114 research outputs found

    Neutrino Signatures From Young Neutron Stars

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    After a successful core collapse supernova (CCSN) explosion, a hot dense proto-neutron star (PNS) is left as a remnant. Over a time of 20 or so seconds, this PNS emits the majority of the neutrinos that come from the CCSN, contracts, and loses most of its lepton number. This is the process by which all neutron stars in our galaxy are likely born. The emitted neutrinos were detected from supernova (SN) 1987A, and they will be detected in much greater numbers from any future galactic CCSN. These detections can provide a direct window into the properties of the dense matter encountered inside neutron stars, and they can affect nucleosynthesis in the material ejected during the CCSN. In this chapter, we review the basic physics of PNS cooling, including the basic equations of PNS structure and neutrino diffusion in dense matter. We then discuss how the nuclear equation of state, neutrino opacities in dense matter, and convection can shape the temporal behavior of the neutrino signal. We also discuss what was learned from the late-time SN 1987A neutrinos, the prospects for detection of these neutrinos from future galactic CCSNe, and the effects these neutrinos can have on nucleosynthesis

    IL-10R Blockade during Chronic Schistosomiasis Mansoni Results in the Loss of B Cells from the Liver and the Development of Severe Pulmonary Disease

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    In schistosomiasis patients, parasite eggs trapped in hepatic sinusoids become foci for CD4+ T cell-orchestrated granulomatous cellular infiltrates. Since the immune response is unable to clear the infection, the liver is subjected to ongoing cycles of focal inflammation and healing that lead to vascular obstruction and tissue fibrosis. This is mitigated by regulatory mechanisms that develop over time and which minimize the inflammatory response to newly deposited eggs. Exploring changes in the hepatic inflammatory infiltrate over time in infected mice, we found an accumulation of schistosome egg antigen-specific IgG1-secreting plasma cells during chronic infection. This population was significantly diminished by blockade of the receptor for IL-10, a cytokine implicated in plasma cell development. Strikingly, IL-10R blockade precipitated the development of portal hypertension and the accumulation of parasite eggs in the lungs and heart. This did not reflect more aggressive Th2 cell responsiveness, increased hepatic fibrosis, or the emergence of Th1 or Th17 responses. Rather, a role for antibody in the prevention of severe disease was suggested by the finding that pulmonary involvement was also apparent in mice unable to secrete class switched antibody. A major effect of anti-IL-10R treatment was the loss of a myeloid population that stained positively for surface IgG1, and which exhibited characteristics of regulatory/anti-inflammatory macrophages. This finding suggests that antibody may promote protective effects within the liver through local interactions with macrophages. In summary, our data describe a role for IL-10-dependent B cell responses in the regulation of tissue damage during a chronic helminth infection

    Differential Function of Lip Residues in the Mechanism and Biology of an Anthrax Hemophore

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    To replicate in mammalian hosts, bacterial pathogens must acquire iron. The majority of iron is coordinated to the protoporphyrin ring of heme, which is further bound to hemoglobin. Pathogenic bacteria utilize secreted hemophores to acquire heme from heme sources such as hemoglobin. Bacillus anthracis, the causative agent of anthrax disease, secretes two hemophores, IsdX1 and IsdX2, to acquire heme from host hemoglobin and enhance bacterial replication in iron-starved environments. Both proteins contain NEAr-iron Transporter (NEAT) domains, a conserved protein module that functions in heme acquisition in Gram-positive pathogens. Here, we report the structure of IsdX1, the first of a Gram-positive hemophore, with and without bound heme. Overall, IsdX1 forms an immunoglobin-like fold that contains, similar to other NEAT proteins, a 310-helix near the heme-binding site. Because the mechanistic function of this helix in NEAT proteins is not yet defined, we focused on the contribution of this region to hemophore and NEAT protein activity, both biochemically and biologically in cultured cells. Site-directed mutagenesis of amino acids in and adjacent to the helix identified residues important for heme and hemoglobin association, with some mutations affecting both properties and other mutations affecting only heme stabilization. IsdX1 with mutations that reduced the ability to associate with hemoglobin and bind heme failed to restore the growth of a hemophore-deficient strain of B. anthracis on hemoglobin as the sole iron source. These data indicate that not only is the 310-helix important for NEAT protein biology, but also that the processes of hemoglobin and heme binding can be both separate as well as coupled, the latter function being necessary for maximal heme-scavenging activity. These studies enhance our understanding of NEAT domain and hemophore function and set the stage for structure-based inhibitor design to block NEAT domain interaction with upstream ligands

    MLH1 mediates PARP-dependent cell death in response to the methylating agent N-methyl-N-nitrosourea

