Methotrexate promotes platelet apoptosis via JNK-mediated mitochondrial damage: Alleviation by N-acetylcysteine and N-acetylcysteine amide

Thrombocytopenia in methotrexate (MTX)-treated cancer and rheumatoid arthritis (RA) patients connotes the interference of MTX with platelets. Hence, it seemed appealing to appraise the effect of MTX on platelets. Thereby, the mechanism of action of MTX on platelets was dissected. MTX (10 μM) induced activation of pro-apoptotic proteins Bid, Bax and Bad through JNK phosphorylation leading to Îm dissipation, cytochrome c release and caspase activation, culminating in apoptosis. The use of specific inhibitor for JNK abrogates the MTX-induced activation of pro-apoptotic proteins and downstream events confirming JNK phosphorylation by MTX as a key event. We also demonstrate that platelet mitochondria as prime sources of ROS which plays a central role in MTX-induced apoptosis. Further, MTX induces oxidative stress by altering the levels of ROS and glutathione cycle. In parallel, the clinically approved thiol antioxidant N-acetylcysteine (NAC) and its derivative N-acetylcysteine amide (NACA) proficiently alleviate MTX-induced platelet apoptosis and oxidative damage. These findings underpin the dearth of research on interference of therapeutic drugs with platelets, despite their importance in human health and disease. Therefore, the use of antioxidants as supplementary therapy seems to be a safe bet in pathologies associated with altered platelet functions. © 2015 Paul et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited

AzTEC/ASTE 1.1-mm survey of SSA22: Counterpart identification and photometric redshift survey of submillimetre galaxies

This article has been accepted for publication in Monthly Notices Of The Royal Astronomical Society ©: 2014 H. Umehata et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We present the results from a 1.1-mm imaging survey of the SSA22 field, known for having an overdensity of z = 3.1 Lyman α emitting galaxies (LAEs), taken with the astronomical thermal emission camera (AzTEC) on the Atacama Submillimeter Telescope Experiment (ASTE). We imaged a 950-arcmin^(2) field down to a 1σ sensitivity of 0.7–1.3 mJy beam^(−1) to find 125 submillimetre galaxies (SMGs) with a signal-to-noise ratio ≥3.5. Counterpart identification using radio and near/mid-infrared data was performed and one or more counterpart candidates were found for 59 SMGs. Photometric redshifts based on optical to near-infrared images were evaluated for 45 of these SMGs with Spitzer/IRAC data and the median value is found to be z = 2.4. By combining these estimations with estimates from the literature, we determined that 10 SMGs might lie within the large-scale structure at z = 3.1. The two-point angular cross-correlation function between LAEs and SMGs indicates that the positions of the SMGs are correlated with the z = 3.1 protocluster. These results suggest that the SMGs were formed and evolved selectively in the high dense environment of the high-redshift Universe. This picture is consistent with the predictions of the standard model of hierarchical structure formation

An AzTEC 1.1-mm survey for ULIRGs in the field of the Galaxy Cluster MS 0451.6−0305

This article has been accepted for publication in Monthly Notices Of The Royal Astronomical Society ©: 2010 J. L. Wardlow et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We have undertaken a deep (σ∼ 1.1 mJy) 1.1-mm survey of the z= 0.54 cluster MS 0451.6−0305 using the AzTEC camera on the James Clerk Maxwell Telescope. We detect 36 sources with signal-to-noise ratio (S/N) ≥ 3.5 in the central 0.10 deg2 and present the AzTEC map, catalogue and number counts. We identify counterparts to 18 sources (50 per cent) using radio, mid-infrared, Spitzer InfraRed Array Camera (IRAC) and Submillimetre Array data. Optical, near- and mid-infrared spectral energy distributions are compiled for the 14 of these galaxies with detectable counterparts, which are expected to contain all likely cluster members. We then use photometric redshifts and colour selection to separate background galaxies from potential cluster members and test the reliability of this technique using archival observations of submillimetre galaxies. We find two potential MS 0451−03 members, which, if they are both cluster galaxies, have a total star formation rate (SFR) of ∼100 M⊙ yr−1– a significant fraction of the combined SFR of all the other galaxies in MS 0451−03. We also examine the stacked rest-frame mid-infrared, millimetre and radio emission of cluster members below our AzTEC detection limit, and find that the SFRs of mid-IR-selected galaxies in the cluster and redshift-matched field populations are comparable. In contrast, the average SFR of the morphologically classified late-type cluster population is nearly three times less than the corresponding redshift-matched field galaxies. This suggests that these galaxies may be in the process of being transformed on the red sequence by the cluster environment. Our survey demonstrates that although the environment of MS 0451−03 appears to suppress star formation in late-type galaxies, it can support active, dust-obscured mid-IR galaxies and potentially millimetre-detected LIRGs

