Oral vitamin C supplementation to patients with myeloid cancer on azacitidine treatment: Normalization of plasma vitamin C induces epigenetic changes

Background Patients with haematological malignancies are often vitamin C deficient, and vitamin C is essential for the TET-induced conversion of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), the first step in active DNA demethylation. Here, we investigate whether oral vitamin C supplementation can correct vitamin C deficiency and affect the 5hmC/5mC ratio in patients with myeloid cancers treated with DNA methyltransferase inhibitors (DNMTis). Results We conducted a randomized, double-blinded, placebo-controlled pilot trial (NCT02877277) in Danish patients with myeloid cancers performed during 3 cycles of DNMTi-treatment (5-azacytidine, 100 mg/m2/d for 5 days in 28-day cycles) supplemented by oral dose of 500 mg vitamin C (n = 10) or placebo (n = 10) daily during the last 2 cycles. Fourteen patients (70%) were deficient in plasma vitamin C (< 23 μM) and four of the remaining six patients were taking vitamin supplements at inclusion. Global DNA methylation was significantly higher in patients with severe vitamin C deficiency (< 11.4 μM; 4.997 vs 4.656% 5mC relative to deoxyguanosine, 95% CI [0.126, 0.556], P = 0.004). Oral supplementation restored plasma vitamin C levels to the normal range in all patients in the vitamin C arm (mean increase 34.85 ± 7.94 μM, P = 0.0004). We show for the first time that global 5hmC/5mC levels were significantly increased in mononuclear myeloid cells from patients receiving oral vitamin C compared to placebo (0.037% vs − 0.029%, 95% CI [− 0.129, − 0.003], P = 0.041). Conclusions Normalization of plasma vitamin C by oral supplementation leads to an increase in the 5hmC/5mC ratio compared to placebo-treated patients and may enhance the biological effects of DNMTis. The clinical efficacy of oral vitamin C supplementation to DNMTis should be investigated in a large randomized, placebo-controlled clinical trial

Nifedipin ublažava djelovanje kokaina na enzimsku aktivnost u mozgu i jetri te smanjuje njegovo izlučivanje putem mokraće

The aim of this study was to see how nifedipine counters the effects of cocaine on hepatic and brain enzymatic activity in rats and whether it affects urinary excretion of cocaine. Male Wistar rats were divided in four groups of six: control, nifedipine group (5 mg kg-1 i.p. a day for five days); cocaine group (15 mg kg-1 i.p. a day for five days), and the nifedipine+cocaine group. Twenty-four hours after the last administration, we measured neuronal nitric oxide synthase (nNOS) activity in the brain and cytochrome P450 quantity, ethylmorphine-N-demethylase, and anilinehydroxylase activity in the liver. Urine samples were collected 24 h after the last cocaine and cocaine+nifedipine administration. Urinary cocaine concentration was determined using the GC/MS method. Cocaine administration increased brain nNOS activity by 55 % (p<0.05) in respect to control, which indicates the development of tolerance and dependence. In the combination group, nifedipine decreased the nNOS activity in respect to the cocaine-only group. In the liver, cocaine significantly decreased and nifedipine significantly increased cytochrome P450, ethylmorphine-N-demethylase, and anilinehydroxylase in respect to control. In combination, nifedipine successfully countered cocaine effects on these enzymes. Urine cocaine excretion in the cocaine+nifedipine group significantly dropped (by 35 %) compared to the cocaine-only group. Our results have confirmed the effects of nifedipine against cocaine tolerance and development of dependence, most likely due to metabolic interactions between them.Cilj je ovoga istraživanja bio utvrditi kako nifedipin ublažava djelovanje kokaina na enzimsku aktivnost u mozgu i jetri Wistar štakora te utječe li na njegovo izlučivanje putem mokraće. Mužjaci su podijeljeni u četiri skupine po šest jedinki: kontrolnu skupinu, nifedipinsku skupinu koja je pet dana intraperitonealno primala nifedipin u dozi od 5 mg kg-1; skupinu koja je pet dana primala kokain u dozi od 15 mg kg-1 na dan te skupinu koja je zajedno primala nifedipin i kokain u odgovarajućim dozama. Dvadeset i četiri sata nakon posljednje doze izmjerena je enzimska aktivnost sintaze dušičnoga oksida (nNOS) u mozgu, razina citokroma P450 te aktivnosti enzima etilmorfi n-N-demetilaze i anilinhidroksilaze u jetri štakora. Uzorci mokraće prikupljeni su 24 sata nakon posljednje doze kokaina odnosno kombinacije nifedipina i kokaina. Koncentracija kokaina u mokraći izmjerena je s pomoću vezanog sustava plinske kromatografi je i spektrometrije masa. Kokain je povećao aktivnost nNOS-a u mozgu za 55 % (p<0,05) u odnosu na kontrolnu skupinu, što upućuje na stvaranje tolerancije i ovisnosti. U kombiniranoj skupini nifedipin je značajno smanjio aktivnost nNOS-a u odnosu na skupinu koja je primila samo kokain. Kokain je značajno snizio, a nifedipin značajno povisio razinu citokroma P450 u jetri te aktivnost etilmorfi n-N-demetilaze i anilinhidroksilaze u odnosu na kontrolnu skupinu. U kombiniranoj skupini nifedipin je uspješno ublažio djelovanje kokaina na aktivnost spomenutih enzima. Izlučivanje kokaina putem mokraće u kombiniranoj skupini bilo je značajno manje (35 %) nego u skupini koja je primala samo kokain. Ovi rezultati potvrđuju da nifedipin štiti od djelovanja kokaina i stvaranja ovisnosti, najvjerojatnije zbog interakcija u metabolizmu dvaju spojeva