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    Background:Methylating agents such as N-methyl-N-nitrosourea (MNU) can cause cell cycle arrest and death either via caspase-dependent apoptosis or via a poly(ADP-ribose) polymerase (PARP)-dependent form of apoptosis. We wished to investigate the possible role of MLH1 in signalling cell death through PARP.Methods:Fibroblasts are particularly dependent on a PARP-mediated cell death response to methylating agents. We used hTERT-immortalised normal human fibroblasts (WT) to generate isogenic MLH1-depleted cells, confirmed by quantitative PCR and western blotting. Drug resistance was measured by clonogenic and cell viability assays and effects on the cell cycle by cell sorting. Damage signalling was additionally investigated using immunostaining.Results:MLH1-depleted cells were more resistant to MNU, as expected. Despite having an intact G2/M checkpoint, the WT cells did not initially undergo cell cycle arrest but instead triggered cell death directly by PARP overactivation and nuclear translocation of apoptosis-inducing factor (AIF). The MLH1-depleted cells showed defects in this pathway, with decreased staining for phosphorylated H2AX, altered PARP activity and reduced AIF translocation. Inhibitors of PARP, but not of caspases, blocked AIF translocation and greatly decreased short-term cell death in both WT and MLH1-depleted cells. This MLH1-dependent response to MNU was not blocked by inhibitors of ATM/ATR or p53.Conclusion:These novel data indicate an important role for MLH1 in signalling PARP-dependent cell death in response to the methylating agent MNU

    Expensive Egos: Narcissistic Males Have Higher Cortisol

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    Background: Narcissism is characterized by grandiosity, low empathy, and entitlement. There has been limited research regarding the hormonal correlates of narcissism, despite the potential health implications. This study examined the role of participant narcissism and sex on basal cortisol concentrations in an undergraduate population. Methods and Findings: Participants were 106 undergraduate students (79 females, 27 males, mean age 20.1 years) from one Midwestern and one Southwestern American university. Narcissism was assessed using the Narcissistic Personality Inventory, and basal cortisol concentrations were collected from saliva samples in a laboratory setting. Regression analyses examined the effect of narcissism and sex on cortisol (log). There were no sex differences in basal cortisol, F(1,97) =.20, p =.65, and narcissism scores, F(1,97) =.00, p =.99. Stepwise linear regression models of sex and narcissism and their interaction predicting cortisol concentrations showed no main effects when including covariates, but a significant interaction, b =.27, p =.04. Narcissism was not related to cortisol in females, but significantly predicted cortisol in males. Examining the effect of unhealthy versus healthy narcissism on cortisol found that unhealthy narcissism was marginally related to cortisol in females, b =.27, p =.06, but significantly predicted higher basal cortisol in males, b =.72, p =.01, even when controlling for potential confounds. No relationship was found between sex, narcissism, or their interaction on selfreported stress

    Iron Behaving Badly: Inappropriate Iron Chelation as a Major Contributor to the Aetiology of Vascular and Other Progressive Inflammatory and Degenerative Diseases

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    The production of peroxide and superoxide is an inevitable consequence of aerobic metabolism, and while these particular "reactive oxygen species" (ROSs) can exhibit a number of biological effects, they are not of themselves excessively reactive and thus they are not especially damaging at physiological concentrations. However, their reactions with poorly liganded iron species can lead to the catalytic production of the very reactive and dangerous hydroxyl radical, which is exceptionally damaging, and a major cause of chronic inflammation. We review the considerable and wide-ranging evidence for the involvement of this combination of (su)peroxide and poorly liganded iron in a large number of physiological and indeed pathological processes and inflammatory disorders, especially those involving the progressive degradation of cellular and organismal performance. These diseases share a great many similarities and thus might be considered to have a common cause (i.e. iron-catalysed free radical and especially hydroxyl radical generation). The studies reviewed include those focused on a series of cardiovascular, metabolic and neurological diseases, where iron can be found at the sites of plaques and lesions, as well as studies showing the significance of iron to aging and longevity. The effective chelation of iron by natural or synthetic ligands is thus of major physiological (and potentially therapeutic) importance. As systems properties, we need to recognise that physiological observables have multiple molecular causes, and studying them in isolation leads to inconsistent patterns of apparent causality when it is the simultaneous combination of multiple factors that is responsible. This explains, for instance, the decidedly mixed effects of antioxidants that have been observed, etc...Comment: 159 pages, including 9 Figs and 2184 reference

    Epithelial cancers in the post-genomic era: should we reconsider our lifestyle?

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    The age-related epithelial cancers of the breast, colorectum and prostate are the most prevalent and are increasing in our aging populations. Epithelial cells turnover rapidly and mutations naturally accumulate throughout life. Most epithelial cancers arise from this normal mutation rate. All elderly individuals will harbour many cells with the requisite mutations and most will develop occult neoplastic lesions. Although essential for initiation, these mutations are not sufficient for the progression of cancer to a life-threatening disease. This progression appears to be dependent on context: the tissue ecosystem within individuals and lifestyle exposures across populations of individuals. Together, this implies that the seeds may be plentiful but they only germinate in the right soil. The incidence of these cancers is much lower in Eastern countries but is increasing with Westernisation and increases more acutely in migrants to the West. A Western lifestyle is strongly associated with perturbed metabolism, as evidenced by the epidemics of obesity and diabetes: this may also provide the setting enabling the progression of epithelial cancers. Epidemiology has indicated that metabolic biomarkers are prospectively associated with cancer incidence and prognosis. Furthermore, within cancer research, there has been a rediscovery that a switch in cell metabolism is critical for cancer progression but this is set within the metabolic status of the host. The seed may only germinate if the soil is fertile. This perspective brings together the different avenues of investigation implicating the role that metabolism may play within the context of post-genomic concepts of cancer

    Akt mediated mitochondrial protection in the heart: metabolic and survival pathways to the rescue

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