverses the mitochondrial phenotype (proteome and function) of old mitochondria.

Impaired mitochondrial oxidative phosphorylation and supercomplex assembly in rectus abdominis muscle of diabetic obese individuals.

PubMed

Antoun, Ghadi; McMurray, Fiona; Thrush, A Brianne; Patten, David A; Peixoto, Alyssa C; Slack, Ruth S; McPherson, Ruth; Dent, Robert; Harper, Mary-Ellen

2015-12-01

Skeletal muscle mitochondrial dysfunction has been documented in patients with type 2 diabetes mellitus; however, specific respiratory defects and their mechanisms are poorly understood. The aim of the current study was to examine oxidative phosphorylation and electron transport chain (ETC) supercomplex assembly in rectus abdominis muscles of 10 obese diabetic and 10 obese non-diabetic individuals. Twenty obese women undergoing Roux-en-Y gastric bypass surgery were recruited for this study. Muscle samples were obtained intraoperatively and subdivided for multiple analyses, including high-resolution respirometry and assessment of supercomplex assembly. Clinical data obtained from referring physicians were correlated with laboratory findings. Participants in both groups were of a similar age, weight and BMI. Mitochondrial respiration rates were markedly reduced in diabetic vs non-diabetic patients. This defect was observed during maximal ADP-stimulated respiration in the presence of complex I-linked substrates and complex I- and II-linked substrates, and during maximal uncoupled respiration. There were no differences in fatty acid (octanoyl carnitine) supported respiration, leak respiration or isolated activity of cytochrome c oxidase. Intriguingly, significant correlations were found between glycated haemoglobin (HbA1c) levels and maximal respiration or respiration supported by complex I, complex I and II or fatty acid. In the muscle of diabetic patients, blue native gel electrophoresis revealed a striking decrease in complex I, III and IV containing ETC supercomplexes. These findings support the hypothesis that ETC supercomplex assembly may be an important underlying mechanism of muscle mitochondrial dysfunction in type 2 diabetes mellitus.

Small Molecule Suppressors of Drosophila Kinesin Deficiency Rescue Motor Axon Development in a Zebrafish Model of Spinal Muscular Atrophy

PubMed Central

Gassman, Andrew; Hao, Le T.; Bhoite, Leena; Bradford, Chad L.; Chien, Chi-Bin; Beattie, Christine E.; Manfredi, John P.

2013-01-01

Proximal spinal muscular atrophy (SMA) is the most common inherited motor neuropathy and the leading hereditary cause of infant mortality. Currently there is no effective treatment for the disease, reflecting a need for pharmacologic interventions that restore performance of dysfunctional motor neurons or suppress the consequences of their dysfunction. In a series of assays relevant to motor neuron biology, we explored the activities of a collection of tetrahydroindoles that were reported to alter the metabolism of amyloid precursor protein (APP). In Drosophila larvae the compounds suppressed aberrant larval locomotion due to mutations in the Khc and Klc genes, which respectively encode the heavy and light chains of kinesin-1. A representative compound of this class also suppressed the appearance of axonal swellings (alternatively termed axonal spheroids or neuritic beads) in the segmental nerves of the kinesin-deficient Drosophila larvae. Given the importance of kinesin-dependent transport for extension and maintenance of axons and their growth cones, three members of the class were tested for neurotrophic effects on isolated rat spinal motor neurons. Each compound stimulated neurite outgrowth. In addition, consistent with SMA being an axonopathy of motor neurons, the three axonotrophic compounds rescued motor axon development in a zebrafish model of SMA. The results introduce a collection of small molecules as pharmacologic suppressors of SMA-associated phenotypes and nominate specific members of the collection for development as candidate SMA therapeutics. More generally, the results reinforce the perception of SMA as an axonopathy and suggest novel approaches to treating the disease. PMID:24023935

Diabetic retinopathy pathogenesis and the ameliorating effects of melatonin; involvement of autophagy, inflammation and oxidative stress.

PubMed

Dehdashtian, Ehsan; Mehrzadi, Saeed; Yousefi, Bahman; Hosseinzadeh, Azam; Reiter, Russel J; Safa, Majid; Ghaznavi, Habib; Naseripour, Masood

2018-01-15

Diabetic retinopathy (DR), a microvascular complication of diabetes mellitus (DM), remains as one of the major causes of vision loss worldwide. The release of pro-inflammatory cytokines and the adhesion of leukocytes to retinal capillaries are initial events in DR development. Inflammation, ER stress, oxidative stress and autophagy are major causative factors involved in the pathogenesis of DR. Diabetes associated hyperglycemia leads to mitochondrial electron transport chain dysfunction culminating in a rise in ROS generation. Since mitochondria are the major source of ROS production, oxidative stress induced by mitochondrial dysfunction also contributes to the development of diabetic retinopathy. Autophagy increases in the retina of diabetic patients and is regulated by ER stress, oxidative stress and inflammation-related pathways. Autophagy functions as a double-edged sword in DR. Under mild stress, autophagic activity can lead to cell survival while during severe stress, dysregulated autophagy results in massive cell death and may have a role in initiation and exacerbation of DR. Melatonin and its metabolites play protective roles against inflammation, ER stress and oxidative stress due to their direct free radical scavenger activities and indirect antioxidant activity via the stimulation antioxidant enzymes including glutathione reductase, glutathione peroxidase, superoxide dismutase and catalase. Melatonin also acts as a cell survival agent by modulating autophagy in various cell types and under different conditions through amelioration of oxidative stress, ER stress and inflammation. Herein, we review the possible effects of melatonin on diabetic retinopathy, focusing on its ability to regulate autophagy processes. Copyright © 2017. Published by Elsevier Inc.

Discrete mitochondrial aberrations in the spinal cord of sporadic ALS patients.

PubMed

Delic, Vedad; Kurien, Crupa; Cruz, Josean; Zivkovic, Sandra; Barretta, Jennifer; Thomson, Avery; Hennessey, Daniel; Joseph, Jaheem; Ehrhart, Jared; Willing, Alison E; Bradshaw, Patrick; Garbuzova-Davis, Svitlana

2018-08-01

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease characterized by progressive motor neuron degeneration in the brain and spinal cord leading to muscle atrophy, paralysis, and death. Mitochondrial dysfunction is a major contributor to motor neuron degeneration associated with ALS progression. Mitochondrial abnormalities have been determined in spinal cords of animal disease models and ALS patients. However, molecular mechanisms leading to mitochondrial dysfunction in sporadic ALS (sALS) patients remain unclear. Also, segmental or regional variation in mitochondrial activity in the spinal cord has not been extensively examined in ALS. In our study, the activity of mitochondrial electron transport chain complex IV was examined in post-mortem gray and white matter of the cervical and lumbar spinal cords from male and female sALS patients and controls. Mitochondrial distribution and density in spinal cord motor neurons, lateral funiculus, and capillaries in gray and white matter were analyzed by immunohistochemistry. Results showed that complex IV activity was significantly decreased only in gray matter in both cervical and lumbar spinal cords from ALS patients. In ALS cervical and lumbar spinal cords, significantly increased mitochondrial density and altered distribution were observed in motor neurons, lateral funiculus, and cervical white matter capillaries. Discrete decreased complex IV activity in addition to changes in mitochondria distribution and density determined in the spinal cord in sALS patients are novel findings. These explicit mitochondrial defects in the spinal cord may contribute to ALS pathogenesis and should be considered in development of therapeutic approaches for this disease. © 2018 Wiley Periodicals, Inc.

Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report.

PubMed

Brown, Bradley D; Rais, Theodore

2015-01-01

The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a "zebra" (i.e., an obscure diagnosis that is made when a more common explanation is more likely).

Autism in the Son of a Woman with Mitochondrial Myopathy and Dysautonomia: A Case Report

PubMed Central

Rais, Theodore

2015-01-01

The relationship between autism spectrum disorders and mitochondrial dysfunction, including mitochondrial myopathies and other mitochondrial diseases, is an area of ongoing research. All autism spectrum disorders are known to be heritable, via genetic and/or epigenetic mechanisms, but specific modes of inheritance are not well characterized. Nevertheless, autism spectrum disorders have been linked to many specific genes associated with mitochondrial function, especially to genes involved in mitochondrial tRNA and the electron transport chain, both particularly vulnerable to point mutations, and clinical research also supports a relationship between the two pathologies. Although only a small minority of patients with autism have a mitochondrial disease, many patients with mitochondrial myopathies have autism spectrum disorder symptoms, and these symptoms may be the presenting symptoms, which presents a diagnostic challenge for clinicians. The authors report the case of a 15-year-old boy with a history of autism spectrum disorder and neurocardiogenic syncope, admitted to the inpatient unit for self-injury, whose young mother, age 35, was discovered to suffer from mitochondrial myopathy, dysautonomia, neurocardiogenic syncope, Ehler-Danlos syndrome, and other uncommon multisystem pathologies likely related to mitochondrial dysfunction. This case illustrates the need for a high index of suspicion for mitochondrial disease in patients with autism, as they have two orders of magnitude greater risk for such diseases than the general population. The literature shows that mitochondrial disease is underdiagnosed in autism spectrum disorder patients and should not be viewed as a “zebra” (i.e., an obscure diagnosis that is made when a more common explanation is more likely). PMID:26634179

Pathophysiology and molecular basis of selected metabolic abnormalities in Huntington's disease.

PubMed

Krzysztoń-Russjan, Jolanta

2016-12-30

Huntington's disease (HD) is an incurable, devastating neurodegenerative disease with a known genetic background and autosomally dominant inheritance pattern. HTT gene mutation (mHTT) is associated with polymorphic fragment elongation above 35 repeats of the CAG triplet. The mHTT product is an altered protein with a poly-Q elongated fragment, with the highest expression determined in the central nervous system (CNS) and with differentiated expression outside the CNS. A drastic loss of striatal and deeper layers of the cerebral cortex neurons was determined in the CNS, but muscle and body weight mass loss with dysfunction of many organs was also observed. HD symptoms include neurological disturbances, such as choreal movements with dystonia, speech and swallowing impairments, and additionally a variety of psychiatric and behavioral symptoms with cognitive decline have been described. They are the result of disturbances of several cellular pathways related to signal transmission, mitochondrial dysfunction and energy metabolism impairment shown by gene and protein expression and alteration of their functions. Impairment of energy processes demonstrated by a decrease of ATP production and increase of oxidative stress markers was determined in- and outside of the CNS in glycolysis, the Krebs cycle and the electron transport chain. A correlation between the increase of energy metabolism impairment level and the increase in number of CAG repeats in HTT has often been described. The energy metabolism study is an initial stage of sensitive biomarkers and a new therapeutic investigative option for early application in order to inhibit pathological processes in HD. Identification of pathological changes outside the CNS requires a reevaluation of diagnostic and therapeutic rules in HD.

N-acetylcysteine modulates glutamatergic dysfunction and depressive behavior in Huntington's disease.

PubMed

Wright, Dean J; Gray, Laura J; Finkelstein, David I; Crouch, Peter J; Pow, David; Pang, Terence Y; Li, Shanshan; Smith, Zoe M; Francis, Paul S; Renoir, Thibault; Hannan, Anthony J

2016-07-15

Glutamatergic dysfunction has been implicated in the pathogenesis of depressive disorders and Huntington's disease (HD), in which depression is the most common psychiatric symptom. Synaptic glutamate homeostasis is regulated by cystine-dependent glutamate transporters, including GLT-1 and system x c - In HD, the enzyme regulating cysteine (and subsequently cystine) production, cystathionine-γ-lygase, has recently been shown to be lowered. The aim of the present study was to establish whether cysteine supplementation, using N-acetylcysteine (NAC) could ameliorate glutamate pathology through the cystine-dependent transporters, system x c - and GLT-1. We demonstrate that the R6/1 transgenic mouse model of HD has lower basal levels of cystine, and showed depressive-like behaviors in the forced-swim test. Administration of NAC reversed these behaviors. This effect was blocked by co-administration of the system x c - and GLT-1 inhibitors CPG and DHK, showing that glutamate transporter activity was required for the antidepressant effects of NAC. NAC was also able to specifically increase glutamate in HD mice, in a glutamate transporter-dependent manner. These in vivo changes reflect changes in glutamate transporter protein in HD mice and human HD post-mortem tissue. Furthermore, NAC was able to rescue changes in key glutamate receptor proteins related to excitotoxicity in HD, including NMDAR2B. Thus, we have shown that baseline reductions in cysteine underlie glutamatergic dysfunction and depressive-like behavior in HD and these changes can be rescued by treatment with NAC. These findings have implications for the development of new therapeutic approaches for depressive disorders. © The Author 2016. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Perturbations in Endothelial Dysfunction-Associated Pathways in the Nitrofen-Induced Congenital Diaphragmatic Hernia Model.

PubMed

Zhaorigetu, Siqin; Bair, Henry; Lu, Jonathan; Jin, Di; Olson, Scott D; Harting, Matthew T

2018-01-01

Although it is well known that nitrofen induces congenital diaphragmatic hernia (CDH), including CDH-associated lung hypoplasia and pulmonary hypertension (PH) in rodents, the mechanism of pathogenesis remains largely unclear. It has been reported that pulmonary artery (PA) endothelial cell (EC) dysfunction contributes to the development of PH in CDH. Thus, we hypothesized that there is significant alteration of endothelial dysfunction-associated proteins in nitrofen-induced CDH PAs. Pregnant SD rats received either nitrofen or olive oil on gestational day 9.5. The newborn rats were sacrificed and divided into a CDH (n = 81) and a control (n = 23) group. After PA isolation, the expression of PA endothelial dysfunction-associated proteins was assessed on Western blot and immunostaining. We demonstrate that the expression of C-reactive protein and endothelin-1 and its receptors, ETA and ETB, were significantly increased in the CDH PAs. Levels of phosphorylated myosin light chain were significantly elevated, but those of phosphorylated endothelial nitric oxide synthase, caveolin-1, and mechanistic target of rapamycin were significantly decreased in the CDH PAs. In this work, we elucidate alterations in the expression of endothelial dysfunction-associated proteins specific to nitrofen-induced CDH rodent PAs, thereby advancing our understanding of the critical role of endothelial dysfunction-associated pathways in the pathogenesis of nitrofen-induced CDH. © 2017 S. Karger AG, Basel.

The Whitening of Brown Fat and Its Implications for Weight Management in Obesity.

PubMed

Shimizu, Ippei; Walsh, Kenneth

2015-06-01

Systemic inflammation resulting from dysfunction of white adipose tissue (WAT) accelerates the pathologies of diabetes and cardiovascular diseases. In contrast to WAT, brown adipose tissue (BAT) is abundant in mitochondria that produce heat by uncoupling respiratory chain process of ATP synthesis. Besides BAT's role in thermogenesis, accumulating evidence has shown that it is involved in regulating systemic metabolism. Studies have analyzed the "browning" processes of WAT as a means to combat obesity, whereas few studies have focused on the impact and molecular mechanisms that contribute to obesity-linked BAT dysfunction--a process that is associated with the "whitening" of this tissue. Compared to WAT, a dense vascular network is required to support the high energy consumption of BAT. Recently, vascular rarefaction was shown to be a significant causal factor in the whitening of BAT in mouse models. Vascular insufficiency leads to mitochondrial dysfunction and loss in BAT and contributes to systemic insulin resistance. These data suggest that BAT "whitening," resulting from vascular dysfunction, can impact obesity and obesity-linked diseases. Conversely, agents that promote BAT function could have utility in the treatment of these conditions.

Transport and selective chaining of bidisperse particles in a travelling wave potential.

PubMed

Tierno, Pietro; Straube, Arthur V

2016-05-01

We combine experiments, theory and numerical simulation to investigate the dynamics of a binary suspension of paramagnetic colloidal particles dispersed in water and transported above a stripe-patterned magnetic garnet film. The substrate generates a one-dimensional periodic energy landscape above its surface. The application of an elliptically polarized rotating magnetic field causes the landscape to translate, inducing direct transport of paramagnetic particles placed above the film. The ellipticity of the applied field can be used to control and tune the interparticle interactions, from net repulsive to net attractive. When considering particles of two distinct sizes, we find that, depending on their elevation above the surface of the magnetic substrate, the particles feel effectively different potentials, resulting in different mobilities. We exploit this feature to induce selective chaining for certain values of the applied field parameters. In particular, when driving two types of particles, we force only one type to condense into travelling parallel chains. These chains confine the movement of the other non-chaining particles within narrow colloidal channels. This phenomenon is explained by considering the balance of pairwise magnetic forces between the particles and their individual coupling with the travelling landscape.

Development of coordination system model on single-supplier multi-buyer for multi-item supply chain with probabilistic demand

NASA Astrophysics Data System (ADS)

Olivia, G.; Santoso, A.; Prayogo, D. N.

2017-11-01

Nowadays, the level of competition between supply chains is getting tighter and a good coordination system between supply chains members is very crucial in solving the issue. This paper focused on a model development of coordination system between single supplier and buyers in a supply chain as a solution. Proposed optimization model was designed to determine the optimal number of deliveries from a supplier to buyers in order to minimize the total cost over a planning horizon. Components of the total supply chain cost consist of transportation costs, handling costs of supplier and buyers and also stock out costs. In the proposed optimization model, the supplier can supply various types of items to retailers whose item demand patterns are probabilistic. Sensitivity analysis of the proposed model was conducted to test the effect of changes in transport costs, handling costs and production capacities of the supplier. The results of the sensitivity analysis showed a significant influence on the changes in the transportation cost, handling costs and production capacity to the decisions of the optimal numbers of product delivery for each item to the buyers.

Tubular Unimolecular Transmembrane Channels: Construction Strategy and Transport Activities.

PubMed

Si, Wen; Xin, Pengyang; Li, Zhan-Ting; Hou, Jun-Li

2015-06-16

Lipid bilayer membranes separate living cells from their environment. Membrane proteins are responsible for the processing of ion and molecular inputs and exports, sensing stimuli and signals across the bilayers, which may operate in a channel or carrier mechanism. Inspired by these wide-ranging functions of membrane proteins, chemists have made great efforts in constructing synthetic mimics in order to understand the transport mechanisms, create materials for separation, and develop therapeutic agents. Since the report of an alkylated cyclodextrin for transporting Cu(2+) and Co(2+) by Tabushi and co-workers in 1982, chemists have constructed a variety of artificial transmembrane channels by making use of either the multimolecular self-assembly or unimolecular strategy. In the context of the design of unimolecular channels, important advances have been made, including, among others, the tethering of natural gramicidin A or alamethicin and the modification of various macrocycles such as crown ethers, cyclodextrins, calixarenes, and cucurbiturils. Many of these unimolecular channels exhibit high transport ability for metal ions, particularly K(+) and Na(+). Concerning the development of artificial channels based on macrocyclic frameworks, one straightforward and efficient approach is to introduce discrete chains to reinforce their capability to insert into bilayers. Currently, this approach has found the widest applications in the systems of crown ethers and calixarenes. We envisioned that for macrocycle-based unimolecular channels, control of the arrangement of the appended chains in the upward and/or downward direction would favor the insertion of the molecular systems into bilayers, while the introduction of additional interactions among the chains would further stabilize a tubular conformation. Both factors should be helpful for the formation of new efficient channels. In this Account, we discuss our efforts in designing new unimolecular artificial channels from tubular pillar[n]arenes by extending their lengths with various ester, hydrazide, and short peptide chains. We have utilized well-defined pillar[5]arene and pillar[6]arene as rigid frameworks that allow the appended chains to afford extended tubular structures. We demonstrate that the hydrazide and peptide chains form intramolecular N-H···O═C hydrogen bonds that enhance the tubular conformation of the whole molecule. The new pillar[n]arene derivatives have been successfully applied as unimolecular channels for the selective transport of protons, water, and amino acids and the voltage-gated transport of K(+). We also show that aromatic hydrazide helices and macrocycles appended with peptide chains are able to mediate the selective transport of NH4(+).

Mitochondrial Dysfunction and Disturbed Coherence: Gate to Cancer

PubMed Central

Pokorný, Jiří; Pokorný, Jan; Foletti, Alberto; Kobilková, Jitka; Vrba, Jan; Vrba, Jan

2015-01-01

Continuous energy supply, a necessary condition for life, excites a state far from thermodynamic equilibrium, in particular coherent electric polar vibrations depending on water ordering in the cell. Disturbances in oxidative metabolism and coherence are a central issue in cancer development. Oxidative metabolism may be impaired by decreased pyruvate transfer to the mitochondrial matrix, either by parasitic consumption and/or mitochondrial dysfunction. This can in turn lead to disturbance in water molecules’ ordering, diminished power, and coherence of the electromagnetic field. In tumors with the Warburg (reverse Warburg) effect, mitochondrial dysfunction affects cancer cells (fibroblasts associated with cancer cells), and the electromagnetic field generated by microtubules in cancer cells has low power (high power due to transport of energy-rich metabolites from fibroblasts), disturbed coherence, and a shifted frequency spectrum according to changed power. Therapeutic strategies restoring mitochondrial function may trigger apoptosis in treated cells; yet, before this step is performed, induction (inhibition) of pyruvate dehydrogenase kinases (phosphatases) may restore the cancer state. In tumor tissues with the reverse Warburg effect, Caveolin-1 levels should be restored and the transport of energy-rich metabolites interrupted to cancer cells. In both cancer phenotypes, achieving permanently reversed mitochondrial dysfunction with metabolic-modulating drugs may be an effective, specific anti-cancer strategy. PMID:26437417

Freight planning for Texas : expanding the dialogue.

DOT National Transportation Integrated Search

2011-02-01

Efficient, reliable, and safe freight transportation is critical to the economic prosperity of any region. An : efficient multimodal and intermodal transportation system reduces transportation and supply chain transaction : costs and increases connec...

Transportation and dynamic networks: Models, theory, and applications to supply chains, electric power, and financial networks

NASA Astrophysics Data System (ADS)

Liu, Zugang

Network systems, including transportation and logistic systems, electric power generation and distribution networks as well as financial networks, provide the critical infrastructure for the functioning of our societies and economies. The understanding of the dynamic behavior of such systems is also crucial to national security and prosperity. The identification of new connections between distinct network systems is the inspiration for the research in this dissertation. In particular, I answer two questions raised by Beckmann, McGuire, and Winsten (1956) and Copeland (1952) over half a century ago, which are, respectively, how are electric power flows related to transportation flows and does money flow like water or electricity? In addition, in this dissertation, I achieve the following: (1) I establish the relationships between transportation networks and three other classes of complex network systems: supply chain networks, electric power generation and transmission networks, and financial networks with intermediation. The establishment of such connections provides novel theoretical insights as well as new pricing mechanisms, and efficient computational methods. (2) I develop new modeling frameworks based on evolutionary variational inequality theory that capture the dynamics of such network systems in terms of the time-varying flows and incurred costs, prices, and, where applicable, profits. This dissertation studies the dynamics of such network systems by addressing both internal competition and/or cooperation, and external changes, such as varying costs and demands. (3) I focus, in depth, on electric power supply chains. By exploiting the relationships between transportation networks and electric power supply chains, I develop a large-scale network model that integrates electric power supply chains and fuel supply markets. The model captures both the economic transactions as well as the physical transmission constraints. The model is then applied to the New England electric power supply chain consisting of 6 states, 5 fuel types, 82 power generators, with a total of 573 generating units, and 10 demand markets. The empirical case study demonstrates that the regional electricity prices simulated by the model match very well the actual electricity prices in New England. I also utilize the model to study interactions between electric power supply chains and energy fuel markets.

Triplet Transport to and Trapping by Acceptor End Groups on Conjugated Polyfluorene Chains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Sreearunothai, P.; Miller, J.; Estrada, A.

2011-08-31

Triplet excited states created in polyfluorene (pF) molecules having average lengths up to 170 repeat units were transported to and captured by trap groups at the ends in less {approx}40 ns. Almost all of the triplets attached to the chains reached the trap groups, ruling out the presence of substantial numbers of defects that prevent transport. The transport yields a diffusion coefficient D of at least 3 x 10{sup -4} cm{sup 2} s{sup -1}, which is 30 times typical molecular diffusion and close to a value for triplet transport reported by Keller (J. Am. Chem. Soc.2011, 133, 11289-11298). The tripletmore » states were created in solution by pulse radiolysis; time resolution was limited by the rate of attachment of triplets to the pF chains. Naphthylimide (NI) or anthraquinone (AQ) groups attached to the ends of the chains acted as traps for the triplets, although AQ would not have been expected to serve as a trap on the basis of triplet energies of the separate molecules. The depths of the NI and AQ triplet traps were determined by intermolecular triplet transfer equilibria and temperature dependence. The trap depths are shallow, just a few times thermal energy for both, so a small fraction of the triplets reside in the pF chains in equilibrium with the end-trapped triplets. Trapping by AQ appears to arise from charge transfer interactions between the pF chains and the electron-accepting AQ groups. Absorption bands of the end-trapped triplet states are similar in peak wavelength (760 nm) and shape to the 760 nm bands of triplets in the pF chains but have reduced intensities. When an electron donor, N,N,N',N'-tetramethyl-p-phenylenediamine (TMPD), is added to the solution, it reacts with the end-trapped triplets to remove the 760 nm bands and to make the trapping irreversible. New bands created upon reaction with TMPD may be due to charge transfer states.« less

Integrating multimodal transport into cellulosic biofuel supply chain design under feedstock seasonality with a case study based on California.

PubMed

Xie, Fei; Huang, Yongxi; Eksioglu, Sandra

2014-01-01

A multistage, mixed integer programing model was developed that fully integrates multimodal transport into the cellulosic biofuel supply chain design under feedstock seasonality. Three transport modes are considered: truck, single railcar, and unit train. The goal is to minimize the total cost for infrastructure, feedstock harvesting, biofuel production, and transportation. Strategic decisions including the locations and capacities of transshipment hubs, biorefineries, and terminals and tactical decisions on system operations are optimized in an integrated manner. When the model was implemented to a case study of cellulosic ethanol production in California, it was found that trucks are convenient for short-haul deliveries while rails are more effective for long-haul transportation. Taking the advantage of these benefits, the multimodal transport provides more cost effective solutions than the single-mode transport (truck). Copyright © 2013 Elsevier Ltd. All rights reserved.

Surface Connectivity and Interocean Exchanges From Drifter-Based Transition Matrices

NASA Astrophysics Data System (ADS)

McAdam, Ronan; van Sebille, Erik

2018-01-01

Global surface transport in the ocean can be represented by using the observed trajectories of drifters to calculate probability distribution functions. The oceanographic applications of the Markov Chain approach to modeling include tracking of floating debris and water masses, globally and on yearly-to-centennial time scales. Here we analyze the error inherent with mapping trajectories onto a grid and the consequences for ocean transport modeling and detection of accumulation structures. A sensitivity analysis of Markov Chain parameters is performed in an idealized Stommel gyre and western boundary current as well as with observed ocean drifters, complementing previous studies on widespread floating debris accumulation. Focusing on two key areas of interocean exchange—the Agulhas system and the North Atlantic intergyre transport barrier—we assess the capacity of the Markov Chain methodology to detect surface connectivity and dynamic transport barriers. Finally, we extend the methodology's functionality to separate the geostrophic and nongeostrophic contributions to interocean exchange in these key regions.

A Comparative Proteome Profile of Female Mouse Gonads Suggests a Tight Link between the Electron Transport Chain and Meiosis Initiation.

PubMed

Shen, Cong; Li, Mingrui; Zhang, Pan; Guo, Yueshuai; Zhang, Hao; Zheng, Bo; Teng, Hui; Zhou, Tao; Guo, Xuejiang; Huo, Ran

2018-01-01

Generation of haploid gametes by meiosis is a unique property of germ cells and is critical for sexual reproduction. Leaving mitosis and entering meiosis is a key step in germ cell development. Several inducers or intrinsic genes are known to be important for meiotic initiation, but the regulation of meiotic initiation, especially at the protein level, is still not well understood. We constructed a comparative proteome profile of female mouse fetal gonads at specific time points (11.5, 12.5, and 13.5 days post coitum), spanning a critical window for initiation of meiosis in female germ cells. We identified 3666 proteins, of which 473 were differentially expressed. Further bioinformatics analysis showed that these differentially expressed proteins were enriched in the mitochondria, especially in the electron transport chain and, notably, 9 proteins in electron transport chain Complex I were differentially expressed. We disrupted the mitochondrial electron transport chain function by adding the complex I inhibitor, rotenone to 11.5 days post coitum female gonads cultured in vitro. This treatment resulted in a decreased proportion of meiotic germ cells, as assessed by staining for histone γH2AX. Rotenone treatment also caused decreased ATP levels, increased reactive oxygen species levels and failure of the germ cells to undergo premeiotic DNA replication. These effects were partially rescued by adding Coenzyme Q10. Taken together, our results suggested that a functional electron transport chain is important for meiosis initiation. Our characterization of the quantitative proteome of female gonads provides an inventory of proteins, useful for understanding the mechanisms of meiosis initiation and female fertility. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

PINK1 alleviates myocardial hypoxia-reoxygenation injury by ameliorating mitochondrial dysfunction

DOE Office of Scientific and Technical Information (OSTI.GOV)

Li, Yang; Qiu, Liangxian; Liu, Xiping

PTEN inducible kinase-1 (PINK1) mutant induces mitochondrial dysfunction of cells, resulting in an inherited form of Parkinson's disease. However its exact role in the cardiomyocytes is unclear. The present study examined the function of PINK1 in hypoxia-reoxygenation (H/R) induced H9c2 cell damage and its potential mechanism. The H/R model in H9c2 cells was established by 6 h of hypoxia and 12 h of reoxygenation. The CCK8 and LDH assay indicated that the cell viability was obviously reduced after H/R. The expression of PINK1 was decreased in H/R-induced H9c2 cells compared with control group. The vector overexpressing PINK1 was constructed to transfect intomore » H/R-induced H9c2 cells. Our results showed that cell viability was increased, cell apoptosis and caspase 3, cytochrome C (Cyto C) levels were decreased after LV-PINK1 transfection. Furthermore, PINK1 overexpression stabilized electron transport chain (ETC) activity, increased ATP production, mPTP opening and mitochondrial membrane potential (MMP), inhibited ROS-generating mitochondria, implying PINK1 alleviates H/R induced mitochondrial dysfunction in cardiomyocytes. In addition, the TRAP-1 siRNA was transfected into PINK1 treated H9c2 cells after H/R to detected the molecular mechanism of PINK1 protecting cardiomyocytes. The results indicated that silence of TRAP-1 reversed the effects of PINK1 in H/R-induced H9c2 cells. In conclusion, these results suggest that PINK1 overexpression alleviates H/R-induced cell damage of H9c2 cells by phosphorylation of TRAP-1, and that is a valid approach for protection from myocardial I/R injury. - Highlights: • Effects of H/R on cell viability and PINK1 expression in H9c2 cells. • Effects of PINK1 on cell viability in H9c2 cells with H/R model. • Effects of PINK1 on mitochondrial dysfunction in H9c2 cells with H/R model. • PINK1 ameliorates H/R-induced H9c2 cells injury by activating p-TRAP-1.« less

The life cycle assessment of alternative fuel chains for urban buses and trolleybuses.

PubMed

Kliucininkas, L; Matulevicius, J; Martuzevicius, D

2012-05-30

This paper describes a comparative analysis of public transport alternatives in the city of Kaunas, Lithuania. An LCA (Life Cycle Assessment) inventory analysis of fuel chains was undertaken using the midi urban bus and a similar type of trolleybus. The inventory analysis of fuel chains followed the guidelines provided by the ISO 14040 and ISO 14044 standards. The ReCiPe Life Cycle Impact Assessment (LCIA) methodology was used to quantify weighted damage originating from five alternative fuel chains. The compressed biogas fuel chain had the lowest weighted damage value, namely 45.7 mPt/km, whereas weighted damage values of the fuel chains based on electricity generation for trolleybuses were 60.6 mPt/km (for natural gas) and 78.9 mPt/km (for heavy fuel oil). The diesel and compressed natural gas fuel chains exhibited considerably higher damage values of 114.2 mPt/km and 132.6 mPt/km, respectively. The comparative life cycle assessment of fuel chains suggested that biogas-powered buses and electric trolleybuses can be considered as the best alternatives to use when modernizing the public transport fleet in Kaunas. Copyright © 2012 Elsevier Ltd. All rights reserved.

DOE Office of Scientific and Technical Information (OSTI.GOV)

An, Yipeng, E-mail: ypan@htu.edu.cn; Zhang, Mengjun; Wang, Tianxing

Very recently, boron nitride atomic chains were successively prepared and observed in experiments [O. Cretu et al., ACS Nano 8, 11950 (2015)]. Herein, using a first-principles technique, we study the magnetism and spin-dependent electronic transport properties of three types of BN atomic chains whose magnetic moment is 1 μ{sub B} for B{sub n}N{sub n−1}, 2 μ{sub B} for B{sub n}N{sub n}, and 3 μ{sub B} for B{sub n}N{sub n+1} type atomic chains, respectively. The spin-dependent electronic transport results demonstrate that the short B{sub n}N{sub n+1} chain presents an obvious spin-filtering effect with high spin polarization ratio (>90%) under low biasmore » voltages. Yet, this spin-filtering effect does not occur for long B{sub n}N{sub n+1} chains under high bias voltages and other types of BN atomic chains (B{sub n}N{sub n−1} and B{sub n}N{sub n}). The proposed short B{sub n}N{sub n+1} chain is predicted to be an effective low-bias spin filters. Moreover, the length-conductance relationships of these BN atomic chains were also studied.« less

Enzymes involved in branched-chain amino acid metabolism in humans.

PubMed

Adeva-Andany, María M; López-Maside, Laura; Donapetry-García, Cristóbal; Fernández-Fernández, Carlos; Sixto-Leal, Cristina

2017-06-01

Branched-chain amino acids (leucine, isoleucine and valine) are structurally related to branched-chain fatty acids. Leucine is 2-amino-4-methyl-pentanoic acid, isoleucine is 2-amino-3-methyl-pentanoic acid, and valine is 2-amino-3-methyl-butanoic acid. Similar to fatty acid oxidation, leucine and isoleucine produce acetyl-coA. Additionally, leucine generates acetoacetate and isoleucine yields propionyl-coA. Valine oxidation produces propionyl-coA, which is converted into methylmalonyl-coA and succinyl-coA. Branched-chain aminotransferase catalyzes the first reaction in the catabolic pathway of branched-chain amino acids, a reversible transamination that converts branched-chain amino acids into branched-chain ketoacids. Simultaneously, glutamate is converted in 2-ketoglutarate. The branched-chain ketoacid dehydrogenase complex catalyzes the irreversible oxidative decarboxylation of branched-chain ketoacids to produce branched-chain acyl-coA intermediates, which then follow separate catabolic pathways. Human tissue distribution and function of most of the enzymes involved in branched-chain amino acid catabolism is unknown. Congenital deficiencies of the enzymes involved in branched-chain amino acid metabolism are generally rare disorders. Some of them are associated with reduced pyruvate dehydrogenase complex activity and respiratory chain dysfunction that may contribute to their clinical phenotype. The biochemical phenotype is characterized by accumulation of the substrate to the deficient enzyme and its carnitine and/or glycine derivatives. It was established at the beginning of the twentieth century that the plasma level of the branched-chain amino acids is increased in conditions associated with insulin resistance such as obesity and diabetes mellitus. However, the potential clinical relevance of this elevation is uncertain.

Press Releases | Argonne National Laboratory

Science.gov Websites

Electrochemical Energy Science --Center for Transportation Research --Chain Reaction Innovations --Computation renewable energy such as wind and solar power. April 25, 2018 John Carlisle, director of Chain Reaction across nation to grow startups Argonne announces second cohort of Chain Reaction Innovations. April 18

Double path integral method for obtaining the mobility of the one-dimensional charge transport in molecular chain.

PubMed

Yoo-Kong, Sikarin; Liewrian, Watchara

2015-12-01

We report on a theoretical investigation concerning the polaronic effect on the transport properties of a charge carrier in a one-dimensional molecular chain. Our technique is based on the Feynman's path integral approach. Analytical expressions for the frequency-dependent mobility and effective mass of the carrier are obtained as functions of electron-phonon coupling. The result exhibits the crossover from a nearly free particle to a heavily trapped particle. We find that the mobility depends on temperature and decreases exponentially with increasing temperature at low temperature. It exhibits large polaronic-like behaviour in the case of weak electron-phonon coupling. These results agree with the phase transition (A.S. Mishchenko et al., Phys. Rev. Lett. 114, 146401 (2015)) of transport phenomena related to polaron motion in the molecular chain.

Naringin Improves Diet-Induced Cardiovascular Dysfunction and Obesity in High Carbohydrate, High Fat Diet-Fed Rats

PubMed Central

Alam, Md. Ashraful; Kauter, Kathleen; Brown, Lindsay

2013-01-01

Obesity, insulin resistance, hypertension and fatty liver, together termed metabolic syndrome, are key risk factors for cardiovascular disease. Chronic feeding of a diet high in saturated fats and simple sugars, such as fructose and glucose, induces these changes in rats. Naturally occurring compounds could be a cost-effective intervention to reverse these changes. Flavonoids are ubiquitous secondary plant metabolites; naringin gives the bitter taste to grapefruit. This study has evaluated the effect of naringin on diet-induced obesity and cardiovascular dysfunction in high carbohydrate, high fat-fed rats. These rats developed increased body weight, glucose intolerance, increased plasma lipid concentrations, hypertension, left ventricular hypertrophy and fibrosis, liver inflammation and steatosis with compromised mitochondrial respiratory chain activity. Dietary supplementation with naringin (approximately 100 mg/kg/day) improved glucose intolerance and liver mitochondrial dysfunction, lowered plasma lipid concentrations and improved the structure and function of the heart and liver without decreasing total body weight. Naringin normalised systolic blood pressure and improved vascular dysfunction and ventricular diastolic dysfunction in high carbohydrate, high fat-fed rats. These beneficial effects of naringin may be mediated by reduced inflammatory cell infiltration, reduced oxidative stress, lowered plasma lipid concentrations and improved liver mitochondrial function in rats. PMID:23446977

First principles calculation of the structural, electronic, and magnetic properties of Au-Pd atomic chains

DOE Office of Scientific and Technical Information (OSTI.GOV)

Dave, Mudra R., E-mail: mdave-phy@yahoo.co.in; Sharma, A. C.

2015-06-24

The structural, electronic and magnetic properties of free standing Au-Pd bimetallic atomic chain is studied using ab-initio method. It is found that electronic and magnetic properties of chains depend on position of atoms and number of atoms. Spin polarization factor for different atomic configuration of atomic chain is calculated predicting a half metallic behavior. It suggests a total spin polarised transport in these chains.

Comparative assessment of the global fate and transport pathways of long-chain perfluorocarboxylic acids (PFCAs) and perfluorocarboxylates (PFCs) emitted from direct sources.

PubMed

Armitage, James M; Macleod, Matthew; Cousins, Ian T

2009-08-01

A global-scale multispecies mass balance model was used to simulate the long-term fate and transport of perfluorocarboxylic acids (PFCAs) with eight to thirteen carbons (C8-C13) and their conjugate bases, the perfluorocarboxylates (PFCs). The main purpose of this study was to assess the relative long-range transport (LRT) potential of each conjugate pair, collectively termed PFC(A)s, considering emissions from direct sources (i.e., manufacturing and use) only. Overall LRT potential (atmospheric + oceanic) varied as a function of chain length and depended on assumptions regarding pKa and mode of entry. Atmospheric transport makes a relatively higher contribution to overall LRT potential for PFC(A)s with longer chain length, which reflects the increasing trend in the air-water partition coefficient (K(AW)) of the neutral PFCA species with chain length. Model scenarios using estimated direct emissions of the C8, C9, and C11 PFC(A)s indicate that the mass fluxes to the Arctic marine environment associated with oceanic transport are in excess of mass fluxes from indirect sources (i.e., atmospheric transport of precursor substances such as fluorotelomer alcohols and subsequent degradation to PFCAs). Modeled concentrations of C8 and C9 in the abiotic environment are broadly consistent with available monitoring data in surface ocean waters. Furthermore, the modeled concentration ratios of C8 to C9 are reconcilable with the homologue pattern frequently observed in biota, assuming a positive correlation between bioaccumulation potential and chain length. Modeled concentration ratios of C11 to C10 are more difficult to reconcile with monitoring data in both source and remote regions. Our model results for C11 and C10 therefore imply that either (i) indirect sources are dominant or (ii) estimates of direct emission are not accurate for these homologues.

Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins.

PubMed

Gillard, Baiba K; Rosales, Corina; Xu, Bingqing; Gotto, Antonio M; Pownall, Henry J

2018-04-12

Human plasma high-density lipoprotein cholesterol concentrations are a negative risk factor for atherosclerosis-linked cardiovascular disease. Pharmacological attempts to reduce atherosclerotic cardiovascular disease by increasing plasma high-density lipoprotein cholesterol have been disappointing so that recent research has shifted from HDL quantity to HDL quality, that is, functional vs dysfunctional HDL. HDL has varying degrees of dysfunction reflected in impaired reverse cholesterol transport (RCT). In the context of atheroprotection, RCT occurs by 2 mechanisms: one is the well-known trans-hepatic pathway comprising macrophage free cholesterol (FC) efflux, which produces early forms of FC-rich nascent HDL (nHDL). Lecithin:cholesterol acyltransferase converts HDL-FC to HDL-cholesteryl ester while converting nHDL from a disc to a mature spherical HDL, which transfers its cholesteryl ester to the hepatic HDL receptor, scavenger receptor B1 for uptake, conversion to bile salts, or transfer to the intestine for excretion. Although widely cited, current evidence suggests that this is a minor pathway and that most HDL-FC and nHDL-FC rapidly transfer directly to the liver independent of lecithin:cholesterol acyltransferase activity. A small fraction of plasma HDL-FC enters the trans-intestinal efflux pathway comprising direct FC transfer to the intestine. SR-B1 -/- mice, which have impaired trans-hepatic FC transport, are characterized by high plasma levels of a dysfunctional FC-rich HDL that increases plasma FC bioavailability in a way that produces whole-body hypercholesterolemia and multiple pathologies. The design of future therapeutic strategies to improve RCT will have to be formulated in the context of these dual RCT mechanisms and the role of FC bioavailability. Copyright © 2018 National Lipid Association. Published by Elsevier Inc. All rights reserved.

Ameliorating Endothelial Mitochondrial Dysfunction Restores Coronary Function via Transient Receptor Potential Vanilloid 1-Mediated Protein Kinase A/Uncoupling Protein 2 Pathway.

PubMed

Xiong, Shiqiang; Wang, Peijian; Ma, Liqun; Gao, Peng; Gong, Liuping; Li, Li; Li, Qiang; Sun, Fang; Zhou, Xunmei; He, Hongbo; Chen, Jing; Yan, Zhencheng; Liu, Daoyan; Zhu, Zhiming

2016-02-01

Coronary heart disease arising from atherosclerosis is a leading cause of cardiogenic death worldwide. Mitochondria are the principal source of reactive oxygen species (ROS), and defective oxidative phosphorylation by the mitochondrial respiratory chain contributes to ROS generation. Uncoupling protein 2 (UCP2), an adaptive antioxidant defense factor, protects against mitochondrial ROS-induced endothelial dysfunction in atherosclerosis. The activation of transient receptor potential vanilloid 1 (TRPV1) attenuates vascular dysfunction. Therefore, whether TRPV1 activation antagonizes coronary lesions by alleviating endothelial mitochondrial dysfunction and enhancing the activity of the protein kinase A/UCP2 pathway warrants examination. ApoE(-/-), ApoE(-/-)/TRPV1(-/-), and ApoE(-/-)/UCP2(-/-) mice were fed standard chow, a high-fat diet (HFD), or the HFD plus 0.01% capsaicin. HFD intake profoundly impaired coronary vasodilatation and myocardial perfusion and shortened the survival duration of ApoE(-/-) mice. TRPV1 or UCP2 deficiency exacerbated HFD-induced coronary dysfunction and was associated with increased ROS generation and reduced nitric oxide production in the endothelium. The activation of TRPV1 by capsaicin upregulated UCP2 expression via protein kinase A phosphorylation, thereby alleviating endothelial mitochondrial dysfunction and inhibiting mitochondrial ROS generation. In vivo, dietary capsaicin supplementation enhanced coronary relaxation and prolonged the survival duration of HFD-fed ApoE(-/-) mice. These effects were not observed in ApoE(-/-) mice lacking the TRPV1 or UCP2 gene. The upregulation of protein kinase A /UCP2 via TRPV1 activation ameliorates coronary dysfunction and prolongs the lifespan of atherosclerotic mice by ameliorating endothelial mitochondrial dysfunction. Dietary capsaicin supplementation may represent a promising intervention for the primary prevention of coronary heart disease. © 2015 American Heart Association, Inc.

Challenges in scaling up biofuels infrastructure.

PubMed

Richard, Tom L

2010-08-13

Rapid growth in demand for lignocellulosic bioenergy will require major changes in supply chain infrastructure. Even with densification and preprocessing, transport volumes by mid-century are likely to exceed the combined capacity of current agricultural and energy supply chains, including grain, petroleum, and coal. Efficient supply chains can be achieved through decentralized conversion processes that facilitate local sourcing, satellite preprocessing and densification for long-distance transport, and business models that reward biomass growers both nearby and afar. Integrated systems that are cost-effective and energy-efficient will require new ways of thinking about agriculture, energy infrastructure, and rural economic development. Implementing these integrated systems will require innovation and investment in novel technologies, efficient value chains, and socioeconomic and policy frameworks; all are needed to support an expanded biofuels infrastructure that can meet the challenges of scale.

Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction.

PubMed

Ramsden, David B; Ho, Philip W-L; Ho, Jessica W-M; Liu, Hui-Fang; So, Danny H-F; Tse, Ho-Man; Chan, Koon-Ho; Ho, Shu-Leong

2012-07-01

Uncoupling proteins (UCPs) belong to a large family of mitochondrial solute carriers 25 (SLC25s) localized at the inner mitochondrial membrane. UCPs transport protons directly from the intermembrane space to the matrix. Of five structural homologues (UCP1 to 5), UCP4 and 5 are principally expressed in the central nervous system (CNS). Neurons derived their energy in the form of ATP that is generated through oxidative phosphorylation carried out by five multiprotein complexes (Complexes I-V) embedded in the inner mitochondrial membrane. In oxidative phosphorylation, the flow of electrons generated by the oxidation of substrates through the electron transport chain to molecular oxygen at Complex IV leads to the transport of protons from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates a proton gradient (mitochondrial membrane potential; MMP) across the inner membrane. Complex V (ATP synthase) uses this MMP to drive the conversion of ADP to ATP. Some electrons escape to oxygen-forming harmful reactive oxygen species (ROS). Proton leakage back to the matrix which bypasses Complex V resulting in a major reduction in ROS formation while having a minimal effect on MMP and hence, ATP synthesis; a process termed "mild uncoupling." UCPs act to promote this proton leakage as means to prevent excessive build up of MMP and ROS formation. In this review, we discuss the structure and function of mitochondrial UCPs 4 and 5 and factors influencing their expression. Hypotheses concerning the evolution of the two proteins are examined. The protective mechanisms of the two proteins against neurotoxins and their possible role in regulating intracellular calcium movement, particularly with regard to the pathogenesis of Parkinson's disease are discussed.

Mechanisms of Lipid Accumulation in the Bone Morphogenetic Protein Receptor Type 2 Mutant Right Ventricle

PubMed Central

Brittain, Evan L.; Fessel, Joshua P.; Penner, Niki; Atkinson, James; Funke, Mitch; Grueter, Carrie; Jerome, W. Gray; Freeman, Michael; Newman, John H.; West, James; Hemnes, Anna R.

2016-01-01

Rationale: In heritable pulmonary arterial hypertension with germline mutation in the bone morphogenetic protein receptor type 2 (BMPR2) gene, right ventricle (RV) dysfunction is associated with RV lipotoxicity; however, the underlying mechanism for lipid accumulation is not known. Objectives: We hypothesized that lipid accumulation in cardiomyocytes with BMPR2 mutation occurs owing to alterations in lipid transport and impaired fatty acid oxidation (FAO), which is exacerbated by a high-lipid (Western) diet (WD). Methods: We used a transgenic mouse model of pulmonary arterial hypertension with mutant BMPR2 and generated a cardiomyocyte cell line with BMPR2 mutation. Electron microscopy and metabolomic analysis were performed on mouse RVs. Measurements and Main Results: By metabolomics analysis, we found an increase in long-chain fatty acids in BMPR2 mutant mouse RVs compared with controls, which correlated with cardiac index. BMPR2-mutant cardiomyocytes had increased lipid compared with controls. Direct measurement of FAO in the WD-fed BMPR2-mutant RV showed impaired palmitate-linked oxygen consumption, and metabolomics analysis showed reduced indices of FAO. Using both mutant BMPR2 mouse RVs and cardiomyocytes, we found an increase in the uptake of 14C-palmitate and fatty acid transporter CD36 that was further exacerbated by WD. Conclusions: Taken together, our data suggest that impaired FAO and increased expression of the lipid transporter CD36 are key mechanisms underlying lipid deposition in the BMPR2-mutant RV, which are exacerbated in the presence of dietary lipids. These findings suggest important features leading to RV lipotoxicity in pulmonary arterial hypertension and may point to novel areas of therapeutic intervention. PMID:27077479

Gathering Information from Transport Systems for Processing in Supply Chains

NASA Astrophysics Data System (ADS)

Kodym, Oldřich; Unucka, Jakub

2016-12-01

Paper deals with complex system for processing information from means of transport acting as parts of train (rail or road). It focuses on automated information gathering using AutoID technology, information transmission via Internet of Things networks and information usage in information systems of logistic firms for support of selected processes on MES and ERP levels. Different kinds of gathered information from whole transport chain are discussed. Compliance with existing standards is mentioned. Security of information in full life cycle is integral part of presented system. Design of fully equipped system based on synthesized functional nodes is presented.

Efficient DFT+U calculations of ballistic electron transport: Application to Au monatomic chains with a CO impurity

NASA Astrophysics Data System (ADS)

Sclauzero, Gabriele; Dal Corso, Andrea

2013-02-01

An efficient method for computing the Landauer-Büttiker conductance of an open quantum system within DFT+U is presented. The Hubbard potential is included in electronic-structure and transport calculations as a simple renormalization of the nonlocal pseudopotential coefficients by restricting the integration for the onsite occupations within the cutoff spheres of the pseudopotential. We apply the methodology to the case of an Au monatomic chain in the presence of a CO molecule adsorbed on it. We show that the Hubbard U correction removes the spurious magnetization in the pristine Au chain at the equilibrium spacing, as well as the unphysical contribution of d electrons to the conductance, resulting in a single (spin-degenerate) transmission channel and a more realistic conductance of 1G0. We find that the conductance reduction due to CO adsorption is much larger for the atop site than for the bridge site, so that the general picture of electron transport in stretched Au chains given by the local density approximation remains valid at the equilibrium Au-Au spacing within DFT+U.

Cost-effective strategy to mitigate transportation disruptions in supply chain

NASA Astrophysics Data System (ADS)

Albertzeth, G.; Pujawan, I. N.

2018-04-01

Supply chain disruptions have gained significant attention by scholars. But, even though transportation plays a central role in supply chain, only few studies address transportation disruptions. This research demonstrates a real case of an order delivery process from a focal company (FC) to a single distributor, where transportation disruptions stochastically occurs. Considering the possibility of sales loss during the disruption duration, we proposed a redundant stock, flexible route, and combined flexibility-redundancy (ReFlex) as mitigation strategies and a base case as a risk acceptance strategy. The objective is to find out the best strategy that promotes cost-effectiveness against transportation disruptions. To fulfill this objective, we use simulation modeling and cost-effectiveness analysis (CEA) as our research method. We simulate the delivery process of 5 brands using each strategy to produce two different responses: loss of sales percentage and the incurred costs. Next, using these responses, we evaluate and compare the cost-effectiveness ratio of each strategy using CEA. We found that redundant stock gave the best effectiveness on all brands, ReFlex as the second best, while flexible route gave the least effectiveness. Finally, we recommend which strategy should be applied based on the decision maker willingness to pay.

Stimulation by epinephrine of the membrane transport of long chain fatty acid in the adipocyte

DOE Office of Scientific and Technical Information (OSTI.GOV)

Abumrad, N.A.; Perry, P.R.; Whitesell, R.R.

1985-08-25

In isolated rat adipocytes, epinephrine rapidly stimulates the transport of long chain fatty acid across the plasma membrane. At a concentration of unbound oleate of 0.1 microM and 5 min exposure to the hormone, the minimal effective concentration of epinephrine is 0.03 and the optimal concentration 0.3 microM (0.01 and 0.1 microgram/ml). The stimulated rates are 5-10-fold the basal rate of influx or efflux. The hormone effect is on the transport process specifically as shown by isolation of the product of transport in either direction as unesterified fatty acid and inhibition by the transport inhibitors phloretin and 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid. Thismore » effect of epinephrine on transport coordinates physiologically with lipase activation to bring about fatty acid release from adipose tissue.« less

4-haloethenylphenyl tropane:serotonin transporter imaging agents

DOEpatents

Goodman, Mark M.; Martarello, Laurent

2005-01-18

A series of compounds in the 4-fluoroalkyl-3-halophenyl nortropanes and 4-haloethenylphenyl tropane families are described as diagnostic and therapeutic agents for diseases associated with serotonin transporter dysfunction. These compounds bind to serotonin transporter protein with high affinity and selectivity. The invention provides methods of synthesis which incorporate radioisotopic halogens at a last step which permit high radiochemical yield and maximum usable product life. The radiolabeled compounds of the invention are useful as imaging agents for visualizing the location and density of serotonin transporter by PET and SPECT imaging.

De novo mutation in the dopamine transporter gene associates dopamine dysfunction with autism spectrum disorder.

PubMed

Hamilton, P J; Campbell, N G; Sharma, S; Erreger, K; Herborg Hansen, F; Saunders, C; Belovich, A N; Sahai, M A; Cook, E H; Gether, U; McHaourab, H S; Matthies, H J G; Sutcliffe, J S; Galli, A

2013-12-01

De novo genetic variation is an important class of risk factors for autism spectrum disorder (ASD). Recently, whole-exome sequencing of ASD families has identified a novel de novo missense mutation in the human dopamine (DA) transporter (hDAT) gene, which results in a Thr to Met substitution at site 356 (hDAT T356M). The dopamine transporter (DAT) is a presynaptic membrane protein that regulates dopaminergic tone in the central nervous system by mediating the high-affinity reuptake of synaptically released DA, making it a crucial regulator of DA homeostasis. Here, we report the first functional, structural and behavioral characterization of an ASD-associated de novo mutation in the hDAT. We demonstrate that the hDAT T356M displays anomalous function, characterized as a persistent reverse transport of DA (substrate efflux). Importantly, in the bacterial homolog leucine transporter, substitution of A289 (the homologous site to T356) with a Met promotes an outward-facing conformation upon substrate binding. In the substrate-bound state, an outward-facing transporter conformation is required for substrate efflux. In Drosophila melanogaster, the expression of hDAT T356M in DA neurons-lacking Drosophila DAT leads to hyperlocomotion, a trait associated with DA dysfunction and ASD. Taken together, our findings demonstrate that alterations in DA homeostasis, mediated by aberrant DAT function, may confer risk for ASD and related neuropsychiatric conditions.

Microarray RNA expression analysis of cerebral white matter lesions reveals changes in multiple functional pathways.

PubMed

Simpson, Julie E; Hosny, Ola; Wharton, Stephen B; Heath, Paul R; Holden, Hazel; Fernando, Malee S; Matthews, Fiona; Forster, Gill; O'Brien, John T; Barber, Robert; Kalaria, Raj N; Brayne, Carol; Shaw, Pamela J; Lewis, Claire E; Ince, Paul G

2009-02-01

White matter lesions (WML) in brain aging are linked to dementia and depression. Ischemia contributes to their pathogenesis but other mechanisms may contribute. We used RNA microarray analysis with functional pathway grouping as an unbiased approach to investigate evidence for additional pathogenetic mechanisms. WML were identified by MRI and pathology in brains donated to the Medical Research Council Cognitive Function and Ageing Study Cognitive Function and Aging Study. RNA was extracted to compare WML with nonlesional white matter samples from cases with lesions (WM[L]), and from cases with no lesions (WM[C]) using RNA microarray and pathway analysis. Functional pathways were validated for selected genes by quantitative real-time polymerase chain reaction and immunocytochemistry. We identified 8 major pathways in which multiple genes showed altered RNA transcription (immune regulation, cell cycle, apoptosis, proteolysis, ion transport, cell structure, electron transport, metabolism) among 502 genes that were differentially expressed in WML compared to WM[C]. In WM[L], 409 genes were altered involving the same pathways. Genes selected to validate this microarray data all showed the expected changes in RNA levels and immunohistochemical expression of protein. WML represent areas with a complex molecular phenotype. From this and previous evidence, WML may arise through tissue ischemia but may also reflect the contribution of additional factors like blood-brain barrier dysfunction. Differential expression of genes in WM[L] compared to WM[C] indicate a "field effect" in the seemingly normal surrounding white matter.

A Search Algorithm for Determination of Economic Order Quantity in a Two-Level Supply Chain System with Transportation Cost

NASA Astrophysics Data System (ADS)

Pirayesh Neghab, Mohammadali; Haji, Rasoul

This study considers a two-level supply chain system consisting of one warehouse and a number of identical retailers. In this system, we incorporate transportation costs into inventory replenishment decisions. The transportation cost contains a fixed cost and a variable cost. We assume that the demand rate at each retailer is known and the demand is confined to a single item. First, we derive the total cost which is the sum of the holding and ordering cost at the warehouse and retailers as well as the transportation cost from the warehouse to retailers. Then, we propose a search algorithm to find the economic order quantities for the warehouse and retailers which minimize the total cost.

Novel guanidine-containing molecular transporters based on lactose scaffolds: lipophilicity effect on the intracellular organellar selectivity.

PubMed

Biswas, Goutam; Jeon, Ock-Youm; Lee, Woo Sirl; Kim, Dong-Chan; Kim, Kyong-Tai; Lee, Suho; Chang, Sunghoe; Chung, Sung-Kee

2008-01-01

We have synthesized two lactose-based molecular transporters, each containing seven guanidine residues attached to the lactose scaffold through omega-aminocarboxylate linker chains of two different lengths, and have examined their cellular uptakes and intracellular and organellar localizations in HeLa cells, as well as their tissue distributions in mice. Both molecular transporters showed higher cellular uptake efficiencies than Arg8, and wide tissue distributions including the brain. Mitochondrial localization is of special interest because of its potential relevance to "mitochondrial diseases". Interestingly, it has been found that the intracellular localization sites of the G7 molecular transporters-namely either mitochondria or lysosomes and endocytic vesicles-are largely determined by the linker chain lengths, or their associated lipophilicities.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Peterson, Steven K

The U.S. Department of Energy (DOE) has a significant programmatic interest in the safe and secure routing and transportation of Spent Nuclear Fuel (SNF) and High Level Waste (HLW) in the United States, including shipments entering the country from locations outside U.S borders. In any shipment of SNF/HLW, there are multiple chains; a jurisdictional chain as the material moves between jurisdictions (state, federal, tribal, administrative), a physical supply chain (which mode), as well as a custody chain (which stakeholder is in charge/possession) of the materials being transported. Given these interconnected networks, there lies vulnerabilities, whether in lack of communication betweenmore » interested stakeholders or physical vulnerabilities such as interdiction. By identifying key links and nodes as well as administrative weaknesses, decisions can be made to harden the physical network and improve communication between stakeholders. This paper examines the parallel chains of oversight and custody as well as the chain of stakeholder interests for the shipments of SNF/HLW and the potential impacts on systemic resiliency. Using the Crystal River shutdown location as well as a hypothetical international shipment brought into the United States, this paper illustrates the parallel chains and maps them out visually.« less

28 CFR 97.17 - Mandatory restraints to be used while transporting violent prisoners.

Code of Federal Regulations, 2010 CFR

2010-07-01

... transporting violent prisoners. 97.17 Section 97.17 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED... used while transporting violent prisoners. Companies covered under this part must, at a minimum, require that violent prisoners be transported wearing handcuffs, leg irons, and waist chains unless the...

28 CFR 97.17 - Mandatory restraints to be used while transporting violent prisoners.

Code of Federal Regulations, 2011 CFR

2011-07-01

... transporting violent prisoners. 97.17 Section 97.17 Judicial Administration DEPARTMENT OF JUSTICE (CONTINUED... used while transporting violent prisoners. Companies covered under this part must, at a minimum, require that violent prisoners be transported wearing handcuffs, leg irons, and waist chains unless the...

Fluid breakup in carbon nanotubes: An explanation of ultrafast ion transport

NASA Astrophysics Data System (ADS)

Gao, Xiang; Zhao, Tianshou; Li, Zhigang

2017-09-01

Ultrafast ion transport in carbon nanotubes (CNTs) has been experimentally observed, but the underlying mechanism is unknown. In this work, we investigate ion transport in CNTs through molecular dynamics (MD) simulations. It is found that the flow in CNTs undergoes a transition from the passage of a continuous liquid chain to the transport of isolated ion-water clusters as the CNT length or the external electric filed strength is increased. The breakup of the liquid chain in CNTs greatly reduces the resistance caused by the hydrogen bonds of water and significantly enhances the ionic mobility, which explains the two-order-magnitude enhancement of ionic conductance in CNTs reported in the literature. A theoretical criterion for fluid breakup is proposed, which agrees well with MD results. The fluid breakup phenomenon provides new insights into enhancing ion transport in nanoconfinements.

Characterizing Oregon's supply chains.

DOT National Transportation Integrated Search

2013-03-01

In many regions throughout the world, freight models are used to aid infrastructure investment and : policy decisions. Since freight is such an integral part of efficient supply chains, more realistic : transportation models can be of greater assista...

Crystal structure and charge transport properties of poly(arylene-ethynylene) derivatives: A DFT approach

NASA Astrophysics Data System (ADS)

Garzón, Andrés; Granadino-Roldán, José M.; García, Gregorio; Moral, Mónica; Fernández-Gómez, Manuel

2013-04-01

In the present study, a series of crystalline poly(arylene-ethynylene) copolymers containing phenylethynylene and 2,5-dialkoxy-phenylethynylene units together with 1,3,4-thiadiazole rings has been modeled by means of periodic calculations. Optimized three-dimensional polymeric structures show interchain distances that are consistent with the experimental values reported for a related polymer. It has also been observed that the presence of pendant alkoxy chains brings on both a further flattening and a separation of the coplanar chains. This fact is linked to a decrease of the interchain cofacial distance. The electron transport character of the polymer crystal structures was assessed through Marcus theory. Electronic coupling between neighboring polymer chains is most influenced by the presence of alkoxy chains giving rise to an expectable enhancement of the electron hopping mobility.

First-principles study on electron transport properties of carbon-silicon mixed chains

NASA Astrophysics Data System (ADS)

Hu, Wei; Zhou, Qinghua; Liang, Yan; Liu, Wenhua; Wang, Tao; Wan, Haiqing

2018-03-01

In this paper, the transport properties of carbon-silicon mixed chains are studied by using the first-principles. We studied five atomic chain models. In these studies, we found that the equilibrium conductances of atomic chains appear to oscillate, the maximum conductance and the minimum conductance are more than twice the difference. Their I-V curves are linear and show the behavior of metal resistance, M5 system and M2 system current ratio is the largest in 0.9 V, which is 3.3, showing a good molecular switch behavior. In the case of bias, while the bias voltage increases, the transmission peaks move from the Fermi level. The resonance transmission peak height is reduced near the Fermi level. In the higher energy range, a large resonance transmission peak reappears, there is still no energy cut-off range.

Occurrence, bioaccumulation and long-range transport of short-chain chlorinated paraffins on the Fildes Peninsula at King George Island, Antarctica.

PubMed

Li, Huijuan; Fu, Jianjie; Zhang, Aiqian; Zhang, Qinghua; Wang, Yawei

2016-09-01

As a candidate persistent organic pollutant of the Stockholm Convention, short-chain chlorinated paraffins (SCCPs) have recently received particular attention. In this study, we investigated, for the first time, the concentrations of SCCPs in biota samples collected from the Fildes Peninsula at King George Island and Ardley Island, Antarctica. The concentrations of SCCPs ranged from 3.5 to 256.6ng/g (dry weight, dw), with a mean of 76.6±61.8ng/g dw, which was lower than those detected in mid- and low-latitude regions. The long-range transport behaviour of SCCPs was confirmed by both the detection of SCCPs in Antarctic remote areas and their special congener profiles. Short carbon chain (C10) congeners predominated in the Antarctic samples, which accounted for 56.1% of the total SCCP contamination. Such enrichment of C10 congeners indicated the high potential for the long-range transport of shorter chain congeners. In addition, SCCPs tended to be enriched in the species with high lipid contents. The biomagnification potential of SCCPs was found between Archeogastropoda (Agas) and Neogastropoda (Ngas), and the biomagnification factors of shorter chain congeners of SCCPs were higher than that of the longer chain ones. Considering that the endemic species in polar regions may be sensitive and vulnerable to the adverse effects of environmental contaminants, more attention should be paid on the bioaccumulation and toxicological risks of SCCPs in polar environments. Copyright © 2016. Published by Elsevier Ltd.

Ion transport and selectivity in biomimetic nanopores with pH-tunable zwitterionic polyelectrolyte brushes.

PubMed

Zeng, Zhenping; Yeh, Li-Hsien; Zhang, Mingkan; Qian, Shizhi

2015-10-28

Inspired by nature, functionalized nanopores with biomimetic structures have attracted growing interests in using them as novel platforms for applications of regulating ion and nanoparticle transport. To improve these emerging applications, we study theoretically for the first time the ion transport and selectivity in short nanopores functionalized with pH tunable, zwitterionic polyelectrolyte (PE) brushes. In addition to background salt ions, the study takes into account the presence of H(+) and OH(-) ions along with the chemistry reactions between functional groups on PE chains and protons. Due to ion concentration polarization, the charge density of PE layers is not homogeneously distributed and depends significantly on the background salt concentration, pH, grafting density of PE chains, and applied voltage bias, thereby resulting in many interesting and unexpected ion transport phenomena in the nanopore. For example, the ion selectivity of the biomimetic nanopore can be regulated from anion-selective (cation-selective) to cation-selective (anion-selective) by diminishing (raising) the solution pH when a sufficiently small grafting density of PE chains, large voltage bias, and low background salt concentration are applied.

SmartWay

EPA Pesticide Factsheets

SmartWay is an EPA program that helps the freight transportation sector improve supply chain efficiency. SmartWay reduces transportation-related emissions, environmental risks for companies and increases global energy security.

[Are there counterfeit medicines in Croatia?].

PubMed

Tomić, Sinisa; Milcić, Neven; Sokolić, Milenko; Sucić, Anita Filipović; Martinac, Adrijana Ilić

2010-01-01

Counterfeit medicines are a growing problem in the world, for their use may endanger patient's health and therefore they pose an enormous public health risk. The manufacture of counterfeit medicines usually involves organised crime groups which place the counterfeit medicines on the market for reasons of profit. Detection and prevention of trade in counterfeit medicines requires close cooperation between medicine regulatory authorities, police, customs, judiciary and pharmaceutical industry. To this day, there have been no recorded cases of counterfeit medicines in the legal supply chain in Croatia. However, medicines without marketing authorisation in Croatia, originating from different countries, could be found on the illegal market. Most frequently, this includes medicines for the treatment of erectile dysfunction such as: sildenafil, tadalafil, vardenafil. In this study, 26 medicines for the treatment of erectile dysfunction, seized in illegal supply chain, were tested. High performance liquid chromatography (HPLC) was used for identification and quantification of active substances in the tested samples. It was determined that 13 out of 26 samples did not comply with declared composition of medicine and quality specification. Furthermore, two samples did not contain declared active substance vardenafil and that may indicate that these medicines are counterfeit.

The Metabolome in Finnish Carriers of the MYBPC3-Q1061X Mutation for Hypertrophic Cardiomyopathy.

PubMed

Jørgenrud, Benedicte; Jalanko, Mikko; Heliö, Tiina; Jääskeläinen, Pertti; Laine, Mika; Hilvo, Mika; Nieminen, Markku S; Laakso, Markku; Hyötyläinen, Tuulia; Orešič, Matej; Kuusisto, Johanna

2015-01-01

Mutations in the cardiac myosin-binding protein C gene (MYBPC3) are the most common genetic cause of hypertrophic cardiomyopathy (HCM) worldwide. The molecular mechanisms leading to HCM are poorly understood. We investigated the metabolic profiles of mutation carriers with the HCM-causing MYBPC3-Q1061X mutation with and without left ventricular hypertrophy (LVH) and non-affected relatives, and the association of the metabolome to the echocardiographic parameters. 34 hypertrophic subjects carrying the MYBPC3-Q1061X mutation, 19 non-hypertrophic mutation carriers and 20 relatives with neither mutation nor hypertrophy were examined using comprehensive echocardiography. Plasma was analyzed for molecular lipids and polar metabolites using two metabolomics platforms. Concentrations of branched chain amino acids, triglycerides and ether phospholipids were increased in mutation carriers with hypertrophy as compared to controls and non-hypertrophic mutation carriers, and correlated with echocardiographic LVH and signs of diastolic and systolic dysfunction in subjects with the MYBPC3-Q1061X mutation. Our study implicates the potential role of branched chain amino acids, triglycerides and ether phospholipids in HCM, as well as suggests an association of these metabolites with remodeling and dysfunction of the left ventricle.

Identification of vibrational signatures from short chains of interlinked molecule-nanoparticle junctions obtained by inelastic electron tunnelling spectroscopy

NASA Astrophysics Data System (ADS)

Jafri, S. H. M.; Löfås, H.; Fransson, J.; Blom, T.; Grigoriev, A.; Wallner, A.; Ahuja, R.; Ottosson, H.; Leifer, K.

2013-05-01

Short chains containing a series of metal-molecule-nanoparticle nanojunctions are a nano-material system with the potential to give electrical signatures close to those from single molecule experiments while enabling us to build portable devices on a chip. Inelastic electron tunnelling spectroscopy (IETS) measurements provide one of the most characteristic electrical signals of single and few molecules. In interlinked molecule-nanoparticle (NP) chains containing typically 5-7 molecules in a chain, the spectrum is expected to be a superposition of the vibrational signatures of individual molecules. We have established a stable and reproducible molecule-AuNP multi-junction by placing a few 1,8-octanedithiol (ODT) molecules onto a versatile and portable nanoparticle-nanoelectrode platform and measured for the first time vibrational molecular signatures at complex and coupled few-molecule-NP junctions. From quantum transport calculations, we model the IETS spectra and identify vibrational modes as well as the number of molecules contributing to the electron transport in the measured spectra.Short chains containing a series of metal-molecule-nanoparticle nanojunctions are a nano-material system with the potential to give electrical signatures close to those from single molecule experiments while enabling us to build portable devices on a chip. Inelastic electron tunnelling spectroscopy (IETS) measurements provide one of the most characteristic electrical signals of single and few molecules. In interlinked molecule-nanoparticle (NP) chains containing typically 5-7 molecules in a chain, the spectrum is expected to be a superposition of the vibrational signatures of individual molecules. We have established a stable and reproducible molecule-AuNP multi-junction by placing a few 1,8-octanedithiol (ODT) molecules onto a versatile and portable nanoparticle-nanoelectrode platform and measured for the first time vibrational molecular signatures at complex and coupled few-molecule-NP junctions. From quantum transport calculations, we model the IETS spectra and identify vibrational modes as well as the number of molecules contributing to the electron transport in the measured spectra. Electronic supplementary information (ESI) available: Methods and materials. Details of the ab initio calculation of molecular vibrations and inelastic spectra of ODT between two Au electrodes. A model of carrier transport through the molecular junctions. See DOI: 10.1039/c3nr00505d

49 CFR 1580.107 - Chain of custody and control requirements.

Code of Federal Regulations, 2010 CFR

2010-10-01

... businesses, housing, schools, and hospitals. (4) Any information regarding threats to the facility. (5) Other...) TRANSPORTATION SECURITY ADMINISTRATION, DEPARTMENT OF HOMELAND SECURITY MARITIME AND LAND TRANSPORTATION SECURITY RAIL TRANSPORTATION SECURITY Freight Rail Including Freight Railroad Carriers, Rail Hazardous Materials...

Hydraulic patterns and safety margins, from stem to stomata, in three eastern US tree species

Treesearch

D.M. Johnson; K.A. McCulloh; F.C. Meinzer; D.R. Woodruff; D.M. Eissenstat

2011-01-01

Adequate water transport is necessary to prevent stomatal closure and allow for photosynthesis. Dysfunction in the water transport pathway can result in stomatal closure, and can be deleterious to overall plant health and survival. Although much is known about small branch hydraulics, little is known about the coordination of leaf and stem hydraulic function....

Decreased endothelial nitric oxide synthase expression and function contribute to impaired mitochondrial biogenesis and oxidative stress in fetal lambs with persistent pulmonary hypertension.

PubMed

Afolayan, Adeleye J; Eis, Annie; Alexander, Maxwell; Michalkiewicz, Teresa; Teng, Ru-Jeng; Lakshminrusimha, Satyan; Konduri, Girija G

2016-01-01

Impaired vasodilation in persistent pulmonary hypertension of the newborn (PPHN) is characterized by mitochondrial dysfunction. We investigated the hypothesis that a decreased endothelial nitric oxide synthase level leads to impaired mitochondrial biogenesis and function in a lamb model of PPHN induced by prenatal ductus arteriosus constriction. We ventilated PPHN lambs with 100% O2 alone or with inhaled nitric oxide (iNO). We treated pulmonary artery endothelial cells (PAECs) from normal and PPHN lambs with detaNONOate, an NO donor. We observed decreased mitochondrial (mt) DNA copy number, electron transport chain (ETC) complex subunit levels, and ATP levels in PAECs and lung tissue of PPHN fetal lambs at baseline compared with gestation matched controls. Phosphorylation of AMP-activated kinase (AMPK) and levels of peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) and sirtuin-1, which facilitate mitochondrial biogenesis, were decreased in PPHN. Ventilation with 100% O2 was associated with larger decreases in ETC subunits in the lungs of PPHN lambs compared with unventilated PPHN lambs. iNO administration, which facilitated weaning of FiO2 , partly restored mtDNA copy number, ETC subunit levels, and ATP levels. DetaNONOate increased eNOS phosphorylation and its interaction with heat shock protein 90 (HSP90); increased levels of superoxide dismutase 2 (SOD2) mRNA, protein, and activity; and decreased the mitochondrial superoxide levels in PPHN-PAECs. Knockdown of eNOS decreased ETC protein levels in control PAECs. We conclude that ventilation with 100% O2 amplifies oxidative stress and mitochondrial dysfunction in PPHN, which are partly improved by iNO and weaning of oxygen. Copyright © 2016 the American Physiological Society.

Reduction in Reactive Oxygen Species Production by Mitochondria From Elderly Subjects With Normal and Impaired Glucose Tolerance

PubMed Central

Ghosh, Sangeeta; Lertwattanarak, Raweewan; Lefort, Natalie; Molina-Carrion, Marjorie; Joya-Galeana, Joaquin; Bowen, Benjamin P.; de Jesus Garduno-Garcia, Jose; Abdul-Ghani, Muhammad; Richardson, Arlan; DeFronzo, Ralph A.; Mandarino, Lawrence; Van Remmen, Holly; Musi, Nicolas

2011-01-01

OBJECTIVE Aging increases the risk of developing impaired glucose tolerance (IGT) and type 2 diabetes. It has been proposed that increased reactive oxygen species (ROS) generation by dysfunctional mitochondria could play a role in the pathogenesis of these metabolic abnormalities. We examined whether aging per se (in subjects with normal glucose tolerance [NGT]) impairs mitochondrial function and how this relates to ROS generation, whether older subjects with IGT have a further worsening of mitochondrial function (lower ATP production and elevated ROS generation), and whether exercise reverses age-related changes in mitochondrial function. RESEARCH DESIGN AND METHODS Mitochondrial ATP and ROS production were measured in muscle from younger individuals with NGT, older individuals with NGT, and older individuals with IGT. Measurements were performed before and after 16 weeks of aerobic exercise. RESULTS ATP synthesis was lower in older subjects with NGT and older subjects with IGT versus younger subjects. Notably, mitochondria from older subjects (with NGT and IGT) displayed reduced ROS production versus the younger group. ATP and ROS production were similar between older groups. Exercise increased ATP synthesis in the three groups. Mitochondrial ROS production also increased after training. Proteomic analysis revealed downregulation of several electron transport chain proteins with aging, and this was reversed by exercise. CONCLUSIONS Old mitochondria from subjects with NGT and IGT display mitochondrial dysfunction as manifested by reduced ATP production but not with respect to increased ROS production. When adjusted to age, the development of IGT in elderly individuals does not involve changes in mitochondrial ATP and ROS production. Lastly, exercise reverses the mitochondrial phenotype (proteome and function) of old mitochondria. PMID:21677280

Could Alzheimer's Disease Originate in the Periphery and If So How So?

PubMed

Morris, Gerwyn; Berk, Michael; Maes, Michael; Puri, Basant K

2018-04-29

The classical amyloid cascade model for Alzheimer's disease (AD) has been challenged by several findings. Here, an alternative molecular neurobiological model is proposed. It is shown that the presence of the APOE ε4 allele, altered miRNA expression and epigenetic dysregulation in the promoter region and exon 1 of TREM2, as well as ANK1 hypermethylation and altered levels of histone post-translational methylation leading to increased transcription of TNFA, could variously explain increased levels of peripheral and central inflammation found in AD. In particular, as a result of increased activity of triggering receptor expressed on myeloid cells 2 (TREM-2), the presence of the apolipoprotein E4 (ApoE4) isoform, and changes in ANK1 expression, with subsequent changes in miR-486 leading to altered levels of protein kinase B (Akt), mechanistic (previously mammalian) target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3), all of which play major roles in microglial activation, proliferation and survival, there is activation of microglia, leading to the subsequent (further) production of cytokines, chemokines, nitric oxide, prostaglandins, reactive oxygen species, inducible nitric oxide synthase and cyclooxygenase-2, and other mediators of inflammation and neurotoxicity. These changes are associated with the development of amyloid and tau pathology, mitochondrial dysfunction (including impaired activity of the electron transport chain, depleted basal mitochondrial potential and oxidative damage to key tricarboxylic acid enzymes), synaptic dysfunction, altered glycogen synthase kinase-3 (GSK-3) activity, mTOR activation, impairment of autophagy, compromised ubiquitin-proteasome system, iron dyshomeostasis, changes in APP translation, amyloid plaque formation, tau hyperphosphorylation and neurofibrillary tangle formation.

Naringin Ameliorates HIV-1 Nucleoside Reverse Transcriptase Inhibitors- Induced Mitochondrial Toxicity.

PubMed

Oluwafeyisetan, Adebiyi; Olubunmi, Adebiyi; Peter, Owira

2016-01-01

Mitochondrial reactive oxygen species (ROS) generation and defective oxidative phosphorylation (OXPHOS) have been proposed as possible mechanisms underlying the development of nucleoside reverse transcriptase inhibitors (NRTIs)-induced mitochondrial toxicities. Available options in managing these complications have, so far, produced controversial results, thus necessitating further research into newer agents with promise. Antioxidant and free-radical scavenging effects of naringin, a plant-derived flavonoid, have previously been demonstrated. This study was designed to investigate the effects of naringin on NRTIs-induced mitochondrial toxicity. Wistar rats were randomly divided into Zidovudine (AZT)-only (100 mg/kg body weight BW); AZT+Naringin (100+50 mg/kg BW); AZT+Vitamin E (100+100 mg/kg BW); Stavudine (d4T)- only (50 mg/kg BW); d4T+Naringin (50+50 mg/kg BW); d4T+Vitamin E (50+100 mg/kg BW) and Vehicle (3.0 mL/kg BW)-treated groups, respectively. After 56 days of oral daily dosing, rats were euthanized by halothane overdose, blood collected by cardiac puncture and livers promptly excised for further biochemical and ultrastructural analyses. </p> Results: AZT- or d4T-only caused significant mitochondrial dysfunction and mitochondrial ultrastructural damage compared to controls, while either naringin or vitamin E reversed indices of mitochondrial dysfunction evidenced by significantly reduced mitochondrial malondialdehyde (MDA) and blood lactate concentrations, increased liver manganese superoxide dismutase (MnSOD) activity and upregulate expression of mitochondrial-encoded subunit of electron transport chain (ETC) complex IV protein compared to AZT- or d4T-only treated rats. Furthermore, naringin or vitamin E, respectively, ameliorated mitochondrial damage observed in AZT- or d4T-only treated rats. Naringin ameliorated oxidative stress and NRTI-induced mitochondrial damage and might, therefore, be beneficial in managing toxicities and complications arising from NRTI use.

