Role of Copper and Tor Signaling in Reactive Oxygen Species Induced Cell Aging

Chronological lifespan assays in yeast rely on promoting a culture’s quiescent stationary phase by calorie restriction, a phase characterized by curtailed overall metabolic rate and a shift from fermentation to mitochondrial respiration. This shift in glucose utilization can be accomplished by reduced TOR (Target of Rapamycin) pathway signaling, a complex regulator of cell growth and cell cycle in which various environmental growth and nutrient signals are integrated to activate or inhibit the Ser/Thr kinase activity of Tor1 protein. Optimal growth conditions promote TOR signaling causing macromolecule biosynthesis, sugar fermentation, increased metabolism, and progression through cell cycle. Many downstream effects of TOR signaling can be silenced by cell treatment with Rapamycin, a drug which binds to Tor1 and inhibits kinase domain function, drastically increasing a cell culture’s chronological lifespan. Mitochondrial electron transport chain (ETC) machinery, whose activity and expression is modulated by TOR signaling, is the primary site of superoxide formation. Superoxide is a reactive oxygen species (ROS) produced by premature electron leakage directly to oxygen, producing dangerous hydroxyl radicals, via the Haber-Weiss reaction, that diffuse throughout the cell causing damage to DNA, lipid peroxidation, and mitochondrial dysfunction associated with premature cell aging and death most prevalent in neuronal tissue afflicted with neurodegenerative disease. A primary defense of free radical damage as a respiratory by-product is the neutralization of superoxide by superoxide dismutase 1 (SOD1), which requires copper and zinc as cofactors in the conversion of superoxide to less harmful hydrogen peroxide. Copper is additionally utilized in cytochrome c oxidase as an electron transferring group and is required for the continuous movement of high energy electrons through the ETC, thereby limiting the potential for electron leakage and ROS. Copper, given its two roles in defending against ROS production and induced cell aging, is here modulated by extracellular supplementation to further elucidate its functionality in the context of possible lifespan extension by Rapamycin treatment of SOD1 deletion strains

Sagnac Effect of Goedel's Universe

We present exact expressions for the Sagnac effect of Goedel's Universe. For this purpose we first derive a formula for the Sagnac time delay along a circular path in the presence of an arbitrary stationary metric in cylindrical coordinates. We then apply this result to Goedel's metric for two different experimental situations: First, the light source and the detector are at rest relative to the matter generating the gravitational field. In this case we find an expression that is formally equivalent to the familiar nonrelativistic Sagnac time delay. Second, the light source and the detector are rotating relative to the matter. Here we show that for a special rotation rate of the detector the Sagnac time delay vanishes. Finally we propose a formulation of the Sagnac time delay in terms of invariant physical quantities. We show that this result is very close to the analogous formula of the Sagnac time delay of a rotating coordinate system in Minkowski spacetime.Comment: 26 pages, including 4 figures, corrected typos, changed reference

Semifluxons in Superconductivity and Cold Atomic Gases

Josephson junctions and junction arrays are well studied devices in superconductivity. With external magnetic fields one can modulate the phase in a long junction and create traveling, solitonic waves of magnetic flux, called fluxons. Today, it is also possible to device two different types of junctions: depending on the sign of the critical current density, they are called 0- or pi-junction. In turn, a 0-pi junction is formed by joining two of such junctions. As a result, one obtains a pinned Josephson vortex of fractional magnetic flux, at the 0-pi boundary. Here, we analyze this arrangement of superconducting junctions in the context of an atomic bosonic quantum gas, where two-state atoms in a double well trap are coupled in an analogous fashion. There, an all-optical 0-pi Josephson junction is created by the phase of a complex valued Rabi-frequency and we a derive a discrete four-mode model for this situation, which qualitatively resembles a semifluxon.Comment: 15 pages (Latex), 6 color figures (eps

Copper, ROS, and Mitochondrial Stress: Understanding the Pathways that Govern Metabolic Homeostasis

