2,560 research outputs found
Evaluating 5-nitrofurans as trypanocidal agents
The nitroheterocycle nifurtimox, as part of a nifurtimox-eflornithine combination therapy, represents one of a limited number of treatments targeting Trypanosoma brucei, the causative agent of human African trypanosomiasis. The mode of action of this prodrug involves an initial activation reaction catalysed by a type I nitroreductase (NTR), an enzyme found predominantly in prokaryotes, leading to the formation of a cytotoxic unsaturated open chain nitrile metabolite. Here, we evaluate the trypanocidal activity of a library of other 5-nitrofurans against bloodstream form T. brucei as a preliminary step in the identification of additional nitroaromatic compounds that could potentially partner eflornithine. Biochemical screening against purified enzyme revealed that all 5-nitrofurans were effective substrates for TbNTR with the preferred compounds having apparent kcat/KM values approximately 50-fold greater than nifurtimox. For several compounds, in vitro reduction by this nitroreductase yielded products characterized by mass spectroscopy as either unsaturated or saturated open chain nitriles. When tested against bloodstream form T. brucei, many of the derivatives displayed significant growth inhibitory properties with the most potent compounds generating IC50 values around 200 nM. The anti-parasitic activity of the most potent agents was demonstrated to be NTR dependent as parasites having reduced levels of the enzyme displayed resistance to the compounds while parasites over expressing TbNTR showed hypersensitivity. We conclude that other members of the 5-nitrofurans class of nitroheterocycles have potential to treat human African trypanosomiasis perhaps as an alternative partner prodrug to nifurtimox in the next generation of eflornithine-based combinational therapies
Enhancement of Electrical Conduction and Phonon Scattering in Ga2O3(ZnO)9-In2O3(ZnO)9 Compounds by Modification of Interfaces at the Nanoscale
The Ga2O3(ZnO)9 and In2O3(ZnO)9 homologous phases have attracted attention as thermoelectric (TE) oxides due to their layered structures. Ga2O3(ZnO)9 exhibits low thermal conductivity, while In2O3(ZnO)9 possesses higher electrical conductivity. The TE properties of the solid solution of Ga2O3(ZnO)9-In2O3(ZnO)9 were explored and correlated with changes in the crystal structure. High-quality (1−x)Ga2O3(ZnO)9-(ZnO)9 (x = 0.0 to 1.0) ceramics were prepared by the solid-state route using B2O3 and Nd2O3 as additives. The crystal structures were analysed by x-ray diffraction, high-resolution transmission electron microscopy and atomic resolution scanning transmission electron microscopy–high-angle annular dark field imaging–energy dispersive x-ray spectroscopy (STEM–HAADF–EDS) techniques. A layered superstructure with compositional modulations was observed in all samples in the (1−x)Ga2O3(ZnO)9-xIn2O3(ZnO)9 system. All the ceramics exhibited nanoscale structural features identified as Ga- and In-rich inversion boundaries (IBs). Substitution of 20 mol.% In (x = 0.2) in the Ga2O3(ZnO)9 compounds generated basal and pyramidal indium IBs typically found in the In2O3(ZnO)m system. The (Ga0.8In0.2)2O3(ZnO)9 compound does not exhibit the structural features of the Cmcm Ga2O3(ZnO)9 compound, which is formed by a stacking of Ga-rich IBs along the pyramidal plane of the wurtzite ZnO, but features that resemble the crystal structure exhibited by the R3¯¯¯m In2O3(ZnO)m with basal and pyramidal indium IBs. The structural changes led to improved TE performance. For example, (Ga0.8In0.2)2O3(ZnO)9 showed a low thermal conductivity of 2 W/m K and a high power factor of 150 μW/m K2 giving a figure of merit (ZT) of 0.07 at 900 K. This is the highest ZT for Ga2O3(ZnO)9-based homologous compounds and is comparable with the highest ZT reported for In2O3(ZnO)9 homologous compounds
Molecular Genetics of T Cell Development
T cell development is guided by a complex set of transcription factors that act recursively, in different combinations, at each of the developmental choice points from T-lineage specification to peripheral T cell specialization. This review describes the modes of action of the major T-lineage-defining transcription factors and the signal pathways that activate them during intrathymic differentiation from pluripotent precursors. Roles of Notch and its effector RBPSuh (CSL), GATA-3, E2A/HEB and Id proteins, c-Myb, TCF-1, and members of the Runx, Ets, and Ikaros families are critical. Less known transcription factors that are newly recognized as being required for T cell development at particular checkpoints are also described. The transcriptional regulation of T cell development is contrasted with that of B cell development, in terms of their different degrees of overlap with the stem-cell program and the different roles of key transcription factors in gene regulatory networks leading to lineage commitment
Exact vortex solutions in a CP^N Skyrme-Faddeev type model
We consider a four dimensional field theory with target space being CP^N
which constitutes a generalization of the usual Skyrme-Faddeev model defined on
CP^1. We show that it possesses an integrable sector presenting an infinite
number of local conservation laws, which are associated to the hidden
symmetries of the zero curvature representation of the theory in loop space. We
construct an infinite class of exact solutions for that integrable submodel
where the fields are meromorphic functions of the combinations (x^1+i x^2) and
(x^3+x^0) of the Cartesian coordinates of four dimensional Minkowski
space-time. Among those solutions we have static vortices and also vortices
with waves traveling along them with the speed of light. The energy per unity
of length of the vortices show an interesting and intricate interaction among
