The Drosophila Inhibitor of Apoptosis (IAP) DIAP2 Is Dispensable for Cell Survival, Required for the Innate Immune Response to Gram-negative Bacterial Infection, and Can Be Negatively Regulated by the Reaper/Hid/Grim Family of IAP-binding Apoptosis Inducers

Many inhibitor of apoptosis (IAP) family proteins inhibit apoptosis. IAPs contain N-terminal baculovirus IAP repeat domains and a C-terminal RING ubiquitin ligase domain. Drosophila IAP DIAP1 is essential for the survival of many cells, protecting them from apoptosis by inhibiting active caspases. Apoptosis initiates when proteins such as Reaper, Hid, and Grim bind a surface groove in DIAP1 baculovirus IAP repeat domains via an N-terminal IAP-binding motif. This evolutionarily conserved interaction disrupts DIAP1-caspase interactions, unleashing apoptosis-inducing caspase activity. A second Drosophila IAP, DIAP2, also binds Rpr and Hid and inhibits apoptosis in multiple contexts when overexpressed. However, due to a lack of mutants, little is known about the normal functions of DIAP2. We report the generation of diap2 null mutants. These flies are viable and show no defects in developmental or stress-induced apoptosis. Instead, DIAP2 is required for the innate immune response to Gram-negative bacterial infection. DIAP2 promotes cytoplasmic cleavage and nuclear translocation of the NF-{kappa}B homolog Relish, and this requires the DIAP2 RING domain. Increasing the genetic dose of diap2 results in an increased immune response, whereas expression of Rpr or Hid results in down-regulation of DIAP2 protein levels. Together these observations suggest that DIAP2 can regulate immune signaling in a dose-dependent manner, and this can be regulated by IBM-containing proteins. Therefore, diap2 may identify a point of convergence between apoptosis and immune signaling pathways

Is Quantum Spacetime Foam Unstable?

A very simple wormhole geometry is considered as a model of a mode of topological fluctutation in Planck-scale spacetime foam. Quantum dynamics of the hole reduces to quantum mechanics of one variable, throat radius, and admits a WKB analysis. The hole is quantum-mechanically unstable: It has no bound states. Wormhole wave functions must eventually leak to large radii. This suggests that stability considerations along these lines may place strong constraints on the nature and even the existence of spacetime foam.Comment: 15 page

Response to Maccio et al, - Multifactorial pathogenesis of COVID- 19- related coagulopathy: Can defibrotide have a role in the early phases of coagulation disorders?-

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/163392/2/jth15088_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/163392/1/jth15088.pd

Quantum Dynamics of Lorentzian Spacetime Foam

A simple spacetime wormhole, which evolves classically from zero throat radius to a maximum value and recontracts, can be regarded as one possible mode of fluctuation in the microscopic ``spacetime foam'' first suggested by Wheeler. The dynamics of a particularly simple version of such a wormhole can be reduced to that of a single quantity, its throat radius; this wormhole thus provides a ``minisuperspace model'' for a structure in Lorentzian-signature foam. The classical equation of motion for the wormhole throat is obtained from the Einstein field equations and a suitable equation of state for the matter at the throat. Analysis of the quantum behavior of the hole then proceeds from an action corresponding to that equation of motion. The action obtained simply by calculating the scalar curvature of the hole spacetime yields a model with features like those of the relativistic free particle. In particular the Hamiltonian is nonlocal, and for the wormhole cannot even be given as a differential operator in closed form. Nonetheless the general solution of the Schr\"odinger equation for wormhole wave functions, i.e., the wave-function propagator, can be expressed as a path integral. Too complicated to perform exactly, this can yet be evaluated via a WKB approximation. The result indicates that the wormhole, classically stable, is quantum-mechanically unstable: A Feynman-Kac decomposition of the WKB propagator yields no spectrum of bound states. Though an initially localized wormhole wave function may oscillate for many classical expansion/recontraction periods, it must eventually leak to large radius values. The possibility of such a mode unstable against growth, combined withComment: 37 pages, 93-

The Distances of the Magellanic Clouds

The present status of our knowledge of the distances to the Magellanic Clouds is evaluated from a post-Hipparcos perspective. After a brief summary of the effects of structure, reddening, age and metallicity, the primary distance indicators for the Large Magellanic Cloud are reviewed: The SN 1987A ring, Cepheids, RR Lyraes, Mira variables, and Eclipsing Binaries. Distances derived via these methods are weighted and combined to produce final "best" estimates for the Magellanic Clouds distance moduli.Comment: Invited review article to appear in ``Post Hipparcos Cosmic Candles'', F. Caputo & A. Heck (Eds.), Kluwer Academic Publ., Dordrecht, in pres

What do cluster counts really tell us about the Universe?

