A cardinal role for cathepsin D in co-ordinating the host-mediated apoptosis of macrophages and killing of pneumococci

The bactericidal function of macrophages against pneumococci is enhanced by their apoptotic demise, which is controlled by the anti-apoptotic protein Mcl-1. Here, we show that lysosomal membrane permeabilization (LMP) and cytosolic translocation of activated cathepsin D occur prior to activation of a mitochondrial pathway of macrophage apoptosis. Pharmacological inhibition or knockout of cathepsin D during pneumococcal infection blocked macrophage apoptosis. As a result of cathepsin D activation, Mcl-1 interacted with its ubiquitin ligase Mule and expression declined. Inhibition of cathepsin D had no effect on early bacterial killing but inhibited the late phase of apoptosis-associated killing of pneumococci in vitro. Mice bearing a cathepsin D-/- hematopoietic system demonstrated reduced macrophage apoptosis in vivo, with decreased clearance of pneumococci and enhanced recruitment of neutrophils to control pulmonary infection. These findings establish an unexpected role for a cathepsin D-mediated lysosomal pathway of apoptosis in pulmonary host defense and underscore the importance of apoptosis-associated microbial killing to macrophage function

Inability to sustain intraphagolysosomal killing of Staphylococcus aureus predisposes to bacterial persistence in macrophages

Macrophages are critical effectors of the early innate response to bacteria in tissues. Phagocytosis and killing of bacteria are interrelated functions essential for bacterial clearance but the rate-limiting step when macrophages are challenged with large numbers of the major medical pathogen Staphylococcus aureus is unknown. We show that macrophages have a finite capacity for intracellular killing and fail to match sustained phagocytosis with sustained microbial killing when exposed to large inocula of S. aureus (Newman, SH1000 and USA300 strains). S. aureus ingestion by macrophages is associated with a rapid decline in bacterial viability immediately after phagocytosis. However, not all bacteria are killed in the phagolysosome, and we demonstrate reduced acidification of the phagolysosome, associated with failure of phagolysosomal maturation and reduced activation of cathepsin D. This results in accumulation of viable intracellular bacteria in macrophages. We show macrophages fail to engage apoptosis-associated bacterial killing. Ultittop mately macrophages with viable bacteria undergo cell lysis, and viable bacteria are released and can be internalized by other macrophages. We show that cycles of lysis and reuptake maintain a pool of viable intracellular bacteria over time when killing is overwhelmed and demonstrate intracellular persistence in alveolar macrophages in the lungs in a murine model

Edge reconstructions in fractional quantum Hall systems

Two dimensional electron systems exhibiting the fractional quantum Hall effects are characterized by a quantized Hall conductance and a dissipationless bulk. The transport in these systems occurs only at the edges where gapless excitations are present. We present a {\it microscopic} calculation of the edge states in the fractional quantum Hall systems at various filling factors using the extended Hamiltonian theory of the fractional quantum Hall effect. We find that at $\nu=1/3$ the quantum Hall edge undergoes a reconstruction as the background potential softens, whereas quantum Hall edges at higher filling factors, such as $\nu=2/5, 3/7$, are robust against reconstruction. We present the results for the dependence of the edge states on various system parameters such as temperature, functional form and range of electron-electron interactions, and the confining potential. Our results have implications for the tunneling experiments into the edge of a fractional quantum Hall system.Comment: 11 pages, 9 figures; minor typos corrected; added 2 reference

Numerical Test of Disk Trial Wave function for Half-Filled Landau Level

The analyticity of the lowest Landau level wave functions and the relation between filling factor and the total angular momentum severely limits the possible forms of trial wave functions of a disk of electrons subject to a strong perpendicular magnetic field. For N, the number of electrons, up to 12 we have tested these disk trial wave functions for the half filled Landau level using Monte Carlo and exact diagonalization methods. The agreement between the results for the occupation numbers and ground state energies obtained from these two methods is excellent. We have also compared the profile of the occupation number near the edge with that obtained from a field-theoretical method. The results give qualitatively identical edge profiles. Experimental consequences are briefly discussed.Comment: To be published in Phys. Rev. B. 9 pages, 6 figure

Hamiltonian theory of gaps, masses and polarization in quantum Hall states: full disclosure

