RESUMEN
Multiple sclerosis (MS) is an autoimmune, neurological disease. We investigated genome-wide DNA methylation profiles of CD4+ and CD8+ T cells from MS patients and healthy controls at baseline and a follow-up visit. Patients were all treatment-naïve at baseline, and either on treatment or remained untreated at the follow-up visit. MS patients show more changes in their T cell DNA methylation profiles as compared to healthy controls over time, with the most pronounced differences observed in the untreated MS patients. These findings underline the potential of DNA methylation as biomarkers in MS.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Metilación de ADN/inmunología , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/inmunología , Adulto , Femenino , Humanos , Inmunosupresores/uso terapéutico , Persona de Mediana Edad , TranscriptomaRESUMEN
BACKGROUND: Genetic and clinical observations have indicated T cells are involved in MS pathology. There is little insight in how T cells are involved and whether or not these can be used as markers for MS. OBJECTIVES: Analysis of the gene expression profiles of circulating CD8+ T cells of MS patients compared to healthy controls. METHODS: RNA from purified CD8+ T cells was sequenced and analyzed for differential gene expression. Pathway analyses of genes at several p-value cutoffs were performed to identify putative pathways involved. RESULTS: We identified 36 genes with significant differential gene expression in MS patients. Four genes reached at least 2-fold differences in expression. The majority of differentially expressed genes was higher expressed in MS patients. Genes associated to MS in GWAS showed enrichment amongst the differentially expressed genes. We did not identify enrichment of specific pathways amongst the differentially expressed genes in MS patients. CONCLUSIONS: CD8+ T cells of MS patients show differential gene expression, with predominantly higher activity of genes in MS patients. We do not identify specific biological pathways in our study. More detailed analysis of CD8+ T cells and subtypes of these may increase understanding of how T cells are involved in MS.
RESUMEN
Recent advances have attracted attention to nonstandard Josephson junctions in which a supercurrent can flow despite zero phase difference between the constituent superconducting leads. Here, we propose a zero-phase-difference nanoelectromechanical junction which, in contrast to other considered systems, exhibits symmetry between leftward and rightward tunneling through the junction. We show that a supercurrent is, nevertheless, possible as a result of spontaneous symmetry breaking. In the suggested junction, the supercurrent is mediated by tunneling via a superconducting Cooper-pair box on a mechanical resonator. An alternating electric potential parametrically excites mechanical oscillations which are synchronized with charge oscillations of the box. This leads to coherent transfer of Cooper pairs through the junction. The direction of the supercurrent is a result of spontaneous symmetry breaking and thus it can be reversed without changing the parameters.
RESUMEN
We theoretically show that a nanoelectromechanical system can be mechanically actuated by a heat flow through it via an electron-electron interaction. In contrast to most known actuation mechanisms in similar systems, this new mechanism does not involve an electronic current nor external ac fields. Instead, the mechanism relies on deflection-dependent tunneling rates and a heat flow which is mediated by an electron-electron interaction while an electronic current through the device is prohibited by, for instance, a spin-valve effect. Therefore, the system resembles a nanoelectromechanical heat engine. We derive a criterion for the mechanical instability and estimate the amplitude of the resulting self-sustained oscillations. Estimations show that the suggested phenomenon can be studied using available experimental techniques.
RESUMEN
We study circular nanomechanical graphene resonators by means of continuum elasticity theory, treating them as membranes. We derive dynamic equations for the flexural mode amplitudes. Due to the geometrical nonlinearity the mode dynamics can be modeled by coupled Duffing equations. By solving the Airy stress problem we obtain analytic expressions for the eigenfrequencies and nonlinear coefficients as functions of the radius, suspension height, initial tension, back-gate voltage and elastic constants, which we compare with finite element simulations. Using perturbation theory, we show that it is necessary to include the effects of the non-uniform stress distribution for finite deflections. This correctly reproduces the spectrum and frequency tuning of the resonator, including frequency crossings.