Mitochondrial dysfunction due to oxidative mitochondrial DNA damage is reduced through cooperative actions of diverse proteins.

PubMed

O'Rourke, Thomas W; Doudican, Nicole A; Mackereth, Melinda D; Doetsch, Paul W; Shadel, Gerald S

2002-06-01

The mitochondrial genome is a significant target of exogenous and endogenous genotoxic agents; however, the determinants that govern this susceptibility and the pathways available to resist mitochondrial DNA (mtDNA) damage are not well characterized. Here we report that oxidative mtDNA damage is elevated in strains lacking Ntg1p, providing the first direct functional evidence that this mitochondrion-localized, base excision repair enzyme functions to protect mtDNA. However, ntg1 null strains did not exhibit a mitochondrial respiration-deficient (petite) phenotype, suggesting that mtDNA damage is negotiated by the cooperative actions of multiple damage resistance pathways. Null mutations in ABF2 or PIF1, two genes implicated in mtDNA maintenance and recombination, exhibit a synthetic-petite phenotype in combination with ntg1 null mutations that is accompanied by enhanced mtDNA point mutagenesis in the corresponding double-mutant strains. This phenotype was partially rescued by malonic acid, indicating that reactive oxygen species generated by the electron transport chain contribute to mitochondrial dysfunction in abf2 Delta strains. In contrast, when two other genes involved in mtDNA recombination, CCE1 and NUC1, were inactivated a strong synthetic-petite phenotype was not observed, suggesting that the effects mediated by Abf2p and Pif1p are due to novel activities of these proteins other than recombination. These results document the existence of recombination-independent mechanisms in addition to base excision repair to cope with oxidative mtDNA damage in Saccharomyces cerevisiae. Such systems are likely relevant to those operating in human cells where mtDNA recombination is less prevalent, validating yeast as a model system in which to study these important issues.

Conserved regional patterns of GABA-related transcript expression in the neocortex of subjects with schizophrenia.

PubMed

Hashimoto, Takanori; Bazmi, H Holly; Mirnics, Karoly; Wu, Qiang; Sampson, Allan R; Lewis, David A

2008-04-01

Individuals with schizophrenia exhibit disturbances in a number of cognitive, affective, sensory, and motor functions that depend on the circuitry of different cortical areas. The cognitive deficits associated with dysfunction of the dorsolateral prefrontal cortex result, at least in part, from abnormalities in GABA neurotransmission, as reflected in a specific pattern of altered expression of GABA-related genes. Consequently, the authors sought to determine whether this pattern of altered gene expression is restricted to the dorsolateral prefrontal cortex or could also contribute to the dysfunction of other cortical areas in subjects with schizophrenia. Real-time quantitative polymerase chain reaction was used to assess the levels of eight GABA-related transcripts in four cortical areas (dorsolateral prefrontal cortex, anterior cingulate cortex, and primary motor and primary visual cortices) of subjects (N=12) with schizophrenia and matched normal comparison subjects. Expression levels of seven transcripts were lower in subjects with schizophrenia, with the magnitude of reduction for each transcript comparable across the four areas. The largest reductions were detected for mRNA encoding somatostatin and parvalbumin, followed by moderate decreases in mRNA expression for the 67-kilodalton isoform of glutamic acid decarboxylase, the GABA membrane transporter GAT-1, and the alpha 1 and delta subunits of GABA(A) receptors. In contrast, the expression of calretinin mRNA did not differ between the subject groups in any of the four areas. Because the areas examined represent the major functional domains (e.g., association, limbic, motor, and sensory) of the cerebral cortex, our findings suggest that a conserved set of molecular alterations affecting GABA neurotransmission contribute to the pathophysiology of different clinical features of schizophrenia.

Brain Mitochondria, Aging, and Parkinson's Disease.

PubMed

Rango, Mario; Bresolin, Nereo

2018-05-11

This paper reconsiders the role of mitochondria in aging and in Parkinson's Disease (PD). The most important risk factor for PD is aging. Alterations in mitochondrial activity are typical of aging. Mitochondrial aging is characterized by decreased oxidative phosphorylation, proteasome activity decrease, altered autophagy, and mitochondrial dysfunction. Beyond declined oxidative phosphorylation, mitochondrial dysfunction consists of a decline of beta-oxidation as well as of the Krebs cycle. Not inherited mitochondrial DNA (mtDNA) mutations are acquired over time and parallel the decrease in oxidative phosphorylation. Many of these mitochondrial alterations are also found in the PD brain specifically in the substantia nigra (SN). mtDNA deletions and development of respiratory chain deficiency in SN neurons of aged individuals as well as of individuals with PD converge towards a shared pathway, which leads to neuronal dysfunction and death. Finally, several nuclear genes that are mutated in hereditary PD are usually implicated in mitochondrial functioning to a various extent and their mutation may cause mitochondrial impairment. In conclusion, a tight link exists between mitochondria, aging, and PD.

Rescue of neonatal cardiac dysfunction in mice by administration of cardiac progenitor cells in utero

PubMed Central

Liu, Xiaoli; Hall, Sean R. R.; Wang, Zhihong; Huang, He; Ghanta, Sailaja; Di Sante, Moises; Leri, Annarosa; Anversa, Piero; Perrella, Mark A.

2015-01-01

Striated preferentially expressed gene (Speg) is a member of the myosin light chain kinase family. We previously showed that disruption of the Speg gene locus in mice leads to a dilated cardiomyopathy with immature-appearing cardiomyocytes. Here we show that cardiomyopathy of Speg−/− mice arises as a consequence of defects in cardiac progenitor cell (CPC) function, and that neonatal cardiac dysfunction can be rescued by in utero injections of wild-type CPCs into Speg−/− foetal hearts. CPCs harvested from Speg−/− mice display defects in clone formation, growth and differentiation into cardiomyocytes in vitro, which are associated with cardiac dysfunction in vivo. In utero administration of wild-type CPCs into the hearts of Speg−/− mice results in CPC engraftment, differentiation and myocardial maturation, which rescues Speg−/− mice from neonatal heart failure and increases the number of live births by fivefold. We propose that in utero administration of CPCs may have future implications for treatment of neonatal heart diseases. PMID:26593099

Bioenergetic Defects and Oxidative Damage in Transgenic Mouse Models of Neurodegenerative Disorders

DTIC Science & Technology

2003-05-01

transport chain enzyme activities in G93A ALS mice at 60 and 120d. A^^; The laboratory moved from Massachussetts General Hospital, Boston, MA, to...glucose use changes by measurement at 42d, 56d and 84d of age. 7) Measurement of electron transport chain enzyme activities in R6/2 HD mice. 8) NMR...lactate imaging; in vitro spectrophotometric oxidative phosphorylation enzyme assays; HPLC detection of metabolites), and to investigate the

Space system operations and support cost analysis using Markov chains

NASA Technical Reports Server (NTRS)

Unal, Resit; Dean, Edwin B.; Moore, Arlene A.; Fairbairn, Robert E.

1990-01-01

This paper evaluates the use of Markov chain process in probabilistic life cycle cost analysis and suggests further uses of the process as a design aid tool. A methodology is developed for estimating operations and support cost and expected life for reusable space transportation systems. Application of the methodology is demonstrated for the case of a hypothetical space transportation vehicle. A sensitivity analysis is carried out to explore the effects of uncertainty in key model inputs.

Effect of Structure on Transport Properties (Viscosity, Ionic Conductivity, and Self-Diffusion Coefficient) of Aprotic Heterocyclic Anion (AHA) Room Temperature Ionic Liquids. 2. Variation of Alkyl Chain Length in the Phosphonium Cation.

PubMed

Sun, Liyuan; Morales-Collazo, Oscar; Xia, Han; Brennecke, Joan F

2016-06-30

A series of room-temperature ionic liquids (ILs) composed of triethyl(alkyl)phosphonium cations paired with three different aprotic heterocyclic anions (AHAs) (alkyl = butyl ([P2224](+)) and octyl ([P2228](+))) were prepared to investigate the effect of cationic alkyl chain length on transport properties. The transport properties and density of these ILs were measured from 283.15 to 343.15 K at ambient pressure. The dependence of the transport properties (viscosity, ionic conductivity, diffusivity, and molar conductivity) on temperature can be described by the Vogel-Fulcher-Tamman (VFT) equation. The ratio of the molar conductivity obtained from the molar concentration and ionic conductivity measurements to that calculated from self-diffusion coefficients (measured by pulsed gradient spin-echo nuclear magnetic resonance spectroscopy) using the Nernst-Einstein equation was used to quantify the ionicity of these ILs. The molar conductivity ratio decreases with increasing number of carbon atoms in the alkyl chain, indicating that the reduced Coulombic interactions resulting from lower density are more than balanced by the increased van der Waals interactions between the alkyl chains. The results of this study may provide insight into the design of ILs with enhanced dynamics that may be suitable as electrolytes in lithium ion batteries and other electrochemical applications.

[The H+/e- ratio in the photosynthetic electron transport chain].

PubMed

Ivanov, B N; Shmeleva, V L; Ovchinnikova, V I

1983-06-01

The number of protons adsorbed by tylakoids during one electron passage along the photosynthetic electron transport chain (i.e. the H+/e- ratio) was measured in isolated pea chloroplasts upon continuous illumination. Methylviologen was used as electron acceptor on the reducing side of PS I. It was found that at pH 6.0 upon illumination with red light (lambda greater than 620 nm) at an intensity of 2 . 10(5) erg/cm2 . s ("intensive" light) the H+/e- ratio is equal to 3. Upon illumination of dark-adapted chloroplasts with a "weak" light (900 erg/cm2 . s) the H+/e- ratio is equal to 2. Upon illumination of the chloroplasts with a "weak" after "intensive" light the value of this ratio is close to 3. Azide when added to the reaction mixture may interfere with the accuracy of measurements of the value of the H+/e- ratio by affecting proton exchange. Based on the changes in the H+/e- ratio induced by illumination it was assumed that at saturating intensity of the illuminating light the electron transport chain passes into a so-called "light" state when the mechanisms of proton-electron coupling differing from those of rare electron transfer ("weak" light, flashes) are triggered on. At pH 6.0 the "light" state of the electron transport chain is maintained for some time in the dark.

Transmission eigenchannels for coherent phonon transport

NASA Astrophysics Data System (ADS)

Klöckner, J. C.; Cuevas, J. C.; Pauly, F.

2018-04-01

We present a procedure to determine transmission eigenchannels for coherent phonon transport in nanoscale devices using the framework of nonequilibrium Green's functions. We illustrate our procedure by analyzing a one-dimensional chain, where all steps can be carried out analytically. More importantly, we show how the procedure can be combined with ab initio calculations to provide a better understanding of phonon heat transport in realistic atomic-scale junctions. In particular, we study the phonon eigenchannels in a gold metallic atomic-size contact and different single-molecule junctions based on molecules such as an alkane chain, a brominated benzene-diamine, where destructive phonon interference effects take place, and a C60 junction.

From neurocognition to community participation in serious mental illness: the intermediary role of dysfunctional attitudes and motivation.

PubMed

Thomas, E C; Luther, L; Zullo, L; Beck, A T; Grant, P M

2017-04-01

Evidence for a relationship between neurocognition and functional outcome in important areas of community living is robust in serious mental illness research. Dysfunctional attitudes (defeatist performance beliefs and asocial beliefs) have been identified as intervening variables in this causal chain. This study seeks to expand upon previous research by longitudinally testing the link between neurocognition and community participation (i.e. time in community-based activity) through dysfunctional attitudes and motivation. Adult outpatients with serious mental illness (N = 175) participated, completing follow-up assessments approximately 6 months after initial assessment. Path analysis tested relationships between baseline neurocognition, emotion perception, functional skills, dysfunctional attitudes, motivation, and outcome (i.e. community participation) at baseline and follow-up. Path models demonstrated two pathways to community participation. The first linked neurocognition and community participation through functional skills, defeatist performance beliefs, and motivation. A second pathway linked asocial beliefs and community participation, via a direct path passing through motivation. Model fit was excellent for models predicting overall community participation at baseline and, importantly, at follow-up. The existence of multiple pathways to community participation in a longitudinal model supports the utility of multi-modal interventions for serious mental illness (i.e. treatment packages that build upon individuals' strengths while addressing the array of obstacles to recovery) that feature dysfunctional attitudes and motivation as treatment targets.

Mitochondrial Dysfunction in Lysosomal Storage Disorders

PubMed Central

de la Mata, Mario; Cotán, David; Villanueva-Paz, Marina; de Lavera, Isabel; Álvarez-Córdoba, Mónica; Luzón-Hidalgo, Raquel; Suárez-Rivero, Juan M.; Tiscornia, Gustavo; Oropesa-Ávila, Manuel

2016-01-01

Lysosomal storage diseases (LSDs) describe a heterogeneous group of rare inherited metabolic disorders that result from the absence or loss of function of lysosomal hydrolases or transporters, resulting in the progressive accumulation of undigested material in lysosomes. The accumulation of substances affects the function of lysosomes and other organelles, resulting in secondary alterations such as impairment of autophagy, mitochondrial dysfunction, inflammation and apoptosis. LSDs frequently involve the central nervous system (CNS), where neuronal dysfunction or loss results in progressive neurodegeneration and premature death. Many LSDs exhibit signs of mitochondrial dysfunction, which include mitochondrial morphological changes, decreased mitochondrial membrane potential (ΔΨm), diminished ATP production and increased generation of reactive oxygen species (ROS). Furthermore, reduced autophagic flux may lead to the persistence of dysfunctional mitochondria. Gaucher disease (GD), the LSD with the highest prevalence, is caused by mutations in the GBA1 gene that results in defective and insufficient activity of the enzyme β-glucocerebrosidase (GCase). Decreased catalytic activity and/or instability of GCase leads to accumulation of glucosylceramide (GlcCer) and glucosylsphingosine (GlcSph) in the lysosomes of macrophage cells and visceral organs. Mitochondrial dysfunction has been reported to occur in numerous cellular and mouse models of GD. The aim of this manuscript is to review the current knowledge and implications of mitochondrial dysfunction in LSDs. PMID:28933411

Towards bridging the gap between acid-base transporters and neuronal excitability modulation

PubMed Central

Liu, Ying; Chen, Li-Ming

2014-01-01

pH homeostasis is a fundamental regulator of the function of the central nervous system. Dysfunction of acid-base transporters often results in disturbance of neuronal excitability. In a latest issue of Journal of Neuroscience, Jones et al. report that increasing intracellular bicarbonate concentration substantially stimulates the excitability of pyramidal neurons from mouse hippocampus by inhibiting KCNQ potassium channel. The finding shed important new light in understanding the molecular mechanism underlying the regulation of neuronal excitability by acid-base transporters. PMID:25755844

Fluoralkenyl nortropanes

DOEpatents

Goodman, Mark M.; Chen, Ping

2002-02-05

Provided are compounds of the following formula: ##STR1## wherein R is C2-C6 mono- or multi-unsaturated hydrocarbon having one or more ethylene, acetylene or allene groups, A is 18 or 19, and X is H or halogen. The compounds of the invention bind to dopamine transporter with high affinity and selectivity and are thus useful as diagnostic and therapeutic agents for diseases associated with dopamine transporter dysfunction. The radiolabeled compounds are useful as imaging agents for visualizing the location and density of dopamine transporter by PET imaging.

4-fluoroalkyl-3-halophenyl nortropanes

DOEpatents

Goodman, Mark M.; Chen, Ping

2002-06-04

A series of compounds in the 4-fluoroalkyl-3-halophenyl nortropanes family are described as diagnostic and therapeutic agents for diseases associated with serotonin transporter dysfunction. These compounds bind to serotonin transporter protein with high affinity and selectivity. The invention provides methods of synthesis which incorporate radioisotopic halogens at a last step which permit high radiochemical yield and maximum usable product life. The radiolabeled compounds of the invention are useful as imaging agents for visualizing the location and density of serotonin transporter by PET and SPECT imaging.

Myofilament dysfunction contributes to impaired myocardial contraction in the infarct border zone

PubMed Central

Shimkunas, Rafael; Makwana, Om; Spaulding, Kimberly; Bazargan, Mona; Khazalpour, Michael; Takaba, Kiyoaki; Soleimani, Mehrdad; Myagmar, Bat-Erdene; Lovett, David H.; Simpson, Paul C.; Ratcliffe, Mark B.

2014-01-01

After myocardial infarction, a poorly contracting nonischemic border zone forms adjacent to the infarct. The cause of border zone dysfunction is unclear. The goal of this study was to determine the myofilament mechanisms involved in postinfarction border zone dysfunction. Two weeks after anteroapical infarction of sheep hearts, we studied in vitro isometric and isotonic contractions of demembranated myocardium from the infarct border zone and a zone remote from the infarct. Maximal force development (Fmax) of the border zone myocardium was reduced by 31 ± 2% versus the remote zone myocardium (n = 6/group, P < 0.0001). Decreased border zone Fmax was not due to a reduced content of contractile material, as assessed histologically, and from myosin content. Furthermore, decreased border zone Fmax did not involve altered cross-bridge kinetics, as assessed by muscle shortening velocity and force development kinetics. Decreased border zone Fmax was associated with decreased cross-bridge formation, as assessed from muscle stiffness in the absence of ATP where cross-bridge formation should be maximized (rigor stiffness was reduced 34 ± 6%, n = 5, P = 0.011 vs. the remote zone). Furthermore, the border zone myocardium had significantly reduced phosphorylation of myosin essential light chain (ELC; 41 ± 10%, n = 4, P < 0.05). However, for animals treated with doxycycline, an inhibitor of matrix metalloproteinases, rigor stiffness and ELC phosphorylation were not reduced in the border zone myocardium, suggesting that doxycycline had a protective effect. In conclusion, myofilament dysfunction contributes to postinfarction border zone dysfunction, myofilament dysfunction involves impaired cross-bridge formation and decreased ELC phosphorylation, and matrix metalloproteinase inhibition may be beneficial for limiting postinfarct border zone dysfunction. PMID:25128171

Overexpression of Human Fatty Acid Transport Protein 2/Very Long Chain Acyl-CoA Synthetase 1 (FATP2/Acsvl1) Reveals Distinct Patterns of Trafficking of Exogenous Fatty Acids

PubMed Central

Melton, Elaina M.; Cerny, Ronald L.; DiRusso, Concetta C.; Black, Paul N.

2014-01-01

In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4, for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4hr. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous fatty acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the transport and activation of exogenous fatty acids. We discuss the differential roles of FATP2 and its role in both fatty acid transport and fatty acid activation in the context of lipid homeostasis. PMID:24113382

Overexpression of human fatty acid transport protein 2/very long chain acyl-CoA synthetase 1 (FATP2/Acsvl1) reveals distinct patterns of trafficking of exogenous fatty acids.

PubMed

Melton, Elaina M; Cerny, Ronald L; DiRusso, Concetta C; Black, Paul N

2013-11-01

In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4, for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous fatty acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the transport and activation of exogenous fatty acids. We discuss the differential roles of FATP2 and its role in both fatty acid transport and fatty acid activation in the context of lipid homeostasis. Copyright © 2013 Elsevier Inc. All rights reserved.

Influences of Electromagnetic Energy on Bio-Energy Transport through Protein Molecules in Living Systems and Its Experimental Evidence

PubMed Central

Pang, Xiaofeng; Chen, Shude; Wang, Xianghui; Zhong, Lisheng

2016-01-01

The influences of electromagnetic fields (EMFs) on bio-energy transport and its mechanism of changes are investigated through analytic and numerical simulation and experimentation. Bio-energy transport along protein molecules is performed by soliton movement caused by the dipole–dipole electric interactions between neighboring amino acid residues. As such, EMFs can affect the structure of protein molecules and change the properties of the bio-energy transported in living systems. This mechanism of biological effect from EMFs involves the amino acid residues in protein molecules. To study and reveal this mechanism, we simulated numerically the features of the movement of solitons along protein molecules with both a single chain and with three channels by using the Runge–Kutta method and Pang’s soliton model under the action of EMFs with the strengths of 25,500, 51,000, 76,500, and 102,000 V/m in the single-chain protein, as well as 17,000, 25,500, and 34,000 V/m in the three-chain protein, respectively. Results indicate that electric fields (EFs) depress the binding energy of the soliton, decrease its amplitude, and change its wave form. Also, the soliton disperses at 102,000 V/m in a single-chain protein and at 25,500 and 34,000 V/m in three-chain proteins. These findings signify that the influence of EMFs on the bio-energy transport cannot be neglected; however, these variations depend on both the strength and the direction of the EF in the EMF. This direction influences the biological effects of EMF, which decrease with increases in the angle between the direction of the EF and that of the dipole moment of amino acid residues; however, randomness at the macroscopic level remains. Lastly, we experimentally confirm the existence of a soliton and the validity of our conclusion by using the infrared spectra of absorption of the collagens, which is activated by another type of EF. Thus, we can affirm that both the described mechanism and the corresponding theory are correct and that EMFs or EFs can influence the features of energy transport in living systems and thus have certain biological effects. PMID:27463708

Influences of Electromagnetic Energy on Bio-Energy Transport through Protein Molecules in Living Systems and Its Experimental Evidence.

PubMed

Pang, Xiaofeng; Chen, Shude; Wang, Xianghui; Zhong, Lisheng

2016-07-25

The influences of electromagnetic fields (EMFs) on bio-energy transport and its mechanism of changes are investigated through analytic and numerical simulation and experimentation. Bio-energy transport along protein molecules is performed by soliton movement caused by the dipole-dipole electric interactions between neighboring amino acid residues. As such, EMFs can affect the structure of protein molecules and change the properties of the bio-energy transported in living systems. This mechanism of biological effect from EMFs involves the amino acid residues in protein molecules. To study and reveal this mechanism, we simulated numerically the features of the movement of solitons along protein molecules with both a single chain and with three channels by using the Runge-Kutta method and Pang's soliton model under the action of EMFs with the strengths of 25,500, 51,000, 76,500, and 102,000 V/m in the single-chain protein, as well as 17,000, 25,500, and 34,000 V/m in the three-chain protein, respectively. Results indicate that electric fields (EFs) depress the binding energy of the soliton, decrease its amplitude, and change its wave form. Also, the soliton disperses at 102,000 V/m in a single-chain protein and at 25,500 and 34,000 V/m in three-chain proteins. These findings signify that the influence of EMFs on the bio-energy transport cannot be neglected; however, these variations depend on both the strength and the direction of the EF in the EMF. This direction influences the biological effects of EMF, which decrease with increases in the angle between the direction of the EF and that of the dipole moment of amino acid residues; however, randomness at the macroscopic level remains. Lastly, we experimentally confirm the existence of a soliton and the validity of our conclusion by using the infrared spectra of absorption of the collagens, which is activated by another type of EF. Thus, we can affirm that both the described mechanism and the corresponding theory are correct and that EMFs or EFs can influence the features of energy transport in living systems and thus have certain biological effects.

Dioxins contamination in the feed additive (feed grade cupric sulfate) tied to chlorine industry

PubMed Central

Wang, Pu; Zhang, Qinghua; Lan, Yonghui; Xu, Shiai; Gao, Renfu; Li, Gang; Zhang, Haidong; Shang, Hongtao; Ren, Daiwei; Zhu, Chaofei; Li, Yingming; Li, Xiaomin; Jiang, Guibin

2014-01-01

The sources of polychlorinated dibenzo-p-dioxins/dibenzofurans (PCDD/Fs) found in animal feed additive (feed grade cupric sulfate, CuSO4) were investigated and traced back to the formation of chlorinated organic compounds in the chlor-alkali industry. PCDD/Fs could be transported through the supply chain: hydrochloric acid (HCl) by-produced during formation of chlorinated organic compounds in chlor-alkali industry → spent acid etching solution (acid-SES) generated in printed circuit board production → industrial cupric salt → CuSO4 in animal feed, and finally enter the food chain. The concentration ranges in HCl and acid-SES were similar, of which the level in acid-SES was also consistent with that in various cupric salt products including CuSO4 based on Cu element content. PCDD/Fs also showed very similar congener profiles in all the sample types. This indicates a probable direct transport pathway of PCDD/Fs into the food chain, which may eventually be exposed to humans through consumption. To date this is the first study in China that systematically reports on the PCDD/Fs transport from industrial pollution sources to industrial processes and finally enters the human food chain. PMID:25102073

Hybrid life-cycle assessment of natural gas based fuel chains for transportation.

PubMed

Strømman, Anders Hammer; Solli, Christian; Hertwich, Edgar G

2006-04-15

This research compares the use of natural gas, methanol, and hydrogen as transportation fuels. These three fuel chains start with the extraction and processing of natural gas in the Norwegian North Sea and end with final use in Central Europe. The end use is passenger transportation with a sub-compact car that has an internal combustion engine for the natural gas case and a fuel cell for the methanol and hydrogen cases. The life cycle assessment is performed by combining a process based life-cycle inventory with economic input-output data. The analysis shows that the potential climate impacts are lowest for the hydrogen fuel scenario with CO2 deposition. The hydrogen fuel chain scenario has no significant environmental disadvantage compared to the other fuel chains. Detailed analysis shows that the construction of the car contributes significantly to most impact categories. Finally, it is shown how the application of a hybrid inventory model ensures a more complete inventory description compared to standard process-based life-cycle assessment. This is particularly significant for car construction which would have been significantly underestimated in this study using standard process life-cycle assessment alone.

Study on transport packages used for food freshness preservation based on thermal analysis

NASA Astrophysics Data System (ADS)

Yu, Ying

2016-12-01

In recent time, as the Chinese consumption level increases, the consumption quantity of high-value fruits, vegetables and seafood products have been increasing year by year. As a consequence, the traffic volume of refrigerated products also increases yearly and the popularization degree of the cold-chain transportation enhances. A low-temperature environment should be guaranteed during transportation, thus there is about 40% of diesel oil should be consumed by the refrigerating system and the cold-chain transportation becomes very costly. This study aimed to explore methods that could reduce the cost of transport packages of refrigerated products. On the basis of the heat transfer theory and the fluid mechanics theory, the heat exchanging process of corrugated cases during the operation of refrigerating system was analyzed, the heat transfer process of corrugated cases and refrigerator van was theoretically analyzed and the heat balance equation of corrugated cases was constructed.

A model and simulation of fast space charge pulses in polymers

NASA Astrophysics Data System (ADS)

Lv, Zepeng; Rowland, Simon M.; Wu, Kai

2017-11-01

The transport of space charge packets across polyethylene and epoxy resin in high electric fields has been characterized as fast or slow depending on packet mobility. Several explanations for the formation and transport of slow space charge packets have been proposed, but the origins of fast space charge pulses, with mobilities above 10-11 m2 V-1 s-1, are unclear. In one suggested model, it is assumed that the formation of fast charge pulses is due to discontinuous electromechanical compression and charge injection at the electrode-insulation interface, and their transport is related to corresponding relaxation processes. In that model, charges travel as a pulse because of group polarization. This paper provides an alternative model based on the reduction of charge carrier activation energy due to charge density triggered polymer chain movement and subsequent chain relaxation times. The generation and transport of fast charge pulses are readily simulated by a bipolar charge transport model with three additional parameters: reduced activation energy, charge density threshold, and chain relaxation time. Such a model is shown to reproduce key features of fast space charge pulses including speed, duration, repetition rate and pulse size. This model provides the basis for a deep understanding of the physical origins of fast space charge pulses in polymers.

Quantized thermal transport in single-atom junctions

NASA Astrophysics Data System (ADS)

Cui, Longji; Jeong, Wonho; Hur, Sunghoon; Matt, Manuel; Klöckner, Jan C.; Pauly, Fabian; Nielaba, Peter; Cuevas, Juan Carlos; Meyhofer, Edgar; Reddy, Pramod

2017-03-01

Thermal transport in individual atomic junctions and chains is of great fundamental interest because of the distinctive quantum effects expected to arise in them. By using novel, custom-fabricated, picowatt-resolution calorimetric scanning probes, we measured the thermal conductance of gold and platinum metallic wires down to single-atom junctions. Our work reveals that the thermal conductance of gold single-atom junctions is quantized at room temperature and shows that the Wiedemann-Franz law relating thermal and electrical conductance is satisfied even in single-atom contacts. Furthermore, we quantitatively explain our experimental results within the Landauer framework for quantum thermal transport. The experimental techniques reported here will enable thermal transport studies in atomic and molecular chains, which will be key to investigating numerous fundamental issues that thus far have remained experimentally inaccessible.

Augmented endothelial l-arginine transport ameliorates pressure-overload-induced cardiac hypertrophy.

PubMed

Rajapakse, Niwanthi W; Johnston, Tamara; Kiriazis, Helen; Chin-Dusting, Jaye P; Du, Xiao-Jun; Kaye, David M

2015-07-01

What is the central question of this study? What is the potential role of endothelial NO production via overexpression of the l-arginine transporter, CAT1, as a mitigator of cardiac hypertrophy? What is the main finding and its importance? Augmentation of endothelium-specific l-arginine transport via CAT1 can attenuate pressure-overload-dependent cardiac hypertrophy and fibrosis. Our findings support the conclusion that interventions that improve endothelial l-arginine transport may provide therapeutic utility in the setting of myocardial hypertrophy. Such modifications may be introduced by exercise training or locally delivered gene therapy, but further experimental and clinical studies are required. Endothelial dysfunction has been postulated to play a central role in the development of cardiac hypertrophy, probably as a result of reduced NO bioavailability. We tested the hypothesis that increased endothelial NO production, mediated by increased l-arginine transport, could attenuate pressure-overload-induced cardiac hypertrophy. Echocardiography and blood pressure measurements were performed 15 weeks after transverse aortic constriction (TAC) in wild-type (WT) mice (n = 12) and in mice with endothelium-specific overexpression of the l-arginine transporter, CAT1 (CAT+; n = 12). Transverse aortic constriction induced greater increases in heart weight to body weight ratio in WT (by 47%) than CAT+ mice (by 25%) compared with the respective controls (P ≤ 0.05). Likewise, the increase in left ventricular wall thickness induced by TAC was significantly attenuated in CAT+ mice (P = 0.05). Cardiac collagen type I mRNA expression was greater in WT mice with TAC (by 22%; P = 0.03), but not in CAT+ mice with TAC, compared with the respective controls. Transverse aortic constriction also induced lesser increases in β-myosin heavy chain mRNA expression in CAT+ mice compared with WT (P ≤ 0.05). Left ventricular systolic pressure after TAC was 36 and 39% greater in WT and CAT+ mice, respectively, compared with the respective controls (P ≤ 0.001). Transverse aortic constriction had little effect on left ventricular end-diastolic pressure in both genotypes. Taken together, these data indicate that augmenting endothelial function by overexpression of l-arginine transport can attenuate pressure-overload-induced cardiac hypertrophy. © 2015 The Authors. Experimental Physiology © 2015 The Physiological Society.

Deoxyribonucleoside kinases in mitochondrial DNA depletion.

PubMed

Saada-Reisch, Ann

2004-10-01

Mitochondrial DNA (mtDNA) depletion syndromes (MDS) are a heterogeneous group of mitochondrial disorders, manifested by a decreased mtDNA copy number and respiratory chain dysfunction. Primary MDS are inherited autosomally and may affect a single organ or multiple tissues. Mutated mitochondrial deoxyribonucleoside kinases; deoxyguanosine kinase (dGK) and thymidine kinase 2 (TK2), were associated with the hepatocerebral and myopathic forms of MDS respectively. dGK and TK2 are key enzymes in the mitochondrial nucleotide salvage pathway, providing the mitochondria with deoxyribonucleotides (dNP) essential for mtDNA synthesis. Although the mitochondrial dNP pool is physically separated from the cytosolic one, dNP's may still be imported through specific transport. Non-replicating tissues, where cytosolic dNP supply is down regulated, are thus particularly vulnerable to dGK and TK2 deficiency. The overlapping substrate specificity of deoxycytidine kinase (dCK) may explain the relative sparing of muscle in dGK deficiency, while low basal TK2 activity render this tissue susceptible to TK2 deficiency. The precise pathophysiological mechanisms of mtDNA depletion due to dGK and TK2 deficiencies remain to be determined, though recent findings confirm that it is attributed to imbalanced dNTP pools.

Peroxisome proliferator activator receptor gamma coactivator-1alpha (PGC-1α) improves motor performance and survival in a mouse model of amyotrophic lateral sclerosis

PubMed Central

2011-01-01

Background Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease that affects spinal cord and cortical motor neurons. An increasing amount of evidence suggests that mitochondrial dysfunction contributes to motor neuron death in ALS. Peroxisome proliferator-activated receptor gamma co-activator-1α (PGC-1α) is a principal regulator of mitochondrial biogenesis and oxidative metabolism. Results In this study, we examined whether PGC-1α plays a protective role in ALS by using a double transgenic mouse model where PGC-1α is over-expressed in an SOD1 transgenic mouse (TgSOD1-G93A/PGC-1α). Our results indicate that PGC-1α significantly improves motor function and survival of SOD1-G93A mice. The behavioral improvements were accompanied by reduced blood glucose level and by protection of motor neuron loss, restoration of mitochondrial electron transport chain activities and inhibition of stress signaling in the spinal cord. Conclusion Our results demonstrate that PGC-1α plays a beneficial role in a mouse model of ALS, suggesting that PGC-1α may be a potential therapeutic target for ALS therapy. PMID:21771318

Phellinus rimosus improves mitochondrial energy status and attenuates nephrotoxicity in diabetic rats.

PubMed

Rony, K A; Ajith, T A; Kuttikadan, Tony A; Blaze, R; Janardhanan, K K

2017-09-26

Mitochondrial dysfunction and increase in reactive oxygen species during diabetes can lead to pathological consequences in kidneys. The present study was aimed to investigate the effect of Phellinus rimosus in the streptozotocin (STZ)-induced diabetic rat renal mitochondria and the possible mechanism of protection. Phellinus rimosus (50 and 250 mg/kg, p.o) was treated after inducing diabetes by STZ (45 mg/kg, i.p) in rats. The serum samples were subjected to creatinine and urea estimation. Mitochondrial antioxidant status such as mitochondrial superoxide dismutase, glutathione peroxidase, and reduced glutathione; adenosine triphosphate level; and lipid peroxidation were measured. The activities of Krebs cycle enzymes such as isocitrate dehydrogenase, α-ketoglutarate dehydrogenase, succinate dehydrogenase, and malate dehydrogenase as well as mitochondrial complexes I, III, and IV in kidney mitochondria were also determined. Administration of P. rimosus (250 mg/kg b.wt) once daily for 30 days, significantly (p<0.05) enhanced the activities of Krebs cycle dehydrogenases, mitochondrial electron transport chain complexes, and ATP level. Further, P. rimosus had significantly protected the renal mitochondrial antioxidant status and lipid peroxidation. The results of the study concluded that by limiting the extent of renal mitochondrial damage in the hyperglycemic state, P. rimosus alleviated nephrotoxicity.

The mitochondria-targeted antioxidant MitoQ extends lifespan and improves healthspan of a transgenic Caenorhabditis elegans model of Alzheimer disease.

PubMed

Ng, Li Fang; Gruber, Jan; Cheah, Irwin K; Goo, Chong Kit; Cheong, Wei Fun; Shui, Guanghou; Sit, Kim Ping; Wenk, Markus R; Halliwell, Barry

2014-06-01

β-Amyloid (Aβ)-induced toxicity and oxidative stress have been postulated to play critical roles in the pathogenic mechanism of Alzheimer disease (AD). We investigated the in vivo ability of a mitochondria-targeted antioxidant, MitoQ, to protect against Aβ-induced toxicity and oxidative stress in a Caenorhabditis elegans model overexpressing human Aβ. Impairment of electron transport chain (ETC) enzymatic activity and mitochondrial dysfunction are early features of AD. We show that MitoQ extends lifespan, delays Aβ-induced paralysis, ameliorates depletion of the mitochondrial lipid cardiolipin, and protects complexes IV and I of the ETC. Despite its protective effects on lifespan, healthspan, and ETC function, we find that MitoQ does not reduce DCFDA fluorescence, protein carbonyl levels or modulate steadystate ATP levels or oxygen consumption rate. Moreover, MitoQ does not attenuate mitochondrial DNA (mtDNA) oxidative damage. In agreement with its design, the protective effects of MitoQ appear to be targeted specifically to the mitochondrial membrane and our findings suggest that MitoQ may have therapeutic potential for Aβ- and oxidative stress-associated neurodegenerative disorders, particularly AD. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Mitochondrial DNA sequence data reveals association of haplogroup U with psychosis in bipolar disorder.

PubMed

Frye, Mark A; Ryu, Euijung; Nassan, Malik; Jenkins, Gregory D; Andreazza, Ana C; Evans, Jared M; McElroy, Susan L; Oglesbee, Devin; Highsmith, W Edward; Biernacka, Joanna M

2017-01-01

Converging genetic, postmortem gene-expression, cellular, and neuroimaging data implicate mitochondrial dysfunction in bipolar disorder. This study was conducted to investigate whether mitochondrial DNA (mtDNA) haplogroups and single nucleotide variants (SNVs) are associated with sub-phenotypes of bipolar disorder. MtDNA from 224 patients with Bipolar I disorder (BPI) was sequenced, and association of sequence variations with 3 sub-phenotypes (psychosis, rapid cycling, and adolescent illness onset) was evaluated. Gene-level tests were performed to evaluate overall burden of minor alleles for each phenotype. The haplogroup U was associated with a higher risk of psychosis. Secondary analyses of SNVs provided nominal evidence for association of psychosis with variants in the tRNA, ND4 and ND5 genes. The association of psychosis with ND4 (gene that encodes NADH dehydrogenase 4) was further supported by gene-level analysis. Preliminary analysis of mtDNA sequence data suggests a higher risk of psychosis with the U haplogroup and variation in the ND4 gene implicated in electron transport chain energy regulation. Further investigation of the functional consequences of this mtDNA variation is encouraged. Copyright © 2016. Published by Elsevier Ltd.

Overexpression of DNA ligase III in mitochondria protects cells against oxidative stress and improves mitochondrial DNA base excision repair.

PubMed

Akbari, Mansour; Keijzers, Guido; Maynard, Scott; Scheibye-Knudsen, Morten; Desler, Claus; Hickson, Ian D; Bohr, Vilhelm A

2014-04-01

Base excision repair (BER) is the most prominent DNA repair pathway in human mitochondria. BER also results in a temporary generation of AP-sites, single-strand breaks and nucleotide gaps. Thus, incomplete BER can result in the generation of DNA repair intermediates that can disrupt mitochondrial DNA replication and transcription and generate mutations. We carried out BER analysis in highly purified mitochondrial extracts from human cell lines U2OS and HeLa, and mouse brain using a circular DNA substrate containing a lesion at a specific position. We found that DNA ligation is significantly slower than the preceding mitochondrial BER steps. Overexpression of DNA ligase III in mitochondria improved the rate of overall BER, increased cell survival after menadione induced oxidative stress and reduced autophagy following the inhibition of the mitochondrial electron transport chain complex I by rotenone. Our results suggest that the amount of DNA ligase III in mitochondria may be critical for cell survival following prolonged oxidative stress, and demonstrate a functional link between mitochondrial DNA damage and repair, cell survival upon oxidative stress, and removal of dysfunctional mitochondria by autophagy. Copyright © 2014. Published by Elsevier B.V.

Protonic transport through solitons in hydrogen-bonded systems

NASA Astrophysics Data System (ADS)

Kavitha, L.; Jayanthi, S.; Muniyappan, A.; Gopi, D.

2011-09-01

We offer an alternative route for investigating soliton solutions in hydrogen-bonded (HB) chains. We invoke the modified extended tangent hyperbolic function method coupled with symbolic computation to solve the governing equation of motion for proton dynamics. We investigate the dynamics of proton transfer in HB chains through bell-shaped soliton excitations, which trigger the bio-energy transport in most biological systems. This solitonic mechanism of proton transfer could play functional roles in muscular contraction, enzymatic activity and oxidative phosphorylation.