A Low Dimensional Description of Globally Coupled Heterogeneous Neural Networks of Excitatory and Inhibitory Neurons

Neural networks consisting of globally coupled excitatory and inhibitory nonidentical neurons may exhibit a complex dynamic behavior including synchronization, multiclustered solutions in phase space, and oscillator death. We investigate the conditions under which these behaviors occur in a multidimensional parametric space defined by the connectivity strengths and dispersion of the neuronal membrane excitability. Using mode decomposition techniques, we further derive analytically a low dimensional description of the neural population dynamics and show that the various dynamic behaviors of the entire network can be well reproduced by this reduced system. Examples of networks of FitzHugh-Nagumo and Hindmarsh-Rose neurons are discussed in detail

The James Webb Space Telescope Mission

Twenty-six years ago a small committee report, building on earlier studies, expounded a compelling and poetic vision for the future of astronomy, calling for an infrared-optimized space telescope with an aperture of at least $4m$. With the support of their governments in the US, Europe, and Canada, 20,000 people realized that vision as the $6.5m$ James Webb Space Telescope. A generation of astronomers will celebrate their accomplishments for the life of the mission, potentially as long as 20 years, and beyond. This report and the scientific discoveries that follow are extended thank-you notes to the 20,000 team members. The telescope is working perfectly, with much better image quality than expected. In this and accompanying papers, we give a brief history, describe the observatory, outline its objectives and current observing program, and discuss the inventions and people who made it possible. We cite detailed reports on the design and the measured performance on orbit.Comment: Accepted by PASP for the special issue on The James Webb Space Telescope Overview, 29 pages, 4 figure

Roedores del Holoceno tardío de la Puna de Atacama, sitio arqueológico Tebenquiche Chico, Catamarca, Argentina

Se estudió una muestra de roedores proveniente del yacimiento arqueológico de Tebenquiche Chico, situado en el departamento Antofagasta de la Sierra, provincia de Cata- marca, a 520 m de altitud y próximo al salar de Antofalla. El sitio corresponde a un pequeño asentamiento habitado entre los siglos IV y XII y reocupado en el siglo XVII de nuestra era. Los restos óseos fueron recuperados en el interior de las estructuras habitacionales del sitio arqueo- lógico, situado en las proximidades de una pequeña vega, antiguas acequias de riego y campos agrícolas. Se han registrado los taxones Abrothrix andinus, Phyllotis xanthopygus, Phyllotis sp., Neotomys ebriosus, Chinchilla chinchilla, Lagidium sp., Ctenomys sp. y Abrocoma cinerea. Se describen en detalle los numerosos caracteres cráneo-dentarios que permiten la distinción entre los géneros Chinchilla y Lagidium a partir de restos fragmentarios, dos taxones ampliamente utilizados como recurso básico en la economía de los pueblos de los Andes centrales. Con la excepción de Neotomys ebriosus, todas las especies registradas en el yacimiento habitan actual- mente en esta región de la Puna. Destaca el registro de N. ebriosus, sólo documentada actual- mente en los sectores montañosos húmedos orientales de la región. La amplitud temporal, el carácter exiguo de la muestra, la ausencia de muestras modernas comparables y la modificación antrópica del paisaje local impiden la reconstrucción de las condiciones paleoambientales a par- tir de los roedores de Tebenquiche Chico.We study a sample of rodents coming from the archaeological site Tebenquiche Chico, situated on the Antofagasta de la Sierra Department, Catamarca Province, near to the Antofalla salt-flat at 520 m elevation. The site is a small settlement inhabited between the IV and XII centuries and repopulated in the XVII century. The remains were recovered from the buildings of the archaeological site, near a small vega, old irrigation canals, and agricultural fields. We report the following taxa: Abrothrix andinus, Phyllotis xanthopygus, Phyllotis sp., Neotomys ebriosus, Chinchilla chinchilla, Lagidium sp., Ctenomys sp. y Abrocoma cinerea. Several craniodental characters that differentiate Chinchilla from Lagidium on the basis of fragmentary remains are described in detail, two taxa widely used as a basic resource in the economy of human populations in the Central Andes. Excepting Neotomys ebriosus, all the species of the archaeological site live in this area of the argentine Puna. The record of this species is noteworthy because their modern populations have been only documented in the more humid eastern mountain ranges of the region. The temporal amplitude, the exiguity of the archaeological sample, the absence of comparable modern samples, as well as the anthropogenic transformation of the local landscape prevent the reconstruction of paleoenvironmental conditions based on the Tebenquiche Chico rodents.Fil: Ortiz, Pablo Edmundo. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; ArgentinaFil: Jayat, Jorge Pablo. Universidad Nacional de Tucumán. Instituto de Ecología Regional. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto de Ecología Regional; ArgentinaFil: Nasif, N. L.. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Tucumán. Instituto Superior de Correlación Geológica. Universidad Nacional de Tucumán. Facultad de Ciencias Naturales e Instituto Miguel Lillo. Departamento de Geología. Cátedra Geología Estructural. Instituto Superior de Correlación Geológica; ArgentinaFil: Teta, Pablo Vicente. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Centro Nacional Patagónico; ArgentinaFil: Haber, Alejandro. Universidad Nacional de Catamarca. Escuela de Arqueología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

'Repentant' artists in Egypt: debating gender, performing arts and religion

Contains fulltext : 68454.pdf (publisher's version ) (Open Access)20 p