Mycobacterium tuberculosis progresses through two phases of latent infection in humans

Little is known about the physiology of latent Mycobacterium tuberculosis infection. We studied the mutational rates of 24 index tuberculosis (TB) cases and their latently infected household contacts who developed active TB up to 5.25 years later, as an indication of bacterial physiological state and possible generation times during latent TB infection in humans. Here we report that the rate of new mutations in the M. tuberculosis genome decline dramatically after two years of latent infection (two-sided p < 0.001, assuming an 18 h generation time equal to log phase M. tuberculosis, with latency period modeled as a continuous variable). Alternatively, assuming a fixed mutation rate, the generation time increases over the latency duration. Mutations indicative of oxidative stress do not increase with increasing latency duration suggesting a lack of host or bacterial derived mutational stress. These results suggest that M. tuberculosis enters a quiescent state during latency, decreasing the risk for mutational drug resistance and increasing generation time, but potentially increasing bacterial tolerance to drugs that target actively growing bacteria.publishersversionpublishe

A Nonintrusive Method of Measuring the Local Mechanical Properties of Soft Hydrogels Using Magnetic Microneedles

Soft hydrogels serving as substrates for cell attachment are used to culture many types of cells. The mechanical properties of these gels influence cell morphology, growth, and differentiation. For studies of cell growth on inhomogeneous gels, techniques by which the mechanical properties of the substrate can be measured within the proximity of a given cell are of interest. We describe an apparatus that allows the determination of local gel elasticity by measuring the response of embedded micron-sized magnetic needles to applied magnetic fields. This microscope-based four-magnet apparatus can apply both force and torque on the microneedles. The force and the torque are manipulated by changing the values of the magnetic field at the four poles of the magnet using a feedback circuit driven by LABVIEW. Using Hall probes, we have mapped out the magnetic field and field gradients produced by each pole when all the other poles are held at zero magnetic field. We have verified that superposition of these field maps allows one to obtain field maps for the case when the poles are held at arbitrary field values. This allows one to apply known fields and field gradients to a given microneedle. An imaging system is employed to measure the displacement and rotation of the needles. Polyacrylamide hydrogels of known elasticity were used to determine the relationship between the field gradient at the location of the needles and the force acting on the needles. This relationship allows the force on the microneedle to be determined from a known field gradient. This together with a measurement of the displacement of the needle in a given gel allows one to determine the stiffness (F/δ) of the gel and the elastic modulus, provided Poison\u27s ratio is known. Using this method, the stiffness and the modulus of elasticity of type-I collagen gels were found to be 2.64±0.05 nN/µm and 284.6±5.9 Pa, respectively. This apparatus is presently being employed to track the mechanical stiffness of the DNA-cross-linked hydrogels, developed by our group, whose mechanical properties can be varied on demand by adding or removing cross-linker strands. Thus a system that can be utilized to track the local properties of soft media as a function of time with minimum mechanical disturbance in the presence of cells is presented

Finite Element Approximations To The System Of Shallow Water Equations, Part I: Continuous Time A Priori Error Estimates

. Various sophisticated finite element models for surface water flow based on the shallow water equations exist in the literature. Gray, Kolar, Luettich, Lynch and Westerink have developed a hydrodynamic model based on the generalized wave continuity equation (GWCE) formulation, and have formulated a Galerkin finite element procedure based on combining the GWCE with the nonconservative momentum equations. Numerical experiments suggest that this method is robust, accurate and suppresses spurious oscillations which plague other models. We analyze a slightly modified Galerkin model which uses the conservative momentum equations (CME). For this GWCE-CME system of equations, we present a continous-time a priori error estimate based on an L 2 projection. Key words. shallow water equations, surface water flow, mass conservation, momentum conservation, finite element method, a priori error estimate AMS subject classifications. 35Q35, 35L65 65N30, 65N15 1. Introduction. In recent years, t..

A Godunov-Type Finite Volume Method for Systems of Shallow Water Equations

A finite volume based numerical algorithm has been developed for the numerical solution of the system of shallow water equations. The algorithm is a Godunov type method and solves the Riemann problem approximately using Roe&apos;s technique. The algorithm is developed in 2-D with arbitrary triangulations and conserves all primary variables such as mass and momentum. The procedure is implemented on some simple test cases and some complex coastal flow problems. The algorithm is shown to produce excellent results without spurious oscillations and agrees very well with known analytical results and predictions made by wave equation formulations of the shallow water equations. The basic Godunov method is also extended to second-order accuracy through a slope-limiter type algorithm. 1 INTRODUCTION The Shallow Water Equations (SWE) are used to describe free surface hydrodynamics in vertically wellmixed water bodies where the horizontal length scales are much greater than the fluid depth (i.e., lo..

Finite Element Approximation to the System of Shallow Water Equations, Part II: Discrete Time A Priori Error Estimates

. Various sophisticated finite element models for surface water flow exist in the literature. Gray, Kolar, Luettich, Lynch and Westerink have developed a hydrodynamic model based on the generalized wave continuity equation (GWCE) formulation, and have formulateda Galerkin finite element procedure based on combining the GWCE with the nonconservative momentum equations. Numerical experiments suggest that this method is robust, accurate and suppresses spurious oscillations which plague other models. In this paper, we analyze a closely related Galerkin method which uses the conservative momentum equations (CME). For this GWCE-CME system of equations, we present, for discrete time, an a priori error estimate based on an L 2 projection. Key words. shallow water equations, surface flow, mass conservation, momentum conservation, finite element model, error estimate, stability AMS subject classifications. 35Q35, 35L65 65N30, 65N15 1. Introduction. In this paper, we derive a-priori error es..