AzTEC/ASTE 1.1-mm survey of the AKARI Deep Field South: source catalogue and number counts

This article has been accepted for publication in Monthly Notices Of The Royal Astronomical Society ©: 2010 K. B. Hatsukade et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.We present results of a 1.1-mm deep survey of the AKARI Deep Field South (ADF-S) with AzTEC mounted on the Atacama Submillimetre Telescope Experiment (ASTE). We obtained a map of 0.25-deg2 area with an rms noise level of 0.32–0.71 mJy. This is one of the deepest and widest maps thus far at millimetre and submillimetre wavelengths. We uncovered 198 sources with a significance of 3.5σ–15.6σ, providing the largest catalogue of 1.1-mm sources in a contiguous region. Most of the sources are not detected in the far-infrared bands of the AKARI satellite, suggesting that they are mostly at z≥ 1.5 given the detection limits. We constructed differential and cumulative number counts in the ADF-S, the Subaru/XMM–Newton Deep Field and the SSA 22 field surveyed by AzTEC/ASTE, which provide currently the tightest constraints on the faint end. The integration of the best-fitting number counts in the ADF-S finds that the contribution of 1.1-mm sources with fluxes of ≥1 mJy to the cosmic infrared background (CIB) at 1.1 mm is 12–16 per cent, suggesting that the large fraction of the CIB originates from faint sources of which the number counts are not yet constrained. We estimate the cosmic star formation rate density contributed by 1.1-mm sources with ≥1 mJy using the best-fitting number counts in the ADF-S and find that it is lower by about a factor of 5–10 compared to those derived from UV/optically selected galaxies at z∼ 2–3. The fraction of stellar mass of the present-day universe produced by 1.1-mm sources with ≥1 mJy at z≥ 1 is ∼20 per cent, calculated by the time integration of the star formation rate density. If we consider the recycled fraction of >0.4, which is the fraction of materials forming stars returned to the interstellar medium, the fraction of stellar mass produced by 1.1-mm sources decreases to ≲10 per cent

Deep 1.1 mm-wavelength imaging of the GOODS-S field by AzTEC/ASTE – I. Source catalogue and number counts

This article has been accepted for publication in Monthly Notices Of The Royal Astronomical Society ©: 2010 K. S. Scott et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved

A bright, dust-obscured, millimetre-selected galaxy beyond the Bullet Cluster (1E0657−56)

This article has been accepted for publication in Monthly notices of the Royal Astronomical Society ©: 2008 G. W. Wilson et al. Published by Oxford University Press on behalf of the Royal Astronomical Society. All rights reserved.Deep 1.1 mm continuum observations of 1E0657−56 (the ‘Bullet Cluster’) taken with the millimeter-wavelength camera AzTEC on the 10-m Atacama Submillimeter Telescope Experiment (ASTE), have revealed an extremely bright (S1.1 mm= 15.9 mJy) unresolved source. This source, MMJ065837−5557.0, lies close to a maximum in the density of underlying mass distribution, towards the larger of the two interacting clusters as traced by the weak-lensing analysis of Clowe et al. Using optical–infrared (IR) colours, we argue that MMJ065837−5557.0 lies at a redshift of z= 2.7 ± 0.2. A lensing-derived mass model for the Bullet Cluster shows a critical line (caustic) of magnification within a few arcsec of the AzTEC source, sufficient to amplify the intrinsic millimetre-wavelength flux of the AzTEC galaxy by a factor of ≫20. After subtraction of the foreground cluster emission at 1.1 mm due to the Sunyaev-Zel'dovich effect, and correcting for the magnification, the rest-frame far-IR luminosity of MMJ065837−5557.0 is ≤1012L⊙, characteristic of a luminous infrared galaxy (LIRG). We explore various scenarios to explain the colours, morphologies and positional offsets between the potential optical and IR counterparts, and their relationship with MMJ065837−5557.0. Until higher resolution and more sensitive (sub)millimetre observations are available, the detection of background galaxies close to the caustics of massive lensing clusters offers the only opportunity to study this intrinsically faint millimetre-galaxy population

