Moxifloxacin Replacement in Contemporary Tuberculosis Drug Regimens Is Ineffective against Persistent Mycobacterium tuberculosis in the Cornell Mouse Model

Tuberculosis (TB) caused by Mycobacterium tuberculosis remains a leading killer worldwide, and disease control is hampered by ineffective control of persistent infections. Substitution of moxifloxacin for isoniazid or ethambutol in standard TB regimens reduces treatment duration and relapse rates in animal studies and four-month regimens were not non-inferior in clinical trials. Resuscitation promoting factor (RPF) dependent bacilli have recently been implicated in M. tuberculosis persistence. We aimed to investigate the therapeutic effects of moxifloxacin substitution in the standard drug regimen for eradicating colony forming count (CFU) positive and RPF-dependent persistent M. tuberculosis using the Cornell murine model. M. tuberculosis infected mice were treated with regimens in which either isoniazid or ethambutol were replaced by moxifloxacin to the standard regimen. The efficacy of the regimens was compared to the standard regimen for bacterial CFU count elimination and removal of persistent tubercle bacilli evaluated using culture filtrate (CF) derived from M. tuberculosis strain H37Rv. We also measured disease relapse rates. Moxifloxacin-isoniazid substituted regimen achieved total organ CFU count clearance at 11 weeks post-treatment, faster than standard regimen (14 weeks), and with a 34% lower relapse rate. Moxifloxacin-ethambutol substituted regimen was similar to standard regimens in these regards. Importantly, neither moxifloxacin-substituted regimens nor the standard regimen could remove CF-dependent persistent bacilli. Evaluation of CF-dependent persistent M. tuberculosis requires confirmation in human studies, and has implications in future drug design, testing and clinical applications

Transition Phenomena Induced by Internal Noise and Quasi-absorbing State

We study a simple chemical reaction system and effects of the internal noise. The chemical reaction system causes the same transition phenomenon discussed by Togashi and Kaneko [Phys. Rev. Lett. 86 (2001) 2459; J. Phys. Soc. Jpn. 72 (2003) 62]. By using the simpler model than Togashi-Kaneko's one, we discuss the transition phenomenon by means of a random walk model and an effective model. The discussion makes it clear that quasi-absorbing states, which are produced by the change of the strength of the internal noise, play an important role in the transition phenomenon. Stabilizing the quasi-absorbing states causes bifurcation of the peaks in the stationary probability distribution discontinuously.Comment: 6 pages, 5 figure

The Indian family on UK reality television: Convivial culture in salient contexts

This is the author's accepted manuscript. The final published article is available from the link below, copyright 2012 @ the author.This article demonstrates how The Family (2009), a fly-on-the wall UK reality series about a British Indian family, facilitates both current public service broadcasting requirements and mass audience appeal. From a critical cultural studies perspective, the author examines the journalistic and viewer responses to the series where authenticity, universality, and comedy emerge as major themes. Textual analysis of the racialized screen representations also helps locate the series within the contexts of contested multiculturalism, genre developments in reality television and public service broadcasting. Paul Gilroy’s concept of convivial culture is used as a frame in understanding how meanings of the series are produced within a South Asian popular representational space. The author suggests that the social comedy taxonomy is a prerequisite for the making of this particular observational documentary. Further, the popular (comedic) mode of conviviality on which the series depends is both expedient and necessary within the various sociopolitical contexts outlined

Low-Temperature Thermochronology of the Chatkal-Kurama Terrane (Uzbekistan-Tajikistan): Insights Into the Meso-Cenozoic Thermal History of the Western Tian Shan

The Chatkal-Kurama terrane represents a key region in understanding the tectonic evolution of the western Tian Shan. In this contribution, we present new thermochronological data (zircon [U-Th-Sm]/He, apatite fission track, and apatite [U-Th-Sm]/He) and the associated thermal history models for 30 igneous samples from the Chatkal-Kurama terrane within Uzbekistan and Tajikistan (west of the Talas-Fergana Fault) and integrate our data with published data from the central Tian Shan (east of the Talas-Fergana Fault). The Chatkal-Kurama terrane experienced a phase of rapid cooling during the Triassic-Jurassic at ca. 225–190 Ma, which we interpret as a far-field response to the closure of the Palaeo-Asian Ocean or the accretion of the Qiangtang terrane on to the Eurasian margin. In the Late Jurassic to the Early Cretaceous, the Chatkal-Kurama terrane experienced a period of tectonic stability and denudation, before transitioning into a period of marine incursions of the Paratethys Sea. In contrast, fast cooling is recorded for the Kyrgyz central Tian Shan to the east of the Talas-Fergana Fault. The differing thermal histories at either side of the Talas-Fergana Fault suggest that the fault induced a topographic divide during the Late Jurassic-Early Cretaceous, with high relief in the east (Kyrgyz Tian Shan) and low relief to the west (Uzbek-Tajik Tian Shan). Finally, the Chatkal-Kurama terrane experienced renewed tectonic activity since ca. 30 Ma, related with the distant India-Eurasia collision and Pamir indentation. The Cenozoic reactivation induced crustal tilting of the Chatkal-Kurama terrane, progressively exposing deeper rocks to the southwest