the vortices and waves.Comment: 21 pages, plain latex, no figure
Co-pyrolysis of Rice Husk with Underutilized Biomass Species: A Sustainable Route for Production of Precursors for Fuels and Valuable Chemicals
In this study, co-pyrolysis of rice husk with
underutilized biomass, Napier grass and sago waste was
carried out in a fixed bed reactor at 600 �C, 30 �C/min and
5 L/min nitrogen flowrate. Two-phase bio-oil (organic and
aqueous) was collected and characterized using standard
analytical techniques. 34.13–45.55 wt% total boil-oil yield
was recorded using assorted biomass compared to pure risk
husk biomass with 31.51 wt% yield. The organic phase
consist mainly benzene derivatives with higher proportion
in the oil from the co-pyrolysis process relative to the
organic phase from the pyrolysis of the individual biomass
while the aqueous phase in all cases was predominantly
water, acids, ketones, aldehydes, sugars and traces of
phenolics. This study has demonstrated a good approach
towards increasing valorization of rice husk in a single
reaction step for the production of high grade bio-oil,
which can be transformed into fuel and valuable chemicals
Direct evidence for microdomain-specific localization and remodeling of functional L-type calcium channels in rat and human atrial myocytes
Background—Distinct subpopulations of L-type calcium channels (LTCCs) with different functional properties exist in cardiomyocytes. Disruption of cellular structure may affect LTCC in a microdomain-specific manner and contribute to the pathophysiology of cardiac diseases, especially in cells lacking organized transverse tubules (T-tubules) such as atrial myocytes (AMs). Methods and Results—Isolated rat and human AMs were characterized by scanning ion conductance, confocal, and electron microscopy. Half of AMs possessed T-tubules and structured topography, proportional to cell width. A bigger proportion of myocytes in the left atrium had organized T-tubules and topography than in the right atrium. Super-resolution scanning patch clamp showed that LTCCs distribute equally in T-tubules and crest areas of the sarcolemma, whereas, in ventricular myocytes, LTCCs primarily cluster in T-tubules. Rat, but not human, T-tubule LTCCs had open probability similar to crest LTCCs, but exhibited ≈40% greater current. Optical mapping of Ca2+ transients revealed that rat AMs presented ≈3-fold as many spontaneous Ca2+ release events as ventricular myocytes. Occurrence of crest LTCCs and spontaneous Ca2+ transients were eliminated by either a caveolae-targeted LTCC antagonist or disrupting caveolae with methyl-β-cyclodextrin, with an associated ≈30% whole-cell ICa,L reduction. Heart failure (16 weeks post–myocardial infarction) in rats resulted in a T-tubule degradation (by ≈40%) and significant elevation of spontaneous Ca2+ release events. Although heart failure did not affect LTCC occurrence, it led to ≈25% decrease in T-tubule LTCC amplitude. Conclusions—We provide the first direct evidence for the existence of 2 distinct subpopulations of functional LTCCs in rat and human AMs, with their biophysical properties modulated in heart failure in a microdomain-specific manner
Supersymmetry and Duality in Field Theory and String Theory
This is a set of lectures given at the 99' Cargese Summer School: Particle
Physics : Ideas and Recent Developments. They contain a pedestrian exposition
of recent theoretical progress in non-perturbative field theory and string
theory based on ideas of duality.Comment: JHEP LateX, 56 pages, 13 eps figures;v2 References adde
The a-theorem and conformal symmetry breaking in holographic RG flows
We study holographic models describing an RG flow between two fixed points
driven by a relevant scalar operator. We show how to introduce a spurion field
to restore Weyl invariance and compute the anomalous contribution to the
generating functional in even dimensional theories. We find that the
coefficient of the anomalous term is proportional to the difference of the
conformal anomalies of the UV and IR fixed points, as expected from anomaly
matching arguments in field theory. For any even dimensions the coefficient is
positive as implied by the holographic a-theorem. For flows corresponding to
spontaneous breaking of conformal invariance, we also compute the two-point
functions of the energy-momentum tensor and the scalar operator and identify
the dilaton mode. Surprisingly we find that in the simplest models with just
one scalar field there is no dilaton pole in the two-point function of the
scalar operator but a stronger singularity. We discuss the possible
implications.Comment: 50 pages. v2: minor changes, added references, extended discussion.
v3: we have clarified some of the calculations and assumptions, results
unchanged. v4: published version in JHE
Early star-forming galaxies and the reionization of the Universe
Star forming galaxies represent a valuable tracer of cosmic history. Recent
observational progress with Hubble Space Telescope has led to the discovery and
study of the earliest-known galaxies corresponding to a period when the
Universe was only ~800 million years old. Intense ultraviolet radiation from
these early galaxies probably induced a major event in cosmic history: the
reionization of intergalactic hydrogen. New techniques are being developed to
understand the properties of these most distant galaxies and determine their
influence on the evolution of the universe.Comment: Review article appearing in Nature. This posting reflects a submitted
version of the review formatted by the authors, in accordance with Nature
publication policies. For the official, published version of the review,
please see http://www.nature.com/nature/archive/index.htm
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