Metabolism of formycin B by Leishmania amastigotes in vitro. Comparative metabolism in infected and uninfected human macrophages.

Formycin B is metabolized by cutaneous Leishmania amastigotes within cultured human macrophages to give formycin B 5'-monophosphate and formycin A 5'-mono-, di-, and triphosphates. Formycin A is also incorporated into RNA. The activity of formycin B against amastigotes was correlated with the levels of formycin A metabolites formed in the parasites. Uninfected macrophages also convert formycin B into the same products, but the levels are markedly lower than those seen in infected macrophages. The results suggest that a sufficient therapeutic index exists to warrant consideration of formycin B as an anti-leishmanial drug in humans

Efficacy of Thermotherapy to Treat Cutaneous Leishmaniasis Caused by Leishmania tropica in Kabul, Afghanistan: A Randomized, Controlled Trial

BACKGROUND: Pentavalent antimony is the agent recommended for treatment of cutaneous leishmaniasis (CL). Its use is problematic, because it is expensive and because of the potential for drug-associated adverse effects during a lengthy and painful treatment course. METHODS: We tested the efficacy of thermotherapy for the treatment of CL due to Leishmania tropica in a randomized, controlled trial in Kabul, Afghanistan. We enrolled 401 patients with a single CL lesion and administered thermotherapy using radio-frequency waves (1 treatment of ≥1 consecutive application at 50°C for 30 s) or sodium stibogluconate (SSG), administered either intralesionally (a total of 5 injections of 25 mL every 57 days, depending on lesion size) or intramuscularly (20 mg/kg daily for 21 days). RESULTS: Cure, defined as complete reepithelialization at 100 days after treatment initiation, was observed in 75 (69.4%) of 108 patients who received thermotherapy, 70 (75.3%) of 93 patients who received intralesional SSG, and 26 (44.8%) of 58 patients who received intramuscular SSG. The OR for cure with thermotherapy was 2.80 (95% confidence interval [CI], 1.455.41), compared with intramuscular SSG treatment (P = .002). No statistically significant difference was observed in the odds of cure in comparison of intralesional SSG and thermotherapy treatments. The OR for cure with intralesional SSG treatment was 3.75 (95% CI, 1.867.54), compared with intramuscular SSG treatment (P 100 days, respectively; P = .003). CONCLUSIONS: Thermotherapy is an effective, comparatively well-tolerated, and rapid treatment for CL, and it should be considered as an alternative to antimony treatment

Evaluation of the Multilook Size in Polarimetric Optimization of Differential SAR Interferograms

The interferometric coherence is a measure of the correlation between two SAR images and constitutes a commonly used estimator of the phase quality. Its estimation requires a spatial average within a 2-D window, usually named as multilook. The multilook processing allows reducing noise at the expenses of a resolution loss. In this letter, we analyze the influence of the multilook size while applying a polarimetric optimization of the coherence. The same optimization algorithm has been carried out with different multilook sizes and also with the nonlocal SAR filter filter, which has the advantage of preserving the original resolution of the interferogram. Our experiments have been carried out with a single pair of quad-polarimetric RADARSAT-2 images mapping the Mount Etna's volcanic eruption of May 2008. Results obtained with this particular data set show that the coherence is increased notably with respect to conventional channels when small multilook sizes are employed, especially over low-vegetated areas. Conversely, very decorrelated areas benefit from larger multilook sizes but do not exhibit an additional improvement with the polarimetric optimization

Exploring the Levinthal limit in protein folding

According to the thermodynamic hypothesis, the native state of proteins is uniquely defined by their amino acid sequence. On the other hand, according to Levinthal, the native state is just a local minimum of the free energy and a given amino acid sequence, in the same thermodynamic conditions, can assume many, very different structures that are as thermodynamically stable as the native state. This is the Levinthal limit explored in this work. Using computer simulations, we compare the interactions that stabilize the native state of four different proteins with those that stabilize three non-native states of each protein and find that the nature of the interactions is very similar for all such 16 conformers. Furthermore, an enhancement of the degree of fluctuation of the non-native conformers can be explained by an insufficient relaxation to their local free energy minimum. These results favor Levinthal's hypothesis that protein folding is a kinetic non-equilibrium process.FCT - Foundation for Science and Technology, Portugal [UID/Multi/04326/2013]; Fundacao de Amparo a Pesquisa do Estado de Sao Paulo (FAPESP); Conselho Nacional de Desenvolvimento Cientia co e Tecnologico (CNPq

