The Hubble Space Telescope Cluster Supernova Survey: II. The Type Ia Supernova Rate in High-Redshift Galaxy Clusters

We report a measurement of the Type Ia supernova (SN Ia) rate in galaxy clusters at 0.9 < z < 1.45 from the Hubble Space Telescope (HST) Cluster Supernova Survey. This is the first cluster SN Ia rate measurement with detected z > 0.9 SNe. Finding 8 +/- 1 cluster SNe Ia, we determine a SN Ia rate of 0.50 +0.23-0.19 (stat) +0.10-0.09 (sys) SNuB (SNuB = 10^-12 SNe L_{sun,B}^-1 yr^-1). In units of stellar mass, this translates to 0.36 +0.16-0.13 (stat) +0.07-0.06 (sys) SNuM (SNuM = 10^-12 SNe M_sun^-1 yr^-1). This represents a factor of approximately 5 +/- 2 increase over measurements of the cluster rate at z < 0.2. We parameterize the late-time SN Ia delay time distribution with a power law (proportional to t^s). Under the assumption of a cluster formation redshift of z_f = 3, our rate measurement in combination with lower-redshift cluster SN Ia rates constrains s = -1.41 +0.47/-0.40, consistent with measurements of the delay time distribution in the field. This measurement is generally consistent with expectations for the "double degenerate" scenario and inconsistent with some models for the "single degenerate" scenario predicting a steeper delay time distribution at large delay times. We check for environmental dependence and the influence of younger stellar populations by calculating the rate specifically in cluster red-sequence galaxies and in morphologically early-type galaxies, finding results similar to the full cluster rate. Finally, the upper limit of one host-less cluster SN Ia detected in the survey implies that the fraction of stars in the intra-cluster medium is less than 0.47 (95% confidence), consistent with measurements at lower redshifts.Comment: 29 pages, 14 figures. Accepted for publication in ApJ on 16 February 2011. See the HST Cluster Supernova Survey website at http://supernova.lbl.gov/2009ClusterSurvey for a version with full-resolution images and a complete listing of transient candidates from the survey. This version fixes a typo in the metadata; the paper is unchanged from v

Dual Triumphalist Heritage Narrative And The Sungai Buloh Leprosy Settlement

Unlike other heritage movements in Malaysia, which are largely ethnicbased and culture obsessed (Cartier 1996; Worden 2001), the preservation movement of the Sungai Bulah Leprosy Settlement (SBLS thereafter), also widely referred to as the "Valley of Hope", 1 is concerned with the conservation of a site that is associated with a socially stigmatised disease. Built at a jungle fringe in Selangor in 1930, SBLS was constructed as a place for the treatment, and forced isolation from wider society, of people suffering from leprosy. Although leprosy knows no racial boundaries as people of any background can be afflicted with the disease, nearly eighty per cent of the patients admitted to SBLS have been ethnic Chinese. Of the rest, about fifteen per cent were ethnic Malays with ethnic Indians making up five per cent. Former patients who were cured but left with differing degrees of disfigurement and disability are also residents of the SBLS today.2 SBLS's population reached its peal<. with 2400 people in 1958, but today their number is just slightly over one hundred (JoshuaRaghavar 1983; Wong and Phang 2006)

Direct Evidence of Two-component Ejecta in Supernova 2016gkg from Nebular Spectroscopy*

Spectral observations of the type-IIb supernova (SN) 2016gkg at 300-800 days are reported. The spectra show nebular characteristics, revealing emission from the progenitor star's metal-rich core and providing clues to the kinematics and physical conditions of the explosion. The nebular spectra are dominated by emission lines of [O i] lambda lambda 6300, 6364 and [Ca ii] lambda lambda 7292, 7324. Other notable, albeit weaker, emission lines include Mg I] lambda 4571, [Fe ii] lambda 7155, O I lambda 7774, Ca II triplet, and a broad, boxy feature at the location of H alpha. Unlike in other stripped-envelope SNe, the [O i] doublet is clearly resolved due to the presence of strong narrow components. The doublet shows an unprecedented emission line profile consisting of at least three components for each [O i]lambda 6300, 6364 line: a broad component (width similar to 2000 km s(-1)), and a pair of narrow blue and red components (width similar to 300 km s(-1)) mirrored against the rest velocity. The narrow component appears also in other lines, and is conspicuous in [O i]. This indicates the presence of multiple distinct kinematic components of material at low and high velocities. The low-velocity components are likely to be produced by a dense, slow-moving emitting region near the center, while the broad components are emitted over a larger volume. These observations suggest an asymmetric explosion, supporting the idea of two-component ejecta that influence the resulting late-time spectra and light curves. SN 2016gkg thus presents striking evidence for significant asymmetry in a standard-energy SN explosion. The presence of material at low velocity, which is not predicted in 1D simulations, emphasizes the importance of multidimensional explosion modeling of SNe

