Heating Hot Atmospheres with Active Galactic Nuclei

High resolution X-ray spectroscopy of the hot gas in galaxy clusters has shown that the gas is not cooling to low temperatures at the predicted rates of hundreds to thousands of solar masses per year. X-ray images have revealed giant cavities and shock fronts in the hot gas that provide a direct and relatively reliable means of measuring the energy injected into hot atmospheres by active galactic nuclei (AGN). Average radio jet powers are near those required to offset radiative losses and to suppress cooling in isolated giant elliptical galaxies, and in larger systems up to the richest galaxy clusters. This coincidence suggests that heating and cooling are coupled by feedback, which suppresses star formation and the growth of luminous galaxies. How jet energy is converted to heat and the degree to which other heating mechanisms are contributing, eg. thermal conduction, are not well understood. Outburst energies require substantial late growth of supermassive black holes. Unless all of the approximately 10E62 erg required to suppress star formation is deposited in the cooling regions of clusters, AGN outbursts must alter large-scale properties of the intracluster medium.Comment: 60 pages, 12 figures, to appear in 1997 Annual Reviews of Astronomy and Astrophysics. This version supersedes the April 2007 version in Reviews in Advance (references and minor corrections were added), and is similar to the one scheduled to appear in Volume 45 of ARA

Integrative analysis of 3604 GWAS reveals multiple novel cell type-specific regulatory associations

BACKGROUND: Genome-wide association study (GWAS) single nucleotide polymorphisms (SNPs) are known to preferentially co-locate to active regulatory elements in tissues and cell types relevant to disease aetiology. Further characterisation of associated cell type-specific regulation can broaden our understanding of how GWAS signals may contribute to disease risk. RESULTS: To gain insight into potential functional mechanisms underlying GWAS associations, we developed FORGE2 ( https://forge2.altiusinstitute.org/ ), which is an updated version of the FORGE web tool. FORGE2 uses an expanded atlas of cell type-specific regulatory element annotations, including DNase I hotspots, five histone mark categories and 15 hidden Markov model (HMM) chromatin states, to identify tissue- and cell type-specific signals. An analysis of 3,604 GWAS from the NHGRI-EBI GWAS catalogue yielded at least one significant disease/trait-tissue association for 2,057 GWAS, including > 400 associations specific to epigenomic marks in immune tissues and cell types, > 30 associations specific to heart tissue, and > 60 associations specific to brain tissue, highlighting the key potential of tissue- and cell type-specific regulatory elements. Importantly, we demonstrate that FORGE2 analysis can separate previously observed accessible chromatin enrichments into different chromatin states, such as enhancers or active transcription start sites, providing a greater understanding of underlying regulatory mechanisms. Interestingly, tissue-specific enrichments for repressive chromatin states and histone marks were also detected, suggesting a role for tissue-specific repressed regions in GWAS-mediated disease aetiology. CONCLUSION: In summary, we demonstrate that FORGE2 has the potential to uncover previously unreported disease-tissue associations and identify new candidate mechanisms. FORGE2 is a transparent, user-friendly web tool for the integrative analysis of loci discovered from GWAS

Effects of biologically induced differential heating in an eddy-permitting coupled ocean-ecosystem model

On the basis of integrations of an eddy-permitting coupled physical-biological model of the tropical Pacific we explore changes in the simulated mean circulation as well as its intraseasonal to interannual variability driven by the biologically modulated vertical absorption profiles of solar radiation. Three sensitivity ocean hind-cast experiments, covering the period from 1948 to 2003, are performed. In the first one, simulated chlorophyll affects the attenuation of light in the water column, while in the second experiment, the chlorophyll concentration is kept constant in time by prescribing an empirically derived spatial pattern. The third experiment uses a spatially and temporally constant value for the attenuation depth. The biotically induced differential heating is generated by increased absorption of light in the surface layers, leading to a surface warming and subsurface cooling. The effect is largest in the eastern equatorial Pacific. However, the initial vertical redistribution of heat leads to considerable changes of the near-surface ocean circulation subsequently influencing the near-surface temperature structure. In general, including biophysical coupling improves the model performance in terms of temperature and ocean circulation patterns. In particular, the upwelling in the eastern equatorial Pacific is enhanced, the mixed layer becomes shallower, the warm bias in the eastern Pacific is reduced, and the zonal temperature gradient increases. This leads to stronger La Niña events and an associated increase in the variability of the Niño3 SSTA time series. Furthermore, the eddy kinetic energy (EKE) associated with mesoscale eddies in the eastern equatorial Pacific increases by almost 100% because of enhanced EKE production due to enhanced horizontal and vertical shear of the mean currents

Data-Driven Inference of Representation Invariants

A representation invariant is a property that holds of all values of abstract type produced by a module. Representation invariants play important roles in software engineering and program verification. In this paper, we develop a counterexample-driven algorithm for inferring a representation invariant that is sufficient to imply a desired specification for a module. The key novelty is a type-directed notion of visible inductiveness, which ensures that the algorithm makes progress toward its goal as it alternates between weakening and strengthening candidate invariants. The algorithm is parameterized by an example-based synthesis engine and a verifier, and we prove that it is sound and complete for first-order modules over finite types, assuming that the synthesizer and verifier are as well. We implement these ideas in a tool called Hanoi, which synthesizes representation invariants for recursive data types. Hanoi not only handles invariants for first-order code, but higher-order code as well. In its back end, Hanoi uses an enumerative synthesizer called Myth and an enumerative testing tool as a verifier. Because Hanoi uses testing for verification, it is not sound, though our empirical evaluation shows that it is successful on the benchmarks we investigated.Comment: 18 Pages, Full version of PLDI 2020 pape