RESUMEN
We recently demonstrated that severe thymic and splenic atrophy occur upon dietary treatment of mice with potent peroxisome proliferators (PPs), e.g. perfluorooctanoic acid (PFOA), WY-14,643, nafenopin, and di(2-ethylhexyl)phthalate (DEHP). In the present study, we investigated this phenomenon further employing a relative inert PP, PFOA. Comparison of the dose-dependencies and time-courses indicated that the peroxisome proliferative effect occurred prior to atrophy of both the thymus and spleen. However, following withdrawal of PFOA from the diet, the weight of the thymus and spleen rapidly returned to normal within 10 and 5 days, respectively, in contrast to the more persistent peroxisome proliferation. Furthermore, the changes in thymus and spleen weight upon PFOA treatment and the following withdrawal from diet paralleled the changes in total thymocyte and splenocyte counts, respectively. It was found previously that the decreases in the thymocyte populations present in the S and G2/M phases, as well as in the number of CD4+CD8+ cells upon PFOA treatment, were the most dramatic, perhaps reflecting inhibition of thymocyte proliferation in connection with thymocyte development. Here, the recovery of thymocytes began with increases in the populations in these same phases of the cell cycle, with CD4+CD8+ cells recovering most rapidly, lending further support to our previous hypothesis. The possible relationship of these immunotoxic effects of PPs to the changes they cause in fatty acid metabolism is discussed.
Asunto(s)
Caprilatos/farmacología , Fluorocarburos/farmacología , Proliferadores de Peroxisomas/farmacología , Bazo/efectos de los fármacos , Síndrome de Abstinencia a Sustancias/fisiopatología , Timo/efectos de los fármacos , Animales , Atrofia , Peso Corporal/efectos de los fármacos , Caprilatos/administración & dosificación , Ciclo Celular/efectos de los fármacos , División Celular/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Fluorocarburos/administración & dosificación , Hipertrofia , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Modelos Animales , Tamaño de los Órganos/efectos de los fármacos , Proliferadores de Peroxisomas/administración & dosificación , Peroxisomas/efectos de los fármacos , Peroxisomas/fisiología , Fenotipo , Bazo/patología , Timo/patología , Factores de TiempoRESUMEN
In this study, we have examined intratype human papillomavirus (HPV) sequence variation in a worldwide collection of cervical specimens. Twelve different HPV types including HPV-18, HPV-33, HPV-35, HPV-39, HPV-45, HPV-51, HPV-52, HPV-58, HPV-59, HPV-68 (ME180), MM9/PAP238A (recently designated HPV-73), and a novel partial genomic HPV sequence designated MM4/Wl3B were analyzed in this study. Cervical specimens were collected as part of epidemiological investigations conducted in New Mexico and an international study of invasive cervical cancer (IBSCC). Specimens from several countries including Argentina, Brazil, Bolivia, Benin, Cuba, Colombia, Chile, Germany, Mali, Panama, Paraguay, Spain, Algeria, Uganda, Guinea, Tanzania, Indonesia, Philippines, Thailand, and the United States were evaluated. Specimen DNAs were subjected to amplification with the MY09/11 L1 consensus PCR system. The PCR products were cloned, and an approximately 410-bp region in the L1 open reading frame was sequenced from 146 specimens (approximately 60,000 bp). Within a single HPV type, nucleotide diversity varied between 0.2 and 2.9% (i.e., between any pair of variants) and the majority of nucleotide changes were synonymous (amino acid conserving). These data provide information pertinent to HPV diagnostic probe development and are potentially relevant to future rational vaccine strategies. Similarly, amino acid diversity varied between 0 and 5.1%. Some of these amino acid changes may represent markers of intertype evolutionary relationships. Presuming that HPVs have evolved under the same constraints as their corresponding hosts, the limited genetic diversity observed for all HPVs studied to date may reflect an evolutionary bottleneck occurring in both virus and host populations.
