Psychostimulant drugs abuse is associated with an increased risk of stroke. Cytochromes P450 (CYP), especially the astrocytic members of the CYP2C subfamily may play an important role in the ...modulation of cerebrovascular functions, by generating vasodilatator metabolites from arachidonic acid (AA). Our study examined the regulation of CYP2C genes in response to cocaine or amphetamine in the human astrocyte-like U373 MG cells, using reverse transcription-polymerase chain reaction (RT-PCR) and western-blot analysis. A treatment for 48
h with increasing concentrations of cocaine caused a significant down-regulation of CYP2C8 and CYP2C9 genes and decreased the protein level. These effects were not observed with amphetamine. One mechanism of the CYP2C mRNA regulation implicates various specific receptors including glucocorticoid receptor (GR) and constitutive androstane receptor (CAR). Effects of cocaine on CYP2C were accompanied by a decrease in the GR and CAR gene expression suggesting that these nuclear receptors could be involved in the CYP2C repression by cocaine in the U373 MG cell line. These findings represent a possible molecular mechanism involved in the cerebrovascular risk associated with cocaine abuse.
Context. Recently, the high-energy (HE, 0.1–100 GeV) γ-ray emission from the object LMC P3 in the Large Magellanic Cloud (LMC) has been discovered to be modulated with a 10.3-day period, making it ...the first extra-galactic γ-ray binary. Aim. This work aims at the detection of very-high-energy (VHE, >100 GeV) γ-ray emission and the search for modulation of the VHE signal with the orbital period of the binary system. Methods. LMC P3 has been observed with the High Energy Stereoscopic System (H.E.S.S.); the acceptance-corrected exposure time is 100 h. The data set has been folded with the known orbital period of the system in order to test for variability of the emission. Results. VHE γ-ray emission is detected with a statistical significance of 6.4 σ. The data clearly show variability which is phase-locked to the orbital period of the system. Periodicity cannot be deduced from the H.E.S.S. data set alone. The orbit-averaged luminosity in the 1–10 TeV energy range is (1.4 ± 0.2) × 1035 erg s−1. A luminosity of (5 ± 1) × 1035 erg s−1 is reached during 20% of the orbit. HE and VHE γ-ray emissions are anti-correlated. LMC P3 is the most luminous γ-ray binary known so far.
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It was recently discovered that parasitic nematodes of plants, animals and humans secrete a structurally novel Fatty Acid and Retinol (FAR) Binding Protein into the tissues they occupy. ...The lipid‐binding characteristics of FAR proteins across multiple families of parasitic nematodes, and their presence at the host‐parasite interface, lends support to the idea that this nematode‐restricted family of proteins may play a crucial role in the life cycle of the roundworms. To investigate the possible role of these highly conserved nematode‐specific FAR proteins, our lab designed experiments to address the following hypotheses: 1) the FAR proteins are involved in lipid sequestration and delivery from the host to the nematode of a broad range of essential fatty acids, retinoids and other nutrients the parasites cannot synthesize themselves, 2) FAR proteins interfere with intercellular lipid signaling to manipulate the defense reactions of the host, and lastly, as these hypotheses are not mutually exclusive, 3) both mechanisms (hypotheses 1 and 2) are working together to allow for parasite survival and the establishment of chronic infection. To test these hypotheses, mice were dosed with acute, high levels of retinol and/or oleic acid prior to hookworm infection, to determine the impact on worm burden levels and circulating IL‐4. Our preliminary results demonstrate both a statistically significant increase in worm burdens and a significant decrease in circulating IL‐4, after treatments containing ether retinol or oleic acid, results which support hypothesis #3.
The central region of the Milky Way is one of the foremost locations to look for dark matter (DM) signatures. We report the first results on a search for DM particle annihilation signals using new ...observations from an unprecedented gamma-ray survey of the Galactic Center (GC) region, i.e., the Inner Galaxy Survey, at very high energies (& GSIM;100 GeV) performed with the H.E.S.S. array of five ground-based Cherenkov telescopes. No significant gamma-ray excess is found in the search region of the 2014-2020 dataset and a profile likelihood ratio analysis is carried out to set exclusion limits on the annihilation cross section (sigma v). Assuming Einasto and Navarro-Frenk-White (NFW) DM density profiles at the GC, these constraints are the strongest obtained so far in the TeV DM mass range. For the Einasto profile, the constraints reach (sigma v) values of 3.7 x 10-26 cm3 s-1 for 1.5 TeV DM mass in the W+W- annihilation channel, and 1.2 x 10-26 cm3 s-1 for 0.7 TeV DM mass in the tau+tau- annihilation channel. With the H.E.S.S. Inner Galaxy Survey, ground-based gamma-ray observations thus probe (sigma v) values expected from thermal-relic annihilating TeV DM particles.
