Structural Simplification of Bedaquiline: the Discovery of 3-(4-(N,N-dimethylaminomethyl)phenyl)quinoline Derived Antitubercular Lead Compounds

Bedaquiline (BDQ) is a novel and highly potent last-line antituberculosis drug that was approved by the US FDA in 2013. Owing to its stereo-structural complexity, chemical synthesis and compound optimization are rather difficult and expensive. This study describes the structural simplification of bedaquiline while preserving antitubercular activity. The compound's structure was split into fragments and reassembled in various combinations while replacing the two chiral carbon atoms with an achiral linkage instead. Four series of analogues were designed; these candidates retained their potent antitubercular activity at sub-microgram per mL concentrations against both sensitive and multidrug-resistant (MDR) Mycobacterium tuberculosis strains. Six out of the top nine MIC-ranked candidates were found to inhibit mycobacterial ATP synthesis activity with IC50 values between 20 and 40 μm, one had IC50>66 μm, and two showed no inhibition, despite their antitubercular activity. These results provide a basis for the development of chemically less complex, lower-cost bedaquiline derivatives and describe the identification of two derivatives with antitubercular activity against non-ATP synthase related targets

Local Thermometry of Neutral Modes on the Quantum Hall Edge

A system of electrons in two dimensions and strong magnetic fields can be tuned to create a gapped 2D system with one dimensional channels along the edge. Interactions among these edge modes can lead to independent transport of charge and heat, even in opposite directions. Measuring the chirality and transport properties of these charge and heat modes can reveal otherwise hidden structure in the edge. Here, we heat the outer edge of such a quantum Hall system using a quantum point contact. By placing quantum dots upstream and downstream along the edge of the heater, we can measure both the chemical potential and temperature of that edge to study charge and heat transport, respectively. We find that charge is transported exclusively downstream, but heat can be transported upstream when the edge has additional structure related to fractional quantum Hall physics.Comment: 24 pages, 18 figure

The DNA Methylation Inhibitor Zebularine Controls CD4(+) T Cell Mediated Intraocular Inflammation

CD4+ T cell mediated uveitis is conventionally treated with systemic immunosuppressive agents, including corticosteroids and biologics targeting key inflammatory cytokines. However, their long-term utility is limited due to various side effects. Here, we investigated whether DNA methylation inhibitor zebularine can target CD4+ T cells and control intraocular inflammation. Our results showed that zebularine restrained the expression of inflammatory cytokines IFN-γ and IL-17 in both human and murine CD4+ T cells in vitro. Importantly, it also significantly alleviated intraocular inflammation and retinal tissue damage in the murine experimental autoimmune uveitis (EAU) model in vivo, suggesting that the DNA methylation inhibitor zebularine is a candidate new therapeutic agent for uveitis

Non-Equilibrium Edge Channel Spectroscopy in the Integer Quantum Hall Regime

Heat transport has large potentialities to unveil new physics in mesoscopic systems. A striking illustration is the integer quantum Hall regime, where the robustness of Hall currents limits information accessible from charge transport. Consequently, the gapless edge excitations are incompletely understood. The effective edge states theory describes them as prototypal one-dimensional chiral fermions - a simple picture that explains a large body of observations and calls for quantum information experiments with quantum point contacts in the role of beam splitters. However, it is in ostensible disagreement with the prevailing theoretical framework that predicts, in most situations, additional gapless edge modes. Here, we present a setup which gives access to the energy distribution, and consequently to the energy current, in an edge channel brought out-of-equilibrium. This provides a stringent test of whether the additional states capture part of the injected energy. Our results show it is not the case and thereby demonstrate regarding energy transport, the quantum optics analogy of quantum point contacts and beam splitters. Beyond the quantum Hall regime, this novel spectroscopy technique opens a new window for heat transport and out-of-equilibrium experiments.Comment: 13 pages including supplementary information, Nature Physics in prin

Quantum magnetism and criticality

Magnetic insulators have proved to be fertile ground for studying new types of quantum many body states, and I survey recent experimental and theoretical examples. The insights and methods transfer also to novel superconducting and metallic states. Of particular interest are critical quantum states, sometimes found at quantum phase transitions, which have gapless excitations with no particle- or wave-like interpretation, and control a significant portion of the finite temperature phase diagram. Remarkably, their theory is connected to holographic descriptions of Hawking radiation from black holes.Comment: 39 pages, 10 figures, review article for non-specialists; (v2) added clarifications and references; (v3) minor corrections; (v4) added footnote on hydrodynamic long-time tail

Frailty and Its Impact on Health-Related Quality of Life: A Cross-Sectional Study on Elder Community-Dwelling Preventive Health Service Users

BACKGROUND: The purpose of this study was to identify the incidence of frailty and to investigate the relationship between frailty status and health-related quality of life (HRQoL) in the community-dwelling elderly population who utilize preventive health services. METHODS: People aged 65 years and older who visited a medical center in Taipei City from March to August in 2011 for an annual routine check-up provided by the National Health Insurance were eligible. A total of 374 eligible elderly adults without cognitive impairment had a mean age of 74.6±6.3 years. Frailty status was determined according to the Fried frailty criteria. HRQoL was measured with Short Form-36 (SF-36). Multiple regression analyses examined the relationship between frailty status and the two summary scales of SF-36. Models were adjusted for the participants' sociodemographic and health status. RESULTS: After adjusting for sociodemographic and health-related covariables, frailty was found to be more significantly associated (p<0.001) with lower scores on both physical and mental health-related quality of life summary scales compared with robustness. For the frailty phenotypes, slowness represented the major contributing factor in the physical component scale of SF-36, and exhaustion was the primary contributing factor in the mental component scale. CONCLUSION: The status of frailty is closely associated with HRQoL in elderly Taiwanese preventive health service users. The impacts of frailty phenotypes on physical and mental aspects of HRQoL differ