The Survey of Water and Ammonia in the Galactic Center (SWAG): Molecular Cloud Evolution in the Central Molecular Zone

The Survey of Water and Ammonia in the Galactic Center (SWAG) covers the Central Molecular Zone (CMZ) of the Milky Way at frequencies between 21.2 and 25.4 GHz obtained at the Australia Telescope Compact Array at $\sim 0.9$ pc spatial and $\sim 2.0$ km s$^{-1}$ spectral resolution. In this paper, we present data on the inner $\sim 250$ pc ($1.4^\circ$) between Sgr C and Sgr B2. We focus on the hyperfine structure of the metastable ammonia inversion lines (J,K) = (1,1) - (6,6) to derive column density, kinematics, opacity and kinetic gas temperature. In the CMZ molecular clouds, we find typical line widths of $8-16$ km s$^{-1}$ and extended regions of optically thick ($\tau > 1$) emission. Two components in kinetic temperature are detected at $25-50$ K and $60-100$ K, both being significantly hotter than dust temperatures throughout the CMZ. We discuss the physical state of the CMZ gas as traced by ammonia in the context of the orbital model by Kruijssen et al. (2015) that interprets the observed distribution as a stream of molecular clouds following an open eccentric orbit. This allows us to statistically investigate the time dependencies of gas temperature, column density and line width. We find heating rates between $\sim 50$ and $\sim 100$ K Myr$^{-1}$ along the stream orbit. No strong signs of time dependence are found for column density or line width. These quantities are likely dominated by cloud-to-cloud variations. Our results qualitatively match the predictions of the current model of tidal triggering of cloud collapse, orbital kinematics and the observation of an evolutionary sequence of increasing star formation activity with orbital phase

The Molecular Gas Environment in the 20 KMS−1 Cloud in the Central Molecular Zone

We recently reported a population of protostellar candidates in the 20 kms−1 cloud in the Central Molecular Zone of the Milky Way, traced by H2O masers in gravitationally bound dense cores. In this paper, we report high-angular-resolution (_3′′) molecular line studies of the environment of star formation in this cloud. Maps of various molecular line transitions as well as the continuum at 1.3 mm are obtained using the Submillimeter Array. Five NH3 inversion lines and the 1.3 cm continuum are observed with the Karl G. Jansky Very Large Array. The interferometric observations are complemented with single-dish data. We find that the CH3OH, SO, and HNCO lines, which are usually shock tracers, are better correlated spatially with the compact dust emission from dense cores among the detected lines. These lines also show enhancement in intensities with respect to SiO intensities toward the compact dust emission, suggesting the presence of slow shocks or hot cores in these regions. We find gas temperatures of &100 K at 0.1-pc scales based on RADEX modelling of the H2CO and NH3 lines. Although no strong correlations between temperatures and linewidths/H2O maser luminosities are found, in high-angular-resolution maps we notice several candidate shock heated regions offset from any dense cores, as well as signatures of localized heating by protostars in several dense cores. Our findings suggest that at 0.1-pc scales in this cloud star formation and strong turbulence may together affect the chemistry and temperature of the molecular gas