Cellular respiration is accomplished by the mitochondrial electron transport chain (ETC) that utilizes the movement of high energy electrons, yielded from the breakdown of larger metabolites, to produce usable energy for the cell in the form of ATP. However, this important metabolic process can lead to the production of the cytotoxic by-product superoxide, a member of a class of free radicals known as reactive oxygen species (ROS), which can then react with vital cell components to induce cell dysfunction or apoptosis. The buildup of this ROS-mediated cellular damage over time has strong links to the initiation and progression of neurodegenerative diseases, such as Alzheimer’s and Parkinson’s, and it is therefore imperative to understand the mechanisms that govern its production. To this aim, chronological life span and growth studies were conducted in a S. cerevisiae model, in which we observed strong protective effects against ROS-mediated damage by supplementing cells with exogenous copper. These results suggest that lower concentrations of cellular copper, as a necessary redox co-factor for cytochrome c oxidase in the ETC, may lead to higher rates of ROS production by limiting the number of functional ETC complexes that can properly shuttle electrons

Formation of Pairing Fields in Resonantly Coupled Atomic and Molecular Bose-Einstein Condensates

In this paper, we show that pair-correlations may play an important role in the quantum statistical properties of a Bose-Einstein condensed gas composed of an atomic field resonantly coupled with a corresponding field of molecular dimers. Specifically, pair-correlations in this system can dramatically modify the coherent and incoherent transfer between the atomic and molecular fields.Comment: 4 pages, 4 figure

Long-term effects of a new ketoacid–amino acid supplement in patients with chronic renal failure

Long-term effects of a new ketoacid–amino acid supplement in patients with chronic renal failure. Nine patients with severe chronic renal failure (mean glomerular filtration rate 4.8 ml/min; mean serum creatinine 11.3 mg/dl) who were previously on a protein-restricted diet were treated with a diet containing an average of 33 kcal/kg and 22.5 g/day of mixed quality protein, supplemented by a combination of amino acids and mixed salts formed between basic amino acids and keto-analogues of essential amino acids. The supplement was designed to minimize or reverse the amino acid abnormalities of chronic renal failure rather than to meet the normal requirements for the essential amino acids; it contained tyrosine, ornithine, and a high proportion of branched-chain ketoacids, but no phenylalanine or tryptophan and very little methionine. Within one month, serum urea nitrogen fell and serum albumin and transferrin rose significantly; serum creatinine fell slightly. Hyperphosphatemia (present in three patients) was corrected. Nitrogen balance, measured in seven of the nine patients, on the average was neutral, as it was in a preceding control period on a 40 to 50 g/day protein diet. Plasma tyrosine and threonine, which were subnormal before therapy, rose to normal or high normal levels. Branched-chain amino acids did not change. During a total of 63 patient-months of therapy, no side effects or toxicity were observed, and serum albumin and transferrin did not change further. It is concluded that this specially designed supplement added to a 20 to 25 g/d protein diet is an acceptable regimen which can improve or maintain protein nutrition in patients with severe chronic renal failure who would otherwise require dialysis.Effet à long terme d'un nouveau mélange de cétoacides – d'amino acides chez des malades ayant une insuffisance rénale chronique. Neuf malades ayant une insuffisance rénale chronique sévère (filtration glomérulaire moyenne 4,8 ml/mn, créatininémie moyenne 11,3 mg/dl) recevant préalablement un régime pauvre en protéines, ont été traités avec un régime apportant en moyenne 33 kcal/kg et 22,5 g/j de protéines mixtes, auquel a été ajouté un mélange d'acides aminés et de sels d'acides aminés basiques et de céto-analogues d'acides aminés essentiels. Ce supplément a été conçu plus pour diminuer ou supprimer les anomalies des acides aminés au cours de l'insuffisance rénale chronique que pour fournir les besoins normaux en acides aminés essentiels; il contenait de la tyrosine, de l'ornithine et une grande proportion de cétoacides à chaînes ramifiées, mais ni phénylalanine, ni tryptophane, et très peu de méthionine. En moins d'un mois, l'azote uréique plasmatique a baissé; la sérum albumine et la transférine se sont élevées significativement, la créatininémie a légèrement diminué. L'hyperphosphatémie (présente chez trois malades) a été corrigée. La balance azotée, mesurée chez sept des neuf malades était nulle en moyenne, comme elle l'était au cours de la période contrôle précédente, avec un régime comportant 40 à 50 g/j de protéines. La tyrosine et la thréonine plasmatiques, inférieures à la normale avant traitement, se sont normalisées, ou ont atteint des valeurs à la limite supérieure de la normale. Il n'y a pas eu de modification des concentrations d'acides aminés à chaînes ramifiées. Pendant un traitement durant au total 63 mois-malade, il n'a pas été observé d'effet secondaire ni de toxicité, et il n'y a pas eu d'autre modification de l'albumine ou de la transferrine plasmatique. Il est conclu que ce mélange spécialement conçu, rajouté à un régime apportant 20 à 25 g/j de protéines constitue un régime acceptable, permettant d'améliorer ou de maintenir l'apport protidique chez des malades ayant une insuffisance rénale chronique sévère qui, autrement, nécessiteraient la dialyse