Analysis of the LIV System of Campylobacter jejuni Reveals Alternative Roles for LivJ and LivK in Commensalism beyond Branched-Chain Amino Acid Transport ▿

PubMed Central

Ribardo, Deborah A.; Hendrixson, David R.

2011-01-01

Campylobacter jejuni is a leading cause of diarrheal disease in humans and an intestinal commensal in poultry and other agriculturally important animals. These zoonotic infections result in significant amounts of C. jejuni present in the food supply to contribute to disease in humans. We previously found that a transposon insertion in Cjj81176_1038, encoding a homolog of the Escherichia coli LivJ periplasmic binding protein of the leucine, isoleucine, and valine (LIV) branched-chain amino acid transport system, reduced the commensal colonization capacity of C. jejuni 81-176 in chicks. Cjj81176_1038 is the first gene of a six-gene locus that encodes homologous components of the E. coli LIV system. By analyzing mutants with in-frame deletions of individual genes or pairs of genes, we found that this system constitutes a LIV transport system in C. jejuni responsible for a high level of leucine acquisition and, to a lesser extent, isoleucine and valine acquisition. Despite each LIV protein being required for branched-chain amino acid transport, only the LivJ and LivK periplasmic binding proteins were required for wild-type levels of commensal colonization of chicks. All LIV permease and ATPase components were dispensable for in vivo growth. These results suggest that the biological functions of LivJ and LivK for colonization are more complex than previously hypothesized and extend beyond a role for binding and acquiring branched-chain amino acids during commensalism. In contrast to other studies indicating a requirement and utilization of other specific amino acids for colonization, acquisition of branched-chain amino acids does not appear to be a determinant for C. jejuni during commensalism. PMID:21949065

Next Generation Waste Tracking: Linking Legacy Systems with Modern Networking Technologies

DOE Office of Scientific and Technical Information (OSTI.GOV)

Walker, Randy M.; Resseguie, David R.; Shankar, Mallikarjun

2010-01-01

This report describes results from a preliminary analysis to satisfy the Department of Energy (DOE) objective to ensure the safe, secure, efficient packaging and transportation of materials both hazardous and non hazardous [1, 2]. The DOE Office of Environmental Management (OEM) through Oak Ridge National Laboratory (ORNL) has embarked on a project to further this objective. OEM and ORNL have agreed to develop, demonstrate and make available modern day cost effective technologies for characterization, identification, tracking, monitoring and disposal of radioactive waste when transported by, or between, motor, air, rail, and water modes. During the past 8 years ORNL hasmore » investigated and deployed Web 2.0 compliant sensors into the transportation segment of the supply chain. ORNL has recently demonstrated operational experience with DOE Oak Ridge Operations Office (ORO) and others in national test beds and applications within this domain of the supply chain. Furthermore, in addition to DOE, these hazardous materials supply chain partners included Federal and State enforcement agencies, international ports, and commercial sector shipping operations in a hazardous/radioactive materials tracking and monitoring program called IntelligentFreight. IntelligentFreight is an ORNL initiative encompassing 5 years of research effort associated with the supply chain. The ongoing ORNL SmartFreight programs include RadSTraM [3], GRadSTraM , Trusted Corridors, SensorPedia [4], SensorNet, Southeastern Transportation Corridor Pilot (SETCP) and Trade Data Exchange [5]. The integration of multiple technologies aimed at safer more secure conveyance has been investigated with the core research question being focused on testing distinctly different distributed supply chain information sharing systems. ORNL with support from ORO have demonstrated capabilities when transporting Environmental Management (EM) waste materials for disposal over an onsite haul road. ORNL has unified the operations of existing legacy hazardous, radioactive and related informational databases and systems using emerging Web 2.0 technologies. These capabilities were used to interoperate ORNL s waste generating, packaging, transportation and disposal with other DOE ORO waste management contractors. Importantly, the DOE EM objectives were accomplished in a cost effective manner without altering existing information systems. A path forward is to demonstrate and share these technologies with DOE EM, contractors and stakeholders. This approach will not alter existing DOE assets, i.e. Automated Traffic Management Systems (ATMS), Transportation Tracking and Communications System (TRANSCOM), the Argonne National Laboratory (ANL) demonstrated package tracking system, etc« less

TMEM16A Contributes to Endothelial Dysfunction by Facilitating Nox2 NADPH Oxidase-Derived Reactive Oxygen Species Generation in Hypertension.

PubMed

Ma, Ming-Ming; Gao, Min; Guo, Kai-Min; Wang, Mi; Li, Xiang-Yu; Zeng, Xue-Lin; Sun, Lu; Lv, Xiao-Fei; Du, Yan-Hua; Wang, Guan-Lei; Zhou, Jia-Guo; Guan, Yong-Yuan

2017-05-01

Ca 2+ -activated Cl - channels play a crucial role in various physiological processes. However, the role of TMEM16A in vascular endothelial dysfunction during hypertension is unclear. In this study, we investigated the specific involvement of TMEM16A in regulating endothelial function and blood pressure and the underlying mechanism. Reverse transcription-polymerase chain reaction, Western blotting, coimmunoprecipitation, confocal imaging, patch-clamp recordings, and TMEM16A endothelial-specific transgenic and knockout mice were used. We found that TMEM16A was expressed abundantly and functioned as a Ca 2+ -activated Cl - channel in endothelial cells. Angiotensin II induced endothelial dysfunction with an increase in TMEM16A expression. The knockout of endothelial-specific TMEM16A significantly lowered the blood pressure and ameliorated endothelial dysfunction in angiotensin II-induced hypertension, whereas the overexpression of endothelial-specific TMEM16A resulted in the opposite effects. These results were related to the increased reactive oxygen species production, Nox2-containing NADPH oxidase activation, and Nox2 and p22phox protein expression that were facilitated by TMEM16A on angiotensin II-induced hypertensive challenge. Moreover, TMEM16A directly bound with Nox2 and reduced the degradation of Nox2 through the proteasome-dependent degradation pathway. Therefore, TMEM16A is a positive regulator of endothelial reactive oxygen species generation via Nox2-containing NADPH oxidase, which induces endothelial dysfunction and hypertension. Modification of TMEM16A may be a novel therapeutic strategy for endothelial dysfunction-associated diseases. © 2017 American Heart Association, Inc.

The STRONG STAR Multidisciplinary PTSD Research Consortium

DTIC Science & Technology

2009-09-01

superior A.5 Role of the Serotonin Transporter and Serotonergic Hypotheses related to Alcoholism Vulnerability Due to Low Serotonin. Strong...evidence shows that the biological vulnerability of EOA patients may be related to a serotonergic dysfunction (Johnson, 2000; Johnson and Ait-Daoud...transporter (Johnson et al., 2008). These findings of reduced serotonergic functioning in L-carriers is contrary to previous data indicating that the L

The Outward Spiral: A vicious cycle model of obesity and cognitive dysfunction.

PubMed

Hargrave, Sara L; Jones, Sabrina; Davidson, Terry L

2016-06-01

Chronic failure to suppress intake during states of positive energy balance leads to weight gain and obesity. The ability to use context - including interoceptive satiety states - to inhibit responding to previously rewarded cues appears to depend on the functional integrity of the hippocampus. Recent evidence implicates energy dense Western diets in several types of hippocampal dysfunction, including reduced expression of neurotrophins and nutrient transporters, increased inflammation, microglial activation, and blood brain barrier permeability. The functional consequences of such insults include impairments in an animal's ability to modulate responding to a previously reinforced cues. We propose that such deficits promote overeating, which can further exacerbate hippocampal dysfunction and thus initiate a vicious cycle of both obesity and progressive cognitive decline.

Bicarbonate transport in health and disease.

PubMed

Alka, Kumari; Casey, Joseph R

2014-09-01

Bicarbonate (HCO3(-)) has a central place in human physiology as the waste product of mitochondrial energy production and for its role in pH buffering throughout the body. Because bicarbonate is impermeable to membranes, bicarbonate transport proteins are necessary to enable control of bicarbonate levels across membranes. In humans, 14 bicarbonate transport proteins, members of the SLC4 and SLC26 families, function by differing transport mechanisms. In addition, some anion channels and ZIP metal transporters contribute to bicarbonate movement across membranes. Defective bicarbonate transport leads to diseases, including systemic acidosis, brain dysfunction, kidney stones, and hypertension. Altered expression levels of bicarbonate transporters in patients with breast, colon, and lung cancer suggest an important role of these transporters in cancer. © 2014 International Union of Biochemistry and Molecular Biology.

Analyzing the impact of carbon regulatory mechanisms on supply chain management.

DOT National Transportation Integrated Search

2014-07-01

The objective of this research is developing a toolset for designing and managing cost : efficient and environmentally friendly supply chains for perishable products. : The models we propose minimize transportation and inventory holding costs in the ...

Mutation of EpCAM leads to intestinal barrier and ion transport dysfunction.

PubMed

Kozan, Philip A; McGeough, Matthew D; Peña, Carla A; Mueller, James L; Barrett, Kim E; Marchelletta, Ronald R; Sivagnanam, Mamata

2015-05-01

Congenital tufting enteropathy (CTE) is a devastating diarrheal disease seen in infancy that is typically associated with villous changes and the appearance of epithelial tufts. We previously found mutations in epithelial cell adhesion molecule (EpCAM) to be causative in CTE. We developed a knock-down cell model of CTE through transfection of an EpCAM shRNA construct into T84 colonic epithelial cells to elucidate the in vitro role of EpCAM in barrier function and ion transport. Cells with EpCAM deficiency exhibited decreased electrical resistance, increased permeability, and decreased ion transport. Based on mutations in CTE patients, an in vivo mouse model was developed, with tamoxifen-inducible deletion of exon 4 in Epcam resulting in mutant protein with decreased expression. Tamoxifen treatment of Epcam (Δ4/Δ4) mice resulted in pathological features of villous atrophy and epithelial tufts, similar to those in human CTE patients, within 4 days post induction. Epcam (Δ4/Δ4) mice also showed decreased expression of tight junctional proteins, increased permeability, and decreased ion transport in the intestines. Taken together, these findings reveal mechanisms that may underlie disease in CTE. Knock-down EpCAM cell model of congenital tufting enteropathy was developed. In vivo inducible mouse model was developed resulting in mutant EpCAM protein. Cells with EpCAM deficiency demonstrated barrier and ion transport dysfunction. Tamoxifen-treated Epcam (Δ4/Δ4) mice demonstrated pathological features. Epcam (Δ4/Δ4) mice showed improper barrier function and ion transport.

Urtica dioica extract attenuates depressive like behavior and associative memory dysfunction in dexamethasone induced diabetic mice.

PubMed

Patel, Sita Sharan; Udayabanu, Malairaman

2014-03-01

Evidences suggest that glucocorticoids results in depression and is a risk factor for type 2 diabetes. Further diabetes induces oxidative stress and hippocampal dysfunction resulting in cognitive decline. Traditionally Urtica dioica has been used for diabetes mellitus and cognitive dysfunction. The present study investigated the effect of the hydroalcoholic extract of Urtica dioica leaves (50 and 100 mg/kg, p.o.) in dexamethasone (1 mg/kg, i.m.) induced diabetes and its associated complications such as depressive like behavior and cognitive dysfunction. We observed that mice administered with chronic dexamethasone resulted in hypercortisolemia, oxidative stress, depressive like behavior, cognitive impairment, hyperglycemia with reduced body weight, increased water intake and decreased hippocampal glucose transporter-4 (GLUT4) mRNA expression. Urtica dioica significantly reduced hyperglycemia, plasma corticosterone, oxidative stress and depressive like behavior as well as improved associative memory and hippocampal GLUT4 mRNA expression comparable to rosiglitazone (5 mg/kg, p.o.). Further, Urtica dioica insignificantly improved spatial memory and serum insulin. In conclusion, Urtica dioica reversed dexamethasone induced hyperglycemia and its associated complications such as depressive like behavior and cognitive dysfunction.

Muscle biopsies from human muscle diseases with myopathic pathology reveal common alterations in mitochondrial function.

PubMed

Sunitha, Balaraju; Gayathri, Narayanappa; Kumar, Manish; Keshava Prasad, Thottethodi Subrahmanya; Nalini, Atchayaram; Padmanabhan, Balasundaram; Srinivas Bharath, Muchukunte Mukunda

2016-07-01

Muscle diseases are clinically and genetically heterogeneous and manifest as dystrophic, inflammatory and myopathic pathologies, among others. Our previous study on the cardiotoxin mouse model of myodegeneration and inflammation linked muscle pathology with mitochondrial damage and oxidative stress. In this study, we investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from muscle disease patients, represented by dysferlinopathy (dysfy) (dystrophic pathology; n = 43), polymyositis (PM) (inflammatory pathology; n = 24), and distal myopathy with rimmed vacuoles (DMRV) (distal myopathy; n = 31) were analyzed. Mitochondrial damage (ragged blue and COX-deficient fibers) was revealed in dysfy, PM, and DMRV cases by enzyme histochemistry (SDH and COX-SDH), electron microscopy (vacuolation and altered cristae) and biochemical assays (significantly increased ADP/ATP ratio). Proteomic analysis of muscle mitochondria from all three muscle diseases by isobaric tag for relative and absolute quantitation labeling and liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis demonstrated down-regulation of electron transport chain (ETC) complex subunits, assembly factors and Krebs cycle enzymes. Interestingly, 80 of the under-expressed proteins were common among the three pathologies. Assay of ETC and Krebs cycle enzyme activities validated the MS data. Mitochondrial proteins from muscle pathologies also displayed higher tryptophan (Trp) oxidation and the same was corroborated in the cardiotoxin model. Molecular modeling predicted Trp oxidation to alter the local structure of mitochondrial proteins. Our data highlight mitochondrial alterations in muscle pathologies, represented by morphological changes, altered mitochondrial proteome and protein oxidation, thereby establishing the role of mitochondrial damage in human muscle diseases. We investigated whether human muscle diseases display mitochondrial changes. Muscle biopsies from dysferlinopathy (Dysfy), polymyositis (PM), and distal myopathy with rimmed vacuoles (DMRV) displayed morphological and biochemical evidences of mitochondrial dysfunction. Proteomic analysis revealed down-regulation of electron transport chain (ETC) subunits, assembly factors, and tricarboxylic acid (TCA) cycle enzymes, with 80 proteins common among the three pathologies. Mitochondrial proteins from muscle pathologies also displayed higher Trp oxidation that could alter the local structure. Cover image for this issue: doi: 10.1111/jnc.13324. © 2016 International Society for Neurochemistry.

Tuning the thermal conductivity of solar cell polymers through side chain engineering.

PubMed

Guo, Zhi; Lee, Doyun; Liu, Yi; Sun, Fangyuan; Sliwinski, Anna; Gao, Haifeng; Burns, Peter C; Huang, Libai; Luo, Tengfei

2014-05-07

Thermal transport is critical to the performance and reliability of polymer-based energy devices, ranging from solar cells to thermoelectrics. This work shows that the thermal conductivity of a low band gap conjugated polymer, poly(4,8-bis-alkyloxybenzo[1,2-b:4,5-b']dithiophene-2,6-diyl-alt-(alkylthieno[3,4-b]thiophene-2-carboxylate)-2,6-diyl) (PBDTTT), for photovoltaic applications can be actively tuned through side chain engineering. Compared to the original polymer modified with short branched side chains, the engineered polymer using all linear and long side chains shows a 160% increase in thermal conductivity. The thermal conductivity of the polymer exhibits a good correlation with the side chain lengths as well as the crystallinity of the polymer characterized using small-angle X-ray scattering (SAXS) experiments. Molecular dynamics simulations and atomic force microscopy are used to further probe the molecular level local order of different polymers. It is found that the linear side chain modified polymer can facilitate the formation of more ordered structures, as compared to the branched side chain modified ones. The effective medium theory modelling also reveals that the long linear side chain enables a larger heat carrier propagation length and the crystalline phase in the bulk polymer increases the overall thermal conductivity. It is concluded that both the length of the side chains and the induced polymer crystallization are important for thermal transport. These results offer important guidance for actively tuning the thermal conductivity of conjugated polymers through molecular level design.

Heptachlor induced mitochondria-mediated cell death via impairing electron transport chain complex III

DOE Office of Scientific and Technical Information (OSTI.GOV)

Hong, Seokheon; Kim, Joo Yeon; Hwang, Joohyun

Highlights: •Heptachlor inhibited mitochondrial electron transport chain complex III activity. •Heptachlor promoted generation of reactive oxygen species. •Heptachlor induced Bax activation. •Heptachlor induced mitochondria-mediated and caspase-dependent apoptosis. -- Abstract: Environmental toxins like pesticides have been implicated in the pathogenesis of Parkinson’s disease (PD). Epidemiological studies suggested that exposures to organochlorine pesticides have an association with an increased PD risk. In the present study, we examined the mechanism of toxicity induced by an organochlorine pesticide heptachlor. In a human dopaminergic neuroblastoma SH-SY5Y cells, heptachlor induced both morphological and functional damages in mitochondria. Interestingly, the compound inhibited mitochondrial electron transport chain complexmore » III activity. Rapid generation of reactive oxygen species and the activation of Bax were then detected. Subsequently, mitochondria-mediated, caspase-dependent apoptosis followed. Our results raise a possibility that an organochlorine pesticide heptachlor can act as a neurotoxicant associated with PD.« less

Life cycle cost optimization of biofuel supply chains under uncertainties based on interval linear programming.

PubMed

Ren, Jingzheng; Dong, Liang; Sun, Lu; Goodsite, Michael Evan; Tan, Shiyu; Dong, Lichun

2015-01-01

The aim of this work was to develop a model for optimizing the life cycle cost of biofuel supply chain under uncertainties. Multiple agriculture zones, multiple transportation modes for the transport of grain and biofuel, multiple biofuel plants, and multiple market centers were considered in this model, and the price of the resources, the yield of grain and the market demands were regarded as interval numbers instead of constants. An interval linear programming was developed, and a method for solving interval linear programming was presented. An illustrative case was studied by the proposed model, and the results showed that the proposed model is feasible for designing biofuel supply chain under uncertainties. Copyright © 2015 Elsevier Ltd. All rights reserved.

Human amyloidogenic light chain proteins result in cardiac dysfunction, cell death, and early mortality in zebrafish.

PubMed

Mishra, Shikha; Guan, Jian; Plovie, Eva; Seldin, David C; Connors, Lawreen H; Merlini, Giampaolo; Falk, Rodney H; MacRae, Calum A; Liao, Ronglih

2013-07-01

Systemic amyloid light-chain (AL) amyloidosis is associated with rapidly progressive and fatal cardiomyopathy resulting from the direct cardiotoxic effects of circulating AL light chain (AL-LC) proteins and the indirect effects of AL fibril tissue infiltration. Cardiac amyloidosis is resistant to standard heart failure therapies, and, to date, there are limited treatment options for these patients. The mechanisms underlying the development of cardiac amyloidosis and AL-LC cardiotoxicity are largely unknown, and their study has been limited by the lack of a suitable in vivo model system. Here, we establish an in vivo zebrafish model of human AL-LC-induced cardiotoxicity. AL-LC isolated from AL cardiomyopathy patients or control nonamyloidogenic LC protein isolated from multiple myeloma patients (Con-LC) was directly injected into the circulation of zebrafish at 48 h postfertilization. AL-LC injection resulted in impaired cardiac function, pericardial edema, and increased cell death relative to Con-LC, culminating in compromised survival with 100% mortality within 2 wk, independent of AL fibril deposition. Prior work has implicated noncanonical p38 MAPK activation in the pathogenesis of AL-LC-induced cardiotoxicity, and p38 MAPK inhibition via SB-203580 rescued AL-LC-induced cardiac dysfunction and cell death and attenuated mortality in zebrafish. This in vivo zebrafish model of AL-LC cardiotoxicity demonstrates that antagonism of p38 MAPK within the AL-LC cardiotoxic signaling response may serve to improve cardiac function and mortality in AL cardiomyopathy. Furthermore, this in vivo model system will allow for further study of the molecular underpinnings of AL cardiotoxicity and identification of novel therapeutic strategies.

Transport of a decay chain in homogenous porous media: analytical solutions.

PubMed

Bauer, P; Attinger, S; Kinzelbach, W

2001-06-01

With the aid of integral transforms, analytical solutions for the transport of a decay chain in homogenous porous media are derived. Unidirectional steady-state flow and radial steady-state flow in single and multiple porosity media are considered. At least in Laplace domain, all solutions can be written in closed analytical formulae. Partly, the solutions can also be inverted analytically. If not, analytical calculation of the steady-state concentration distributions, evaluation of temporal moments and numerical inversion are still possible. Formulae for several simple boundary conditions are given and visualized in this paper. The derived novel solutions are widely applicable and are very useful for the validation of numerical transport codes.

Lack of association of the serotonin transporter polymorphism with the sudden infant death syndrome in the San Diego Dataset.

PubMed

Paterson, David S; Rivera, Keith D; Broadbelt, Kevin G; Trachtenberg, Felicia L; Belliveau, Richard A; Holm, Ingrid A; Haas, Elisabeth A; Stanley, Christina; Krous, Henry F; Kinney, Hannah C; Markianos, Kyriacos

2010-11-01

Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS.

Lack of Association of the Serotonin Transporter Polymorphism With the Sudden Infant Death Syndrome in the San Diego Dataset

PubMed Central

Paterson, David S.; Rivera, Keith D.; Broadbelt, Kevin G.; Trachtenberg, Felicia L.; Belliveau, Richard A.; Holm, Ingrid A.; Haas, Elisabeth A.; Stanley, Christina; Krous, Henry F.; Kinney, Hannah C.; Markianos, Kyriacos

2011-01-01

Dysfunction of medullary serotonin (5-HT)-mediated respiratory and autonomic function is postulated to underlie the pathogenesis of the majority of sudden infant death syndrome (SIDS) cases. Several studies have reported an increased frequency of the LL genotype and L allele of the 5-HT transporter (5-HTT) gene promoter polymorphism (5-HTTLPR), which is associated with increased transcriptional activity and 5-HT transport in vitro, in SIDS cases compared with controls. These findings raise the possibility that this polymorphism contributes to or exacerbates existing medullary 5-HT dysfunction in SIDS. In this study, we tested the hypothesis that the frequency of LL genotype and L allele are higher in 179 SIDS cases compared with 139 controls of multiple ethnicities in the San Diego SIDS Dataset. We observed no significant association of genotype or allele with SIDS cases either in the total cohort or on stratification for ethnicity. These observations do not support previous findings that the L allele and/or LL genotype of the 5-HTTLPR are associated with SIDS. PMID:20661167

Photon transport in a dissipative chain of nonlinear cavities

NASA Astrophysics Data System (ADS)

Biella, Alberto; Mazza, Leonardo; Carusotto, Iacopo; Rossini, Davide; Fazio, Rosario

2015-05-01

By means of numerical simulations and the input-output formalism, we study photon transport through a chain of coupled nonlinear optical cavities subject to uniform dissipation. Photons are injected from one end of the chain by means of a coherent source. The propagation through the array of cavities is sensitive to the interplay between the photon hopping strength and the local nonlinearity in each cavity. We characterize photon transport by studying the populations and the photon correlations as a function of the cavity position. When complemented with input-output theory, these quantities provide direct information about photon transmission through the system. The position of single-photon and multiphoton resonances directly reflects the structure of the many-body energy levels. This shows how a study of transport along a coupled cavity array can provide rich information about the strongly correlated (many-body) states of light even in presence of dissipation. The numerical algorithm we use, based on the time-evolving block decimation scheme adapted to mixed states, allows us to simulate large arrays (up to 60 cavities). The scaling of photon transmission with the number of cavities does depend on the structure of the many-body photon states inside the array.

Tunable heat conduction through coupled Fermi-Pasta-Ulam chains

NASA Astrophysics Data System (ADS)

Su, Ruixia; Yuan, Zongqiang; Wang, Jun; Zheng, Zhigang

2015-01-01

We conduct a study on heat conduction through coupled Fermi-Pasta-Ulam (FPU) chains by using classical molecular dynamics simulations. Our attention is dedicated to showing how the phonon transport is affected by the interchain coupling. It has been well accepted that the heat conduction could be impeded by the interchain interaction due to the interface phonon scattering. However, recent theoretical and experimental studies suggest that the thermal conductivity of nanoscale materials can be counterintuitively enhanced by the interaction with the substrate. In the present paper, by consecutively varying the interchain coupling intensity, we observed both enhancement and suppression of thermal transport through the coupled FPU chains. For weak interchain couplings, it is found that the heat flux increases with the coupling intensity, whereas in the case of strong interchain couplings, the energy transport is found to be suppressed by the interchain interaction. Based on the phonon spectral energy density method, we attribute the enhancement of the energy transport to the excited phonon modes (in addition to the intrinsic phonon modes), while the upward shift of the high-frequency phonon branch and the interface phonon-phonon scattering account for the suppressed heat conduction.

Overexpression of human fatty acid transport protein 2/very long chain acyl-CoA synthetase 1 (FATP2/Acsvl1) reveals distinct patterns of trafficking of exogenous fatty acids

DOE Office of Scientific and Technical Information (OSTI.GOV)

Melton, Elaina M.; Center for Cardiovascular Sciences, Albany Medical College, Albany, NY; Cerny, Ronald L.

Highlights: •Roles of FATP2 in fatty acid transport/activation contribute to lipid homeostasis. •Use of 13C- and D-labeled fatty acids provide novel insights into FATP2 function. •FATP2-dependent trafficking of FA into phospholipids results in distinctive profiles. •FATP2 functions in the transport and activation pathways for exogenous fatty acids. -- Abstract: In mammals, the fatty acid transport proteins (FATP1 through FATP6) are members of a highly conserved family of proteins, which function in fatty acid transport proceeding through vectorial acylation and in the activation of very long chain fatty acids, branched chain fatty acids and secondary bile acids. FATP1, 2 and 4,more » for example directly function in fatty acid transport and very long chain fatty acids activation while FATP5 does not function in fatty acid transport but activates secondary bile acids. In the present work, we have used stable isotopically labeled fatty acids differing in carbon length and saturation in cells expressing FATP2 to gain further insights into how this protein functions in fatty acid transport and intracellular fatty acid trafficking. Our previous studies showed the expression of FATP2 modestly increased C16:0-CoA and C20:4-CoA and significantly increased C18:3-CoA and C22:6-CoA after 4 h. The increases in C16:0-CoA and C18:3-CoA suggest FATP2 must necessarily partner with a long chain acyl CoA synthetase (Acsl) to generate C16:0-CoA and C18:3-CoA through vectorial acylation. The very long chain acyl CoA synthetase activity of FATP2 is consistent in the generation of C20:4-CoA and C22:6-CoA coincident with transport from their respective exogenous fatty acids. The trafficking of exogenous fatty acids into phosphatidic acid (PA) and into the major classes of phospholipids (phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidylinositol (PI), and phosphatidyserine (PS)) resulted in distinctive profiles, which changed with the expression of FATP2. The trafficking of exogenous C16:0 and C22:6 into PA was significant where there was 6.9- and 5.3-fold increased incorporation, respectively, over the control; C18:3 and C20:4 also trended to increase in the PA pool while there were no changes for C18:1 and C18:2. The trafficking of C18:3 into PC and PI trended higher and approached significance. In the case of C20:4, expression of FATP2 resulted in increases in all four classes of phospholipid, indicating little selectivity. In the case of C22:6, there were significant increases of this exogenous fatty acids being trafficking into PC and PI. Collectively, these data support the conclusion that FATP2 has a dual function in the pathways linking the transport and activation of exogenous fatty acids. We discuss the differential roles of FATP2 and its role in both fatty acid transport and fatty acid activation in the context of lipid homeostasis.« less

Ligncellulosic feedstock supply systems with intermodal and overseas transportation

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ric Hoefnagels; Kara Cafferty; Erin Searcy

2014-12-01

With growing demand for biomass from industrial uses and international trade, the logistic operations required to economically move the biomass from the field or forest to the end users have become increasingly complex. In addition to economics, understanding energy and GHG emissions is required to design cost effective, sustainable logistic process operations; in order to improve international supply chains it is also important to understate their interdependencies and related uncertainties. This article presents an approach to assess lignocellulosic feedstock supply systems at the operational level. For this purpose, the Biomass Logistic Model (BLM) has been linked with the Geographic Informationmore » Systems based Biomass Intermodal Transportation model (BIT-UU) and extended with inter-continental transport routes. Case studies of herbaceous and woody biomass, produced in the U.S. Midwest and U.S. Southeast, respectively, and shipped to Europe for conversion to Fischer-Tropsch (FT) diesel are included to demonstrate how intermodal transportation and, in particular, overseas shipping integrates with the bioenergy supply chains. For the cases demonstrated, biomass can be supplied at 99 € Mg-1 to 117 € Mg-1 (dry) and converted to FT-diesel at 19 € GJ-1 to 24 € GJ-1 depending on the feedstock type and location, intermediate (chips or pellets) and size of the FT-diesel production plant. With the flexibility to change the design of supply chains as well as input variables, many alternative supply chain cases can be assessed.« less

Medium-chain triglycerides promote macrophage reverse cholesterol transport and improve atherosclerosis in ApoE-deficient mice fed a high-fat diet.

PubMed

Zhang, Xinsheng; Zhang, Yong; Liu, Yinghua; Wang, Jin; Xu, Qing; Yu, Xiaoming; Yang, Xueyan; Liu, Zhao; Xue, Changyong

2016-09-01

We previously observed that medium-chain triglycerides (MCTs) could reduce body fat mass and improve the metabolism of cholesterol. We hypothesized that MCTs can improve atherosclerosis by promoting the reverse cholesterol transport (RCT) process. Therefore, the objective of this study was to investigate the roles of MCTs in macrophage RCT and the progression of atherosclerosis. To test this hypothesis, 30 4-week-old ApoE-deficient (ApoE(-/-)) mice were randomly divided into 2 groups and fed a diet of 2% MCTs or long-chain triglycerides (LCTs) for 16 weeks. Ten age- and sex-matched C57BL/6J mice were fed a diet of 2% LCTs as the control. Macrophage-to-feces RCT was assessed in vivo by intraperitoneal injection of RAW 264.7 macrophages containing (3)H-labeled cholesterol, and atherosclerotic plaques were measured. The mRNA and protein expressions were determined by reverse transcriptase polymerase chain reaction and Western blot analyses, respectively. There was a greater decrease in body fat mass, atherosclerotic plaques, and an improvement in serum lipid profiles. In addition, the MCT mice group showed an increase in (3)H-tracer in the feces and a decrease in the liver. Significantly higher levels of mRNA and protein expression of hepatic ATP-binding cassette transporter A1, ATP-binding cassette transporter G5, cholesterol 7α-hydroxylase, and intestinal ATP-binding cassette transporter G8, as well as lower levels of expression of intestinal Niemann-Pick C1-like 1, were found in the MCT group. These results suggest that MCTs could obviously promote macrophage RCT and improve atherosclerosis in ApoE(-/-) mice, indicating that MCTs have the potential to prevent cardiovascular disease. Copyright © 2016 Elsevier Inc. All rights reserved.

Concepts for the material development of phosphorescent organic materials processable from solution and their application in OLEDs

NASA Astrophysics Data System (ADS)

Janietz, S.; Krueger, H.; Thesen, M.; Salert, B.; Wedel, A.

2014-10-01

One example of organic electronics is the application of polymer based light emitting devices (PLEDs). PLEDs are very attractive for large area and fine-pixel displays, lighting and signage. The polymers are more amenable to solution processing by printing techniques which are favourable for low cost production in large areas. With phosphorescent emitters like Ir-complexes higher quantum efficiencies were obtained than with fluorescent systems, especially if multilayer stack systems with separated charge transport and emitting layers were applied in the case of small molecules. Polymers exhibit the ability to integrate all the active components like the hole-, electron-transport and phosphorescent molecules in only one layer. Here, the active components of a phosphorescent system - triplet emitter, hole- and electron transport molecules - can be linked as a side group to a polystyrene main chain. By varying the molecular structures of the side groups as well as the composition of the side chains with respect to the triplet emitter, hole- and electron transport structure, and by blending with suitable glass-forming, so-called small molecules, brightness, efficiency and lifetime of the produced OLEDs can be optimized. By choosing the triplet emitter, such as iridium complexes, different emission colors can be specially set. Different substituted triazine molecules were introduced as side chain into a polystyrene backbone and applied as electron transport material in PLED blend systems. The influence of alkyl chain lengths of the performance will be discussed. For an optimized blend system with a green emitting phosphorescent Ir-complex efficiencies of 60 cd/A and an lifetime improvement of 66.000 h @ 1000 cd/m2 were achieved.

Probing the conformation of a conserved glutamic acid within the Cl− pathway of a CLC H+/Cl− exchanger

PubMed Central

Vien, Malvin

2017-01-01

The CLC proteins form a broad family of anion-selective transport proteins that includes both channels and exchangers. Despite extensive structural, functional, and computational studies, the transport mechanism of the CLC exchangers remains poorly understood. Several transport models have been proposed but have failed to capture all the key features of these transporters. Multiple CLC crystal structures have suggested that a conserved glutamic acid, Gluex, can adopt three conformations and that the interconversion of its side chain between these states underlies H+/Cl− exchange. One of these states, in which Gluex occupies the central binding site (Scen) while Cl− ions fill the internal and external sites (Sint and Sext), has only been observed in one homologue, the eukaryotic cmCLC. The existence of such a state in other CLCs has not been demonstrated. In this study, we find that during transport, the prototypical prokaryotic CLC exchanger, CLC-ec1, adopts a conformation with functional characteristics that match those predicted for a cmCLC-like state, with Gluex trapped in Scen between two Cl− ions. Transport by CLC-ec1 is reduced when [Cl−] is symmetrically increased on both sides of the membrane and mutations that disrupt the hydrogen bonds stabilizing Gluex in Scen destabilize this trapped state. Furthermore, inhibition of transport by high [Cl−] is abolished in the E148A mutant, in which the Gluex side chain is removed. Collectively, our results suggest that, during the CLC transport cycle, Gluex can occupy Scen as well as the Sext position in which it has been captured crystallographically and that hydrogen bonds with the side chains of residues that coordinate ion binding to Scen play a role in determining the equilibrium between these two conformations. PMID:28246117

How SmartWay Advances Sustainable Transportation Supply Chains

EPA Pesticide Factsheets

This page provides information on how the SmartWay program has achieved reductions in freight transportation-related greenhouse gas emissions and how it will continue to do so with its Vision 2020 strategies.

Structural Ordering of Semiconducting Polymers and Small-Molecules for Organic Electronics

NASA Astrophysics Data System (ADS)

O'Hara, Kathryn Allison

Semiconducting polymers and small-molecules can be readily incorporated into electronic devices such as organic photovoltaics (OPVs), thermoelectrics (OTEs), organic light emitting diodes (OLEDs), and organic thin film transistors (OTFTs). Organic materials offer the advantage of being processable from solution to form flexible and lightweight thin films. The molecular design, processing, and resulting thin film morphology of semiconducting polymers drastically affect the optical and electronic properties. Charge transport within films of semiconducting polymers relies on the nanoscale organization to ensure electronic coupling through overlap of molecular orbitals and to provide continuous transport pathways. While the angstrom-scale packing details can be studied using X-ray scattering methods, an understanding of the mesoscale, or the length scale over which smaller ordered regions connect, is much harder to achieve. Grain boundaries play an important role in semiconducting polymer thin films where the average grain size is much smaller than the total distance which charges must traverse in order to reach the electrodes in a device. The majority of semiconducting polymers adopt a lamellar packing structure in which the conjugated backbones align in parallel pi-stacks separated by the alkyl side-chains. Only two directions of transport are possible--along the conjugated backbone and in the pi-stacking direction. Currently, the discussion of transport between crystallites is centered around the idea of tie-chains, or "bridging" polymer chains connecting two ordered regions. However, as molecular structures become increasingly complex with the development of new donor-acceptor copolymers, additional forms of connectivity between ordered domains should be considered. High resolution transmission electron microscopy (HRTEM) is a powerful tool for directly imaging the crystalline grain boundaries in polymer and small-molecule thin films. Recently, structures comparable to quadrites were discovered in the semiconducting polymer, PSBTBT, where the angle of chain overlap could be predicted by the geometry of the backbone and alkyl side-chains. Such structures are hypothesized to improve the electronic connectivity and enable 3D transport. Now, it has been determined that another semiconducting polymer, PBDTTPD, forms cross-chain structures in thin films. PBDTTPD is a low band-gap donor-acceptor copolymer used in high efficiency OPVs. The effect of the alkyl side-chains on intercrystallite order is determined by examining three different derivatives of the PBDTTPD polymer with HRTEM. Additionally, the expansion and contraction of films during thermal annealing and slow cooling is monitored through in-situ grazing incidence wide-angle X-ray scattering (GIWAXS) measurements. Results show that minor variations in side-chain structure drive both crystallite orientation and the formation of crossed structures. Overall, these studies suggest design principles to continue to advance the field of organic electronics.

Monosialoganglioside-Containing Nanoliposomes Restore Endothelial Function Impaired by AL Amyloidosis Light Chain Proteins.

PubMed

Franco, Daniel A; Truran, Seth; Weissig, Volkmar; Guzman-Villanueva, Diana; Karamanova, Nina; Senapati, Subhadip; Burciu, Camelia; Ramirez-Alvarado, Marina; Blancas-Mejia, Luis M; Lindsay, Stuart; Hari, Parameswaran; Migrino, Raymond Q

2016-06-13

Light chain amyloidosis (AL) is associated with high mortality, especially in patients with advanced cardiovascular involvement. It is caused by toxicity of misfolded light chain proteins (LC) in vascular, cardiac, and other tissues. There is no treatment to reverse LC tissue toxicity. We tested the hypothesis that nanoliposomes composed of monosialoganglioside, phosphatidylcholine, and cholesterol (GM1 ganglioside-containing nanoliposomes [NLGM1]) can protect against LC-induced human microvascular dysfunction and assess mechanisms behind the protective effect. The dilator responses of ex vivo abdominal adipose arterioles from human participants without AL to acetylcholine and papaverine were measured before and after exposure to LC (20 μg/mL) with or without NLGM1 (1:10 ratio for LC:NLGM1 mass). Human umbilical vein endothelial cells were exposed for 18 to 20 hours to vehicle, LC with or without NLGM1, or NLGM1 and compared for oxidative and nitrative stress response and cellular viability. LC impaired arteriole dilator response to acetylcholine, which was restored by co-treatment with NLGM1. LC decreased endothelial cell nitric oxide production and cell viability while increasing superoxide and peroxynitrite; these adverse effects were reversed by NLGM1. NLGM1 increased endothelial cell protein expression of antioxidant enzymes heme oxygenase 1 and NAD(P)H quinone dehydrogenase 1 and increased nuclear factor, erythroid 2 like 2 (Nrf-2) protein. Nrf-2 gene knockdown reduced antioxidant stress response and reversed the protective effects of NLGM1. NLGM1 protects against LC-induced human microvascular endothelial dysfunction through increased nitric oxide bioavailability and reduced oxidative and nitrative stress mediated by Nrf-2-dependent antioxidant stress response. These findings point to a potential novel therapeutic approach for light chain amyloidosis. © 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.

Mechanisms of pertussis toxin-induced barrier dysfunction in bovine pulmonary artery endothelial cell monolayers.

PubMed

Patterson, C E; Stasek, J E; Schaphorst, K L; Davis, H W; Garcia, J G

1995-06-01

We have previously characterized several G proteins in endothelial cells (EC) as substrates for the ADP-ribosyltransferase activity of both pertussis (PT) and cholera toxin and described the modulation of key EC physiological responses, including gap formation and barrier function, by these toxins. In this study, we investigated the mechanisms involved in PT-mediated regulation of bovine pulmonary artery endothelial cells barrier function. PT caused a dose-dependent increase in albumin transfer, dependent upon action of the holotoxin, since neither the heat-inactivated PT, the isolated oligomer, nor the protomer induced EC permeability. PT-induced gap formation and barrier dysfunction were additive to either thrombin- or thrombin receptor-activating peptide-induced permeability, suggesting that thrombin and PT utilize distinct mechanisms. PT did not result in Ca2+ mobilization or alter either basal or thrombin-induced myosin light chain phosphorylation. However, PT stimulated protein kinase C (PKC) activation, and both PKC downregulation and PKC inhibition attenuated PT-induced permeability, indicating that PKC activity is involved in PT-induced barrier dysfunction. Like thrombin-induced permeability, the PT effect was blocked by prior increases in adenosine 3',5'-cyclic monophosphate. Thus PT-catalyzed ADP-ribosylation of a G protein (possibly other than Gi) may regulate cytoskeletal protein interactions, leading to EC barrier dysfunction.