I furnish details of the hamiltonian theory of the FQHE developed with Murthy for the infrared, which I subsequently extended to all distances and apply it to Jain fractions \nu = p/(2ps + 1). The explicit operator description in terms of the CF allows one to answer quantitative and qualitative issues, some of which cannot even be posed otherwise. I compute activation gaps for several potentials, exhibit their particle hole symmetry, the profiles of charge density in states with a quasiparticles or hole, (all in closed form) and compare to results from trial wavefunctions and exact diagonalization. The Hartree-Fock approximation is used since much of the nonperturbative physics is built in at tree level. I compare the gaps to experiment and comment on the rough equality of normalized masses near half and quarter filling. I compute the critical fields at which the Hall system will jump from one quantized value of polarization to another, and the polarization and relaxation rates for half filling as a function of temperature and propose a Korringa like law. After providing some plausibility arguments, I explore the possibility of describing several magnetic phenomena in dirty systems with an effective potential, by extracting a free parameter describing the potential from one data point and then using it to predict all the others from that sample. This works to the accuracy typical of this theory (10 -20 percent). I explain why the CF behaves like free particle in some magnetic experiments when it is not, what exactly the CF is made of, what one means by its dipole moment, and how the comparison of theory to experiment must be modified to fit the peculiarities of the quantized Hall problem

Hamiltonian Theory of the FQHE: Conserving Approximation for Incompressible Fractions

A microscopic Hamiltonian theory of the FQHE developed by Shankar and the present author based on the fermionic Chern-Simons approach has recently been quite successful in calculating gaps and finite tempertature properties in Fractional Quantum Hall states. Initially proposed as a small-$q$ theory, it was subsequently extended by Shankar to form an algebraically consistent theory for all $q$ in the lowest Landau level. Such a theory is amenable to a conserving approximation in which the constraints have vanishing correlators and decouple from physical response functions. Properties of the incompressible fractions are explored in this conserving approximation, including the magnetoexciton dispersions and the evolution of the small-$q$ structure factor as \nu\to\half. Finally, a formalism capable of dealing with a nonuniform ground state charge density is developed and used to show how the correct fractional value of the quasiparticle charge emerges from the theory.Comment: 15 pages, 2 eps figure

Melting transition of an Ising glass driven by magnetic field

The quantum critical behavior of the Ising glass in a magnetic field is investigated. We focus on the spin glass to paramagnet transition of the transverse degrees of freedom in the presence of finite longitudinal field. We use two complementary techniques, the Landau theory close to the T=0 transition and the exact diagonalization method for finite systems. This allows us to estimate the size of the critical region and characterize various crossover regimes. An unexpectedly small energy scale on the disordered side of the critical line is found, and its possible relevance to experiments on metallic glasses is briefly discussed.Comment: 4 pages, 3 figure

Invariant structure of the hierarchy theory of fractional quantum Hall states with spin

We describe the invariant structure common to abelian fractional quantum Hall systems with spin. It appears in a generalization of the lattice description of the polarized hierarchy that encompasses both partially polarized and unpolarized ground state systems. We formulate, using the spin-charge decomposition, conditions that should be satisfied so that the description is SU(2) invariant. In the case of the spin- singlet hierarchy construction, we find that there are as many SU(2) symmetries as there are levels in the construction. We show the existence of a spin and charge lattice for the systems with spin. The ``gluing'' of the charge and spin degrees of freedom in their bulk is described by the gluing theory of lattices.Comment: 21 pages, LaTex, Submitted to Phys. Rev.

Thermodynamics of an Anyon System

We examine the thermal behavior of a relativistic anyon system, dynamically realized by coupling a charged massive spin-1 field to a Chern-Simons gauge field. We calculate the free energy (to the next leading order), from which all thermodynamic quantities can be determined. As examples, the dependence of particle density on the anyon statistics and the anyon anti-anyon interference in the ideal gas are exhibited. We also calculate two and three-point correlation functions, and uncover certain physical features of the system in thermal equilibrium.Comment: 18 pages; in latex; to be published in Phys. Rev.

Truthmakers and modality

This paper attempts to locate, within an actualist ontology, truthmakers for modal truths: truths of the form or . In section 1 I motivate the demand for substantial truthmakers for modal truths. In section 2 I criticise Armstrong’s account of truthmakers for modal truths. In section 3 I examine essentialism and defend an account of what makes essentialist attributions true, but I argue that this does not solve the problem of modal truth in general. In section 4 I discuss, and dismiss, a theistic account of the source of modal truth proposed by Alexander Pruss. In section 5 I offer a means of (dis)solving the problem