Spatio-temporal analysis of malaria incidence at the village level in a malaria-endemic area in Hainan, China

<p>Abstract</p> <p>Background</p> <p>Malaria incidence in China's Hainan province has dropped significantly, since Malaria Programme of China Global Fund Round 1 was launched. To lay a foundation for further studies to evaluate the efficacy of Malaria Programme and to help with public health planning and resource allocation in the future, the temporal and spatial variations of malaria epidemic are analysed and areas and seasons with a higher risk are identified at a fine geographic scale within a malaria endemic county in Hainan.</p> <p>Methods</p> <p>Malaria cases among the residents in each of 37 villages within hyper-endemic areas of Wanning county in southeast Hainan from 2005 to 2009 were geo-coded at village level based on residence once the patients were diagnosed. Based on data so obtained, purely temporal, purely spatial and space-time scan statistics and geographic information systems (GIS) were employed to identify clusters of time, space and space-time with elevated proportions of malaria cases.</p> <p>Results</p> <p>Purely temporal scan statistics suggested clusters in 2005,2006 and 2007 and no cluster in 2008 and 2009. Purely spatial clustering analyses pinpointed the most likely cluster as including three villages in 2005 and 2006 respectively, sixteen villages in 2007, nine villages in 2008, and five villages in 2009, and the south area of Nanqiao town as the most likely to have a significantly high occurrence of malaria. The space-time clustering analysis found the most likely cluster as including three villages in the south of Nanqiao town with a time frame from January 2005 to May 2007.</p> <p>Conclusions</p> <p>Even in a small traditional malaria endemic area, malaria incidence has a significant spatial and temporal heterogeneity on the finer spatial and temporal scales. The scan statistics enable the description of this spatiotemporal heterogeneity, helping with clarifying the epidemiology of malaria and prioritizing the resource assignment and investigation of malaria on a finer geographical scale in endemic areas.</p

Fractional quantum Hall effect in a quantum point contact at filling fraction 5/2

Recent theories suggest that the excitations of certain quantum Hall states may have exotic braiding statistics which could be used to build topological quantum gates. This has prompted an experimental push to study such states using confined geometries where the statistics can be tested. We study the transport properties of quantum point contacts (QPCs) fabricated on a GaAs/AlGaAs two dimensional electron gas that exhibits well-developed fractional quantum Hall effect, including at bulk filling fraction 5/2. We find that a plateau at effective QPC filling factor 5/2 is identifiable in point contacts with lithographic widths of 1.2 microns and 0.8 microns, but not 0.5 microns. We study the temperature and dc-current-bias dependence of the 5/2 plateau in the QPC, as well as neighboring fractional and integer plateaus in the QPC while keeping the bulk at filling factor 3. Transport near QPC filling factor 5/2 is consistent with a picture of chiral Luttinger liquid edge-states with inter-edge tunneling, suggesting that an incompressible state at 5/2 forms in this confined geometry

Dynamics and transport near quantum-critical points

The physics of non-zero temperature dynamics and transport near quantum-critical points is discussed by a detailed study of the O(N)-symmetric, relativistic, quantum field theory of a N-component scalar field in $d$ spatial dimensions. A great deal of insight is gained from a simple, exact solution of the long-time dynamics for the N=1 d=1 case: this model describes the critical point of the Ising chain in a transverse field, and the dynamics in all the distinct, limiting, physical regions of its finite temperature phase diagram is obtained. The N=3, d=1 model describes insulating, gapped, spin chain compounds: the exact, low temperature value of the spin diffusivity is computed, and compared with NMR experiments. The N=3, d=2,3 models describe Heisenberg antiferromagnets with collinear N\'{e}el correlations, and experimental realizations of quantum-critical behavior in these systems are discussed. Finally, the N=2, d=2 model describes the superfluid-insulator transition in lattice boson systems: the frequency and temperature dependence of the the conductivity at the quantum-critical coupling is described and implications for experiments in two-dimensional thin films and inversion layers are noted.Comment: Lectures presented at the NATO Advanced Study Institute on "Dynamical properties of unconventional magnetic systems", Geilo, Norway, April 2-12, 1997, edited by A. Skjeltorp and D. Sherrington, Kluwer Academic, to be published. 46 page

From Luttinger to Fermi liquids in organic conductors

This chapter reviews the effects of interactions in quasi-one dimensional systems, such as the Bechgaard and Fabre salts, and in particular the Luttinger liquid physics. It discusses in details how transport measurements both d.c. and a.c. allow to probe such a physics. It also examine the dimensional crossover and deconfinement transition occurring between the one dimensional case and the higher dimensional one resulting from the hopping of electrons between chains in the quasi-one dimensional structure.Comment: To be published In the book "The Physics of Organic Conductors and Superconductors", Springer, 2007, ed. A. Lebe