Macrophage functions measured by magnetic microparticles in vivo and in vitro

NASA Astrophysics Data System (ADS)

Möller, Winfried; Kreyling, Wolfgang G.; Kohlhäufl, Martin; Häussinger, Karl; Heyder, Joachim

2001-01-01

Monodisperse ferrimagnetic iron-oxide particles of 1.4 μm geometric diameter were used to study alveolar macrophage functions (phagocytosis, phagosome transport) and cytoskeletal integrity in healthy subjects and in patients with idiopathic pulmonary fibrosis as well as in cultured macrophages. Dysfunctions in phagocytosis, in phagosome transport and cytoskeletal integrity correlated with an impaired alveolar clearance and could be induced in vitro by cytoskeletal drugs.

Transport of lipid nano-droplets through MDCK epithelial cell monolayer.

PubMed

Khatri, Pulkit; Shao, Jun

2017-05-01

This study aims to investigate the transport of lipid nano-droplets through MDCK epithelial cell monolayer. Nanoemulsions of self-nano-emulsifying drug delivery systems (SNEDDS) labeled with radioactive C18 triglyceride were developed. The effect of droplet size and lipid composition on the transport was investigated. The results showed that the lipid nano-droplet transport through MDCK cell monolayer was as high as 2.5%. The transport of lipid nano-droplets was higher for nanoemulsions of medium chain glycerides than the long chain glycerides. The transport was reduced by more than half when the average lipid nano-droplet size increased from 38nm to 261nm. The droplet size measurement verified the existence of lipid nano-droplets in the receiver chamber only when the nanoemulsions were added to the donor chamber but not when the surfactant or saline solution was added. Cryo-TEM images confirmed the presence of lipid nano-droplets in both donor and receiver chamber at the end of transport study. In conclusion, lipid nano-droplets can be transported through the cell monolayer. This finding may help to further explore the oral and other non-invasive delivery of macromolecules loaded inside SNEDDS. Copyright © 2017 Elsevier B.V. All rights reserved.

Mitochondrial Fusion/Fission, Transport and Autophagy in Parkinson's Disease: When Mitochondria Get Nasty

PubMed Central

Arduíno, Daniela M.; Esteves, A. Raquel; Cardoso, Sandra M.

2011-01-01

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance. PMID:21403911

Mitochondrial fusion/fission, transport and autophagy in Parkinson's disease: when mitochondria get nasty.

PubMed

Arduíno, Daniela M; Esteves, A Raquel; Cardoso, Sandra M

2011-02-20

Understanding the molecular basis of Parkinson's disease (PD) has proven to be a major challenge in the field of neurodegenerative diseases. Although several hypotheses have been proposed to explain the molecular mechanisms underlying the pathogenesis of PD, a growing body of evidence has highlighted the role of mitochondrial dysfunction and the disruption of the mechanisms of mitochondrial dynamics in PD and other parkinsonian disorders. In this paper, we comment on the recent advances in how changes in the mitochondrial function and mitochondrial dynamics (fusion/fission, transport, and clearance) contribute to neurodegeneration, specifically focusing on PD. We also evaluate the current controversies in those issues and discuss the role of fusion/fission dynamics in the mitochondrial lifecycle and maintenance. We propose that cellular demise and neurodegeneration in PD are due to the interplay between mitochondrial dysfunction, mitochondrial trafficking disruption, and impaired autophagic clearance.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction.

PubMed

Lord, Kevin C; Shenouda, Sylvia K; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A; Varner, Kurt J

2010-07-01

Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Echocardiography and Millar pressure-volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased -dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction.

Oxidative stress contributes to methamphetamine-induced left ventricular dysfunction

PubMed Central

Lord, Kevin C.; Shenouda, Sylvia K.; McIlwain, Elizabeth; Charalampidis, Dimitrios; Lucchesi, Pamela A.; Varner, Kurt J.

2010-01-01

Aims Our aim was to test the hypothesis that the repeated, binge administration of methamphetamine would produce oxidative stress in the myocardium leading to structural remodeling and impaired left ventricular function. Methods and results Echocardiography and Millar pressure–volume catheters were used to monitor left ventricular structure and function in rats subjected to four methamphetamine binges (3 mg/kg, iv for 4 days, separated by a 10-day drug-free period). Hearts from treated and control rats were used for histological or proteomic analysis. When compared with saline treatment, four methamphetamine binges produced eccentric left ventricular hypertrophy. The drug also significantly impaired systolic function (decreased fractional shortening, ejection fraction, and adjusted maximal power) and produced significant diastolic dysfunction (increased −dP/dt and tau). Dihydroethedium staining showed that methamphetamine significantly increased (285%) the levels of reactive oxygen species in the left ventricle. Treatment with methamphetamine also resulted in the tyrosine nitration of myofilament (desmin, myosin light chain) and mitochondrial (ATP synthase, NADH dehydrogenase, cytochrome c oxidase, prohibitin) proteins. Treatment with the superoxide dismutase mimetic, tempol in the drinking water prevented methamphetamine-induced left ventricular dilation and systolic dysfunction; however, tempol (2.5 mM) did not prevent the diastolic dysfunction. Tempol significantly reduced, but did not eliminate dihydroethedium staining in the left ventricle, nor did it prevent the tyrosine nitration of mitochondrial and contractile proteins. Conclusion This study shows that oxidative stress plays a significant role in mediating methamphetamine-induced eccentric left ventricular dilation and systolic dysfunction. PMID:20139112

Isolating the segment of the mitochondrial electron transport chain responsible for mitochondrial damage during cardiac ischemia

DOE Office of Scientific and Technical Information (OSTI.GOV)

Chen, Qun; Yin, Guotian; Stewart, Sarah

2010-07-09

Ischemia damages the mitochondrial electron transport chain (ETC), mediated in part by damage generated by the mitochondria themselves. Mitochondrial damage resulting from ischemia, in turn, leads to cardiac injury during reperfusion. The goal of the present study was to localize the segment of the ETC that produces the ischemic mitochondrial damage. We tested if blockade of the proximal ETC at complex I differed from blockade distal in the chain at cytochrome oxidase. Isolated rabbit hearts were perfused for 15 min followed by 30 min stop-flow ischemia at 37 {sup o}C. Amobarbital (2.5 mM) or azide (5 mM) was used tomore » block proximal (complex I) or distal (cytochrome oxidase) sites in the ETC. Time control hearts were buffer-perfused for 45 min. Subsarcolemmal mitochondria (SSM) and interfibrillar mitochondria (IFM) were isolated. Ischemia decreased cytochrome c content in SSM but not in IFM compared to time control. Blockade of electron transport at complex I preserved the cytochrome c content in SSM. In contrast, blockade of electron transport at cytochrome oxidase with azide did not retain cytochrome c in SSM during ischemia. Since blockade of electron transport at complex III also prevented cytochrome c loss during ischemia, the specific site that elicits mitochondrial damage during ischemia is likely located in the segment between complex III and cytochrome oxidase.« less

Evaluation and analysis of Texas biofuel supply chains originating in the United States Midwest and Brazil.

DOT National Transportation Integrated Search

2009-05-01

This 2009 study, funded by the Southwest Region University Transportation Center, investigates : competing ethanol supply chains terminating in the State of Texas. Midwest corn ethanol and : Brazilian sugarcane ethanol constitute two sources of the b...

Securing global trade through secure freight transportation : final report.

DOT National Transportation Integrated Search

2009-12-16

Given the increased probability of disruptions to global supply chains, and the significant impact these have on national and global economies, the problem is how to secure global trade. The concept of a global trade chain-of-custody has been develop...

Cell Membrane Transport Mechanisms: Ion Channels and Electrical Properties of Cell Membranes.

PubMed

Kulbacka, Julita; Choromańska, Anna; Rossowska, Joanna; Weżgowiec, Joanna; Saczko, Jolanta; Rols, Marie-Pierre

2017-01-01

Cellular life strongly depends on the membrane ability to precisely control exchange of solutes between the internal and external (environmental) compartments. This barrier regulates which types of solutes can enter and leave the cell. Transmembrane transport involves complex mechanisms responsible for passive and active carriage of ions and small- and medium-size molecules. Transport mechanisms existing in the biological membranes highly determine proper cellular functions and contribute to drug transport. The present chapter deals with features and electrical properties of the cell membrane and addresses the questions how the cell membrane accomplishes transport functions and how transmembrane transport can be affected. Since dysfunctions of plasma membrane transporters very often are the cause of human diseases, we also report how specific transport mechanisms can be modulated or inhibited in order to enhance the therapeutic effect.

Controlling the mode of operation of organic transistors through side-chain engineering.

PubMed

Giovannitti, Alexander; Sbircea, Dan-Tiberiu; Inal, Sahika; Nielsen, Christian B; Bandiello, Enrico; Hanifi, David A; Sessolo, Michele; Malliaras, George G; McCulloch, Iain; Rivnay, Jonathan

2016-10-25

Electrolyte-gated organic transistors offer low bias operation facilitated by direct contact of the transistor channel with an electrolyte. Their operation mode is generally defined by the dimensionality of charge transport, where a field-effect transistor allows for electrostatic charge accumulation at the electrolyte/semiconductor interface, whereas an organic electrochemical transistor (OECT) facilitates penetration of ions into the bulk of the channel, considered a slow process, leading to volumetric doping and electronic transport. Conducting polymer OECTs allow for fast switching and high currents through incorporation of excess, hygroscopic ionic phases, but operate in depletion mode. Here, we show that the use of glycolated side chains on a thiophene backbone can result in accumulation mode OECTs with high currents, transconductance, and sharp subthreshold switching, while maintaining fast switching speeds. Compared with alkylated analogs of the same backbone, the triethylene glycol side chains shift the mode of operation of aqueous electrolyte-gated transistors from interfacial to bulk doping/transport and show complete and reversible electrochromism and high volumetric capacitance at low operating biases. We propose that the glycol side chains facilitate hydration and ion penetration, without compromising electronic mobility, and suggest that this synthetic approach can be used to guide the design of organic mixed conductors.

Controlling the mode of operation of organic transistors through side-chain engineering

PubMed Central

Giovannitti, Alexander; Sbircea, Dan-Tiberiu; Inal, Sahika; Nielsen, Christian B.; Bandiello, Enrico; Hanifi, David A.; Sessolo, Michele; Malliaras, George G.; McCulloch, Iain; Rivnay, Jonathan

2016-01-01

Electrolyte-gated organic transistors offer low bias operation facilitated by direct contact of the transistor channel with an electrolyte. Their operation mode is generally defined by the dimensionality of charge transport, where a field-effect transistor allows for electrostatic charge accumulation at the electrolyte/semiconductor interface, whereas an organic electrochemical transistor (OECT) facilitates penetration of ions into the bulk of the channel, considered a slow process, leading to volumetric doping and electronic transport. Conducting polymer OECTs allow for fast switching and high currents through incorporation of excess, hygroscopic ionic phases, but operate in depletion mode. Here, we show that the use of glycolated side chains on a thiophene backbone can result in accumulation mode OECTs with high currents, transconductance, and sharp subthreshold switching, while maintaining fast switching speeds. Compared with alkylated analogs of the same backbone, the triethylene glycol side chains shift the mode of operation of aqueous electrolyte-gated transistors from interfacial to bulk doping/transport and show complete and reversible electrochromism and high volumetric capacitance at low operating biases. We propose that the glycol side chains facilitate hydration and ion penetration, without compromising electronic mobility, and suggest that this synthetic approach can be used to guide the design of organic mixed conductors. PMID:27790983

Association of cultured myotubes and fasting plasma metabolite profiles with mitochondrial dysfunction in type 2 diabetes subjects.

PubMed

Abu Bakar, Mohamad Hafizi; Sarmidi, Mohamad Roji

2017-08-22

Accumulating evidence implicates mitochondrial dysfunction-induced insulin resistance in skeletal muscle as the root cause for the greatest hallmarks of type 2 diabetes (T2D). However, the identification of specific metabolite-based markers linked to mitochondrial dysfunction in T2D has not been adequately addressed. Therefore, we sought to identify the markers-based metabolomics for mitochondrial dysfunction associated with T2D. First, a cellular disease model was established using human myotubes treated with antimycin A, an oxidative phosphorylation inhibitor. Non-targeted metabolomic profiling of intracellular-defined metabolites on the cultured myotubes with mitochondrial dysfunction was then determined. Further, a targeted MS-based metabolic profiling of fasting blood plasma from normal (n = 32) and T2D (n = 37) subjects in a cross-sectional study was verified. Multinomial logical regression analyses for defining the top 5% of the metabolites within a 95% group were employed to determine the differentiating metabolites. The myotubes with mitochondrial dysfunction exhibited insulin resistance, oxidative stress and inflammation with impaired insulin signalling activities. Four metabolic pathways were found to be strongly associated with mitochondrial dysfunction in the cultured myotubes. Metabolites derived from these pathways were validated in an independent pilot investigation of the fasting blood plasma of healthy and diseased subjects. Targeted metabolic analysis of the fasting blood plasma with specific baseline adjustment revealed 245 significant features based on orthogonal partial least square discriminant analysis (PLS-DA) with a p-value < 0.05. Among these features, 20 significant metabolites comprised primarily of branched chain and aromatic amino acids, glutamine, aminobutyric acid, hydroxyisobutyric acid, pyroglutamic acid, acylcarnitine species (acetylcarnitine, propionylcarnitine, dodecenoylcarnitine, tetradecenoylcarnitine hexadecadienoylcarnitine and oleylcarnitine), free fatty acids (palmitate, arachidonate, stearate and linoleate) and sphingomyelin (d18:2/16:0) were identified as predictive markers for mitochondrial dysfunction in T2D subjects. The current study illustrates how cellular metabolites provide potential signatures associated with the biochemical changes in the dysregulated body metabolism of diseased subjects. Our finding yields additional insights into the identification of robust biomarkers for T2D associated with mitochondrial dysfunction in cultured myotubes.

Short-chain fatty acid fermentation products of the gut microbiome: implications in autism spectrum disorders

PubMed Central

MacFabe, Derrick F.

2012-01-01

Recent evidence suggests potential, but unproven, links between dietary, metabolic, infective, and gastrointestinal factors and the behavioral exacerbations and remissions of autism spectrum disorders (ASDs). Propionic acid (PPA) and its related short-chain fatty acids (SCFAs) are fermentation products of ASD-associated bacteria (Clostridia, Bacteriodetes, Desulfovibrio). SCFAs represent a group of compounds derived from the host microbiome that are plausibly linked to ASDs and can induce widespread effects on gut, brain, and behavior. Intraventricular administration of PPA and SCFAs in rats induces abnormal motor movements, repetitive interests, electrographic changes, cognitive deficits, perseveration, and impaired social interactions. The brain tissue of PPA-treated rats shows a number of ASD-linked neurochemical changes, including innate neuroinflammation, increased oxidative stress, glutathione depletion, and altered phospholipid/acylcarnitine profiles. These directly or indirectly contribute to acquired mitochondrial dysfunction via impairment in carnitine-dependent pathways, consistent with findings in patients with ASDs. Of note, common antibiotics may impair carnitine-dependent processes by altering gut flora favoring PPA-producing bacteria and by directly inhibiting carnitine transport across the gut. Human populations that are partial metabolizers of PPA are more common than previously thought. PPA has further bioactive effects on neurotransmitter systems, intracellular acidification/calcium release, fatty acid metabolism, gap junction gating, immune function, and alteration of gene expression that warrant further exploration. These findings are consistent with the symptoms and proposed underlying mechanisms of ASDs and support the use of PPA infusions in rats as a valid animal model of the condition. Collectively, this offers further support that gut-derived factors, such as dietary or enteric bacterially produced SCFAs, may be plausible environmental agents that can trigger ASDs or ASD-related behaviors and deserve further exploration in basic science, agriculture, and clinical medicine. PMID:23990817

Posttranslational Regulation of Human DNA Polymerase ι.

PubMed

McIntyre, Justyna; McLenigan, Mary P; Frank, Ekaterina G; Dai, Xiaoxia; Yang, Wei; Wang, Yinsheng; Woodgate, Roger

2015-11-06

Human DNA polymerases (pols) η and ι are Y-family DNA polymerase paralogs that facilitate translesion synthesis past damaged DNA. Both polη and polι can be monoubiquitinated in vivo. Polη has been shown to be ubiquitinated at one primary site. When this site is unavailable, three nearby lysines may become ubiquitinated. In contrast, mass spectrometry analysis of monoubiquitinated polι revealed that it is ubiquitinated at over 27 unique sites. Many of these sites are localized in different functional domains of the protein, including the catalytic polymerase domain, the proliferating cell nuclear antigen-interacting region, the Rev1-interacting region, and its ubiquitin binding motifs UBM1 and UBM2. Polι monoubiquitination remains unchanged after cells are exposed to DNA-damaging agents such as UV light (generating UV photoproducts), ethyl methanesulfonate (generating alkylation damage), mitomycin C (generating interstrand cross-links), or potassium bromate (generating direct oxidative DNA damage). However, when exposed to naphthoquinones, such as menadione and plumbagin, which cause indirect oxidative damage through mitochondrial dysfunction, polι becomes transiently polyubiquitinated via Lys(11)- and Lys(48)-linked chains of ubiquitin and subsequently targeted for degradation. Polyubiquitination does not occur as a direct result of the perturbation of the redox cycle as no polyubiquitination was observed after treatment with rotenone or antimycin A, which both inhibit mitochondrial electron transport. Interestingly, polyubiquitination was observed after the inhibition of the lysine acetyltransferase KATB3/p300. We hypothesize that the formation of polyubiquitination chains attached to polι occurs via the interplay between lysine acetylation and ubiquitination of ubiquitin itself at Lys(11) and Lys(48) rather than oxidative damage per se. © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Modulating the spin transport behaviors in ZBNCNRs by edge hydrogenation and position of BN chain

DOE Office of Scientific and Technical Information (OSTI.GOV)

Ouyang, Jun; Long, Mengqiu, E-mail: mqlong@csu.edu.cn, E-mail: ygao@csu.edu.cn; Zhang, Dan

2016-03-15

Using the density functional theory and the nonequilibrium Green’s function method, we study the spin transport behaviors in zigzag boron-nitrogen-carbon nanoribbons (ZBNCNRs) by modulating the edge hydrogenation and the position of B-N nanoribbons (BNNRs) chain. The different edge hydrogenations of the ZBNCNRs and the different position relationships of the BNNRs have been considered systematically. Our results show that the metallic, semimetallic and semiconductive properties of the ZBNCNRs can be modulated by the different edge hydrogenations and different position relationships of BN chains. And our proposaled ZBNCNRs devices act as perfect spin-filters with nearly 100% spin polarization. These effects would havemore » potential applications for boron-nitrogen-carbon-based nanomaterials in spintronics nano-devices.« less

Teaching Young Adults with Intellectual and Developmental Disabilities Community-Based Navigation Skills to Take Public Transportation.

PubMed

Price, Richard; Marsh, Abbie J; Fisher, Marisa H

2018-03-01

Facilitating the use of public transportation enhances opportunities for independent living and competitive, community-based employment for individuals with intellectual and developmental disabilities (IDD). Four young adults with IDD were taught through total-task chaining to use the Google Maps application, a self-prompting, visual navigation system, to take the bus to locations around a college campus and the community. Three of four participants learned to use Google Maps to independently navigate public transportation. Google Maps may be helpful in supporting independent travel, highlighting the importance of future research in teaching navigation skills. Learning to independently use public transportation increases access to autonomous activities, such as opportunities to work and to attend postsecondary education programs on large college campuses.Individuals with IDD can be taught through chaining procedures to use the Google Maps application to navigate public transportation.Mobile map applications are an effective and functional modern tool that can be used to teach community navigation.

Structural patterns of the human ABCC4/MRP4 exporter in lipid bilayers rationalize clinically observed polymorphisms.

PubMed

Chantemargue, B; Di Meo, F; Berka, K; Picard, N; Arnion, H; Essig, M; Marquet, P; Otyepka, M; Trouillas, P

2018-03-10

The ABCC4/MRP4 exporter has a clinical impact on membrane transport of a broad range of xenobiotics. It is expressed at key locations for drug disposition or effects such as in the liver, the kidney and blood cells. Several polymorphisms and mutations (e.g., p.Gly187Trp) leading to MRP4 dysfunction are associated with an increased risk of toxicity of some drugs. So far, no human MRP4 structure has been elucidated, precluding rationalization of these dysfunctions at a molecular level. We constructed an atomistic model of the wild type (WT) MRP4 and the p.Gly187Trp mutant embedded in different lipid bilayers and relaxed them for hundreds of nanoseconds by molecular dynamics simulations. The WT MRP4 molecular structure confirmed and ameliorated the general knowledge about the transmembrane helices and the two nucleotide binding domains. Moreover, our model elucidated positions of three generally unresolved domains: L 1 (linker between the two halves of the exporter); L 0 (N-terminal domain); and the zipper helices (between the two NBDs). Each domain was thoroughly described in view of its function. The p.Gly187Trp mutation induced a huge structural impact on MRP4, mainly affecting NBD 1 structure and flexibility. The structure of transporter enabled rationalization of known dysfunctions associated with polymorphism of MRP4. This model is available to the pharmacology community to decipher the impact of any other clinically observed polymorphism and mutation on drug transport, giving rise to in silico predictive pharmacogenetics. Copyright © 2018 Elsevier Ltd. All rights reserved.

Fatal chronic active Epstein-Barr virus infection mimicking autoimmune hepatitis.

PubMed

Chiba, Tetsuhiro; Goto, Shigemasa; Yokosuka, Osamu; Imazeki, Fumio; Tanaka, Masamichi; Fukai, Kenichi; Takahashi, Yoko; Tsujimura, Hideki; Saisho, Hiromitsu

2004-02-01

We report a 22-year-old female who presented with pyrexia, pancytopenia and liver dysfunction. The patient showed mild liver dysfunction with low-grade fever and mild hepatosplenomegaly 6 years previously, and autoimmune hepatitis (AIH) was diagnosed based on the examination of the laboratory data and liver biopsy. On admission, both markers of Epstein-Barr virus (EBV) and in-situ hybridisation from a liver biopsy specimen indicated chronic active EBV infection (CAEBV). The patient was administered an immunosuppressive agent and antiviral drug added to steroid therapy, but ultimately died from liver failure and virus-associated haemophagocytosis 10 months after the definite diagnosis. Retrospective examination of the serum at the diagnosis of AIH revealed extremely high titres of antibody to EBV, and EBV-DNA was also detectable by polymerase chain reaction. These results suggest the possibility that the patient may already have suffered from CAEBV at the initial diagnosis. We presume that hepatic involvement of CAEBV should be considered as differential diagnosis in cases showing liver dysfunction with clinical and biochemical features observed in AIH.

Tunnel current across linear homocatenated germanium chains

NASA Astrophysics Data System (ADS)

Matsuura, Yukihito

2014-01-01

The electronic transport properties of germanium oligomers catenating into linear chains (linear Ge chains) have been theoretically studied using first principle methods. The conduction mechanism of a Ge chain sandwiched between gold electrodes was analyzed based on the density of states and the eigenstates of the molecule in a two-probe environment. Like that of silicon chains (Si chains), the highest occupied molecular orbital of Ge chains contains the extended σ-conjugation of Ge 4p orbitals at energy levels close to the Fermi level; this is in contrast to the electronic properties of linear carbon chains. Furthermore, the conductance of a Ge chain is expected to decrease exponentially with molecular length L. The decay constant β, which is defined as e-βL, of a Ge chain is similar to that of a Si chain, whereas the conductance of the Ge chains is higher than that of Si chains even though the Ge-Ge bond length is longer than the Si-Si bond length.

76 FR 7153 - Secretarial Business Development Mission; Transportation Infrastructure/Multimodal Products and...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-02-09

...- modal freight and intelligent supply chain management, provides significant business [[Page 7154..., including port development, airport development, freight rail systems and technologies, supply chain systems... for U.S. engineers, program management firms, and manufacturers to contribute to the creation of new...

Examining trip-chaining behavior : a comparison of travel by men and women

DOT National Transportation Integrated Search

1999-01-01

This paper uses the 1995 Nationwide Personal Transportation Survey (NPTS) to examine trip chaining behavior by adult men and women traveling Monday through Friday. Whereas travel by single adults of both sexes, and by men and women in households with...

Identification of vibrational signatures from short chains of interlinked molecule-nanoparticle junctions obtained by inelastic electron tunnelling spectroscopy.

PubMed

Jafri, S H M; Löfås, H; Fransson, J; Blom, T; Grigoriev, A; Wallner, A; Ahuja, R; Ottosson, H; Leifer, K

2013-06-07

Short chains containing a series of metal-molecule-nanoparticle nanojunctions are a nano-material system with the potential to give electrical signatures close to those from single molecule experiments while enabling us to build portable devices on a chip. Inelastic electron tunnelling spectroscopy (IETS) measurements provide one of the most characteristic electrical signals of single and few molecules. In interlinked molecule-nanoparticle (NP) chains containing typically 5-7 molecules in a chain, the spectrum is expected to be a superposition of the vibrational signatures of individual molecules. We have established a stable and reproducible molecule-AuNP multi-junction by placing a few 1,8-octanedithiol (ODT) molecules onto a versatile and portable nanoparticle-nanoelectrode platform and measured for the first time vibrational molecular signatures at complex and coupled few-molecule-NP junctions. From quantum transport calculations, we model the IETS spectra and identify vibrational modes as well as the number of molecules contributing to the electron transport in the measured spectra.

[Thermolabile drugs: pharmacist intervention as a guarantee of cold chain maintenance].

PubMed

Ricote-Lobera, I; Santos-Mena, B; Fraile-Gil, S; Ortiz-Martín, B; Hidalgo-Correas, F J; García-Díaz, B

2014-05-01

To determine whether pharmacist is able to guarantee cold chain maintenance of thermolabile drugs during transport using the available information in the reception process and to compare these results with those obtained in a subsequent intervention phase, in which the manufacturing laboratories were contacted. Intervention study, prospective and comparative"before-after". It was analyzed the storage conditions during transport of all thermolabile drugs received in a 400-bed hospital for 3 months, excluding those from clinical trials. The intervention allowed to ensure cold chain maintenance in 76,5% (n = 488) of received drugs, representing an increase of 41,8% (IC 95% 36,7-46,6%; p < 0,001) compared with the percentage obtained before the intervention. The pharmacist isn't able to ensure the cold chain maintenance of received thermolabile drugs without temperature monitoring device (64,6%). Reports requested from laboratories allowed to increase significantly that percentage. Copyright AULA MEDICA EDICIONES 2014. Published by AULA MEDICA. All rights reserved.

Waveguide transport mediated by strong coupling with atoms

NASA Astrophysics Data System (ADS)

Cheng, Mu-Tian; Xu, Jingping; Agarwal, Girish S.

2017-05-01

We investigate single-photon scattering properties in a one-dimensional waveguide coupled to a quantum emitter's chain with dipole-dipole interaction (DDI). The photon transport is extremely sensitive to the location of the evanescently coupled atoms. The analytical expressions of reflection and transmission amplitudes for the chain containing two emitters with DDI are deduced by using a real-space Hamiltonian. Two cases, where the two emitters symmetrically or asymmetrically couple to the waveguide, are discussed in detail. It shows that the reflection and transmission typical spectra split into two peaks due to the DDI. The Fano minimum in the spectra can be used to estimate the strength of the DDI. Furthermore, the DDI makes spectra strongly asymmetric and creates a transmission window in the region where there was zero transmission. The scattering spectra for the chain consisting of multiple emitters are also given. Our key finding is that DDI can broaden the frequency bandwidth for high reflection when the chain consists of many emitters.

A baker's dozen of new particle flows for nonlinear filters, Bayesian decisions and transport

NASA Astrophysics Data System (ADS)

Daum, Fred; Huang, Jim

2015-05-01

We describe a baker's dozen of new particle flows to compute Bayes' rule for nonlinear filters, Bayesian decisions and learning as well as transport. Several of these new flows were inspired by transport theory, but others were inspired by physics or statistics or Markov chain Monte Carlo methods.

Cytomegalovirus retinitis after intravitreal bevacizumab injection in an immunocompetent patient.

PubMed

Bae, So Hyun; Kim, Tae Wan; Chung, Hum; Heo, Jang Won

2013-02-01

We report a case of cytomegalovirus (CMV) retinitis after intravitreal bevacizumab injection. A 61-year-old woman with diabetic macular edema developed dense vitritis and necrotizing retinitis 3 weeks after intravitreal bevacizumab injection. A diagnostic vitrectomy was performed. The undiluted vitreous sample acquired by vitrectomy was analyzed by polymerase chain reaction and culture. Polymerase chain reaction of the vitreous was positive for CMV DNA. Other laboratory results did not show evidence of other infectious retinitis and systemic immune dysfunction. Human immunodeficiency virus antibodies were also negative. After systemic administration of ganciclovir, retinitis has resolved and there has been no recurrence of retinitis during the follow-up period of 12 months. Ophthalmologists should be aware of potential risk for CMV retinitis after intravitreal bevacizumab injection.

Life cycle assessment framework of traffic systems based on microscopic simulation.

DOT National Transportation Integrated Search

2014-03-01

Transportation is an important infrastructure process needed in many steps of the supply chain of any product. Transportation-associated global impacts are therefore important factor influencing the sustainability of any product cycle. Moreover, traf...

Glycogen synthase kinase 3 phosphorylates kinesin light chains and negatively regulates kinesin-based motility

NASA Technical Reports Server (NTRS)

Morfini, Gerardo; Szebenyi, Gyorgyi; Elluru, Ravindhra; Ratner, Nancy; Brady, Scott T.

2002-01-01

Membrane-bounded organelles (MBOs) are delivered to different domains in neurons by fast axonal transport. The importance of kinesin for fast antero grade transport is well established, but mechanisms for regulating kinesin-based motility are largely unknown. In this report, we provide biochemical and in vivo evidence that kinesin light chains (KLCs) interact with and are in vivo substrates for glycogen synthase kinase 3 (GSK3). Active GSK3 inhibited anterograde, but not retrograde, transport in squid axoplasm and reduced the amount of kinesin bound to MBOs. Kinesin microtubule binding and microtubule-stimulated ATPase activities were unaffected by GSK3 phosphorylation of KLCs. Active GSK3 was also localized preferentially to regions known to be sites of membrane delivery. These data suggest that GSK3 can regulate fast anterograde axonal transport and targeting of cargos to specific subcellular domains in neurons.

Anomalous I-V curve for mono-atomic carbon chains

NASA Astrophysics Data System (ADS)

Song, Bo; Sanvito, Stefano; Fang, Haiping

2010-10-01

The electronic transport properties of mono-atomic carbon chains were studied theoretically using a combination of density functional theory and the non-equilibrium Green's functions method. The I-V curves for the chains composed of an even number of atoms and attached to gold electrodes through sulfur exhibit two plateaus where the current becomes bias independent. In contrast, when the number of carbon atoms in the chain is odd, the electric current simply increases monotonically with bias. This peculiar behavior is attributed to dimerization of the chains, directly resulting from their one-dimensional nature. The finding is expected to be helpful in designing molecular devices, such as carbon-chain-based transistors and sensors, for nanoscale and biological applications.

Dysfunction of the Cerebral Glucose Transporter SLC45A1 in Individuals with Intellectual Disability and Epilepsy.

PubMed

Srour, Myriam; Shimokawa, Noriaki; Hamdan, Fadi F; Nassif, Christina; Poulin, Chantal; Al Gazali, Lihadh; Rosenfeld, Jill A; Koibuchi, Noriyuki; Rouleau, Guy A; Al Shamsi, Aisha; Michaud, Jacques L

2017-05-04

Glucose transport across the blood brain barrier and into neural cells is critical for normal cerebral physiologic function. Dysfunction of the cerebral glucose transporter GLUT1 (encoded by SLC2A1) is known to result in epilepsy, intellectual disability (ID), and movement disorder. Using whole-exome sequencing, we identified rare homozygous missense variants (c.526C>T [p.Arg176Trp] and c.629C>T [p.Ala210Val]) in SLC45A1, encoding another cerebral glucose transporter, in two consanguineous multiplex families with moderate to severe ID, epilepsy, and variable neuropsychiatric features. The variants segregate with the phenotype in these families, affect well-conserved amino acids, and are predicted to be damaging by in silico programs. Intracellular glucose transport activity of the p.Arg176Trp and p.Ala210Val SLC45A1 variants, measured in transfected COS-7 cells, was approximately 50% (p = 0.013) and 33% (p = 0.008) lower, respectively, than that of intact SLC45A1. These results indicate that residues at positions 176 and 210 are critical for the glucose transport activity of SLC45A1. All together, our data strongly suggest that recessive mutations in SLC45A1 cause ID and epilepsy. SLC45A1 thus represents the second cerebral glucose transporter, in addition to GLUT1, to be involved in neurodevelopmental disability. Identification of additional individuals with mutations in SLC45A1 will allow better definition of the associated phenotypic spectrum and the exploration of potential targeted treatment options. Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

A specific amino acid formula prevents alcoholic liver disease in rodents.

PubMed

Tedesco, Laura; Corsetti, Giovanni; Ruocco, Chiara; Ragni, Maurizio; Rossi, Fabio; Carruba, Michele O; Valerio, Alessandra; Nisoli, Enzo

2018-05-01

Chronic alcohol consumption promotes mitochondrial dysfunction, oxidative stress, defective protein metabolism, and fat accumulation in hepatocytes (liver steatosis). Inadequate amino acid metabolism is worsened by protein malnutrition, frequently present in alcohol-consuming patients, with reduced circulating branched-chain amino acids (BCAAs). Here we asked whether dietary supplementation with a specific amino acid mixture, enriched in BCAAs (BCAAem) and able to promote mitochondrial function in muscle of middle-aged rodents, would prevent mitochondrial dysfunction and liver steatosis in Wistar rats fed on a Lieber-DeCarli ethanol (EtOH)-containing liquid diet. Supplementation of BCAAem, unlike a mixture based on the amino acid profile of casein, abrogated the EtOH-induced fat accumulation, mitochondrial impairment, and oxidative stress in liver. These effects of BCAAem were accompanied by normalization of leucine, arginine, and tryptophan levels, which were reduced in liver of EtOH-consuming rats. Moreover, although the EtOH exposure of HepG2 cells reduced mitochondrial DNA, mitochondrial transcription factors, and respiratory chain proteins, the BCAAem but not casein-derived amino acid supplementation halted this mitochondrial toxicity. Nicotinamide adenine dinucleotide levels and sirtuin 1 (Sirt1) expression, as well as endothelial nitric oxide (eNOS) and mammalian/mechanistic target of rapamycin (mTOR) signaling pathways, were downregulated in the EtOH-exposed HepG2 cells. BCAAem reverted these molecular defects and the mitochondrial dysfunction, suggesting that the mitochondrial integrity obtained with the amino acid supplementation could be mediated through a Sirt1-eNOS-mTOR pathway. Thus a dietary activation of the mitochondrial biogenesis and function by a specific amino acid supplement protects against the EtOH toxicity and preserves the liver integrity in mammals. NEW & NOTEWORTHY Dietary supplementation of a specific amino acid formula prevents both fat accumulation and mitochondrial dysfunction in hepatocytes of alcohol-consuming rats. These effects are accompanied also by increased expression of anti-reactive oxygen species genes. The amino acid-protective effects likely reflect activation of sirtuin 1-endothelial nitric oxide synthase-mammalian target of rapamycin pathway able to regulate the cellular energy balance of hepatocytes exposed to chronic, alcoholic damage.

Simulation study of the lithium ion transport mechanism in ternary polymer electrolytes: the critical role of the segmental mobility.

PubMed

Diddens, Diddo; Heuer, Andreas

2014-01-30

We present an extensive molecular dynamics (MD) simulation study of the lithium ion transport in ternary polymer electrolytes consisting of poly(ethylene oxide) (PEO), lithium-bis(trifluoromethane)sulfonimide (LiTFSI), and the ionic liquid N-methyl-N-propylpyrrolidinium bis(trifluoromethane)sulfonimide (PYR13TFSI). In particular, we focus on two different strategies by which the ternary electrolytes can be devised, namely by (a) adding the ionic liquid to PEO20LiTFSI and (b) substituting the PEO chains in PEO20LiTFSI by the ionic liquid. To grasp the changes of the overall lithium transport mechanism, we employ an analytical, Rouse-based cation transport model (Maitra et al. Phys. Rev. Lett. 2007, 98, 227802), which has originally been devised for binary PEO-based electrolytes. This model distinguishes three different microscopic transport mechanisms, each quantified by an individual time scale. In the course of our analysis, we extend this mathematical description to account for an entirely new transport mechanism, namely, the TFSI-supported diffusion of lithium ions decoupled from the PEO chains, which emerges for certain stoichiometries. We find that the segmental mobility plays a decisive role in PEO-based polymer electrolytes. That is, whereas the addition of the ionic liquid to PEO20LiTFSI plasticizes the polymer network and thus also increases the lithium diffusion, the amount of free, mobile ether oxygens reduces when substituting the PEO chains by the ionic liquid, which compensates the plasticizing effect. In total, our observations allow us to formulate some general principles about the lithium ion transport mechanism in ternary polymer electrolytes. Moreover, our insights also shed light on recent experimental observations (Joost et al. Electrochim. Acta 2012, 86, 330).

Evaluation of functioning of mitochondrial electron transport chain with NADH and FAD autofluorescence

PubMed

Danylovych, H V

2016-01-01

We prove the feasibility of evaluation of mitochondrial electron transport chain function in isolated mitochondria of smooth muscle cells of rats from uterus using fluorescence of NADH and FAD coenzymes. We found the inversely directed changes in FAD and NADH fluorescence intensity under normal functioning of mitochondrial electron transport chain. The targeted effect of inhibitors of complex I, III and IV changed fluorescence of adenine nucleotides. Rotenone (5 μM) induced rapid increase in NADH fluorescence due to inhibition of complex I, without changing in dynamics of FAD fluorescence increase. Antimycin A, a complex III inhibitor, in concentration of 1 μg/ml caused sharp increase in NADH fluorescence and moderate increase in FAD fluorescence in comparison to control. NaN3 (5 mM), a complex IV inhibitor, and CCCP (10 μM), a protonophore, caused decrease in NADH and FAD fluorescence. Moreover, all the inhibitors caused mitochondria swelling. NO donors, e.g. 0.1 mM sodium nitroprusside and sodium nitrite similarly to the effects of sodium azide. Energy-dependent Ca2+ accumulation in mitochondrial matrix (in presence of oxidation substrates and Mg-ATP2- complex) is associated with pronounced drop in NADH and FAD fluorescence followed by increased fluorescence of adenine nucleotides, which may be primarily due to Ca2+- dependent activation of dehydrogenases of citric acid cycle. Therefore, the fluorescent signal of FAD and NADH indicates changes in oxidation state of these nucleotides in isolated mitochondria, which may be used to assay the potential of effectors of electron transport chain.

Structure-Function of the Cytochrome b 6f Complex of Oxygenic Photosynthesis

DOE Office of Scientific and Technical Information (OSTI.GOV)

Cramer, W. A.; Yamashita, E.; Baniulis, D.