The JWST Galactic Center Survey -- A White Paper

The inner hundred parsecs of the Milky Way hosts the nearest supermassive black hole, largest reservoir of dense gas, greatest stellar density, hundreds of massive main and post main sequence stars, and the highest volume density of supernovae in the Galaxy. As the nearest environment in which it is possible to simultaneously observe many of the extreme processes shaping the Universe, it is one of the most well-studied regions in astrophysics. Due to its proximity, we can study the center of our Galaxy on scales down to a few hundred AU, a hundred times better than in similar Local Group galaxies and thousands of times better than in the nearest active galaxies. The Galactic Center (GC) is therefore of outstanding astrophysical interest. However, in spite of intense observational work over the past decades, there are still fundamental things unknown about the GC. JWST has the unique capability to provide us with the necessary, game-changing data. In this White Paper, we advocate for a JWST NIRCam survey that aims at solving central questions, that we have identified as a community: i) the 3D structure and kinematics of gas and stars; ii) ancient star formation and its relation with the overall history of the Milky Way, as well as recent star formation and its implications for the overall energetics of our galaxy's nucleus; and iii) the (non-)universality of star formation and the stellar initial mass function. We advocate for a large-area, multi-epoch, multi-wavelength NIRCam survey of the inner 100\,pc of the Galaxy in the form of a Treasury GO JWST Large Program that is open to the community. We describe how this survey will derive the physical and kinematic properties of ~10,000,000 stars, how this will solve the key unknowns and provide a valuable resource for the community with long-lasting legacy value.Comment: This White Paper will be updated when required (e.g. new authors joining, editing of content). Most recent update: 24 Oct 202

Familial hypercholesterolaemia in children and adolescents from 48 countries: a cross-sectional study

Background Approximately 450 000 children are born with familial hypercholesterolaemia worldwide every year, yet only 2·1% of adults with familial hypercholesterolaemia were diagnosed before age 18 years via current diagnostic approaches, which are derived from observations in adults. We aimed to characterise children and adolescents with heterozygous familial hypercholesterolaemia (HeFH) and understand current approaches to the identification and management of familial hypercholesterolaemia to inform future public health strategies. Methods For this cross-sectional study, we assessed children and adolescents younger than 18 years with a clinical or genetic diagnosis of HeFH at the time of entry into the Familial Hypercholesterolaemia Studies Collaboration (FHSC) registry between Oct 1, 2015, and Jan 31, 2021. Data in the registry were collected from 55 regional or national registries in 48 countries. Diagnoses relying on self-reported history of familial hypercholesterolaemia and suspected secondary hypercholesterolaemia were excluded from the registry; people with untreated LDL cholesterol (LDL-C) of at least 13·0 mmol/L were excluded from this study. Data were assessed overall and by WHO region, World Bank country income status, age, diagnostic criteria, and index-case status. The main outcome of this study was to assess current identification and management of children and adolescents with familial hypercholesterolaemia. Findings Of 63 093 individuals in the FHSC registry, 11 848 (18·8%) were children or adolescents younger than 18 years with HeFH and were included in this study; 5756 (50·2%) of 11 476 included individuals were female and 5720 (49·8%) were male. Sex data were missing for 372 (3·1%) of 11 848 individuals. Median age at registry entry was 9·6 years (IQR 5·8–13·2). 10 099 (89·9%) of 11 235 included individuals had a final genetically confirmed diagnosis of familial hypercholesterolaemia and 1136 (10·1%) had a clinical diagnosis. Genetically confirmed diagnosis data or clinical diagnosis data were missing for 613 (5·2%) of 11 848 individuals. Genetic diagnosis was more common in children and adolescents from high-income countries (9427 [92·4%] of 10 202) than in children and adolescents from non-high-income countries (199 [48·0%] of 415). 3414 (31·6%) of 10 804 children or adolescents were index cases. Familial-hypercholesterolaemia-related physical signs, cardiovascular risk factors, and cardiovascular disease were uncommon, but were more common in non-high-income countries. 7557 (72·4%) of 10 428 included children or adolescents were not taking lipid-lowering medication (LLM) and had a median LDL-C of 5·00 mmol/L (IQR 4·05–6·08). Compared with genetic diagnosis, the use of unadapted clinical criteria intended for use in adults and reliant on more extreme phenotypes could result in 50–75% of children and adolescents with familial hypercholesterolaemia not being identified. Interpretation Clinical characteristics observed in adults with familial hypercholesterolaemia are uncommon in children and adolescents with familial hypercholesterolaemia, hence detection in this age group relies on measurement of LDL-C and genetic confirmation. Where genetic testing is unavailable, increased availability and use of LDL-C measurements in the first few years of life could help reduce the current gap between prevalence and detection, enabling increased use of combination LLM to reach recommended LDL-C targets early in life. Funding Pfizer, Amgen, Merck Sharp & Dohme, Sanofi–Aventis, Daiichi Sankyo, and Regeneron