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Cuello del Útero/virología , Variación Genética , Papillomaviridae/clasificación , Papillomaviridae/genética , Filogenia , Secuencia de Aminoácidos , Secuencia de Bases , Secuencia de Consenso , ADN Viral/análisis , ADN Viral/genética , Femenino , Humanos , Datos de Secuencia Molecular , Sondas de Oligonucleótidos , Sistemas de Lectura Abierta , Papillomaviridae/aislamiento & purificación , Reacción en Cadena de la Polimerasa , Neoplasias del Cuello Uterino/epidemiología , Neoplasias del Cuello Uterino/virologíaAsunto(s)
Neoplasias Hepáticas/inducido químicamente , Hígado/efectos de los fármacos , Microcuerpos/efectos de los fármacos , Xenobióticos/farmacología , Animales , Carcinógenos/toxicidad , Humanos , Hígado/patología , Hígado/ultraestructura , Neoplasias Hepáticas Experimentales/inducido químicamente , Ratones , Ratones Endogámicos C57BL , Microcuerpos/fisiología , Microcuerpos/ultraestructura , Deficiencia de Vitamina A/patología , Xenobióticos/toxicidadRESUMEN
Perfluorooctane sulfonic acid is almost as potent as perfluorooctanoic acid in causing increases in peroxisomal fatty acid beta-oxidation, peroxisomal catalase activity, omega-hydroxylation of lauric acid, cytosolic epoxide hydrolase activity and cytosolic DT-diaphorase activity. Octane sulfonic acid was ineffective at doses used for perfluorooctane sulfonic acid and perfluorooctanoic acid. The results support the theory of co-regulation of these parameters and peroxisome proliferation. The fact that perfluorooctane sulfonic acid causes peroxisome proliferation challenges the hypothesis that the first step in this process is formation of a thioester between the proliferator (the carboxylic group) and coenzyme A.
Asunto(s)
Alcanosulfonatos/farmacología , Ácidos Alcanesulfónicos , Ácidos Grasos/metabolismo , Fluorocarburos/farmacología , Hipolipemiantes/farmacología , Hígado/metabolismo , Microcuerpos/metabolismo , Acilcoenzima A/metabolismo , Animales , Peso Corporal/efectos de los fármacos , Citosol/enzimología , Dieta , Hígado/efectos de los fármacos , Masculino , Ratones , Ratones Endogámicos C57BL , Microcuerpos/efectos de los fármacos , Microcuerpos/enzimología , Microsomas Hepáticos/efectos de los fármacos , Microsomas Hepáticos/enzimología , Tamaño de los Órganos/efectos de los fármacos , Oxidación-Reducción , Xenobióticos/farmacologíaRESUMEN
The effects of dietary treatment with clofibrate (0.5% w/w for 10 days) on the livers of selenium-deficient male rats were examined. The peroxisome proliferation (as determined by electron microscopy) in the livers of selenium-deficient animals was much less pronounced than in the case of selenium-adequate rats and no increase in peroxisomal fatty acid beta-oxidation (assayed both as antimycin-insensitive palmitoyl-CoA oxidation and lauroyl-CoA oxidase activity) was observed in the deficient animals. On the other hand, in selenium-deficient rats clofibrate caused increases in the specific activity of microsomal lauric acid omega- and omega-1-hydroxylation and an apparent change in mitochondrial size, seen as a redistribution of mitochondria from the 600 x g(av) pellet to the 10,000 x g(av) pellet, which were approximately 50% as great as the corresponding effects on control animals. Obviously, then, these three different effects of clofibrate are not strictly coupled and may involve at least partially distinct underlying mechanisms. Initial experiments demonstrated that peroxisome proliferation could be obtained by exposing primary hepatocyte cultures derived from selenium-deficient rats to clofibric acid (an in vivo hydrolysis product of clofibrate which is the proximate peroxisome proliferator), nafenopin or mono(2-ethylhexyl)phthalate. This finding suggests that selenium deficiency does not have a direct influence on the basic process(es) underlying peroxisome proliferation, but rather has indirect effects, influencing, for example, the pharmacokinetics of clofibrate and/or hormonal factors.