The ALVAC prime/ALVAC + AIDSVAX B/E boost RV144 vaccine trial induced an estimated 31% efficacy in a low-risk cohort where HIV‑1 exposures were likely at mucosal surfaces. An immune correlates study ...demonstrated that antibodies targeting the V2 region and in a secondary analysis antibody-dependent cellular cytotoxicity (ADCC), in the presence of low envelope-specific (Env-specific) IgA, correlated with decreased risk of infection. Thus, understanding the B cell repertoires induced by this vaccine in systemic and mucosal compartments are key to understanding the potential protective mechanisms of this vaccine regimen. We immunized rhesus macaques with the ALVAC/AIDSVAX B/E gp120 vaccine regimen given in RV144, and then gave a boost 6 months later, after which the animals were necropsied. We isolated systemic and intestinal vaccine Env-specific memory B cells. Whereas Env-specific B cell clonal lineages were shared between spleen, draining inguinal, anterior pelvic, posterior pelvic, and periaortic lymph nodes, members of Env‑specific B cell clonal lineages were absent in the terminal ileum. Env‑specific antibodies were detectable in rectal fluids, suggesting that IgG antibodies present at mucosal sites were likely systemically produced and transported to intestinal mucosal sites.
The nearby radio galaxy Centaurus A belongs to a class of active galaxies that are luminous at radio wavelengths. Most show collimated relativistic outflows known as jets, which extend over hundreds ...of thousands of parsecs for the most powerful sources. Accretion of matter onto the central supermassive black hole is believed to fuel these jets and power their emission
. Synchrotron radiation from relativistic electrons causes the radio emission, and it has been suggested that the X-ray emission from Centaurus A also originates in electron synchrotron processes
. Another possible explanation is inverse Compton scattering with cosmic microwave background (CMB) soft photons
. Synchrotron radiation needs ultrarelativistic electrons (about 50 teraelectronvolts) and, given their short cooling times, requires some continuous re-acceleration mechanism
. Inverse Compton scattering, on the other hand, does not require very energetic electrons, but the jets must stay highly relativistic on large scales (exceeding 1 megaparsec). Some recent evidence disfavours inverse Compton-CMB models
, although other work seems to be compatible with them
. In principle, the detection of extended γ-ray emission, which directly probes the presence of ultrarelativistic electrons, could distinguish between these options. At gigaelectronvolt energies there is also an unusual spectral hardening
in Centaurus A that has not yet been explained. Here we report observations of Centaurus A at teraelectronvolt energies that resolve its large-scale jet. We interpret the data as evidence for the acceleration of ultrarelativistic electrons in the jet, and favour the synchrotron explanation for the X-rays. Given that this jet is not exceptional in terms of power, length or speed, it is possible that ultrarelativistic electrons are commonplace in the large-scale jets of radio-loud active galaxies.
The blazar Mrk 501 (z = 0.034) was observed at very-high-energy (VHE, E 100 GeV) gamma-ray wavelengths during a bright flare on the night of 2014 June 23-24 (MJD 56832) with the H.E.S.S. phase-II ...array of Cherenkov telescopes. Data taken that night by H.E.S.S. at large zenith angle reveal an exceptional number of gamma-ray photons at multi-TeV energies, with rapid flux variability and an energy coverage extending significantly up to 20 TeV. This data set is used to constrain Lorentz invariance violation (LIV) using two independent channels: a temporal approach considers the possibility of an energy dependence in the arrival time of gamma-rays, whereas a spectral approach considers the possibility of modifications to the interaction of VHE gamma-rays with extragalactic background light (EBL) photons. The non-detection of energy-dependent time delays and the non-observation of deviations between the measured spectrum and that of a supposed power-law intrinsic spectrum with standard EBL attenuation are used independently to derive strong constraints on the energy scale of LIV (EQG) in the subluminal scenario for linear and quadratic perturbations in the dispersion relation of photons. For the case of linear perturbations, the 95% confidence level limits obtained are EQG,1 > 3.6 × 1017 GeV using the temporal approach and EQG,1 > 2.6 × 1019 GeV using the spectral approach. For the case of quadratic perturbations, the limits obtained are EQG,2 > 8.5 × 1010 GeV using the temporal approach and EQG,2 > 7.8 × 1011 GeV using the spectral approach.
The increased prevalence of the sporadic form of Alzheimer's disease (AD) has become a significant health issue in the elderly population. The need for early diagnosis is imperative because this, ...along with the development of novel therapeutic treatments, would permit the rapid and perhaps more efficient treatment of these debilitating disorders early on.
Over the last decade, the potential use of certain biomarkers in the cerebrospinal fluid (CSF), and more recently, in the plasma has been investigated. Among the candidates studied includes the neurotoxic amyloid beta peptide and the Tau protein. However, although these two proteins have been clearly shown to be directly related to the pathophysiology of this disorder, it has proven difficult to establish a clear relationship between plasma or CSF levels of Abeta and Tau and the incidence and severity of AD in patients. This is due in part to differences in methodologies related to the detection sensitivity, as well as the variations in the biological data and consequent interpretation of the biochemical and biological data. Peripheral cells, in particular platelets and skin fibroblasts, could be an alternative solution as peripheral biological markers for the early diagnosis of AD. These cells are easily accessible from patients. Furthermore, they would provide a means not only to validate potential therapeutic strategies, but also to study the mechanisms involved in the development of AD, including APP processing.
A combined strategy using both a fundamental mechanistic and an analytical approach of patient peripheral cells will allow the identification of new biological markers for AD, and hence permit immediate therapeutic strategies to be implemented.
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