Glutamine Acts as a Neuroprotectant against DNA Damage, Beta-Amyloid and H2O2-Induced Stress

Glutamine is the most abundant free amino acid in the human blood stream and is ‘conditionally essential’ to cells. Its intracellular levels are regulated both by the uptake of extracellular glutamine via specific transport systems and by its intracellular synthesis by glutamine synthetase (GS). Adding to the regulatory complexity, when extracellular glutamine is reduced GS protein levels rise. Unfortunately, this excess GS can be maladaptive. GS overexpression is neurotoxic especially if the cells are in a low-glutamine medium. Similarly, in low glutamine, the levels of multiple stress response proteins are reduced rendering cells hypersensitive to H2O2, zinc salts and DNA damage. These altered responses may have particular relevance to neurodegenerative diseases of aging. GS activity and glutamine levels are lower in the Alzheimer's disease (AD) brain, and a fraction of AD hippocampal neurons have dramatically increased GS levels compared with control subjects. We validated the importance of these observations by showing that raising glutamine levels in the medium protects cultured neuronal cells against the amyloid peptide, Aβ. Further, a 10-day course of dietary glutamine supplementation reduced inflammation-induced neuronal cell cycle activation, tau phosphorylation and ATM-activation in two different mouse models of familial AD while raising the levels of two synaptic proteins, VAMP2 and synaptophysin. Together, our observations suggest that healthy neuronal cells require both intracellular and extracellular glutamine, and that the neuroprotective effects of glutamine supplementation may prove beneficial in the treatment of AD

HTLV-1 bZIP Factor Induces T-Cell Lymphoma and Systemic Inflammation In Vivo

Human T-cell leukemia virus type 1 (HTLV-1) is the causal agent of a neoplastic disease of CD4+ T cells, adult T-cell leukemia (ATL), and inflammatory diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis, dermatitis, and inflammatory lung diseases. ATL cells, which constitutively express CD25, resemble CD25+CD4+ regulatory T cells (Treg). Approximately 60% of ATL cases indeed harbor leukemic cells that express FoxP3, a key transcription factor for Treg cells. HTLV-1 encodes an antisense transcript, HTLV-1 bZIP factor (HBZ), which is expressed in all ATL cases. In this study, we show that transgenic expression of HBZ in CD4+ T cells induced T-cell lymphomas and systemic inflammation in mice, resembling diseases observed in HTLV-1 infected individuals. In HBZ-transgenic mice, CD4+Foxp3+ Treg cells and effector/memory CD4+ T cells increased in vivo. As a mechanism of increased Treg cells, HBZ expression directly induced Foxp3 gene transcription in T cells. The increased CD4+Foxp3+ Treg cells in HBZ transgenic mice were functionally impaired while their proliferation was enhanced. HBZ could physically interact with Foxp3 and NFAT, thereby impairing the suppressive function of Treg cells. Thus, the expression of HBZ in CD4+ T cells is a key mechanism of HTLV-1-induced neoplastic and inflammatory diseases

Assessing childhood maltreatment and mental health correlates of disordered eating profiles in a nationally representative sample of English females

PURPOSE: Previous research suggests that childhood maltreatment is associated with the onset of eating disorders (ED). In turn, EDs are associated with alternative psychopathologies such as depression and posttraumatic stress disorder (PTSD), and with suicidality. Moreover, it has been reported that various ED profiles may exist. The aim of the current study was to examine the profiles of disordered eating and the associations of these with childhood maltreatment and with mental health psychopathology. METHODS: The current study utilised a representative sample of English females (N = 4206) and assessed for the presence of disordered eating profiles using Latent Class Analysis. Multinomial logistic regression was implemented to examine the associations of childhood sexual and physical abuse with the disordered eating profiles and the associations of these with PTSD, depression and suicidality. RESULTS: Results supported those of previous findings in that we found five latent classes of which three were regarded as disordered eating classes. Significant relationships were found between these and measures of childhood trauma and mental health outcomes. CONCLUSIONS: Childhood sexual and physical abuse increased the likelihood of membership in disordered eating classes and these in turn increased the likelihood of adverse mental health and suicidal outcomes