Asunto(s)
Clofibrato/farmacología , Hígado/ultraestructura , Microcuerpos/efectos de los fármacos , Microcuerpos/ultraestructura , Selenio/deficiencia , Animales , Peso Corporal , Células Cultivadas , Clofibrato/administración & dosificación , Dieta , Glutatión Peroxidasa/metabolismo , Glutatión Transferasa/metabolismo , Hígado/efectos de los fármacos , Hígado/patología , Masculino , Microcuerpos/enzimología , Microscopía Electrónica , Mitocondrias Hepáticas/enzimología , Tamaño de los Órganos , Ratas , Ratas WistarRESUMEN
The calmodulin inhibitor calmidazolium chloride inhibited the activity of soluble and particulate Ins(1,4,5)P3-5-phosphatase from GH3 cells, with an IC50 value of approximately 100 microM following a 10-min preincubation with the enzyme. The inhibition was time-dependent and could not be reversed by washing of the particulate fraction. It is concluded that although the inhibitory effect of calmidazolium chloride cannot be related per se to inhibition of calmodulin function, effects of this compound unrelated to actions upon calmodulin function may be found when concentrations that are only moderately supramaximal are used.
Asunto(s)
Imidazoles/farmacología , Monoéster Fosfórico Hidrolasas/antagonistas & inhibidores , Animales , Calmodulina/antagonistas & inhibidores , Línea Celular , Inositol Polifosfato 5-Fosfatasas , Cinética , Ratas , Transducción de Señal , SolubilidadRESUMEN
Dietary treatment of male C57B1/6 mice with clofibrate, nafenopin or WY-14.643 resulted in a modest (at most 2-fold) increase in the total catalase activity in the whole homogenate and mitochondrial fraction prepared from the livers of these animals. On the other hand, the catalase activity recovered in the cytosolic fraction was increased 12- to 18-fold, i.e. 30-35% of the total catalase activity in the hepatic homogenate was present in the high-speed supernatant fraction after treatment with these peroxisome proliferators. A study of the time course of the changes in peroxisomal and cytosolic catalase activities demonstrated that the peroxisomal activity both increased upon initiation of exposure and decreased after termination of treatment several days after the increase and decrease, respectively, in the corresponding cytosolic activity. This finding suggests that the cytosolic catalase may be on its way to incorporation into peroxisomes.
Asunto(s)
Catalasa/biosíntesis , Citosol/enzimología , Hígado/ultraestructura , Microcuerpos/efectos de los fármacos , Animales , Clofibrato/farmacología , Inducción Enzimática , Masculino , Ratones , Ratones Endogámicos C57BL , Microcuerpos/enzimología , Nafenopina/farmacología , Pirimidinas/farmacologíaRESUMEN
Digitonin permeabilization of hepatocytes from control and clofibrate-treated (0.5% by mass, 10 days) male C57bl/6 mice was used to study the intracellular distributions of soluble ('cytosolic') epoxide hydrolase and of catalase. The following conclusions were drawn. (1) About 60% of the total soluble epoxide hydrolase activity in control mouse hepatocytes is situated in the cytosol. (2) The rest is not mitochondrial, but probably peroxisomal. (3) Of the total catalase activity in control mouse hepatocytes, 5-10% is found in the cytosol. (4) Treatment of mice with clofibrate increases the total hepatocyte activity of soluble epoxide hydrolase 4-fold, but does not influence the relative distribution of this enzyme between cytosol and peroxisomes. (5) The total catalase activity is increased 3.5-fold by clofibrate treatment and 15-35% of this activity is shifted from the peroxisomes to the cytosol.