2014-03-20

Structure–function of the major integral membrane cytochrome b 6f complex that functions in cyanobacteria, algae, and green plants to transfer electrons between the two reaction center complexes in the electron transport chain of oxygenic photosynthesis is discussed in the context of recently obtained crystal structures of the complex and soluble domains of cytochrome f and the Rieske iron–sulfur protein. The energy-transducing function of the complex, generation of the proton trans-membrane electrochemical potential gradient, centers on the oxidation/reduction pathways of the plastoquinol/plastoquinone (QH 2/Q), the proton donor/acceptor within the complex. These redox reactions are carried out by five redox prosthetic groupsmore » embedded in each monomer, the high potential two iron–two sulfur cluster and the heme of cytochrome f on the electropositive side (p) of the complex, two noncovalently bound b-type hemes that cross the complex and the membrane, and a covalently bound c-type heme (c n) on the electronegative side (n). These five redox-active groups are organized in high- (cyt f/[2Fe–2S] and low-potential (hemes b p, b n, c n) electron transport pathways that oxidize and reduce the quinol and quinone on the p- and n-sides in a Q-cycle-type mechanism, while translocating as many as 2 H + to the p-side aqueous side for every electron transferred through the high potential chain to the photosystem I reaction center. The presence of heme c n and the connection of the n-side of the membrane and b 6f complex to the cyclic electron transport chain indicate that the Q cycle in the oxygenic photosynthetic electron transport chain differs from those connected to the bc 1 complex in the mitochondrial respiratory chain and the chain in photosynthetic bacteria. Inferences from the structure and C2 symmetry of the complex for the pathway of QH 2/Q transfer within the complex, problems posed by the presence of lipid in the inter-monomer cavity, and the narrow portal for QH2 passage through the p-side oxidation site proximal to the [2Fe–2S] cluster are discussed.« less

Unraveling fatty acid transport and activation mechanisms in Yarrowia lipolytica.

PubMed

Dulermo, Rémi; Gamboa-Meléndez, Heber; Ledesma-Amaro, Rodrigo; Thévenieau, France; Nicaud, Jean-Marc

2015-09-01

Fatty acid (FA) transport and activation have been extensively studied in the model yeast species Saccharomyces cerevisiae but have rarely been examined in oleaginous yeasts, such as Yarrowia lipolytica. Because the latter begins to be used in biodiesel production, understanding its FA transport and activation mechanisms is essential. We found that Y. lipolytica has FA transport and activation proteins similar to those of S. cerevisiae (Faa1p, Pxa1p, Pxa2p, Ant1p) but mechanism of FA peroxisomal transport and activation differs greatly with that of S. cerevisiae. While the ScPxa1p/ScPxa2p heterodimer is essential for growth on long-chain FAs, ΔYlpxa1 ΔYlpxa2 is not impaired for growth on FAs. Meanwhile, ScAnt1p and YlAnt1p are both essential for yeast growth on medium-chain FAs, suggesting they function similarly. Interestingly, we found that the ΔYlpxa1 ΔYlpxa2 ΔYlant1 mutant was unable to grow on short-, medium-, or long-chain FAs, suggesting that YlPxa1p, YlPxa2p, and YlAnt1p belong to two different FA degradation pathways. We also found that YlFaa1p is involved in FA storage in lipid bodies and that FA remobilization largely depended on YlFat1p, YlPxa1p and YlPxa2p. This study is the first to comprehensively examine FA intracellular transport and activation in oleaginous yeast. Copyright © 2015. Published by Elsevier B.V.

Coherence and superconductivity in coupled one-dimensional chains: a case study of YBa2Cu3Oy.

PubMed

Lee, Y-S; Segawa, Kouji; Ando, Yoichi; Basov, D N

2005-04-08

We report the infrared (IR) response of Cu-O chains in the high-T(c) superconductor YBa(2)Cu(3)O(y) over the doping range spanning y=6.28-6.75. We find evidence for a power law scaling at mid-IR frequencies consistent with predictions for Tomonaga-Luttinger liquid, thus supporting the notion of one-dimensional transport in the chains. We analyze the role of coupling to the CuO2 planes in establishing metallicity and superconductivity in disordered chain fragments.

Low-temperature transport in out-of-equilibrium XXZ chains

NASA Astrophysics Data System (ADS)

Bertini, Bruno; Piroli, Lorenzo

2018-03-01

We study the low-temperature transport properties of out-of-equilibrium XXZ spin-1/2 chains. We consider the protocol where two semi-infinite chains are prepared in two thermal states at small but different temperatures and suddenly joined together. We focus on the qualitative and quantitative features of the profiles of local observables, which at large times t and distances x from the junction become functions of the ratio \\zeta=x/t . By means of the generalized hydrodynamic equations, we analyse the rich phenomenology arising by considering different regimes of the phase diagram. In the gapped phases, variations of the profiles are found to be exponentially small in the temperatures, but described by non-trivial functions of ζ. We provide analytical formulae for the latter, which give accurate results also for small but finite temperatures. In the gapless regime, we show how the three-step conformal predictions for the profiles of energy density and energy current are naturally recovered from the hydrodynamic equations. Moreover, we also recover the recent non-linear Luttinger liquid predictions for low-temperature transport: universal peaks of width \

[Respiration of wheat root cells under simultaneous inhibition of parts I and III of the electron transport chain of mitochondria by rotenone and antimycine A].

PubMed

Rakhmatullina, D F; Gordon, L Kh; Ogorodnikova, T I

2005-01-01

Respiration of excised roots of 5 day old wheat seedlings with blocked mitochondrial oxidation under simultaneous action of rotenone and antimycine A was studied. A reduced rate of oxygen uptake was observed within the first hour of root treatment inhibitors. However, after a 5 h exposure there was an increase in oxygen uptake, which was prevented by KCN but amplified by malate and ascorbate. The application of inhibitors caused a considerable increase in the respiratory coefficient (RC) up to 2.1, that suggests a significant CO2 release, when the initial sites of mitochondrial electron transport chain were inhibited. RC did not raise, when ascorbate was added in the presence of inhibitors. We assume that inhibition of mitochondrial oxidation at I and III sites of electron transport chain facilitates switching on the alternative paths of reductant translocation to oxygen. Participation of ATPases and redox system of plasma membrane in the response reactions of respiration directed to the restoration of ion, particularly, proton homeostasis in conditions of inhibited mitochondrial oxidation is discussed.

Non-adiabatic quantum state preparation and quantum state transport in chains of Rydberg atoms

NASA Astrophysics Data System (ADS)

Ostmann, Maike; Minář, Jiří; Marcuzzi, Matteo; Levi, Emanuele; Lesanovsky, Igor

2017-12-01

Motivated by recent progress in the experimental manipulation of cold atoms in optical lattices, we study three different protocols for non-adiabatic quantum state preparation and state transport in chains of Rydberg atoms. The protocols we discuss are based on the blockade mechanism between atoms which, when excited to a Rydberg state, interact through a van der Waals potential, and rely on single-site addressing. Specifically, we discuss protocols for efficient creation of an antiferromagnetic GHZ state, a class of matrix product states including a so-called Rydberg crystal and for the state transport of a single-qubit quantum state between two ends of a chain of atoms. We identify system parameters allowing for the operation of the protocols on timescales shorter than the lifetime of the Rydberg states while yielding high fidelity output states. We discuss the effect of positional disorder on the resulting states and comment on limitations due to other sources of noise such as radiative decay of the Rydberg states. The proposed protocols provide a testbed for benchmarking the performance of quantum information processing platforms based on Rydberg atoms.

Molecular Simulation Evaluation of Macromolecular Transport through Nanofiltration Membranes

NASA Astrophysics Data System (ADS)

Almodovar Arbelo, Noelia; Boudouris, Bryan; Corti, David

A hybrid Monte Carlo and Molecular Dynamics simulation technique was implemented to elucidate the equilibrium behavior and transport properties of a model macromolecule as it navigated across a nanoporous polymer thin film (i.e., a nanofiltration membrane). The model linear homopolymer chosen was one that had interactions that were representative of poly(ethylene oxide) (PEO) due to the known interactions of PEO with solution molecules when a PEO chain is dissolved in an aqueous environment. The structural rearrangements of the PEO chain as it passes through the nanopore under an imposed chemical potential gradient was quantified as a function of solvent quality, polymer chain length, nanopore diameter and shape, and PEO-nanopore wall interactions. Thus, these computational studies provide a more detailed picture of the underlying physical mechanisms that drive macromolecular transport through nanopores, and, in particular, how dimensionally-large macromolecules (i.e., with large radii of gyration) enter and move through dimensionally-small pores (i.e., small radii nanopores). The insights gained from these studies will aid in the development of more cost-effective water purification systems in separation technologies for myriad industrial applications.

Energy transport in the three coupled α-polypeptide chains of collagen molecule with long-range interactions effect

NASA Astrophysics Data System (ADS)

Mvogo, Alain; Ben-Bolie, G. H.; Kofané, T. C.

2015-06-01

The dynamics of three coupled α-polypeptide chains of a collagen molecule is investigated with the influence of power-law long-range exciton-exciton interactions. The continuum limit of the discrete equations reveal that the collagen dynamics is governed by a set of three coupled nonlinear Schrödinger equations, whose dispersive coefficient depends on the LRI parameter r. We construct the analytic symmetric and asymmetric (antisymmetric) soliton solutions, which match with the structural features of collagen related with the acupuncture channels. These solutions are used as initial conditions for the numerical simulations of the discrete equations, which reveal a coherent transport of energy in the molecule for r > 3. The results also indicate that the width of the solitons is a decreasing function of r, which help to stabilize the solitons propagating in the molecule. To confirm further the efficiency of energy transport in the molecule, the modulational instability of the system is performed and the numerical simulations show that the energy can flow from one polypeptide chain to another in the form of nonlinear waves.

Solute transport in a single fracture involving an arbitrary length decay chain with rock matrix comprising different geological layers.

PubMed

Mahmoudzadeh, Batoul; Liu, Longcheng; Moreno, Luis; Neretnieks, Ivars

2014-08-01

A model is developed to describe solute transport and retention in fractured rocks. It accounts for advection along the fracture, molecular diffusion from the fracture to the rock matrix composed of several geological layers, adsorption on the fracture surface, adsorption in the rock matrix layers and radioactive decay-chains. The analytical solution, obtained for the Laplace-transformed concentration at the outlet of the flowing channel, can conveniently be transformed back to the time domain by the use of the de Hoog algorithm. This allows one to readily include it into a fracture network model or a channel network model to predict nuclide transport through channels in heterogeneous fractured media consisting of an arbitrary number of rock units with piecewise constant properties. More importantly, the simulations made in this study recommend that it is necessary to account for decay-chains and also rock matrix comprising at least two different geological layers, if justified, in safety and performance assessment of the repositories for spent nuclear fuel. Copyright © 2014 Elsevier B.V. All rights reserved.

Caloric restriction improves efficiency and capacity of the mitochondrial electron transport chain in Saccharomyces cerevisiae

DOE Office of Scientific and Technical Information (OSTI.GOV)

Choi, Joon-Seok; Choi, Kyung-Mi; Lee, Cheol-Koo, E-mail: cklee2005@korea.ac.kr

2011-06-03

Highlights: {yields} Calorie restriction (CR) increases electron transport chain (ETC) at both RNA and protein level. {yields} CR enhances mitochondrial membrane potential, and, regardless of ages, reduces reactive oxygen species. {yields} CR increases both efficiency and capacity of the ETC. {yields} CR induces intensive modulation at mitochondrial ETC where might be a major site leading to extension of lifespan. -- Abstract: Caloric restriction (CR) is known to extend lifespan in a variety of species; however, the mechanism remains unclear. In this study, we found that CR potentiated the mitochondrial electron transport chain (ETC) at both the transcriptional and translational levels.more » Indeed, mitochondrial membrane potential (MMP) was increased by CR, and, regardless of ages, overall reactive oxygen species (ROS) generation was decreased by CR. With these changes, overall growth rate of cells was maintained under various CR conditions, just like cells under a non-restricted condition. All of these data support increased efficiency and capacity of the ETC by CR, and this change might lead to extension of lifespan.« less

Effect of chronic pre-treatment with angiotensin converting enzyme inhibition on skeletal muscle mitochondrial recovery after ischemia/reperfusion.

PubMed

Thaveau, Fabien; Zoll, Joffrey; Bouitbir, Jamal; N'guessan, Benoît; Plobner, Philippe; Chakfe, Nabil; Kretz, Jean-Georges; Richard, Ruddy; Piquard, François; Geny, Bernard

2010-06-01

Impaired skeletal muscle energetic participates in peripheral arterial disease (PAD) patient's morbidity and mortality. Angiotensin converting enzyme inhibition (ACEi), cornerstone for pharmacologic risk factor management in PAD patients, might also be interesting by protecting skeletal muscle energetic. We therefore determined whether chronic ACEi might reduce ischemia-induced mitochondrial respiratory chain dysfunction in the frequent setting of hindlimb ischemia-reperfusion. Ischemic legs of rats submitted to 5 h ischemia induced by a rubber band tourniquet applied on the root of the hindlimb followed by reperfusion without (IR, n = 11) or after ACEi (n = 14; captopril 40 mg/kg per day during 28 days before surgery) were studied and compared to that of sham-operated animals (n = 11). The effect of ACEi on the non-ischemic contralateral leg was also determined in the ACEi group. Maximal oxidative capacities (V(max)) and complexes I, II and IV activities of the mitochondrial respiratory chain of the gastrocnemius muscle were determined using glutamate-malate, succinate and TMPD-ascorbate substrates. Arterial blood pressure was significantly decreased after ACEi (124 +/- 2.8 vs. 108 +/- 4.19 mmHg; P = 0.01). Ischemia-reperfusion reduced V(max) (4.4 +/- 0.4 vs. 8.7 +/- 0.5 micromol O2/min/g dry weight, -49%, P < 0.001), affecting mitochondrial complexes I, II and IV activities. ACEi failed to modulate ischemia-induced dysfunction (V(max) 5.1 +/- 0.7 micromol O2/min/g dry weight) or the non-ischemic contralateral muscle respiratory rate. Ischemia-reperfusion significantly impaired the mitochondrial respiratory chain I, II and IV complexes of skeletal muscle. Pharmacologic pre-treatment with ACEi did not prevent or increase such alterations. Further studies might be useful to improve the pharmacologic conditioning of PAD patients needing arterial revascularization.

Tailoring Thermal Conductivity of Single-stranded Carbon-chain Polymers through Atomic Mass Modification

PubMed Central

Liao, Quanwen; Zeng, Lingping; Liu, Zhichun; Liu, Wei

2016-01-01

Tailoring the thermal conductivity of polymers is central to enlarge their applications in the thermal management of flexible integrated circuits. Progress has been made over the past decade by fabricating materials with various nanostructures, but a clear relationship between various functional groups and thermal properties of polymers remains to be established. Here, we numerically study the thermal conductivity of single-stranded carbon-chain polymers with multiple substituents of hydrogen atoms through atomic mass modification. We find that their thermal conductivity can be tuned by atomic mass modifications as revealed through molecular dynamics simulations. The simulation results suggest that heavy homogeneous substituents do not assist heat transport and trace amounts of heavy substituents can in fact hinder heat transport substantially. Our analysis indicates that carbon chain has the biggest contribution (over 80%) to the thermal conduction in single-stranded carbon-chain polymers. We further demonstrate that atomic mass modifications influence the phonon bands of bonding carbon atoms, and the discrepancies of phonon bands between carbon atoms are responsible for the remarkable drops in thermal conductivity and large thermal resistances in carbon chains. Our study provides fundamental insight into how to tailor the thermal conductivity of polymers through variable substituents. PMID:27713563

Aspirin Increases Mitochondrial Fatty Acid Oxidation

PubMed Central

Uppala, Radha; Dudiak, Brianne; Beck, Megan E.; Bharathi, Sivakama S.; Zhang, Yuxun; Stolz, Donna B.; Goetzman, Eric S.

2016-01-01

The metabolic effects of salicylates are poorly understood. This study investigated the effects of aspirin on fatty acid oxidation. Aspirin increased mitochondrial long-chain fatty acid oxidation, but inhibited peroxisomal fatty acid oxidation, in two different cell lines. Aspirin increased mitochondrial protein acetylation and was found to be a stronger acetylating agent in vitro than acetyl-CoA. However, aspirin-induced acetylation did not alter the activity of fatty acid oxidation proteins, and knocking out the mitochondrial deacetylase SIRT3 did not affect the induction of long-chain fatty acid oxidation by aspirin. Aspirin did not change oxidation of medium-chain fatty acids, which can freely traverse the mitochondrial membrane. Together, these data indicate that aspirin does not directly alter mitochondrial matrix fatty acid oxidation enzymes, but most likely exerts its effects at the level of long-chain fatty acid transport into mitochondria. The drive on mitochondrial fatty acid oxidation may be a compensatory response to altered mitochondrial morphology and inhibited electron transport chain function, both of which were observed after 24 hr incubation of cells with aspirin. These studies provide insight into the pathophysiology of Reye Syndrome, which is known to be triggered by aspirin ingestion in patients with fatty acid oxidation disorders. PMID:27856258

Applying Alkyl-Chain Surface Functionalizations in Mesoporous Inorganic Structures: Their Impact on Gas Flow and Selectivity Depending on Temperature.

PubMed

Besser, Benjamin; Ahmed, Atiq; Baune, Michael; Kroll, Stephen; Thöming, Jorg; Rezwan, Kurosch

2016-10-12

Porous inorganic capillary membranes are prepared to serve as model structures for the experimental investigation of the gas transport in functionalized mesopores. The porous structures possess a mean pore diameter of 23 nm which is slightly reduced to 20 nm after immobilizing C 16 -alkyl chains on the surface. Gas permeation measurements are performed at temperatures ranging from 0 to 80 °C using Ar, N 2 , and CO 2 . Nonfunctionalized structures feature a gas transport according to Knudsen diffusion with regard to gas flow and selectivity. After C 16 -functionalization, the gas flow is reduced by a factor of 10, and the ideal selectivities deviate from the Knudsen theory. CO 2 adsorption measurements show a decrease in total amount of adsorbed gas and isosteric heat of adsorption. It is hypothesized that the immobilized C 16 -chains sterically influence the gas transport behavior without a contribution from adsorption effects. The reduced gas flow derives from an additional surface resistance caused by the C 16 -chains spacially limiting the adsorption and desorption directions for gas molecules propagating through the structure, resulting in longer diffusion paths. In agreement, the gas flow is found to correlate with the molecular diameter of the gas species (CO 2 < Ar < N 2 ) increasing the resistance for larger molecules. This affects the ideal selectivities with the relation [Formula: see text]. The influence on selectivity increases with increasing temperature which leads to the conclusion that the temperature induced movement of the C 16 -chains is responsible for the stronger interaction between gas molecules and surface functional groups.

Design and modeling of sustainable bioethanol supply chain by minimizing the total ecological footprint in life cycle perspective.

PubMed

Ren, Jingzheng; Manzardo, Alessandro; Toniolo, Sara; Scipioni, Antonio; Tan, Shiyu; Dong, Lichun; Gao, Suzhao

2013-10-01

The purpose of this paper is to develop a model for designing the most sustainable bioethanol supply chain. Taking into consideration of the possibility of multiple-feedstock, multiple transportation modes, multiple alternative technologies, multiple transport patterns and multiple waste disposal manners in bioethanol systems, this study developed a model for designing the most sustainable bioethanol supply chain by minimizing the total ecological footprint under some prerequisite constraints including satisfying the goal of the stakeholders', the limitation of resources and energy, the capacity of warehouses, the market demand and some technological constraints. And an illustrative case of multiple-feedstock bioethanol system has been studied by the proposed method, and a global best solution by which the total ecological footprint is the minimal has been obtained. Copyright © 2013 Elsevier Ltd. All rights reserved.

Bethe-Boltzmann hydrodynamics and spin transport in the XXZ chain

NASA Astrophysics Data System (ADS)

Bulchandani, Vir B.; Vasseur, Romain; Karrasch, Christoph; Moore, Joel E.

2018-01-01

Quantum integrable systems, such as the interacting Bose gas in one dimension and the XXZ quantum spin chain, have an extensive number of local conserved quantities that endow them with exotic thermalization and transport properties. We discuss recently introduced hydrodynamic approaches for such integrable systems from the viewpoint of kinetic theory and extend the previous works by proposing a numerical scheme to solve the hydrodynamic equations for finite times and arbitrary locally equilibrated initial conditions. We then discuss how such methods can be applied to describe nonequilibrium steady states involving ballistic heat and spin currents. In particular, we show that the spin Drude weight in the XXZ chain, previously accessible only by rigorous techniques of limited scope or controversial thermodynamic Bethe ansatz arguments, may be evaluated from hydrodynamics in very good agreement with density-matrix renormalization group calculations.

An ab initio study on the effect of iron atom junction on transport characteristics of carbon-silicon mixed chain

NASA Astrophysics Data System (ADS)

Hu, Wei; Zhou, Qinghua; Liu, Wenhua; Liang, Yan; Wang, Tao; Wan, Haiqing

2018-04-01

The effect of iron atom junction on transport characteristics of carbon-silicon mixed chain has been studied from an ab initio study. At zero bias, the Fe(CSi)n system appears to be the decrease of the conductance as the number of the Si-C pairs in the chain increases (n changes). When n > 5, the conductance tends to zero. These changes are independent of the transferring charge of the system, depending on the coupling of the electrodes and the central region. Under bias, the higher the bias voltage, the bigger the transmission coefficient of the system, and the transmission peak moves closer to the Fermi level. The I-V curves of Fe(CSi)2 and Fe (CSi)3 are linear, showing the behavior of metal resistance.

Inhibition of cyclooxygenase-2 alleviates liver cirrhosis via improvement of the dysfunctional gut-liver axis in rats.

PubMed

Gao, Jin-Hang; Wen, Shi-Lei; Tong, Huan; Wang, Chun-Hui; Yang, Wen-Juan; Tang, Shi-Hang; Yan, Zhao-Ping; Tai, Yang; Ye, Cheng; Liu, Rui; Huang, Zhi-Yin; Tang, Ying-Mei; Yang, Jin-Hui; Tang, Cheng-Wei

2016-06-01

Inflammatory transport through the gut-liver axis may facilitate liver cirrhosis. Cyclooxygenase-2 (COX-2) has been considered as one of the important molecules that regulates intestinal epithelial barrier function. This study was aimed to test the hypothesis that inhibition of COX-2 by celecoxib might alleviate liver cirrhosis via reduction of intestinal inflammatory transport in thiacetamide (TAA) rat model. COX-2/prostaglandin E2 (PGE2)/EP-2/p-ERK integrated signal pathways regulated the expressions of intestinal zonula occludens-1 (ZO-1) and E-cadherin, which maintain the function of intestinal epithelial barrier. Celecoxib not only decreased the intestinal permeability to a 4-kDa FITC-dextran but also significantly increased expressions of ZO-1 and E-cadherin. When celecoxib greatly decreased intestinal levels of LPS, TNF-α, and IL-6, it significantly enhanced T cell subsets reduced by TAA. As a result, liver fibrosis induced by TAA was significantly alleviated in the celecoxib group. These data indicated that celecoxib improved the integrity of intestinal epithelial barrier, blocked inflammatory transport through the dysfunctional gut-liver axis, and ameliorated the progress of liver cirrhosis. Copyright © 2016 the American Physiological Society.

Frameworking memory and serotonergic markers.

PubMed

Meneses, Alfredo

2017-07-26

The evidence for neural markers and memory is continuously being revised, and as evidence continues to accumulate, herein, we frame earlier and new evidence. Hence, in this work, the aim is to provide an appropriate conceptual framework of serotonergic markers associated with neural activity and memory. Serotonin (5-hydroxytryptamine [5-HT]) has multiple pharmacological tools, well-characterized downstream signaling in mammals' species, and established 5-HT neural markers showing new insights about memory functions and dysfunctions, including receptors (5-HT1A/1B/1D, 5-HT2A/2B/2C, and 5-HT3-7), transporter (serotonin transporter [SERT]) and volume transmission present in brain areas involved in memory. Bidirectional influence occurs between 5-HT markers and memory/amnesia. A growing number of researchers report that memory, amnesia, or forgetting modifies neural markers. Diverse approaches support the translatability of using neural markers and cerebral functions/dysfunctions, including memory formation and amnesia. At least, 5-HT1A, 5-HT4, 5-HT6, and 5-HT7 receptors and SERT seem to be useful neural markers and therapeutic targets. Hence, several mechanisms cooperate to achieve synaptic plasticity or memory, including changes in the expression of neurotransmitter receptors and transporters.

Global supply chain management/transportation : building a global network of scholars and educators : phase I

DOT National Transportation Integrated Search

2008-01-01

During the project period two conferences--1st Symposium and Workshop in Global : Supply Chain (http://www.business.utoledo.edu/scm) at University of Toledo, Toledo, : OH, USA (October 6-7, 2007) and 2nd Symposium and Workshop in Global Supply : Chai...

77 FR 25721 - National Maritime Security Advisory Committee; Meeting

Federal Register 2010, 2011, 2012, 2013, 2014

2012-05-01

... meeting will be closed to the public. (2) Global Supply Chain Security Initiative. Per the SAFE Port Act (Pub. L. 109-347) the Coast Guard consults with the NMSAC on the Global Supply Chain Security... submitting comments. Mail: Docket Management Facility (M-30), U.S. Department of Transportation, West...

Unique quadruple immunofluorescence assay demonstrates mitochondrial respiratory chain dysfunction in osteoblasts of aged and PolgA(-/-) mice.

PubMed

Dobson, Philip F; Rocha, Mariana C; Grady, John P; Chrysostomou, Alexia; Hipps, Daniel; Watson, Sharon; Greaves, Laura C; Deehan, David J; Turnbull, Doug M

2016-08-24

Fragility fractures caused by osteoporosis affect millions of people worldwide every year with significant levels of associated morbidity, mortality and costs to the healthcare economy. The pathogenesis of declining bone mineral density is poorly understood but it is inherently related to increasing age. Growing evidence in recent years, especially that provided by mouse models, suggest that accumulating somatic mitochondrial DNA mutations may cause the phenotypic changes associated with the ageing process including osteoporosis. Methods to study mitochondrial abnormalities in individual osteoblasts, osteoclasts and osteocytes are limited and impair our ability to assess the changes seen with age and in animal models of ageing. To enable the assessment of mitochondrial protein levels, we have developed a quadruple immunofluorescence method to accurately quantify the presence of mitochondrial respiratory chain components within individual bone cells. We have applied this technique to a well-established mouse model of ageing and osteoporosis and show respiratory chain deficiency.

Perspectives of drug-based neuroprotection targeting mitochondria.

PubMed

Procaccio, V; Bris, C; Chao de la Barca, J M; Oca, F; Chevrollier, A; Amati-Bonneau, P; Bonneau, D; Reynier, P

2014-05-01

Mitochondrial dysfunction has been reported in most neurodegenerative diseases. These anomalies include bioenergetic defect, respiratory chain-induced oxidative stress, defects of mitochondrial dynamics, increase sensitivity to apoptosis, and accumulation of damaged mitochondria with instable mitochondrial DNA. Significant progress has been made in our understanding of the pathophysiology of inherited mitochondrial disorders but most have no effective therapies. The development of new metabolic treatments will be useful not only for rare mitochondrial disorders but also for the wide spectrum of common age-related neurodegenerative diseases shown to be associated with mitochondrial dysfunction. A better understanding of the mitochondrial regulating pathways raised several promising perspectives of neuroprotection. This review focuses on the pharmacological approaches to modulate mitochondrial biogenesis, the removal of damaged mitochondria through mitophagy, scavenging free radicals and also dietary measures such as ketogenic diet. Copyright © 2014 Elsevier Masson SAS. All rights reserved.

Commercial products to preserve specimens for tuberculosis diagnosis: a systematic review.

PubMed

Reeve, B W P; McFall, S M; Song, R; Warren, R; Steingart, K R; Theron, G

2018-07-01

Eliminating tuberculosis in high-burden settings requires improved diagnostic capacity. Important tests such as Xpert® MTB/RIF and culture are often performed at centralised laboratories that are geographically distant from the point of specimen collection. Preserving specimen integrity during transportation, which could affect test performance, is challenging. To conduct a systematic review of commercial products for specimen preservation for a World Health Organization technical consultation. Databases were searched up to January 2018. Methodological quality was assessed using Quality Assessment of Technical Studies, a new technical study quality-appraisal tool, and Quality Assessment of Diagnostic Accuracy Studies-2. Studies were analysed descriptively in terms of the different products, study designs and diagnostic strategies used. Four products were identified from 16 studies: PrimeStore-Molecular-Transport-Medium (PS-MTM), FTA card, GENO•CARD (all for nucleic acid amplification tests [NAATs]) and OMNIgene•SPUTUM (OMS; culture, NAATs). PS-MTM, but not FTA card or GENO•CARD, rendered Mycobacterium tuberculosis non-culturable. OMS reduced Löwenstein-Jensen but not MGIT™ 960™ contamination, led to delayed MGIT time-to-positivity, resulted in Xpert performance similar to cold chain-transported untreated specimens, and obviated the need for N-acetyl-L-cysteine-sodium hydroxide decontamination. Data from paucibacillary specimens were limited. Evidence that a cold chain improves culture was mixed and absent for Xpert. The effect of the product alone could be discerned in only four studies. Limited evidence suggests that transport products result in test performance comparable to that seen in cold chain-transported specimens.

Quantum phase transition and protected ideal transport in a Kondo chain

DOE PAGES

Tsvelik, A. M.; Yevtushenko, O. M.

2015-11-30

We study the low energy physics of a Kondo chain where electrons from a one-dimensional band interact with magnetic moments via an anisotropic exchange interaction. It is demonstrated that the anisotropy gives rise to two different phases which are separated by a quantum phase transition. In the phase with easy plane anisotropy, Z2 symmetry between sectors with different helicity of the electrons is broken. As a result, localization effects are suppressed and the dc transport acquires (partial) symmetry protection. This effect is similar to the protection of the edge transport in time-reversal invariant topological insulators. The phase with easy axismore » anisotropy corresponds to the Tomonaga-Luttinger liquid with a pronounced spin-charge separation. The slow charge density wave modes have no protection against localizatioin.« less

Specific Interaction between Redox Phospholipid Polymers and Plastoquinone in Photosynthetic Electron Transport Chain.

PubMed

Tanaka, Kenya; Kaneko, Masahiro; Ishikawa, Masahito; Kato, Souichiro; Ito, Hidehiro; Kamachi, Toshiaki; Kamiya, Kazuhide; Nakanishi, Shuji

2017-04-19

Redox phospholipid polymers added in culture media are known to be capable of extracting electrons from living photosynthetic cells across bacterial cell membranes with high cytocompatibility. In the present study, we identify the intracellular redox species that transfers electrons to the polymers. The open-circuit electrochemical potential of an electrolyte containing the redox polymer and extracted thylakoid membranes shift to positive (or negative) under light irradiation, when an electron transport inhibitor specific to plastoquinone is added upstream (or downstream) in the photosynthetic electron transport chain. The same trend is also observed for a medium containing living photosynthetic cells of Synechococcus elongatus PCC7942. These results clearly indicate that the phospholipid redox polymers extract photosynthetic electrons mainly from plastoquinone. © 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Human neuronal uncoupling proteins 4 and 5 (UCP4 and UCP5): structural properties, regulation, and physiological role in protection against oxidative stress and mitochondrial dysfunction

PubMed Central

Ramsden, David B; Ho, Philip W-L; Ho, Jessica W-M; Liu, Hui-Fang; So, Danny H-F; Tse, Ho-Man; Chan, Koon-Ho; Ho, Shu-Leong

2012-01-01

Uncoupling proteins (UCPs) belong to a large family of mitochondrial solute carriers 25 (SLC25s) localized at the inner mitochondrial membrane. UCPs transport protons directly from the intermembrane space to the matrix. Of five structural homologues (UCP1 to 5), UCP4 and 5 are principally expressed in the central nervous system (CNS). Neurons derived their energy in the form of ATP that is generated through oxidative phosphorylation carried out by five multiprotein complexes (Complexes I–V) embedded in the inner mitochondrial membrane. In oxidative phosphorylation, the flow of electrons generated by the oxidation of substrates through the electron transport chain to molecular oxygen at Complex IV leads to the transport of protons from the matrix to the intermembrane space by Complex I, III, and IV. This movement of protons to the intermembrane space generates a proton gradient (mitochondrial membrane potential; MMP) across the inner membrane. Complex V (ATP synthase) uses this MMP to drive the conversion of ADP to ATP. Some electrons escape to oxygen-forming harmful reactive oxygen species (ROS). Proton leakage back to the matrix which bypasses Complex V resulting in a major reduction in ROS formation while having a minimal effect on MMP and hence, ATP synthesis; a process termed “mild uncoupling.” UCPs act to promote this proton leakage as means to prevent excessive build up of MMP and ROS formation. In this review, we discuss the structure and function of mitochondrial UCPs 4 and 5 and factors influencing their expression. Hypotheses concerning the evolution of the two proteins are examined. The protective mechanisms of the two proteins against neurotoxins and their possible role in regulating intracellular calcium movement, particularly with regard to the pathogenesis of Parkinson's disease are discussed. PMID:22950050

Transport of dissolved and suspended material by the Potomac River at Chain Bridge, at Washington, D.C., water years 1978-81

USGS Publications Warehouse

Blanchard, Stephen F.; Hahl, D.C.

1987-01-01

The measuring station Potomac River at Chain Bridge at Washington, D.C., is located at the upstream end of the tidal Potomac River. Water-quality data were collected intensively at this site from December 1977 through September 1981 as part of a study of the tidal Potomac River and Estuary. Analysis of water-discharge data from the long-term gage at Little Falls, just up stream from Chain Bridge, shows that streamflow for the 1979-81 water years had characteristics similar to the 51-year average discharge (1931-81). Loads were computed for various forms of phosphorus and nitrogen, major cations and anions, silica, biochemical oxygen demand, chlorophyll a and pheophytin, and suspended sediment. Load duration curves for the 1979-81 water years show that 50 percent of the time, water passing Chain Bridge carried at least 28 metric tons per day of total nitrogen, 1.0 metric tons per day of total phosphorus, 70 metric tons per day of silica, and 270 metric tons per day of suspended sediment. No consistent seasonal change in constituent concentrations was observed; however, a seasonal trend in loads due to seasonal changes in runoff was noted. Some storm runoff events transported as much dissolved and suspended material as is transported during an entire low-flow year.

[Non-pharmacologic therapy of age-related macular degeneration, based on the etiopathogenesis of the disease].

PubMed

Fischer, Tamás

2015-07-12

It has a great therapeutic significance that the disorder of the vascular endothelium, which supplies the affected ocular structures, plays a major role in the development of age-related macular degeneration. Chronic inflammation is closely linked to diseases associated with endothelial dysfuncition and age-related macular degeneration is accompanied by a general inflammatory response. The vascular wall including those in chorioids may be activated by several repeated and/or prolonged mechanical, physical, chemical, microbiological, immunologic and genetic factors causing a protracted host defence response with a consequent vascular damage, which leads to age-related macular degeneration. Based on this concept, age-related macular degeneration is a local manifestation of the systemic vascular disease. This recognition should have therapeutic implications because restoration of endothelial dysfunction can stabilize the condition of chronic vascular disease including age-related macular degeneration, as well. Restoration of endothelial dysfunction by non-pharmacological or pharmacological interventions may prevent the development or improve endothelial dysfunction resulting in prevention or improvement of age-related macular degeneration. Non-pharmacological interventions which may have beneficial effect in endothelial dysfunction include (1) smoking cessation; (2) reduction of increased body weight; (3) adequate physical activity; (4) appropriate diet (a) proper dose of flavonoids, polyphenols and kurcumin; (b) omega-3 long-chain polyunsaturated fatty acids: docosahexaenoic acid and eicosapentaenoic acid; (c) carotenoids, lutein and zeaxanthins), (d) management of dietary glycemic index, (e) caloric restriction, and (5) elimination of stressful lifestyle. Non-pharmacological interventions should be preferable even if medicaments are also used for the treatment of endothelial dysfunction.

DOE Office of Scientific and Technical Information (OSTI.GOV)

Xi, Liang; Bird, Matthew; Mauro, Gina

Triplet excitons created in poly-2,7-(9,9-dihexyl)fluorene (pF) chains with end trap groups in solution are efficiently transported to and captured by the end groups. The triplets explore the entire lengths of the chains, even for ~100 nm long chains enabling determination of the completeness of end capping. The results show that the chains continuous: they may contain transient barriers or traps, such as those from fluctuations of dihedral angles, but are free of major defects that stop motion of the triplets. Quantitative determinations are aided by the addition of a strong electron donor, TMPD, which removes absorption bands of the end-trappedmore » triplets. For chains having at least one end trap, triplet capture is quantitative on the 1 µs timescale imposed by the use of the donor. Fractions of chains having no end traps were 0.15 for pF samples with anthraquinone (AQ) end traps and 0.063 with naphthylimide (NI) end traps. These determinations agreed with measurements by NMR for short (<40 polymer repeat units (PRU)) chains, where NMR determinations are accurate. The results find no evidence for traps or barriers to transport of triplets, and places limits on the possible presence of defects as impenetrable barriers to less than one per 300 PRU. The present results present a paradigm different from the current consensus, derived from observations of singlet excitons, that conjugated chains are divided into “segments,” perhaps by some kind of defects. For the present pF chains, the segmentation either does not apply to triplet excitons or is transient so that the defects are healed or surmounted in times much shorter than 1 µs. Triplets on chains without end trap groups transfer to chains with end traps on a slower time scale. Rate constants for these bimolecular triplet transfer reactions were found to increase with the length of the accepting chain, as did rate constants for triplet transfer to the chains from small molecules like biphenyl. As a result, a second set of polyfluorenes with 2-butyloctyl side chains was found to have a much lower completeness of end capping.« less

28 CFR 79.61 - Definitions.

Code of Federal Regulations, 2013 CFR

2013-07-01

... the lung or pulmonary fibrosis means chronic inflammation and scarring of the pulmonary interstitium... Criteria for Claims by Ore Transporters § 79.61 Definitions. (a) Chronic renal disease means the chronic... resulting in chronic renal dysfunction. (j) Nonmalignant respiratory disease means fibrosis of the lung...

Low molecular weight guluronate prevents TNF-α-induced oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells.

PubMed

Dun, Yun-lou; Zhou, Xiao-lin; Guan, Hua-shi; Yu, Guang-li; Li, Chun-xia; Hu, Ting; Zhao, Xia; Cheng, Xiao-lei; He, Xiao-xi; Hao, Jie-jie

2015-09-01

Muscle wasting is associated with a variety of chronic or inflammatory disorders. Evidence suggests that inflammatory cytokines play a vital role in muscle inflammatory pathology and this may result in oxidative damage and mitochondrial dysfunction in skeletal muscle. In our study, we used microwave degradation to prepare a water-soluble low molecular weight guluronate (LMG) of 3000 Da from Fucus vesiculosus obtained from Canada, the Atlantic Ocean. We demonstrated the structural characteristics, using HPLC, FTIR and NMR of LMG and investigated its effects on oxidative damage and mitochondrial dysfunction in C2C12 skeletal muscle cells induced by tumor necrosis factor alpha (TNF-α), a cell inflammatory cytokine. The results indicated that LMG could alleviate mitochondrial reactive oxygen species (ROS) production, increase the activities of antioxidant enzymes (GSH and SOD), promote mitochondrial membrane potential (MMP) and upregulate the expression of mitochondrial respiratory chain protein in TNF-α-induced C2C12 cells. LMG supplement also increased the mitochondrial DNA copy number and mitochondrial biogenesis related genes in TNF-α-induced C2C12 cells. LMG may exert these protective effects through the nuclear factor kappa B (NF-κB) signaling pathway. These suggest that LMG is capable of protecting TNF-α-induced C2C12 cells against oxidative damage and mitochondrial dysfunction.

Probing the conformation of a conserved glutamic acid within the Cl- pathway of a CLC H+/Cl- exchanger.

PubMed

Vien, Malvin; Basilio, Daniel; Leisle, Lilia; Accardi, Alessio

2017-04-03

The CLC proteins form a broad family of anion-selective transport proteins that includes both channels and exchangers. Despite extensive structural, functional, and computational studies, the transport mechanism of the CLC exchangers remains poorly understood. Several transport models have been proposed but have failed to capture all the key features of these transporters. Multiple CLC crystal structures have suggested that a conserved glutamic acid, Glu ex , can adopt three conformations and that the interconversion of its side chain between these states underlies H + /Cl - exchange. One of these states, in which Glu ex occupies the central binding site (S cen ) while Cl - ions fill the internal and external sites (S int and S ext ), has only been observed in one homologue, the eukaryotic cmCLC. The existence of such a state in other CLCs has not been demonstrated. In this study, we find that during transport, the prototypical prokaryotic CLC exchanger, CLC-ec1, adopts a conformation with functional characteristics that match those predicted for a cmCLC-like state, with Glu ex trapped in S cen between two Cl - ions. Transport by CLC-ec1 is reduced when [Cl - ] is symmetrically increased on both sides of the membrane and mutations that disrupt the hydrogen bonds stabilizing Glu ex in S cen destabilize this trapped state. Furthermore, inhibition of transport by high [Cl - ] is abolished in the E148A mutant, in which the Glu ex side chain is removed. Collectively, our results suggest that, during the CLC transport cycle, Glu ex can occupy S cen as well as the S ext position in which it has been captured crystallographically and that hydrogen bonds with the side chains of residues that coordinate ion binding to S cen play a role in determining the equilibrium between these two conformations. © 2017 Vien et al.