Cost-effectiveness of an insertable cardiac monitor in a high-risk population in the UK

Objective To evaluate the cost-effectiveness of insertable cardiac monitors (ICMs) compared with standard of care (SoC) for detecting atrial fibrillation (AF) in patients at high risk of stroke (CHADS 2 >2), using a UK National Health Service (NHS) perspective. Methods Using patient characteristics and clinical data from the REVEAL AF trial, a Markov model assessed the cost-effectiveness of detecting AF with an ICM compared with SoC. Costs and benefits were extrapolated across modelled patient lifetime. Ischaemic and haemorrhagic strokes, intracranial and extracranial haemorrhages and minor bleeds were modelled. Diagnostic and device costs were included, plus costs of treating stroke and bleeding events and costs of oral anticoagulants (OACs). Costs and health outcomes, measured as quality-adjusted life years (QALYs), were discounted at 3.5% per annum. One-way deterministic and probabilistic sensitivity analyses (PSA) were undertaken. Results The total per-patient cost for ICM was £13 360 versus £11 936 for SoC (namely, annual 24 hours Holter monitoring). ICMs generated a total of 6.50 QALYs versus 6.30 for SoC. The incremental cost-effectiveness ratio (ICER) was £7140/QALY gained, below the £20 000/QALY acceptability threshold. ICMs were cost-effective in 77.4% of PSA simulations. The number of ICMs needed to prevent one stroke was 21 and to cause a major bleed was 37. ICERs were sensitive to assumed proportions of patients initiating or discontinuing OAC after AF diagnosis, type of OAC used and how intense the traditional monitoring was assumed to be under SoC. Conclusions The use of ICMs to identify AF in a high-risk population is cost-effective for the UK NHS

Implications of MMP9 for Blood Brain Barrier Disruption and Hemorrhagic Transformation Following Ischemic Stroke.

Numerous studies have documented increases in matrix metalloproteinases (MMPs), specifically MMP-9 levels following stroke, with such perturbations associated with disruption of the blood brain barrier (BBB), increased risk of hemorrhagic complications, and worsened outcome. Despite this, controversy remains as to which cells release MMP-9 at the normal and pathological BBB, with even less clarity in the context of stroke. This may be further complicated by the influence of tissue plasminogen activator (tPA) treatment. The aim of the present review is to examine the relationship between neutrophils, MMP-9 and tPA following ischemic stroke to elucidate which cells are responsible for the increases in MMP-9 and resultant barrier changes and hemorrhage observed following stroke

WNT signaling regulates self-renewal and differentiation of prostate cancer cells with stem cell characteristics

Prostate cancer cells with stem cell characteristics were identified in human prostate cancer cell lines by their ability to form from single cells self-renewing prostaspheres in non-adherent cultures. Prostaspheres exhibited heterogeneous expression of proliferation, differentiation and stem cell-associated makers CD44, ABCG2 and CD133. Treatment with WNT inhibitors reduced both prostasphere size and self-renewal. In contrast, addition of Wnt3a caused increased prostasphere size and self-renewal, which was associated with a significant increase in nuclear Β-catenin, keratin 18, CD133 and CD44 expression. As a high proportion of LNCaP and C4-2B cancer cells express androgen receptor we determined the effect of the androgen receptor antagonist bicalutamide. Androgen receptor inhibition reduced prostasphere size and expression of PSA, but did not inhibit prostasphere formation. These effects are consistent with the androgen-independent self-renewal of cells with stem cell characteristics and the androgen-dependent proliferation of transit amplifying cells. As the canonical WNT signaling effector Β-catenin can also associate with the androgen receptor, we propose a model for tumour propagation involving a balance between WNT and androgen receptor activity. That would affect the self-renewal of a cancer cell with stem cell characteristics and drive transit amplifying cell proliferation and differentiation. In conclusion, we provide evidence that WNT activity regulates the self-renewal of prostate cancer cells with stem cell characteristics independently of androgen receptor activity. Inhibition of WNT signaling therefore has the potential to reduce the self-renewal of prostate cancer cells with stem cell characteristics and improve the therapeutic outcome.Peer reviewe

To respond or not to respond - a personal perspective of intestinal tolerance

For many years, the intestine was one of the poor relations of the immunology world, being a realm inhabited mostly by specialists and those interested in unusual phenomena. However, this has changed dramatically in recent years with the realization of how important the microbiota is in shaping immune function throughout the body, and almost every major immunology institution now includes the intestine as an area of interest. One of the most important aspects of the intestinal immune system is how it discriminates carefully between harmless and harmful antigens, in particular, its ability to generate active tolerance to materials such as commensal bacteria and food proteins. This phenomenon has been recognized for more than 100 years, and it is essential for preventing inflammatory disease in the intestine, but its basis remains enigmatic. Here, I discuss the progress that has been made in understanding oral tolerance during my 40 years in the field and highlight the topics that will be the focus of future research