Lipopolysaccharide and Tumor Necrosis Factor Regulate Parkin Expression via Nuclear Factor-Kappa B

Inflammation and oxidative stress have been implicated in the pathophysiology of Parkinson's disease (PD) and inhibition of microglial activation attenuates degeneration of dopaminergic (DA) neurons in animal models of PD. Loss-of-function mutations in the parkin gene, which encodes an E3 ubiquitin ligase, cause autosomal recessive parkinsonism. While most studies on Parkin have focused on its function in neurons, here we demonstrate that Parkin mRNA and protein is detectable in brain-resident microglia and peripheral macrophages. Using pharmacologic and genetic approaches, we found that Parkin levels are regulated by inflammatory signaling. Specifically, exposure to LPS or Tumor Necrosis Factor (TNF) induced a transient and dose-dependent decrease in Parkin mRNA and protein in microglia, macrophages and neuronal cells blockable by inhibitors of Nuclear Factor-Kappa B (NF-κB) signaling and not observed in MyD88-null cells. Moreover, using luciferase reporter assays, we identified an NF-κB response element in the mouse parkin promoter responsible for mediating the transcriptional repression, which was abrogated when the consensus sequence was mutated. Functionally, activated macrophages from Parkin-null mice displayed increased levels of TNF, IL-1β, and iNOS mRNA compared to wild type macrophages but no difference in levels of Nrf2, HO-1, or NQO1. One implication of our findings is that chronic inflammatory conditions may reduce Parkin levels and phenocopy parkin loss-of-function mutations, thereby increasing the vulnerability for degeneration of the nigrostriatal pathway and development of PD

A Role for Thrombospondin-1 Deficits in Astrocyte-Mediated Spine and Synaptic Pathology in Down's Syndrome

Down's syndrome (DS) is the most common genetic cause of mental retardation. Reduced number and aberrant architecture of dendritic spines are common features of DS neuropathology. However, the mechanisms involved in DS spine alterations are not known. In addition to a relevant role in synapse formation and maintenance, astrocytes can regulate spine dynamics by releasing soluble factors or by physical contact with neurons. We have previously shown impaired mitochondrial function in DS astrocytes leading to metabolic alterations in protein processing and secretion. In this study, we investigated whether deficits in astrocyte function contribute to DS spine pathology.Using a human astrocyte/rat hippocampal neuron coculture, we found that DS astrocytes are directly involved in the development of spine malformations and reduced synaptic density. We also show that thrombospondin 1 (TSP-1), an astrocyte-secreted protein, possesses a potent modulatory effect on spine number and morphology, and that both DS brains and DS astrocytes exhibit marked deficits in TSP-1 protein expression. Depletion of TSP-1 from normal astrocytes resulted in dramatic changes in spine morphology, while restoration of TSP-1 levels prevented DS astrocyte-mediated spine and synaptic alterations. Astrocyte cultures derived from TSP-1 KO mice exhibited similar deficits to support spine formation and structure than DS astrocytes.These results indicate that human astrocytes promote spine and synapse formation, identify astrocyte dysfunction as a significant factor of spine and synaptic pathology in the DS brain, and provide a mechanistic rationale for the exploration of TSP-1-based therapies to treat spine and synaptic pathology in DS and other neurological conditions

Disease-associated missense mutations in GluN2B subunit alter NMDA receptor ligand binding and ion channel properties.

Genetic and bioinformatic analyses have identified missense mutations in GRIN2B encoding the NMDA receptor GluN2B subunit in autism, intellectual disability, Lennox Gastaut and West Syndromes. Here, we investigated several such mutations using a near-complete, hybrid 3D model of the human NMDAR and studied their consequences with kinetic modelling and electrophysiology. The mutants revealed reductions in glutamate potency; increased receptor desensitisation; and ablation of voltage-dependent Mg block. In addition, we provide new views on Mg and NMDA channel blocker binding sites. We demonstrate that these mutants have significant impact on excitatory transmission in developing neurons, revealing profound changes that could underlie their associated neurological disorders. Of note, the NMDAR channel mutant GluN2B unusually allowed Mg permeation, whereas nearby N615I reduced Ca permeability. By identifying the binding site for an NMDAR antagonist that is used in the clinic to rescue gain-of-function phenotypes, we show that drug binding may be modified by some GluN2B disease-causing mutations