We study the covariance matrix of the cluster mass function in cosmology. We adopt a two-line attack: firstly, we employ the counts-in-cells framework to derive an analytic expression for the covariance of the mass function. Secondly, we use a large ensemble of N-body simulations in the LCDM framework to test this. Our theoretical results show that the covariance can be written as the sum of two terms: a Poisson term, which dominates in the limit of rare clusters; and a sample variance term, which dominates for more abundant clusters. Our expressions are analogous to those of Hu & Kravtsov (2003) for multiple cells and a single mass tracer. Calculating the covariance depends on: the mass function and bias of clusters, and the variance of mass fluctuations within the survey volume. The predictions show that there is a strong bin-to-bin covariance between measurements. In terms of the cross-correlation coefficient, we find r~0.5 for haloes with M<3e14 Msol at z=0. Comparison of these predictions with estimates from simulations shows excellent agreement. We use the Fisher matrix formalism to explore the cosmological information content of the counts. We compare the Poisson likelihood model, with the more realistic likelihood model of Lima & Hu (2004), and all terms entering the Fisher matrices are evaluated using the simulations. We find that the Poisson approximation should only be used for the rarest objects, M>3e14 Msol, otherwise the information content of a survey of size V~13.5 [Gpc/h]^3 would be overestimated, resulting in errors that are ~2 times smaller. As an auxiliary result, we show that the bias of clusters, obtained from the cluster-mass cross-variance, is linear on scales >50 Mpc/h, whereas that obtained from the auto-variance is nonlinear.Comment: Replaced with version accepted for publication in MNRAS. Minor corrections: references updated, typos corrected. 20 pages; 10 figure

A new approach to assessing the health benefit from obesity interventions in children and adolescents: the assessing cost-effectiveness in obesity project

OBJECTIVE: To report on a new modelling approach developed for the assessing cost-effectiveness in obesity (ACE-Obesity) project and the likely population health benefit and strength of evidence for 13 potential obesity prevention interventions in children and adolescents in Australia. METHODS: We used the best available evidence, including evidence from non-traditional epidemiological study designs, to determine the health benefits as body mass index (BMI) units saved and disability-adjusted life years (DALYs) saved. We developed new methods to model the impact of behaviours on BMI post-intervention where this was not measured and the impacts on DALYs over the child\u27s lifetime (on the assumption that changes in BMI were maintained into adulthood). A working group of stakeholders provided input into decisions on the selection of interventions, the assumptions for modelling and the strength of the evidence. RESULTS: The likely health benefit varied considerably, as did the strength of the evidence from which that health benefit was calculated. The greatest health benefit is likely to be achieved by the \u27Reduction of TV advertising of high fat and/or high sugar foods and drinks to children\u27, \u27Laparoscopic adjustable gastric banding\u27 and the \u27multi-faceted school-based programme with an active physical education component\u27 interventions. CONCLUSIONS: The use of consistent methods and common health outcome measures enables valid comparison of the potential impact of interventions, but comparisons must take into account the strength of the evidence used. Other considerations, including cost-effectiveness and acceptability to stakeholders, will be presented in future ACE-Obesity papers. Information gaps identified include the need for new and more effective initiatives for the prevention of overweight and obesity and for better evaluations of public health interventions

Packages of Care for Alcohol Use Disorders in Low- And Middle-Income Countries

In the fourth in a series of six articles on packages of care for mental disorders in low- and middle-income countries, Vivek Benegal and colleagues discuss the treatment of alcohol use disorders

A General Model for the CO-H2 Conversion Factor in Galaxies with Applications to the Star Formation Law

The most common means of converting an observed CO line intensity into a molecular gas mass requires the use of a conversion factor (Xco). While in the Milky Way this quantity does not appear to vary significantly, there is good reason to believe that Xco will depend on the larger-scale galactic environment. Utilising numerical models, we investigate how varying metallicities, gas temperatures and velocity dispersions in galaxies impact the way CO line emission traces the underlying H2 gas mass, and under what circumstances Xco may differ from the Galactic mean value. We find that, due to the combined effects of increased gas temperature and velocity dispersion, Xco is depressed below the Galactic mean in high surface density environments such as ULIRGs. In contrast, in low metallicity environments, Xco tends to be higher than in the Milky Way, due to photodissociation of CO in metal-poor clouds. At higher redshifts, gas-rich discs may have gravitationally unstable clumps which are warm (due to increased star formation) and have elevated velocity dispersions. These discs tend to have Xco values ranging between present-epoch gas-rich mergers and quiescent discs at low-z. This model shows that on average, mergers do have lower Xco values than disc galaxies, though there is significant overlap. Xco varies smoothly with the local conditions within a galaxy, and is not a function of global galaxy morphology. We combine our results to provide a general fitting formula for Xco as a function of CO line intensity and metallicity. We show that replacing the traditional approach of using one constant Xco for starbursts and another for discs with our best-fit function produces star formation laws that are continuous rather than bimodal, and that have significantly reduced scatter.Comment: Accepted by MNRAS; major revision includes moving the bulk of the equations to an appendi