Finite-size scaling of the error threshold transition in finite population

The error threshold transition in a stochastic (i.e. finite population) version of the quasispecies model of molecular evolution is studied using finite-size scaling. For the single-sharp-peak replication landscape, the deterministic model exhibits a first-order transition at $Q=Q_c=1/a$, where $Q$ is the probability of exact replication of a molecule of length $L \to \infty$, and $a$ is the selective advantage of the master string. For sufficiently large population size, $N$, we show that in the critical region the characteristic time for the vanishing of the master strings from the population is described very well by the scaling assumption \tau = N^{1/2} f_a \left [ \left (Q - Q_c) N^{1/2} \right ] , where $f_a$ is an $a$-dependent scaling function.Comment: 8 pages, 3 ps figures. submitted to J. Phys.

Error threshold in finite populations

A simple analytical framework to study the molecular quasispecies evolution of finite populations is proposed, in which the population is assumed to be a random combination of the constiyuent molecules in each generation,i.e., linkage disequilibrium at the population level is neglected. In particular, for the single-sharp-peak replication landscape we investigate the dependence of the error threshold on the population size and find that the replication accuracy at threshold increases linearly with the reciprocal of the population size for sufficiently large populations. Furthermore, in the deterministic limit our formulation yields the exact steady-state of the quasispecies model, indicating then the population composition is a random combination of the molecules.Comment: 14 pages and 4 figure

Regional policy spillovers : the national impact of demand-side policy in an interregional model of the UK economy

UK regional policy has been advocated as a means of reducing regional disparities and stimulating national growth. However, there is limited understanding of the interregional and national effects of such a policy. This paper uses an interregional computable general equilibrium model to identify the national impact of a policy-induced regional demand shock under alternative labour market closures. Our simulation results suggest that regional policy operating solely on the demand side has significant national impacts. Furthermore, the effects on the nontarget region are particularly sensitive to the treatment of the regional labour market

The interplay of intrinsic and extrinsic bounded noises in genetic networks

After being considered as a nuisance to be filtered out, it became recently clear that biochemical noise plays a complex role, often fully functional, for a genetic network. The influence of intrinsic and extrinsic noises on genetic networks has intensively been investigated in last ten years, though contributions on the co-presence of both are sparse. Extrinsic noise is usually modeled as an unbounded white or colored gaussian stochastic process, even though realistic stochastic perturbations are clearly bounded. In this paper we consider Gillespie-like stochastic models of nonlinear networks, i.e. the intrinsic noise, where the model jump rates are affected by colored bounded extrinsic noises synthesized by a suitable biochemical state-dependent Langevin system. These systems are described by a master equation, and a simulation algorithm to analyze them is derived. This new modeling paradigm should enlarge the class of systems amenable at modeling. We investigated the influence of both amplitude and autocorrelation time of a extrinsic Sine-Wiener noise on: $(i)$ the Michaelis-Menten approximation of noisy enzymatic reactions, which we show to be applicable also in co-presence of both intrinsic and extrinsic noise, $(ii)$ a model of enzymatic futile cycle and $(iii)$ a genetic toggle switch. In $(ii)$ and $(iii)$ we show that the presence of a bounded extrinsic noise induces qualitative modifications in the probability densities of the involved chemicals, where new modes emerge, thus suggesting the possibile functional role of bounded noises

Haptic guidance improves the visuo-manual tracking of trajectories

BACKGROUND: Learning to perform new movements is usually achieved by following visual demonstrations. Haptic guidance by a force feedback device is a recent and original technology which provides additional proprioceptive cues during visuo-motor learning tasks. The effects of two types of haptic guidances-control in position (HGP) or in force (HGF)-on visuo-manual tracking ("following") of trajectories are still under debate. METHODOLOGY/PRINCIPALS FINDINGS: Three training techniques of haptic guidance (HGP, HGF or control condition, NHG, without haptic guidance) were evaluated in two experiments. Movements produced by adults were assessed in terms of shapes (dynamic time warping) and kinematics criteria (number of velocity peaks and mean velocity) before and after the training sessions. CONCLUSION/SIGNIFICANCE: These results show that the addition of haptic information, probably encoded in force coordinates, play a crucial role on the visuo-manual tracking of new trajectories