Kalpaamruthaa ameliorates mitochondrial and metabolic alterations in diabetes mellitus induced cardiovascular damage.

PubMed

Latha, Raja; Shanthi, Palanivelu; Sachdanandam, Panchanadham

2014-12-01

Efficacy of Kalpaamruthaa on the activities of lipid and carbohydrate metabolic enzymes, electron transport chain complexes and mitochondrial ATPases were studied in heart and liver of experimental rats. Cardiovascular damage (CVD) was developed in 8 weeks after type 2 diabetes mellitus induction with high fat diet (2 weeks) and low dose of streptozotocin (2 × 35 mg/kg b.w. i.p. in 24 hr interval). In CVD-induced rats, the activities of total lipase, cholesterol ester hydrolase and cholesterol ester synthetase were increased, while lipoprotein lipase and lecithin-cholesterol acyltransferase activities were decreased. The activities of lipid-metabolizing enzymes were altered by Kalpaamruthaa in CVD-induced rats towards normal. Kalpaamruthaa modulated the activities of glycolytic enzymes (hexokinase, phosphogluco-isomerase, aldolase and glucose-6-phosphate dehydrogenase), gluconeogenic enzymes (glucose-6-phosphatase and fructose-1, 6-bisphosphatase) and glycogenolytic enzyme (glycogen phosphorylase) along with increased glycogen content in the liver of CVD-induced rats. The activities of isocitrate dehydrogenase, succinate dehydrogenase, malate dehydrogenase, α-ketoglutarate dehydrogenase, Complexes and ATPases (Na(+)/K(+)-ATPase, Ca(2+)-ATPase and Mg(2+)-ATPase) were decreased in CVD-induced rats, which were ameliorated by the treatment with Kalpaamruthaa. This study ascertained the efficacy of Kalpaamruthaa for the treatment of CVD in diabetes through the modulation of metabolizing enzymes and mitochondrial dysfunction.

Mitochondrial bioenergetics decay in aging: beneficial effect of melatonin.

PubMed

Paradies, Giuseppe; Paradies, Valeria; Ruggiero, Francesca M; Petrosillo, Giuseppe

2017-11-01

Aging is a biological process characterized by progressive decline in physiological functions, increased oxidative stress, reduced capacity to respond to stresses, and increased risk of contracting age-associated disorders. Mitochondria are referred to as the powerhouse of the cell through their role in the oxidative phosphorylation to generate ATP. These organelles contribute to the aging process, mainly through impairment of electron transport chain activity, opening of the mitochondrial permeability transition pore and increased oxidative stress. These events lead to damage to proteins, lipids and mitochondrial DNA. Cardiolipin, a phospholipid of the inner mitochondrial membrane, plays a pivotal role in several mitochondrial bioenergetic processes as well as in mitochondrial-dependent steps of apoptosis and in mitochondrial membrane stability and dynamics. Cardiolipin alterations are associated with mitochondrial bienergetics decline in multiple tissues in a variety of physiopathological conditions, as well as in the aging process. Melatonin, the major product of the pineal gland, is considered an effective protector of mitochondrial bioenergetic function. Melatonin preserves mitochondrial function by preventing cardiolipin oxidation and this may explain, at least in part, the protective role of this compound in mitochondrial physiopathology and aging. Here, mechanisms through which melatonin exerts its protective role against mitochondrial dysfunction associated with aging and age-associated disorders are discussed.

Mitochondrial origin of extracelullar transferred electrons in yeast-based biofuel cells.

PubMed

Hubenova, Yolina; Mitov, Mario

2015-12-01

The influence of mitochondrial electron transport chain inhibitors on the electricity outputs of Candida melibiosica yeast-based biofuel cell was investigated. The addition of 30 μM rotenone or antimycin A to the yeast suspension results in a decrease in the current generation, corresponding to 25.7±1.3%, respectively 38.8±1.9% reduction in the electric charge passed through the bioelectrochemical system. The latter percentage coincides with the share of aerobic respiration in the yeast catabolic processes, determined by the decrease of the ethanol production during cultivation in the presence of oxygen compared with that obtained under strict anaerobic conditions. It was established that the presence of both inhibitors leads to almost complete mitochondrial dysfunction, expressed by inactivation of cytochrome c oxidase and NADH:ubiquinone oxidoreductase as well as reduced electrochemical activity of isolated yeast mitochondria. It was also found that methylene blue partially neutralized the rotenone poisoning, probably serving as alternative intracellular electron shuttle for by-passing the complex I blockage. Based on the obtained results, we suppose that electrons generated through the aerobic respiration processes in the mitochondria participate in the extracellular electron transfer from the yeast cells to the biofuel cell anode, which contributes to higher current outputs at aerobic conditions. Copyright © 2014 Elsevier B.V. All rights reserved.

mtDNA Mutations and Their Role in Aging, Diseases and Forensic Sciences

PubMed Central

Zapico, Sara C.; Ubelaker, Douglas H.

2013-01-01

Mitochondria are independent organelles with their own DNA. As a primary function, mitochondria produce the energy for the cell through Oxidative Phosphorylation (OXPHOS) in the Electron Transport Chain (ETC). One of the toxic products of this process is Reactive Oxygen Species (ROS), which can induce oxidative damage in macromolecules like lipids, proteins and DNA. Mitochondrial DNA (mtDNA) is less protected and has fewer reparation mechanisms than nuclear DNA (nDNA), and as such is more exposed to oxidative, mutation-inducing damage. This review analyzes the causes and consequences of mtDNA mutations and their relationship with the aging process. Neurodegenerative diseases, related with the aging, are consequences of mtDNA mutations resulting in a decrease in mitochondrial function. Also described are “mitochondrial diseases”, pathologies produced by mtDNA mutations and whose symptoms are related with mitochondrial dysfunction. Finally, mtDNA haplogroups are defined in this review; these groups are important for determination of geographical origin of an individual. Additionally, different haplogroups exhibit variably longevity and risk of certain diseases. mtDNA mutations in aging and haplogroups are of special interest to forensic science research. Therefore this review will help to clarify the key role of mtDNA mutations in these processes and support further research in this area. PMID:24307969

Cold ischemia contributes to the development of chronic rejection and mitochondrial injury after cardiac transplantation.

PubMed

Schneeberger, Stefan; Amberger, Albert; Mandl, Julia; Hautz, Theresa; Renz, Oliver; Obrist, Peter; Meusburger, Hugo; Brandacher, Gerald; Mark, Walter; Strobl, Daniela; Troppmair, Jakob; Pratschke, Johann; Margreiter, Raimund; Kuznetsov, Andrey V

2010-12-01

Chronic rejection (CR) remains an unsolved hurdle for long-term heart transplant survival. The effect of cold ischemia (CI) on progression of CR and the mechanisms resulting in functional deficit were investigated by studying gene expression, mitochondrial function, and enzymatic activity. Allogeneic (Lew→F344) and syngeneic (Lew→Lew) heart transplantations were performed with or without 10 h of CI. After evaluation of myocardial contraction, hearts were excised at 2, 10, 40, and 60 days for investigation of vasculopathy, gene expression, enzymatic activities, and mitochondrial respiration. Gene expression studies identified a gene cluster coding for subunits of the mitochondrial electron transport chain regulated in response to CI and CR. Myocardial performance, mitochondrial function, and mitochondrial marker enzyme activities declined in all allografts with time after transplantation. These declines were more rapid and severe in CI allografts (CR-CI) and correlated well with progression of vasculopathy and fibrosis. Mitochondria related gene expression and mitochondrial function are substantially compromised with the progression of CR and show that CI impacts on progression, gene profile, and mitochondrial function of CR. Monitoring mitochondrial function and enzyme activity might allow for earlier detection of CR and cardiac allograft dysfunction. © 2010 The Authors. Journal compilation © 2010 European Society for Organ Transplantation.

Cyclophilin B protects SH-SY5Y human neuroblastoma cells against MPP(+)-induced neurotoxicity via JNK pathway.

PubMed

Oh, Yoojung; Jeong, Kwon; Kim, Kiyoon; Lee, Young-Seok; Jeong, Suyun; Kim, Sung Soo; Yoon, Kyung-Sik; Ha, Joohun; Kang, Insug; Choe, Wonchae

2016-09-23

Parkinson's disease (PD) is the second most common neurodegenerative disorder of aging. PD involves a progressive loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenyl-1, 2, 3, 6-tetrahydropyidine (MPTP) and its toxic metabolite 1-methyl-4-phenylpyridinium ion (MPP+) inhibit the complex I of the mitochondrial electron transport chain, and have been widely used to construct PD models. Cyclophilin B (CypB) is an endoplasmic reticulum protein that binds to cyclosporine A as a cyclophilin family member. CypB has peptidyl-prolyl cis-trans isomerase (PPIase) activity. We investigated the protective effects of overexpressed CypB on MPP+-induced neurocytotoxicity in SH-SY5Y human neuroblastoma cells. Overexpressed CypB decreased MPP(+)-induced oxidative stress through the modulation of antioxidant enzymes including manganese superoxide dismutase and catalase, and prevented neurocytotoxicity via mitogen-activated protein kinase, especially the c-Jun N-terminal kinase pathway. In addition, CypB inhibited the activation of MPP(+)-induced the pro-apoptotic molecules poly (ADP-ribose) polymerase, Bax, and Bcl-2, and attenuated MPP(+)-induced mitochondrial dysfunction. The data suggest that overexpressed CypB protects neuronal cells from MPP+-induced dopaminergic neuronal cell death. Copyright © 2016 Elsevier Inc. All rights reserved.

Endoplasmic reticulum and mitochondria interplay mediates apoptotic cell death: relevance to Parkinson's disease.

PubMed

Arduíno, Daniela Moniz; Esteves, A Raquel; Cardoso, Sandra M; Oliveira, Catarina R

2009-09-01

Sporadic Parkinson's disease (PD) is a progressive neurodegenerative disease characterized by a loss of dopaminergic neurons in the substantia nigra pars compacta. Many cellular mechanisms are thought to be involved in the death of these specific neurons in PD, including oxidative stress, changes of intracellular calcium homeostasis, and mitochondrial dysfunction. Since recent studies have revealed that also endoplasmic reticulum (ER) stress in conjunction with abnormal protein degradation can contribute to the PD pathophysiology, we investigated here the molecular mechanisms underlying the interplay between ER and mitochondria and its relevance in the control of neuronal cell death in PD. We observed that MPP+ induced changes in the mitochondrial function, affecting mitochondrial membrane potential and electron transport chain function. Likewise, it was also evident the unfolded protein response activation by an overexpression of GRP78 protein. Moreover, stress stimuli caused the release of Ca2+ from the ER that consistently induced mitochondrial Ca2+ uptake, with a rise of mitochondrial matrix free Ca2+. Besides, Ca2+ release inhibition prevented MPP+ mediated mitochondria-dependent caspases activation. Our findings show that ER and mitochondria are in a close communication, establishing a dynamic ER-Ca2+-mitochondria interconnection that can play a prominent role in the neuronal cell death induction under particular stressful circumstances of PD pathology.

Resveratrol induces mitochondrial biogenesis in endothelial cells.

PubMed

Csiszar, Anna; Labinskyy, Nazar; Pinto, John T; Ballabh, Praveen; Zhang, Hanrui; Losonczy, Gyorgy; Pearson, Kevin; de Cabo, Rafael; Pacher, Pal; Zhang, Cuihua; Ungvari, Zoltan

2009-07-01

Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1alpha, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases.

Resveratrol induces mitochondrial biogenesis in endothelial cells

PubMed Central

Csiszar, Anna; Labinskyy, Nazar; Pinto, John T.; Ballabh, Praveen; Zhang, Hanrui; Losonczy, Gyorgy; Pearson, Kevin; de Cabo, Rafael; Pacher, Pal; Zhang, Cuihua; Ungvari, Zoltan

2009-01-01

Pathways that regulate mitochondrial biogenesis are potential therapeutic targets for the amelioration of endothelial dysfunction and vascular disease. Resveratrol was shown to impact mitochondrial function in skeletal muscle and the liver, but its role in mitochondrial biogenesis in endothelial cells remains poorly defined. The present study determined whether resveratrol induces mitochondrial biogenesis in cultured human coronary arterial endothelial cells (CAECs). In CAECs resveratrol increased mitochondrial mass and mitochondrial DNA content, upregulated protein expression of electron transport chain constituents, and induced mitochondrial biogenesis factors (proliferator-activated receptor-coactivator-1α, nuclear respiratory factor-1, mitochondrial transcription factor A). Sirtuin 1 (SIRT1) was induced, and endothelial nitric oxide (NO) synthase (eNOS) was upregulated in a SIRT1-dependent manner. Knockdown of SIRT1 (small interfering RNA) or inhibition of NO synthesis prevented resveratrol-induced mitochondrial biogenesis. In aortas of type 2 diabetic (db/db) mice impaired mitochondrial biogenesis was normalized by chronic resveratrol treatment, showing the in vivo relevance of our findings. Resveratrol increases mitochondrial content in endothelial cells via activating SIRT1. We propose that SIRT1, via a pathway that involves the upregulation of eNOS, induces mitochondrial biogenesis. Resveratrol induced mitochondrial biogenesis in the aortas of type 2 diabetic mice, suggesting the potential for new treatment approaches targeting endothelial mitochondria in metabolic diseases. PMID:19429820

Heart type fatty acid binding protein (H-FABP) is decreased in brains of patients with Down syndrome and Alzheimer's disease.

PubMed

Cheon, M S; Kim, S H; Fountoulakis, M; Lubec, G

2003-01-01

Fatty acid binding proteins (FABPs) are thought to play a role in the binding, targeting and transport of long-chain fatty acids, and at least three types of FABPs are found in human brain; heart type (H)-FABP, brain type (B)-FABP and epidermal type (E)-FABP. Although all three FABPs could be involved in normal brain function in prenatal and postnatal life, a neurobiological role of FABPs in neurodegenerative diseases has not been reported yet. These made us evaluate the protein levels of FABPs in brains from patients with Down syndrome (DS) and Alzheimer's disease (AD) and fetal cerebral cortex with DS using two-dimensional (2-D) gel electrophoresis with subsequent matrix-assisted laser desorption ionization mass spectroscopy (MALDI-MS) identification and specific software for quantification of proteins. In adult brain, B-FABP was significantly increased in occipital cortex of DS, and H-FABP was significantly decreased in DS (frontal, occipital and parietal cortices) and AD (frontal, temporal, occipital and parietal cortices). In fetal brain, B-FABP and epidermal E-FABP levels were comparable in controls and DS. We conclude that aberrant expression of FABPs, especially H-FABP may alter membrane fluidity and signal transduction, and consequently could be involved in cellular dysfunction in neurodegenerative disorders.

Resveratrol improves mitochondrial function in the remnant kidney from 5/6 nephrectomized rats.

PubMed

Hui, Yan; Lu, Miaomiao; Han, Yarong; Zhou, Hongli; Liu, Wei; Li, Lijing; Jin, Ruixia

2017-05-01

Mitochondrial dysfunction is involved in the pathogenesis of chronic kidney disease (CKD). Resveratrol has been demonstrated to be beneficial for the recovery of kidney diseases. In this study, the 5/6 nephrectomized rat was used as a CKD model and the TGF-β1-exposed mouse mesangial cells were used as an in vitro model. Pathological examination showed that resveratrol treatment attenuated glomerular injury in the remnant kidney of 5/6 nephrectomized rat. Additionally, resveratrol improved mitochondrial function in vivo and in vitro, as evidenced by increasing mitochondrial membrane potential, increasing ATP, decreasing reactive oxygen species production and enhancing activities of complex I and III. Furthermore, the dysregulated expressions of electron transport chain proteins and fission/fusion proteins in the kidney of 5/6 nephrectomize rats and TGF-β1-exposed mesangial cells were restored by resveratrol. Finally, upregulated sirt1 and PGC-1α deacetylation were found after treatment with resveratrol in vivo and in vitro, which may contribute to the mitochondrial protective effects of resveratrol. The results demonstrate that resveratrol protects the mitochondria of kidney in 5/6 nephrectomized rats and TGF-β1 induced mesangial cells. The study provides new insights into the renoprotective mechanisms of resveratrol. Copyright © 2017 Elsevier GmbH. All rights reserved.

Targeting mitochondrially mediated plasticity to develop improved therapeutics for bipolar disorder.

PubMed

de Sousa, Rafael T; Machado-Vieira, Rodrigo; Zarate, Carlos A; Manji, Husseini K

2014-10-01

Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology. This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca²⁺) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca²⁺ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients. Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents.

Targeting mitochondrially mediated plasticity to develop improved therapeutics for bipolar disorder

PubMed Central

de Sousa, Rafael T; Machado-Vieira, Rodrigo; Zarate, Carlos A

2014-01-01

Introduction Bipolar disorder (BPD) is a severe illness with few treatments available. Understanding BPD pathophysiology and identifying potential relevant targets could prove useful for developing new treatments. Remarkably, subtle impairments of mitochondrial function may play an important role in BPD pathophysiology. Areas covered This article focuses on human studies and reviews evidence of mitochondrial dysfunction in BPD as a promising target for the development of new, improved treatments. Mitochondria are crucial for energy production, generated mainly through the electron transport chain (ETC) and play an important role in regulating apoptosis and calcium (Ca2+) signaling as well as synaptic plasticity. Mitochondria move throughout the neurons to provide energy for intracellular signaling. Studies showed polymorphisms of mitochondria-related genes as risk factors for BPD. Postmortem studies in BPD also show decreased ETC activity/expression and increased nitrosative and oxidative stress (OxS) in patient brains. BPD has been also associated with increased OxS, Ca2+ dysregulation and increased proapoptotic signaling in peripheral blood. Neuroimaging studies consistently show decreased energy levels and pH in brains of BPD patients. Expert opinion Targeting mitochondrial function, and their role in energy metabolism, synaptic plasticity and cell survival, may be an important avenue for development of new mood-stabilizing agents. PMID:25056514

Triheptanoin: long-term effects in the very long-chain acyl-CoA dehydrogenase-deficient mouse[S

PubMed Central

Tucci, Sara; Floegel, Ulrich; Beermann, Frauke; Behringer, Sidney; Spiekerkoetter, Ute

2017-01-01

A rather new approach in the treatment of long-chain fatty acid oxidation disorders is represented by triheptanoin, a triglyceride with three medium-odd-chain heptanoic acids (C7), due to its anaplerotic potential. We here investigate the effects of a 1-year triheptanoin-based diet on the clinical phenotype of very long-chain-acyl-CoA-dehydrogenase-deficient (VLCAD−/−) mice. The cardiac function was assessed in VLCAD−/− mice by in vivo MRI. Metabolic adaptations were identified by the expression of genes regulating energy metabolism and anaplerotic processes using real-time PCR, and the results were correlated with the measurement of the glycolytic enzymes pyruvate dehydrogenase and pyruvate kinase. Finally, the intrahepatic lipid accumulation and oxidative stress in response to the long-term triheptanoin diet were assessed. Triheptanoin was not able to prevent the development of systolic dysfunction in VLCAD−/− mice despite an upregulation of cardiac glucose oxidation. Strikingly, the anaplerotic effects of triheptanoin were restricted to the liver. Despite this, the hepatic lipic content was increased upon triheptanoin supplementation. Our data demonstrate that the concept of anaplerosis does not apply to all tissues equally. PMID:27884962

A novel mutation in the FGB: c.1105C>T turns the codon for amino acid Bβ Q339 into a stop codon causing hypofibrinogenemia.

PubMed

Marchi, Rita; Brennan, Stephen; Meyer, Michael; Rojas, Héctor; Kanzler, Daniela; De Agrela, Marisela; Ruiz-Saez, Arlette

2013-03-01

Routine coagulation tests on a 14year-old male with frequent epistaxis showed a prolonged thrombin time together with diminished functional (162mg/dl) and gravimetric (122mg/dl) fibrinogen concentrations. His father showed similar aberrant results and sequencing of the three fibrinogen genes revealed a novel heterozygous nonsense mutation in the FGB gene c.1105C>T, which converts the codon for residue Bβ 339Q to stop, causing deletion of Bβ chain residues 339-461. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and RP-HPLC (reverse-phase high-pressure liquid chromatography) of purified fibrinogen showed only normal Aα, Bβ, and γ chains, indicating that molecules with the truncated 37,990Da β chain were not secreted into plasma. Functional analysis showed impaired fibrin polymerization, fibrin porosity, and elasticity compared to controls. By laser scanning confocal microscopy the patient's fibers were slightly thinner than normal. Electrospray ionization mass spectrometry (ESI MS) presented normal sialylation of the oligosaccharide chains, and liver function tests showed no evidence of liver dysfunction that might explain the functional abnormalities. Copyright © 2012 Elsevier Inc. All rights reserved.

Biomarkers in Immunoglobulin Light Chain Amyloidosis.

PubMed

Kufová, Z; Sevcikova, T; Growkova, K; Vojta, P; Filipová, J; Adam, Z; Pour, L; Penka, M; Rysava, R; Němec, P; Brozova, L; Vychytilova, P; Jurczyszyn, A; Grosicki, S; Barchnicka, A; Hajdúch, M; Simicek, M; Hájek, R

2017-01-01

Immunoglobulin light chain amyloidosis (AL amyloidosis - ALA) is a monoclonal gammopathy characterized by presence of aberrant plasma cells producing amyloidogenic immunoglobulin light chains. This leads to formation of amyloid fibrils in various organs and tissues, mainly in heart and kidney, and causes their dysfunction. As amyloid depositing in target organs is irreversible, there is a big effort to identify biomarker that could help to distinguish ALA from other monoclonal gammopathies in the early stages of disease, when amyloid deposits are not fatal yet. High throughput technologies bring new opportunities to modern cancer research as they enable to study disease within its complexity. Sophisticated methods such as next generation sequencing, gene expression profiling and circulating microRNA profiling are new approaches to study aberrant plasma cells from patients with light chain amyloidosis and related diseases. While generally known mutation in multiple myeloma patients (KRAS, NRAS, MYC, TP53) were not found in ALA, number of mutated genes is comparable. Transcriptome of ALA patients proves to be more similar to monoclonal gammopathy of undetermined significance patients, moreover level of circulating microRNA, that are known to correlate with heart damage, is increased in ALA patients, where heart damage in ALA typical symptom.Key words: amyloidosis - plasma cell - genome - transcriptome - microRNA.

PAR-2-mediated control of barrier function and motility differs between early and late phases of postinfectious gut dysfunction in the rat.

PubMed

Fernández-Blanco, Joan Antoni; Fernández-Blanco, Juan A; Hollenberg, Morley D; Martínez, Vicente; Vergara, Patri

2013-02-15

Proteinase-activated receptor-2 (PAR-2) and mast cell (MC) mediators contribute to inflammatory and functional gastrointestinal disorders. We aimed to characterize jejunal PAR-2-mediated responses and the potential MC involvement in the early and late phases of a rat model of postinfectious gut dysfunction. Jejunal tissues of control and Trichinella spiralis-infected (14 and 30 days postinfection) rats, treated or not with the MC stabilizer, ketotifen, were used. Histopathology and immunostaining were used to characterize inflammation, PAR-2 expression, and mucosal and connective tissue MCs. Epithelial barrier function (hydroelectrolytic transport and permeability) and motility were assessed in vitro in basal conditions and after PAR-2 activation. Intestinal inflammation on day 14 postinfection (early phase) was significantly resolved by day 30 (late phase) although MC counts and epithelial permeability remained increased. PAR-2-mediated ion transport (Ussing chambers, in vitro) and epithelial surface PAR-2 expression were reduced in the early phase, with a trend toward normalization during the late phase. In control conditions, PAR-2 activation (organ bath) induced biphasic motor responses (relaxation followed by excitation). At 14 days postinfection, spontaneous contractility and PAR-2-mediated relaxations were enhanced; motor responses were normalized on day 30. Postinfectious changes in PAR-2 functions were not affected by ketotifen treatment. We concluded that, in the rat model of Trichinella spiralis infection, alterations of intestinal PAR-2 function and expression depend on the inflammatory phase considered. A lack of a ketotifen effect suggests no interplay between MCs and PAR-2-mediated motility and ion transport alterations. These observations question the role of MC mediators in PAR-2-modulating postinfectious gut dysfunction.

Oligodendroglia metabolically support axons and contribute to neurodegeneration

PubMed Central

Lee, Youngjin; Morrison, Brett M.; Li, Yun; Lengacher, Sylvain; Farah, Mohamed H.; Hoffman, Paul N.; Liu, Yiting; Tsingalia, Akivaga; Jin, Lin; Zhang, Ping-Wu; Pellerin, Luc; Magistretti, Pierre J.; Rothstein, Jeffrey D.

2012-01-01

Summary Oligodendroglia support axon survival and function through mechanisms independent of myelination and their dysfunction leads to axon degeneration in several diseases. The cause of this degeneration has not been determined, but lack of energy metabolites such as glucose or lactate has been hypothesized. Lactate is transported exclusively by monocarboxylate transporters, and changes to these transporters alter lactate production and utilization. We show the most abundant lactate transporter in the CNS, monocarboxylate transporter 1 (MCT1), is highly enriched within oligodendroglia and that disruption of this transporter produces axon damage and neuron loss in animal and cell culture models. In addition, this same transporter is reduced in patients with, and mouse models of, amyotrophic lateral sclerosis (ALS), suggesting a role for oligodendroglial MCT1 in pathogenesis. The role of oligodendroglia in axon function and neuron survival has been elusive; this study defines a new fundamental mechanism by which oligodendroglia support neurons and axons. PMID:22801498

Stochastic thermodynamics for Ising chain and symmetric exclusion process.

PubMed

Toral, R; Van den Broeck, C; Escaff, D; Lindenberg, Katja

2017-03-01

We verify the finite-time fluctuation theorem for a linear Ising chain in contact with heat reservoirs at its ends. Analytic results are derived for a chain consisting of two spins. The system can be mapped onto a model for particle transport, namely, the symmetric exclusion process in contact with thermal and particle reservoirs. We modify the symmetric exclusion process to represent a thermal engine and reproduce universal features of the efficiency at maximum power.

Examining the value of travel time reliability for freight transportation to support freight planning and decision-Making [summary].

DOT National Transportation Integrated Search

2016-12-01

As consumers demand greater choice and availability of products, suppliers have responded with more just-in-time delivery and less centralized inventories. Keeping this supply chain working efficiently requires reliable freight transportation. Delays...

Open Heisenberg chain under boundary fields: A magnonic logic gate

NASA Astrophysics Data System (ADS)

Landi, Gabriel T.; Karevski, Dragi

2015-05-01

We study the spin transport in the quantum Heisenberg spin chain subject to boundary magnetic fields and driven out of equilibrium by Lindblad dissipators. An exact solution is given in terms of matrix product states, which allows us to calculate exactly the spin current for any chain size. It is found that the system undergoes a discontinuous spin-valve-like quantum phase transition from ballistic to subdiffusive spin current, depending on the value of the boundary fields. Thus, the chain behaves as an extremely sensitive magnonic logic gate operating with the boundary fields as the base element.

Atomic Chain Electronics

NASA Technical Reports Server (NTRS)

Yamada, Toshishige; Saini, Subhash (Technical Monitor)

1998-01-01

Adatom chains, precise structures artificially created on an atomically regulated surface, are the smallest possible candidates for future nanoelectronics. Since all the devices are created by combining adatom chains precisely prepared with atomic precision, device characteristics are predictable, and free from deviations due to accidental structural defects. In this atomic dimension, however, an analogy to the current semiconductor devices may not work. For example, Si structures are not always semiconducting. Adatom states do not always localize at the substrate surface when adatoms form chemical bonds to the substrate atoms. Transport properties are often determined for the entire system of the chain and electrodes, and not for chains only. These fundamental issues are discussed, which will be useful for future device considerations.

Cluster sizes in a classical Lennard-Jones chain

NASA Astrophysics Data System (ADS)

Lee-Dadswell, G. R.; Barrett, Nicholas; Power, Michael

2017-09-01

The definitions of breaks and clusters in a one-dimensional chain in equilibrium are discussed. Analytical expressions are obtained for the expected cluster length, 〈K 〉 , as a function of temperature and pressure in a one-dimensional Lennard-Jones chain. These expressions are compared with results from molecular dynamics simulations. It is found that 〈K 〉 increases exponentially with β =1 /kBT and with pressure, P in agreement with previous results in the literature. A method is illustrated for using 〈K 〉(β ,P ) to generate a "phase diagram" for the Lennard-Jones chain. Some implications for the study of heat transport in Lennard-Jones chains are discussed.

OECD Skills Outlook 2017: Skills and Global Value Chains

ERIC Educational Resources Information Center

OECD Publishing, 2017

2017-01-01

Since the 1990s, the world has entered a new phase of globalisation. Information and communication technology, trade liberalisation and lower transport costs have enabled firms and countries to fragment the production process into global value chains (GVCs). Many products are now designed in one country and assembled in another country from parts…

76 FR 52046 - Final Policy Statement on the Eligibility of Pedestrian and Bicycle Improvements Under Federal...

Federal Register 2010, 2011, 2012, 2013, 2014

2011-08-19

... cyclists, lower greenhouse gas emissions, reduced dependence on fossil fuels, increased trip-chaining, and... traffic use fewer resources and affect the environment less than any other form of transport.'' \\6\\ If we... gas emissions, reduced dependence on fossil fuels, increased trip- chaining, increased overall health...

Numerical simulation of transport and sequential biodegradation of chlorinated aliphatic hydrocarbons using CHAIN_2D

NASA Astrophysics Data System (ADS)

Schaerlaekens, J.; Mallants, D.; Imûnek, J.; van Genuchten, M. Th.; Feyen, J.

1999-12-01

Microbiological degradation of perchloroethylene (PCE) under anaerobic conditions follows a series of chain reactions, in which, sequentially, trichloroethylene (TCE), cis-dichloroethylene (c-DCE), vinylchloride (VC) and ethene are generated. First-order degradation rate constants, partitioning coefficients and mass exchange rates for PCE, TCE, c-DCE and VC were compiled from the literature. The parameters were used in a case study of pump-and-treat remediation of a PCE-contaminated site near Tilburg, The Netherlands. Transport, non-equilibrium sorption and biodegradation chain processes at the site were simulated using the CHAIN_2D code without further calibration. The modelled PCE compared reasonably well with observed PCE concentrations in the pumped water. We also performed a scenario analysis by applying several increased reductive dechlorination rates, reflecting different degradation conditions (e.g. addition of yeast extract and citrate). The scenario analysis predicted considerably higher concentrations of the degradation products as a result of enhanced reductive dechlorination of PCE. The predicted levels of the very toxic compound VC were now an order of magnitude above the maximum permissible concentration levels.

Ubiquitin Lysine 63 Chain–Forming Ligases Regulate Apical Dominance in Arabidopsis[W][OA

PubMed Central

Yin, Xiao-Jun; Volk, Sara; Ljung, Karin; Mehlmer, Norbert; Dolezal, Karel; Ditengou, Franck; Hanano, Shigeru; Davis, Seth J.; Schmelzer, Elmon; Sandberg, Göran; Teige, Markus; Palme, Klaus; Pickart, Cecile; Bachmair, Andreas

2007-01-01

Lys-63–linked multiubiquitin chains play important roles in signal transduction in yeast and in mammals, but the functions for this type of chain in plants remain to be defined. The RING domain protein RGLG2 (for RING domain Ligase2) from Arabidopsis thaliana can be N-terminally myristoylated and localizes to the plasma membrane. It can form Lys-63–linked multiubiquitin chains in an in vitro reaction. RGLG2 has overlapping functions with its closest sequelog, RGLG1, and single mutants in either gene are inconspicuous. rglg1 rglg2 double mutant plants exhibit loss of apical dominance and altered phyllotaxy, two traits critically influenced by the plant hormone auxin. Auxin and cytokinin levels are changed, and the plants show a decreased response to exogenously added auxin. Changes in the abundance of PIN family auxin transport proteins and synthetic lethality with a mutation in the auxin transport regulator BIG suggest that the directional flow of auxin is modulated by RGLG activity. Modification of proteins by Lys-63–linked multiubiquitin chains is thus important for hormone-regulated, basic plant architecture. PMID:17586653

Discovery of J Chain in African Lungfish (Protopterus dolloi, Sarcopterygii) Using High Throughput Transcriptome Sequencing: Implications in Mucosal Immunity

PubMed Central

Tacchi, Luca; Larragoite, Erin; Salinas, Irene

2013-01-01

J chain is a small polypeptide responsible for immunoglobulin (Ig) polymerization and transport of Igs across mucosal surfaces in higher vertebrates. We identified a J chain in dipnoid fish, the African lungfish (Protopterus dolloi) by high throughput sequencing of the transcriptome. P. dolloi J chain is 161 aa long and contains six of the eight Cys residues present in mammalian J chain. Phylogenetic studies place the lungfish J chain closer to tetrapod J chain than to the coelacanth or nurse shark sequences. J chain expression occurs in all P. dolloi immune tissues examined and it increases in the gut and kidney in response to an experimental bacterial infection. Double fluorescent in-situ hybridization shows that 88.5% of IgM+ cells in the gut co-express J chain, a significantly higher percentage than in the pre-pyloric spleen. Importantly, J chain expression is not restricted to the B-cell compartment since gut epithelial cells also express J chain. These results improve our current view of J chain from a phylogenetic perspective. PMID:23967082

Endothelial dysfunction impairs vascular neurotransmission in tail arteries.

PubMed

Sousa, Joana B; Fresco, Paula; Diniz, Carmen

2015-01-01

The present study intends to clarify if endothelium dysfunction impairs vascular sympathetic neurotransmission. Electrically-evoked tritium overflow (100 pulses/5 Hz) was evaluated in arteries (intact and denuded) or exhibiting some degree of endothelium dysfunction (spontaneously hypertensive arteries), pre-incubated with [(3)H]-noradrenaline in the presence of enzymes (nitric oxide synthase (NOS); nicotinamide adenine dinucleotide phosphate (NADPH) oxidase; xanthine oxidase; cyclooxygenase; adenosine kinase) inhibitors and a nucleoside transporter inhibitor. Inhibition of endothelial nitric oxide synthase with L-NIO dihydrochloride reduced tritium overflow in intact arteries whereas inhibition of neuronal nitric oxide synthase with Nω-Propyl-L-arginine hydrochloride was devoid of effect showing that only endothelial nitric oxide synthase is involved in vascular sympathetic neuromodulation. Inhibition of enzymes involved in reactive oxygen species or prostaglandins production with apocynin and allopurinol or indomethacin, respectively, failed to alter tritium overflow. A facilitation or reduction of tritium overflow was observed in the presence of 8-cyclopentyl-1,3-dipropylxanthine (DPCPX) or of 5-iodotubericidin, respectively, but only in intact arteries. These effects can be ascribed to a tonic inhibitory effect mediated by A1 receptors. In denuded and hypertensive arteries, 7-(2-phenylethyl)-5-amino-2-(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c] pyrimidine (SCH 58261) reduced tritium overflow, suggesting the occurrence of a tonic activation of A2A receptors. When endogenous adenosine bioavailability was increased by the nucleoside transporter inhibitor, S-(4-Nitrobenzyl)-6-thioinosine, tritium overflow increased in intact, denuded and hypertensive arteries. Among the endothelium-derived substances studied that could alter vascular sympathetic transmission only adenosine/adenosine receptor mediated mechanisms were clearly impaired by endothelium injury/dysfunction. Copyright © 2014 Elsevier Ltd. All rights reserved.

In vivo dopaminergic and serotonergic dysfunction in DCTN1 gene mutation carriers

PubMed Central

Felicio, Andre C.; Dinelle, Katherine; Agarwal, Pankaj A.; McKenzie, Jessamyn; Heffernan, Nicole; Road, Jeremy D.; Appel-Cresswell, Silke; Wszolek, Zbigniew K.; Farrer, Matthew J.; Schulzer, Michael; Sossi, Vesna; Stoessl, A. Jon

2014-01-01

Introduction We have used positron emission tomography (PET) to assess dopaminergic and serotonergic terminal density in three subjects carrying a mutation in the DCT1 gene, two clinically affected with Perry syndrome. Methods All subjects had brain imaging using 18F-6-fluoro-L-dopa (FDOPA, dopamine synthesis and storage), (+)-11C-dihydrotetrabenazine (DTBZ, vesicular monoamine transporter type 2), and 11C-raclopride (RAC, dopamine D2/D3 receptors). One subject also underwent PET with 11C-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile (DASB, serotonin transporter). Results FDOPA-PET and DTBZ-PET in the affected individuals showed a reduction of striatal tracer uptake. Also, RAC-PET showed higher uptake in these area. DASB-PET showed significant uptake changes in left orbitofrontal cortex, bilateral anterior insula, left dorsolateral prefrontal cortex, left orbitofrontal cortex, left posterior cingulate cortex, left caudate and left ventral striatum. Conclusions Our data showed evidence of both striatal dopaminergic and widespread cortical/subcortical serotonergic dysfunctions in individuals carrying a mutation in the DCTN1 gene. PMID:24797316

High performance current and spin diode of atomic carbon chain between transversely symmetric ribbon electrodes.

PubMed

Dong, Yao-Jun; Wang, Xue-Feng; Yang, Shuo-Wang; Wu, Xue-Mei

2014-08-21

We demonstrate that giant current and high spin rectification ratios can be achieved in atomic carbon chain devices connected between two symmetric ferromagnetic zigzag-graphene-nanoribbon electrodes. The spin dependent transport simulation is carried out by density functional theory combined with the non-equilibrium Green's function method. It is found that the transverse symmetries of the electronic wave functions in the nanoribbons and the carbon chain are critical to the spin transport modes. In the parallel magnetization configuration of two electrodes, pure spin current is observed in both linear and nonlinear regions. However, in the antiparallel configuration, the spin-up (down) current is prohibited under the positive (negative) voltage bias, which results in a spin rectification ratio of order 10(4). When edge carbon atoms are substituted with boron atoms to suppress the edge magnetization in one of the electrodes, we obtain a diode with current rectification ratio over 10(6).

High performance current and spin diode of atomic carbon chain between transversely symmetric ribbon electrodes

PubMed Central

Dong, Yao-Jun; Wang, Xue-Feng; Yang, Shuo-Wang; Wu, Xue-Mei

2014-01-01

We demonstrate that giant current and high spin rectification ratios can be achieved in atomic carbon chain devices connected between two symmetric ferromagnetic zigzag-graphene-nanoribbon electrodes. The spin dependent transport simulation is carried out by density functional theory combined with the non-equilibrium Green's function method. It is found that the transverse symmetries of the electronic wave functions in the nanoribbons and the carbon chain are critical to the spin transport modes. In the parallel magnetization configuration of two electrodes, pure spin current is observed in both linear and nonlinear regions. However, in the antiparallel configuration, the spin-up (down) current is prohibited under the positive (negative) voltage bias, which results in a spin rectification ratio of order 104. When edge carbon atoms are substituted with boron atoms to suppress the edge magnetization in one of the electrodes, we obtain a diode with current rectification ratio over 106. PMID:25142376

Dynamical Negative Differential Resistance in Antiferromagnetically Coupled Few-Atom Spin Chains

NASA Astrophysics Data System (ADS)

Rolf-Pissarczyk, Steffen; Yan, Shichao; Malavolti, Luigi; Burgess, Jacob A. J.; McMurtrie, Gregory; Loth, Sebastian

2017-11-01

We present the appearance of negative differential resistance (NDR) in spin-dependent electron transport through a few-atom spin chain. A chain of three antiferromagnetically coupled Fe atoms (Fe trimer) was positioned on a Cu2 N /Cu (100 ) surface and contacted with the spin-polarized tip of a scanning tunneling microscope, thus coupling the Fe trimer to one nonmagnetic and one magnetic lead. Pronounced NDR appears at the low bias of 7 mV, where inelastic electron tunneling dynamically locks the atomic spin in a long-lived excited state. This causes a rapid increase of the magnetoresistance between the spin-polarized tip and Fe trimer and quenches elastic tunneling. By varying the coupling strength between the tip and Fe trimer, we find that in this transport regime the dynamic locking of the Fe trimer competes with magnetic exchange interaction, which statically forces the Fe trimer into its high-magnetoresistance state and removes the NDR.