Heat-Shock Promoters: Targets for Evolution by <i>P</i> Transposable Elements in <i>Drosophila</i>

Transposable elements are potent agents of genomic change during evolution, but require access to chromatin for insertion—and not all genes provide equivalent access. To test whether the regulatory features of heat-shock genes render their proximal promoters especially susceptible to the insertion of transposable elements in nature, we conducted an unbiased screen of the proximal promoters of 18 heat-shock genes in 48 natural populations of Drosophila. More than 200 distinctive transposable elements had inserted into these promoters; greater than 96% are P elements. By contrast, few or no P element insertions segregate in natural populations in a “negative control” set of proximal promoters lacking the distinctive regulatory features of heat-shock genes. P element transpositions into these same genes during laboratory mutagenesis recapitulate these findings. The natural P element insertions cluster in specific sites in the promoters, with up to eight populations exhibiting P element insertions at the same position; laboratory insertions are into similar sites. By contrast, a “positive control” set of promoters resembling heat-shock promoters in regulatory features harbors few P element insertions in nature, but many insertions after experimental transposition in the laboratory. We conclude that the distinctive regulatory features that typify heat-shock genes (in Drosophila) are especially prone to mutagenesis via P elements in nature. Thus in nature, P elements create significant and distinctive variation in heat-shock genes, upon which evolutionary processes may act.</p

Heat-Shock Promoters: Targets for Evolution by P Transposable Elements in Drosophila

Transposable elements are potent agents of genomic change during evolution, but require access to chromatin for insertion—and not all genes provide equivalent access. To test whether the regulatory features of heat-shock genes render their proximal promoters especially susceptible to the insertion of transposable elements in nature, we conducted an unbiased screen of the proximal promoters of 18 heat-shock genes in 48 natural populations of Drosophila. More than 200 distinctive transposable elements had inserted into these promoters; greater than 96% are P elements. By contrast, few or no P element insertions segregate in natural populations in a “negative control” set of proximal promoters lacking the distinctive regulatory features of heat-shock genes. P element transpositions into these same genes during laboratory mutagenesis recapitulate these findings. The natural P element insertions cluster in specific sites in the promoters, with up to eight populations exhibiting P element insertions at the same position; laboratory insertions are into similar sites. By contrast, a “positive control” set of promoters resembling heat-shock promoters in regulatory features harbors few P element insertions in nature, but many insertions after experimental transposition in the laboratory. We conclude that the distinctive regulatory features that typify heat-shock genes (in Drosophila) are especially prone to mutagenesis via P elements in nature. Thus in nature, P elements create significant and distinctive variation in heat-shock genes, upon which evolutionary processes may act

On the validity of Stokes’ law at the molecular level

In order to investigate the dependence of the viscosity on the mass of the molecules in a liquid, and thus check the validity of Stokes' law for molecules, several molecular dynamics simulations of 'water' molecules with different mass and different molecular mass distributions were performed. The viscosity is shown to be sensitive to the mass but less sensitive to the mass distribution. The product of diffusion coefficient and viscosity, which according to Stokes' law should be independent of the mass, varies. We may therefore conclude that Stokes' law is not valid for small molecules. (C) 1999 Elsevier Science B.V. All rights reserved