Integration of Biosynthesis and Long-Distance Transport Establish Organ-Specific Glucosinolate Profiles in Vegetative Arabidopsis[W

PubMed Central

Andersen, Tonni Grube; Nour-Eldin, Hussam Hassan; Fuller, Victoria Louise; Olsen, Carl Erik; Burow, Meike; Halkier, Barbara Ann

2013-01-01

Although it is essential for plant survival to synthesize and transport defense compounds, little is known about the coordination of these processes. Here, we investigate the above- and belowground source-sink relationship of the defense compounds glucosinolates in vegetative Arabidopsis thaliana. In vivo feeding experiments demonstrate that the glucosinolate transporters1 and 2 (GTR1 and GTR2), which are essential for accumulation of glucosinolates in seeds, are likely to also be involved in bidirectional distribution of glucosinolates between the roots and rosettes, indicating phloem and xylem as their transport pathways. Grafting of wild-type, biosynthetic, and transport mutants show that both the rosette and roots are able to synthesize aliphatic and indole glucosinolates. While rosettes constitute the major source and storage site for short-chained aliphatic glucosinolates, long-chained aliphatic glucosinolates are synthesized both in roots and rosettes with roots as the major storage site. Our grafting experiments thus indicate that in vegetative Arabidopsis, GTR1 and GTR2 are involved in bidirectional long-distance transport of aliphatic but not indole glucosinolates. Our data further suggest that the distinct rosette and root glucosinolate profiles in Arabidopsis are shaped by long-distance transport and spatially separated biosynthesis, suggesting that integration of these processes is critical for plant fitness in complex natural environments. PMID:23995084

Strain effects on the anisotropic thermal transport in crystalline polyethylene

NASA Astrophysics Data System (ADS)

He, Jixiong; Kim, Kyunghoon; Wang, Yangchao; Liu, Jun

2018-01-01

Thermal transport in the axial direction of polymers has been extensively studied, while the strain effect on the thermal conductivity, especially in the radial direction, remains unknown. In this work, we calculated the thermal conductivity in the radial direction of a crystalline polyethylene model and simulated the uniaxial strain effect on the thermal conductivity tensor by molecular dynamics simulations. We found a strong size effect of the thermal transport in the radial direction and estimated that the phonon mean free path can be much larger than the prediction from the classic kinetic theory. We also found that the thermal conductivity in the axial direction increases dramatically with strain, while the thermal conductivity in the radial direction decreases with uniaxial strain. We attribute the reduction of thermal conductivity in the radial direction to the decreases in inter-chain van der Waals forces with strains. The facts that the chains in the crystalline polyethylene became stiffer and more ordered along the chain direction could be the reasons for the increasing thermal conductivity in the axial direction during stretching. Besides, we observed longer phonon lifetime in acoustic branches and higher group velocity in optical branches after uniaxial stretching. Our work provides fundamental understandings on the phonon transport in crystalline polymers, the structure-property relationship in crystalline polymers, and the strain effect in highly anisotropic materials.

Performance of transport and selective media for swine Bordetella bronchiseptica recovery and it comparison to polymerase chain reaction detection

PubMed Central

Coutinho, Tania Alen; Bernardi, Mari Lourdes; de Itapema Cardoso, Marisa Ribeiro; Borowski, Sandra Maria; Moreno, Andrea Micke; de Barcellos, David Emilio Santos Neves

2009-01-01

Three comparative assays were performed seeking to improve the sensitivity of the diagnosis of Bordetella bronchiseptica infection analyzing swine nasal swabs. An initial assay compared the recovery of B. bronchiseptica from swabs simultaneously inoculated with B. bronchiseptica and some interfering bacteria, immersed into three transport formulations (Amies with charcoal, trypticase soy broth and phosphate buffer according to Soerensen supplemented with 5% of bovine fetal serum) and submitted to different temperatures (10°C and 27°C) and periods of incubation (24, 72 and 120 hours). A subsequent assay compared three selective media (MacConkey agar, modified selective medium G20G and a ceftiofur medium) for their recovery capabilities from clinical specimens. One last assay compared the polymerase chain reaction to the three selective media. In the first assay, the recovery of B. bronchiseptica from transport systems was better at 27°C and the three formulations had good performances at this temperature, but the collection of qualitative and quantitative analysis indicated the advantage of Amies medium for nasal swabs transportation. The second assay indicated that MacConkey agar and modified G20G had similar results and were superior to the ceftiofur medium. In the final assay, polymerase chain reaction presented superior capability of B. bronchiseptica detection to culture procedures. PMID:24031390

Photo-induced Mass Transport through Polymer Networks

NASA Astrophysics Data System (ADS)

Meng, Yuan; Anthamatten, Mitchell

2014-03-01

Among adaptable materials, photo-responsive polymers are especially attractive as they allow for spatiotemporal stimuli and response. We have recently developed a macromolecular network capable of photo-induced mass transport of covalently bound species. The system comprises of crosslinked chains that form an elastic network and photosensitive fluorescent arms that become mobile upon irradiation. We form loosely crosslinked polymer networks by Michael-Addition between multifunctional thiols and small molecule containing acrylate end-groups. The arms are connected to the network by allyl sulfide, that undergoes addition-fragmentation chain transfer (AFCT) in the presence of free radicals, releasing diffusible fluorophore. The networks are loaded with photoinitiator to allow for spatial modulation of the AFCT reactions. FRAP experiments within bulk elastomers are conducted to establish correlations between the fluorophore's diffusion coefficient and experimental variables such as network architecture, temperature and UV intensity. Photo-induced mass transport between two contacted films is demonstrated, and release of fluorophore into a solvent is investigated. Spatial and temporal control of mass transport could benefit drug release, printing, and sensing applications.

Redox Conditions Affect Ultrafast Exciton Transport in Photosynthetic Pigment-Protein Complexes.

PubMed

Allodi, Marco A; Otto, John P; Sohail, Sara H; Saer, Rafael G; Wood, Ryan E; Rolczynski, Brian S; Massey, Sara C; Ting, Po-Chieh; Blankenship, Robert E; Engel, Gregory S

2018-01-04

Pigment-protein complexes in photosynthetic antennae can suffer oxidative damage from reactive oxygen species generated during solar light harvesting. How the redox environment of a pigment-protein complex affects energy transport on the ultrafast light-harvesting time scale remains poorly understood. Using two-dimensional electronic spectroscopy, we observe differences in femtosecond energy-transfer processes in the Fenna-Matthews-Olson (FMO) antenna complex under different redox conditions. We attribute these differences in the ultrafast dynamics to changes to the system-bath coupling around specific chromophores, and we identify a highly conserved tyrosine/tryptophan chain near the chromophores showing the largest changes. We discuss how the mechanism of tyrosine/tryptophan chain oxidation may contribute to these differences in ultrafast dynamics that can moderate energy transfer to downstream complexes where reactive oxygen species are formed. These results highlight the importance of redox conditions on the ultrafast transport of energy in photosynthesis. Tailoring the redox environment may enable energy transport engineering in synthetic light-harvesting systems.

Electromagnetic energy transport in nanoparticle chains via dark plasmon modes.

PubMed

Solis, David; Willingham, Britain; Nauert, Scott L; Slaughter, Liane S; Olson, Jana; Swanglap, Pattanawit; Paul, Aniruddha; Chang, Wei-Shun; Link, Stephan

2012-03-14

Using light to exchange information offers large bandwidths and high speeds, but the miniaturization of optical components is limited by diffraction. Converting light into electron waves in metals allows one to overcome this problem. However, metals are lossy at optical frequencies and large-area fabrication of nanometer-sized structures by conventional top-down methods can be cost-prohibitive. We show electromagnetic energy transport with gold nanoparticles that were assembled into close-packed linear chains. The small interparticle distances enabled strong electromagnetic coupling causing the formation of low-loss subradiant plasmons, which facilitated energy propagation over many micrometers. Electrodynamic calculations confirmed the dark nature of the propagating mode and showed that disorder in the nanoparticle arrangement enhances energy transport, demonstrating the viability of using bottom-up nanoparticle assemblies for ultracompact opto-electronic devices. © 2012 American Chemical Society

Protein adsorption to poly(ethylenimine)-modified Sepharose FF: I. a critical ionic capacity for drastically enhanced capacity and uptake kinetics.

PubMed

Yu, Lin-Ling; Tao, Shi-Peng; Dong, Xiao-Yan; Sun, Yan

2013-08-30

To explore the details of protein uptake to polymer-grafted ion exchangers, Sepharose FF was modified with poly(ethylenimine) (PEI) to prepare anion exchanger of 10 different ionic capacities (ICs, 100-1220mmol/L). Adsorption equilibria and kinetics of bovine serum albumin (BSA) were then studied. It is found that ionic capacity, i.e., the coupling density of PEI, had significant effect on both adsorption capacity (qm) and effective protein diffusivity (De). With increasing ionic capacity, the qm value increased rapidly at IC<260mmol/L and then increased slowly till reaching a plateau at IC=600mmol/L. In the IC range of 100-600mmol/L, however, the De values kept at a low level (De/D0<0.07); it first decreased from 0.05±0.01 at IC=100mmol/L to 0.01±0.01 at IC=260mmol/L and then increased to 0.06±0.01 at IC=600mmol/L. Thereafter, sharp increases of the qm and De values [36% (from 201 to 273mg/mL) and 670% (from 0.06±0.01 to 0.49±0.04), respectively] were observed in the narrow range of IC from 600 to 740mmol/L. Finally, at IC>740mmol/L, the qm value decreased significantly while the De value increased moderately with increasing the IC. The results indicate that PEI chains played an important role in protein adsorption and transport. In brief, there was a critical IC (cIC) or PEI chain density, above which protein adsorption and transport behaviors changed drastically. The cIC was identified to be about 600mmol/L. Estimation of PEI grafting-layer thickness suggests that PEI chains formed an extended three-dimensional grafting-layer at IC>cIC, which provided high flexibility as well as accessibility of the chains for protein binding. Therefore, at IC>cIC, the adjacent PEI chains became close and flexible enough, leading to facilitated transport of adsorbed protein molecules by the interactions of neighboring chains mediated by the bound molecules. It is regarded as "chain delivery" effect. At the same time, improved accessibility of binding sites led the significant increase of binding capacity. The decrease of qm value at IC>740mmol/L is considered due to the decrease of effective porosity. The research has thus provided new insight into protein adsorption and transport in polymer-grafted ion-exchange media. Copyright © 2013 Elsevier B.V. All rights reserved.

New Anomalous Lieb-Robinson Bounds in Quasiperiodic XY Chains

NASA Astrophysics Data System (ADS)

Damanik, David; Lemm, Marius; Lukic, Milivoje; Yessen, William

2014-09-01

We announce and sketch the rigorous proof of a new kind of anomalous (or sub-ballistic) Lieb-Robinson (LR) bound for an isotropic XY chain in a quasiperiodic transversal magnetic field. Instead of the usual effective light cone |x|≤v|t|, we obtain |x|≤v|t|α for some 0<α <1. We can characterize the allowed values of α exactly as those exceeding the upper transport exponent αu+ of a one-body Schrödinger operator. To our knowledge, this is the first rigorous derivation of anomalous quantum many-body transport. We also discuss anomalous LR bounds with power-law tails for a random dimer field.

pH regulation of mitochondrial branch chain alpha-keto acid transport and oxidation in rat heart mitochondria.

PubMed

Hutson, S M

1987-07-15

The kinetics of branched chain alpha-keto acid uptake and efflux were studied as a function of varied external and matrix pH. Matrix pH was determined by the distribution of 5,5'-dimethyloxazolidine-2,4-dione. When rat heart mitochondria were incubated under transport conditions at pH 7.0 with succinate as respiratory substrate, the matrix pH was significantly greater than 8.0. Matrix pH remained greater than or equal to 8.0 when the medium pH was varied from 6.3 to 8.3, and it was lowered below 8.0 by addition of 5 mM phosphate or uncoupler. No pH gradient was detectable when mitochondria were incubated in the presence of valinomycin and uncoupler. Efflux of alpha-ketoisocaproate or alpha-ketoisovalerate from rat heart mitochondria obeyed first order kinetics. Varying the external pH from 6.6 to 8.3 had no significant effect on efflux, and at an external pH of 7.0, the first order rate constant for efflux was not affected by decreasing the matrix pH. On the other hand, exchange was sensitive to changes in medium but not matrix pH. The K0.5 for external branched chain alpha-keto acid was lowered by changing the medium pH from 7.6 to 6.3. At medium pH values greater than or equal to 8.0 both K0.5 and Vmax were affected. Uptake was determined either by measuring initial rates or was calculated after measuring the first order approach to a final equilibrium value. Unlike efflux, uptake was sensitive to changes in both external and matrix pH. The rate of branched chain alpha-keto acid uptake was stimulated by decreasing the medium pH from 8.3 to 6.3 and by alkalinization of the mitochondrial matrix. The estimated external pK for proton binding was 6.9. The data indicate that the branched chain alpha-keto acid transporter is asymmetric, that is, binding sites for substrate on the inside and outside of the mitochondrial membrane are not identical. alpha-Ketoisocaproate oxidation was measured at 37 degrees C in isolated mitochondria over the pH range of 6.6 to 8.1. Changes in the rate of branched chain alpha-keto acid oxidation, particularly when ATP was added (increase delta pH), were found to parallel the pH effects observed on branched chain alpha-keto acid uptake. Therefore, transport, and by implication oxidation, can be regulated by pH changes within the physiological range. Furthermore, intracellular pH may affect the degree of compartmentation between the cytosolic and mitochondrial branched chain alpha-keto acid pools.

Tunneling and Origin of Large Access Resistance in Layered-Crystal Organic Transistors

NASA Astrophysics Data System (ADS)

Hamai, Takamasa; Arai, Shunto; Minemawari, Hiromi; Inoue, Satoru; Kumai, Reiji; Hasegawa, Tatsuo

2017-11-01

Layered crystallinity of organic semiconductors is crucial to obtaining high-performance organic thin-film transistors (OTFTs), as it allows both smooth-channel-gate-insulator interface formation and efficient two-dimensional carrier transport along the interface. However, the role of vertical transport across the crystalline molecular layers in device operations has not been a crucial subject so far. Here, we show that the interlayer carrier transport causes unusual nonlinear current-voltage characteristics and enormous access resistance in extremely high-quality single-crystal OTFTs based on 2-decyl-7-phenyl[1]-benzothieno[3 ,2 -b ][1]benzothiophene (Ph -BTBT -C10 ) that involve inherent multiple semiconducting π -conjugated layers interposed, respectively, by electrically inert alkyl-chain layers. The output characteristics present layer-number (n )-dependent nonlinearity that becomes more evident at larger n (1 ≤n ≤15 ), demonstrating tunneling across multiple alkyl-chain layers. The n -dependent device mobility and four-probe measurements reveal that the alkyl-chain layers generate a large access resistance that suppresses the device mobility from the intrinsic value of about 20 cm2 V-1 s-1 . Our findings clarify the reason why device characteristics are distributed in single-crystal OTFTs.

Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery.

PubMed

Angka, Leonard; Khan, Sarwat T; Kilgour, Marisa K; Xu, Rebecca; Kennedy, Michael A; Auer, Rebecca C

2017-08-17

The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery.

Dysfunctional Natural Killer Cells in the Aftermath of Cancer Surgery

PubMed Central

Khan, Sarwat T.; Kilgour, Marisa K.; Xu, Rebecca; Kennedy, Michael A.; Auer, Rebecca C.

2017-01-01

The physiological changes that occur immediately following cancer surgeries initiate a chain of events that ultimately result in a short pro-, followed by a prolonged anti-, inflammatory period. Natural Killer (NK) cells are severely affected during this period in the recovering cancer patient. NK cells play a crucial role in anti-tumour immunity because of their innate ability to differentiate between malignant versus normal cells. Therefore, an opportunity arises in the aftermath of cancer surgery for residual cancer cells, including distant metastases, to gain a foothold in the absence of NK cell surveillance. Here, we describe the post-operative environment and how the release of sympathetic stress-related factors (e.g., cortisol, prostaglandins, catecholamines), anti-inflammatory cytokines (e.g., IL-6, TGF-β), and myeloid derived suppressor cells, mediate NK cell dysfunction. A snapshot of current and recently completed clinical trials specifically addressing NK cell dysfunction post-surgery is also discussed. In collecting and summarizing results from these different aspects of the surgical stress response, a comprehensive view of the NK cell suppressive effects of surgery is presented. Peri-operative therapies to mitigate NK cell suppression in the post-operative period could improve curative outcomes following cancer surgery. PMID:28817109

Mitochondrial mechanisms of neural cell death and neuroprotective interventions in Parkinson's disease.

PubMed

Fiskum, Gary; Starkov, Anatoly; Polster, Brian M; Chinopoulos, Christos

2003-06-01

Mitochondrial dysfunction, due to either environmental or genetic factors, can result in excessive production of reactive oxygen species, triggering the apoptotic death of dopaminergic cells in Parkinson's disease. Mitochondrial free radical production is promoted by the inhibition of electron transport at any point distal to the sites of superoxide production. Neurotoxins that induce parkinsonian neuropathology, such as MPP(+) and rotenone, stimulate superoxide production at complex I of the electron transport chain and also stimulate free radical production at proximal redox sites including mitochondrial matrix dehydrogenases. The oxidative stress caused by elevated mitochondrial production of reactive oxygen species promotes the expression and (or) intracellular distribution of the proapoptotic protein Bax to the mitochondrial outer membrane. Interactions between Bax and BH3 death domain proteins such as tBid result in Bax membrane integration, oligomerization, and permeabilization of the outer membrane to intermembrane proteins such as cytochrome c. Once released into the cytosol, cytochrome c together with other proteins activates the caspase cascade of protease activities that mediate the biochemical and morphological alterations characteristic of apoptosis. In addition, loss of mitochondrial cytochrome c stimulates mitochondrial free radical production, further promoting cell death pathways. Excessive mitochondrial Ca(2+) accumulation can also release cytochrome c and promote superoxide production through a mechanism distinctly different from that of Bax. Ca(2+) activates a mitochondrial inner membrane permeability transition causing osmotic swelling, rupture of the outer membrane, and complete loss of mitochondrial structural and functional integrity. While amphiphilic cations, such as dibucaine and propranolol, inhibit Bax-mediated cytochrome c release, transient receptor potential channel inhibitors inhibit mitochondrial swelling and cytochrome c release induced by the inner membrane permeability transition. These advances in the knowledge of mitochondrial cell death mechanisms and their inhibitors may lead to neuroprotective interventions applicable to Parkinsons's disease.

Thermal Stress Promotes Host Mitochondrial Degradation in Symbiotic Cnidarians: Are the Batteries of the Reef Going to Run Out?

PubMed Central

Dunn, Simon R.; Pernice, Mathieu; Green, Kathryn; Hoegh-Guldberg, Ove; Dove, Sophie G.

2012-01-01

The symbiotic relationship between cnidarians and their dinoflagellate symbionts, Symbiodinium spp, which underpins the formation of tropical coral reefs, can be destabilized by rapid changes to environmental conditions. Although some studies have concluded that a breakdown in the symbiosis begins with increased reactive oxygen species (ROS) generation within the symbiont due to a decoupling of photosynthesis, others have reported the release of viable symbionts via a variety of host cell derived mechanisms. We explored an alternative model focused upon changes in host cnidarian mitochondrial integrity in response to thermal stress. Mitochondria are often likened to being batteries of the cell, providing energy in the form of ATP, and controlling cellular pathway activation and ROS generation. The overall morphology of host mitochondria was compared to that of associated symbionts under an experimental thermal stress using confocal and electron microscopy. The results demonstrate that hyperthermic stress induces the degradation of cnidarian host mitochondria that is independent of symbiont cellular deterioration. The potential sites of host mitochondrial disruption were also assessed by measuring changes in the expression of genes associated with electron transport and ATP synthesis using quantitative RT-PCR. The primary site of degradation appeared to be downstream of complex III of the electron transport chain with a significant reduction in host cytochrome c and ATP synthase expression. The consequences of reduced expression could limit the capacity of the host to mitigate ROS generation and maintain both organelle integrity and cellular energy supplies. The disruption of host mitochondria, cellular homeostasis, and subsequent cell death irrespective of symbiont integrity highlights the importance of the host response to thermal stress and in symbiosis dysfunction that has substantial implications for understanding how coral reefs will survive in the face of climate change. PMID:22815696

Unraveling the mechanism of neuroprotection of curcumin in arsenic induced cholinergic dysfunctions in rats

DOE Office of Scientific and Technical Information (OSTI.GOV)

Srivastava, Pranay; Yadav, Rajesh S.; Department of Crimnology and Forensic Science, Harisingh Gour University, Sagar 470 003

Earlier, we found that arsenic induced cholinergic deficits in rat brain could be protected by curcumin. In continuation to this, the present study is focused to unravel the molecular mechanisms associated with the protective efficacy of curcumin in arsenic induced cholinergic deficits. Exposure to arsenic (20 mg/kg body weight, p.o) for 28 days in rats resulted to decrease the expression of CHRM2 receptor gene associated with mitochondrial dysfunctions as evident by decrease in the mitochondrial membrane potential, activity of mitochondrial complexes and enhanced apoptosis both in the frontal cortex and hippocampus in comparison to controls. The ultrastructural images of arsenicmore » exposed rats, assessed by transmission electron microscope, exhibited loss of myelin sheath and distorted cristae in the mitochondria both in the frontal cortex and hippocampus as compared to controls. Simultaneous treatment with arsenic (20 mg/kg body weight, p.o) and curcumin (100 mg/kg body weight, p.o) for 28 days in rats was found to protect arsenic induced changes in the mitochondrial membrane potential and activity of mitochondrial complexes both in frontal cortex and hippocampus. Alterations in the expression of pro- and anti-apoptotic proteins and ultrastructural damage in the frontal cortex and hippocampus following arsenic exposure were also protected in rats simultaneously treated with arsenic and curcumin. The data of the present study reveal that curcumin could protect arsenic induced cholinergic deficits by modulating the expression of pro- and anti-apoptotic proteins in the brain. More interestingly, arsenic induced functional and ultrastructural changes in the brain mitochondria were also protected by curcumin. - Highlights: • Neuroprotective mechanism of curcumin in arsenic induced cholinergic deficits studied • Curcumin protected arsenic induced enhanced expression of stress markers in rat brain • Arsenic compromised mitochondrial electron transport chain protected by curcumin • Functional and structural changes in mitochondria by arsenic protected by curcumin.« less

Ameliorating mitochondrial dysfunction restores carbon ion-induced cognitive deficits via co-activation of NRF2 and PINK1 signaling pathway.

PubMed

Liu, Yang; Yan, Jiawei; Sun, Cao; Li, Guo; Li, Sirui; Zhang, Luwei; Di, Cuixia; Gan, Lu; Wang, Yupei; Zhou, Rong; Si, Jing; Zhang, Hong

2018-07-01

Carbon ion therapy is a promising modality in radiotherapy to treat tumors, however, a potential risk of induction of late normal tissue damage should still be investigated and protected. The aim of the present study was to explore the long-term cognitive deficits provoked by a high-linear energy transfer (high-LET) carbon ions in mice by targeting to hippocampus which plays a crucial role in memory and learning. Our data showed that, one month after 4 Gy carbon ion exposure, carbon ion irradiation conspicuously resulted in the impaired cognitive performance, neurodegeneration and neuronal cell death, as well as the reduced mitochondrial integrity, the disrupted activities of tricarboxylic acid cycle flux and electron transport chain, and the depressed antioxidant defense system, consequently leading to a decline of ATP production and persistent oxidative damage in the hippocampus region. Mechanistically, we demonstrated the disruptions of mitochondrial homeostasis and redox balance typically characterized by the disordered mitochondrial dynamics, mitophagy and glutathione redox couple, which is closely associated with the inhibitions of PINK1 and NRF2 signaling pathway as the key regulators of molecular responses in the context of neurotoxicity and neurodegenerative disorders. Most importantly, we found that administration with melatonin as a mitochondria-targeted antioxidant promoted the PINK1 accumulation on the mitochondrial membrane, and augmented the NRF2 accumulation and translocation. Moreover, melatonin pronouncedly enhanced the molecular interplay between NRF2 and PINK1. Furthermore, in the mouse hippocampal neuronal cells, overexpression of NRF2/PINK1 strikingly protected the hippocampal neurons from carbon ion-elicited toxic insults. Thus, these data suggest that alleviation of the sustained mitochondrial dysfunction and oxidative stress through co-modulation of NRF2 and PINK1 may be in charge of restoration of the cognitive impairments in a mouse model of high-LET carbon ion irradiation. Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.

Omega-3 fatty acids attenuate constitutive and insulin-induced CD36 expression through a suppression of PPAR α/γ activity in microvascular endothelial cells.

PubMed

Madonna, Rosalinda; Salerni, Sara; Schiavone, Deborah; Glatz, Jan F; Geng, Yong-Jian; De Caterina, Raffaele

2011-09-01

Microvascular dysfunction occurs in insulin resistance and/or hyperinsulinaemia. Enhanced uptake of free fatty acids (FFA) and oxidised low-density lipoproteins (oxLDL) may lead to oxidative stress and microvascular dysfunction interacting with CD36, a PPARα/γ-regulated scavenger receptor and long-chain FFA transporter. We investigated CD36 expression and CD36-mediated oxLDL uptake before and after insulin treatment in human dermal microvascular endothelial cells (HMVECs), ± different types of fatty acids (FA), including palmitic, oleic, linoleic, arachidonic, eicosapentaenoic (EPA), and docosahexaenoic (DHA) acids. Insulin (10(-8) and 10(-7) M) time-dependently increased DiI-oxLDL uptake and CD36 surface expression (by 30 ± 13%, p<0.05 vs. untreated control after 24 hours incubation), as assessed by ELISA and flow cytometry, an effect that was potentiated by the PI3-kinase inhibitor wortmannin and reverted by the ERK1/2 inhibitor PD98059 and the PPARα/γ antagonist GW9662. A ≥ 24 hour exposure to 50 μM DHA or EPA, but not other FA, blunted both the constitutive (by 23 ± 3% and 29 ± 2%, respectively, p<0.05 for both) and insulin-induced CD36 expressions (by 45 ± 27 % and 12 ± 3 %, respectively, p<0.05 for both), along with insulin-induced uptake of DiI-oxLDL and the downregulation of phosphorylated endothelial nitric oxide synthase (P-eNOS). At gel shift assays, DHA reverted insulin-induced basal and oxLDL-stimulated transactivation of PPRE and DNA binding of PPARα/γ and NF-κB. In conclusion, omega-3 fatty acids blunt the increased CD36 expression and activity promoted by high concentrations of insulin. Such mechanisms may be the basis for the use of omega-3 fatty acids in diabetic microvasculopathy.

Mitochondrial transfer from Wharton's jelly-derived mesenchymal stem cells to mitochondria-defective cells recaptures impaired mitochondrial function.

PubMed

Lin, Hung-Yu; Liou, Chia-Wei; Chen, Shang-Der; Hsu, Te-Yao; Chuang, Jiin-Haur; Wang, Pei-Wen; Huang, Sheng-Teng; Tiao, Mao-Meng; Chen, Jin-Bor; Lin, Tsu-Kung; Chuang, Yao-Chung

2015-05-01

Adult mesenchymal stem cell (MSC)-conducted mitochondrial transfer has been recently shown to rescue cellular bioenergetics and prevent cell death caused by mitochondrial dysfunction. Wharton's jelly-derived MSCs (WJMSCs) harvested from postpartum umbilical cords are an accessible and abundant source of stem cells. This study aimed to determine the capability of WJMSCs to transfer their own mitochondria and rescue impaired oxidative phosphorylation (OXPHOS) and bioenergetics caused by mitochondrial DNA defects. To do this, WJMSCs were co-cultured with mitochondrial DNA (mtDNA)-depleted ρ(0) cells and the recapture of mitochondrial function was evaluated. WJMSCs were shown to be capable of transferring their own mitochondria into ρ(0) cells and underwent interorganellar mixture within these cells. Permissive culture media (BrdU-containing and pyruvate- and uridine-free) sieved out a survival cell population from the co-cultured WJMSCs (BrdU-sensitive) and ρ(0) cells (pyruvate/uridine-free). The survival cells had mtDNA identical to that of WJMSCs, whereas they expressed cellular markers identical to that of ρ(0) cells. Importantly, these ρ(0)-plus -WJMSC-mtDNA (ρ(+W)) cells recovered the expression of mtDNA-encoded proteins and exhibited functional oxygen consumption and respiratory control, as well as the activity of electron transport chain (ETC) complexes I, II, III and IV. In addition, ETC complex V-inhibitor-sensitive ATP production and metabolic shifting were also recovered. Furthermore, cellular behaviors including attachment-free proliferation, aerobic viability and OXPHOS-reliant cellular motility were also regained after mitochondrial transfer by WJMSCs. The therapeutic effect of WJMSCs-derived mitochondrial transfer was able to stably sustain for at least 45 passages. In conclusion, this study suggests that WJMSCs may serve as a potential therapeutic strategy for diseases linked to mitochondrial dysfunction through the donation of healthy mitochondria to cells with genetic mitochondrial defects. Copyright © 2015 Elsevier B.V. All rights reserved.

Risk assessment in the upstream crude oil supply chain: Leveraging analytic hierarchy process

NASA Astrophysics Data System (ADS)

Briggs, Charles Awoala

For an organization to be successful, an effective strategy is required, and if implemented appropriately the strategy will result in a sustainable competitive advantage. The importance of decision making in the oil industry is reflected in the magnitude and nature of the industry. Specific features of the oil industry supply chain, such as its longer chain, the complexity of its transportation system, its complex production and storage processes, etc., pose challenges to its effective management. Hence, understanding the risks, the risk sources, and their potential impacts on the oil industry's operations will be helpful in proposing a risk management model for the upstream oil supply chain. The risk-based model in this research uses a three-level analytic hierarchy process (AHP), a multiple-attribute decision-making technique, to underline the importance of risk analysis and risk management in the upstream crude oil supply chain. Level 1 represents the overall goal of risk management; Level 2 is comprised of the various risk factors; and Level 3 represents the alternative criteria of the decision maker as indicated on the hierarchical structure of the crude oil supply chain. Several risk management experts from different oil companies around the world were surveyed, and six major types of supply chain risks were identified: (1) exploration and production, (2) environmental and regulatory compliance, (3) transportation, (4) availability of oil, (5) geopolitical, and (6) reputational. Also identified are the preferred methods of managing risks which include; (1) accept and control the risks, (2) avoid the risk by stopping the activity, or (3) transfer or share the risks to other companies or insurers. The results from the survey indicate that the most important risk to manage is transportation risk with a priority of .263, followed by exploration/production with priority of .198, with an overall inconsistency of .03. With respect to major objectives the most preferred risk management policy option based on the result of the composite score is accept and control risk with a priority of .446, followed by transfer or share risk with a priority of .303. The least likely option is to terminate or forgo activity with a priority of .251.

The cytochrome b6f complex at the crossroad of photosynthetic electron transport pathways.

PubMed

Tikhonov, Alexander N

2014-08-01

Regulation of photosynthetic electron transport at the level of the cytochrome b6f complex provides efficient performance of the chloroplast electron transport chain (ETC). In this review, after brief overview of the structural organization of the chloroplast ETC, the consideration of the problem of electron transport control is focused on the plastoquinone (PQ) turnover and its interaction with the b6f complex. The data available show that the rates of plastoquinol (PQH2) formation in PSII and its diffusion to the b6f complex do not limit the overall rate of electron transfer between photosystem II (PSII) and photosystem I (PSI). Analysis of experimental and theoretical data demonstrates that the rate-limiting step in the intersystem chain of electron transport is determined by PQH2 oxidation at the Qo-site of the b6f complex, which is accompanied by the proton release into the thylakoid lumen. The acidification of the lumen causes deceleration of PQH2 oxidation, thus impeding the intersystem electron transport. Two other mechanisms of regulation of the intersystem electron transport have been considered: (i) "state transitions" associated with the light-induced redistribution of solar energy between PSI and PSII, and (ii) redistribution of electron fluxes between alternative pathways (noncyclic electron transport and cyclic electron flow around PSI). Copyright © 2013 Elsevier Masson SAS. All rights reserved.

The Candida albicans Inhibitory Activity of the Extract from Papaya (Carica papaya L.) Seed Relates to Mitochondria Dysfunction.

PubMed

Zhang, Tao; Chen, Weijun

2017-08-25

The inhibitory activity of the papaya seed extract (PSE) on Candida albicans ( C. albicans ) was determined by turbidimetry method. The inhibitory mechanisms were also evaluated from the prospective of reactive oxygen species (ROS) generation, mitochondrial membrane potential (MMP) decrease, and the activities of four complex enzymes in mitochondria respiratory chain. Results obtained from this study indicated that the PSE exhibited an effective inhibitory activity on C. albicans and induced significant accumulation of ROS and collapse of MMP. The Complex I and Complex III exhibited continues significant decrease in mitochondrial enzyme activity assays, but the Complex II and Complex IV activities were not positively correlated. Furthermore, the GC-MS analysis demonstrated that the PSE represents a rich and high-purity source of benzyl isothiocyanate (BITC), which indicated the BITC may be responsible for the mitochondrial dysfunction.

Mitochondrial Dysfunction in Chemotherapy-Induced Peripheral Neuropathy (CIPN)

PubMed Central

Canta, Annalisa; Pozzi, Eleonora; Carozzi, Valentina Alda

2015-01-01

The mitochondrial dysfunction has a critical role in several disorders including chemotherapy-induced peripheral neuropathies (CIPN). This is due to a related dysregulation of pathways involving calcium signalling, reactive oxygen species and apoptosis. Vincristine is able to affect calcium movement through the Dorsal Root Ganglia (DRG) neuronal mitochondrial membrane, altering its homeostasis and leading to abnormal neuronal excitability. Paclitaxel induces the opening of the mitochondrial permeability transition pore in axons followed by mitochondrial membrane potential loss, increased reactive oxygen species generation, ATP level reduction, calcium release and mitochondrial swelling. Cisplatin and oxaliplatin form adducts with mitochondrial DNA producing inhibition of replication, disruption of transcription and morphological abnormalities within mitochondria in DRG neurons, leading to a gradual energy failure. Bortezomib is able to modify mitochondrial calcium homeostasis and mitochondrial respiratory chain. Moreover, the expression of a certain number of genes, including those controlling mitochondrial functions, was altered in patients with bortezomib-induced peripheral neuropathy. PMID:29056658

Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson's disease.

PubMed

Rolinski, Michal; Griffanti, Ludovica; Piccini, Paola; Roussakis, Andreas A; Szewczyk-Krolikowski, Konrad; Menke, Ricarda A; Quinnell, Timothy; Zaiwalla, Zenobia; Klein, Johannes C; Mackay, Clare E; Hu, Michele T M

2016-08-01

SEE POSTUMA DOI101093/AWW131 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Resting state functional magnetic resonance imaging dysfunction within the basal ganglia network is a feature of early Parkinson's disease and may be a diagnostic biomarker of basal ganglia dysfunction. Currently, it is unclear whether these changes are present in so-called idiopathic rapid eye movement sleep behaviour disorder, a condition associated with a high rate of future conversion to Parkinson's disease. In this study, we explore the utility of resting state functional magnetic resonance imaging to detect basal ganglia network dysfunction in rapid eye movement sleep behaviour disorder. We compare these data to a set of healthy control subjects, and to a set of patients with established early Parkinson's disease. Furthermore, we explore the relationship between resting state functional magnetic resonance imaging basal ganglia network dysfunction and loss of dopaminergic neurons assessed with dopamine transporter single photon emission computerized tomography, and perform morphometric analyses to assess grey matter loss. Twenty-six patients with polysomnographically-established rapid eye movement sleep behaviour disorder, 48 patients with Parkinson's disease and 23 healthy control subjects were included in this study. Resting state networks were isolated from task-free functional magnetic resonance imaging data using dual regression with a template derived from a separate cohort of 80 elderly healthy control participants. Resting state functional magnetic resonance imaging parameter estimates were extracted from the study subjects in the basal ganglia network. In addition, eight patients with rapid eye movement sleep behaviour disorder, 10 with Parkinson's disease and 10 control subjects received (123)I-ioflupane single photon emission computerized tomography. We tested for reduction of basal ganglia network connectivity, and for loss of tracer uptake in rapid eye movement sleep behaviour disorder and Parkinson's disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson's disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson's disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson's disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson's disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder. © The Author (2016). Published by Oxford University Press on behalf of the Guarantors of Brain.

Basal ganglia dysfunction in idiopathic REM sleep behaviour disorder parallels that in early Parkinson’s disease

PubMed Central

Rolinski, Michal; Griffanti, Ludovica; Piccini, Paola; Roussakis, Andreas A.; Szewczyk-Krolikowski, Konrad; Menke, Ricarda A.; Quinnell, Timothy; Zaiwalla, Zenobia; Klein, Johannes C.; Mackay, Clare E.

2016-01-01

Abstract See Postuma (doi:10.1093/aww131) for a scientific commentary on this article. Resting state functional magnetic resonance imaging dysfunction within the basal ganglia network is a feature of early Parkinson’s disease and may be a diagnostic biomarker of basal ganglia dysfunction. Currently, it is unclear whether these changes are present in so-called idiopathic rapid eye movement sleep behaviour disorder, a condition associated with a high rate of future conversion to Parkinson’s disease. In this study, we explore the utility of resting state functional magnetic resonance imaging to detect basal ganglia network dysfunction in rapid eye movement sleep behaviour disorder. We compare these data to a set of healthy control subjects, and to a set of patients with established early Parkinson’s disease. Furthermore, we explore the relationship between resting state functional magnetic resonance imaging basal ganglia network dysfunction and loss of dopaminergic neurons assessed with dopamine transporter single photon emission computerized tomography, and perform morphometric analyses to assess grey matter loss. Twenty-six patients with polysomnographically-established rapid eye movement sleep behaviour disorder, 48 patients with Parkinson’s disease and 23 healthy control subjects were included in this study. Resting state networks were isolated from task-free functional magnetic resonance imaging data using dual regression with a template derived from a separate cohort of 80 elderly healthy control participants. Resting state functional magnetic resonance imaging parameter estimates were extracted from the study subjects in the basal ganglia network. In addition, eight patients with rapid eye movement sleep behaviour disorder, 10 with Parkinson’s disease and 10 control subjects received 123I-ioflupane single photon emission computerized tomography. We tested for reduction of basal ganglia network connectivity, and for loss of tracer uptake in rapid eye movement sleep behaviour disorder and Parkinson’s disease relative to each other and to controls. Connectivity measures of basal ganglia network dysfunction differentiated both rapid eye movement sleep behaviour disorder and Parkinson’s disease from controls with high sensitivity (96%) and specificity (74% for rapid eye movement sleep behaviour disorder, 78% for Parkinson’s disease), indicating its potential as an indicator of early basal ganglia dysfunction. Rapid eye movement sleep behaviour disorder was indistinguishable from Parkinson’s disease on resting state functional magnetic resonance imaging despite obvious differences on dopamine transported single photon emission computerized tomography. Basal ganglia connectivity is a promising biomarker for the detection of early basal ganglia network dysfunction, and may help to identify patients at risk of developing Parkinson’s disease in the future. Future risk stratification using a polymodal approach could combine basal ganglia network connectivity with clinical and other imaging measures, with important implications for future neuroprotective trials in rapid eye movement sleep behaviour disorder. PMID:27297241

Enabling congestion avoidance and reduction in the Michigan-Ohio transportation network to improve supply chain efficiency : freight ATIS.

DOT National Transportation Integrated Search

2010-01-01

We consider dynamic vehicle routing under milk-run tours with time windows in congested : transportation networks for just-in-time (JIT) production. The arc travel times are considered : stochastic and time-dependent. The problem integrates TSP with ...