The Pioneer Anomaly

Radio-metric Doppler tracking data received from the Pioneer 10 and 11 spacecraft from heliocentric distances of 20-70 AU has consistently indicated the presence of a small, anomalous, blue-shifted frequency drift uniformly changing with a rate of ~6 x 10^{-9} Hz/s. Ultimately, the drift was interpreted as a constant sunward deceleration of each particular spacecraft at the level of a_P = (8.74 +/- 1.33) x 10^{-10} m/s^2. This apparent violation of the Newton's gravitational inverse-square law has become known as the Pioneer anomaly; the nature of this anomaly remains unexplained. In this review, we summarize the current knowledge of the physical properties of the anomaly and the conditions that led to its detection and characterization. We review various mechanisms proposed to explain the anomaly and discuss the current state of efforts to determine its nature. A comprehensive new investigation of the anomalous behavior of the two Pioneers has begun recently. The new efforts rely on the much-extended set of radio-metric Doppler data for both spacecraft in conjunction with the newly available complete record of their telemetry files and a large archive of original project documentation. As the new study is yet to report its findings, this review provides the necessary background for the new results to appear in the near future. In particular, we provide a significant amount of information on the design, operations and behavior of the two Pioneers during their entire missions, including descriptions of various data formats and techniques used for their navigation and radio-science data analysis. As most of this information was recovered relatively recently, it was not used in the previous studies of the Pioneer anomaly, but it is critical for the new investigation.Comment: 165 pages, 40 figures, 16 tables; accepted for publication in Living Reviews in Relativit

A comparative framework: how broadly applicable is a 'rigorous' critical junctures framework?

The paper tests Hogan and Doyle's (2007, 2008) framework for examining critical junctures. This framework sought to incorporate the concept of ideational change in understanding critical junctures. Until its development, frameworks utilized in identifying critical junctures were subjective, seeking only to identify crisis, and subsequent policy changes, arguing that one invariably led to the other, as both occurred around the same time. Hogan and Doyle (2007, 2008) hypothesized ideational change as an intermediating variable in their framework, determining if, and when, a crisis leads to radical policy change. Here we test this framework on cases similar to, but different from, those employed in developing the exemplar. This will enable us determine whether the framework's relegation of ideational change to a condition of crisis holds, or, if ideational change has more importance than is ascribed to it by this framework. This will also enable us determined if the framework itself is robust, and fit for the purposes it was designed to perform — identifying the nature of policy change

Identification of target-specific bioisosteric fragments from ligand-protein crystallographic data

Bioisosteres are functional groups or atoms that are structurally different but that can form similar intermolecular interactions. Potential bioisosteres were identified here from analysing the X-ray crystallographic structures for sets of different ligands complexed with a fixed protein. The protein was used to align the ligands with each other, and then pairs of ligands compared to identify substructural features with high volume overlap that occurred in approximately the same region of geometric space. The resulting pairs of substructural features can suggest potential bioisosteric replacements for use in lead-optimisation studies. Experiments with 12 sets of ligand-protein complexes from the Protein Data Bank demonstrate the effectiveness of the procedure

Spatial constancy of attention across eye movements is mediated by the presence of visual objects

Recent studies have shown that attentional facilitation lingers at the retinotopic coordinates of a previously attended position after an eye movement. These results are intriguing, because the retinotopic location becomes behaviorally irrelevant once the eyes have moved. Critically, in these studies participants were asked to maintain attention on a blank location of the screen. In the present study, we examined whether the continuing presence of a visual object at the cued location could affect the allocation of attention across eye movements. We used a trans-saccadic cueing paradigm in which the relevant positions could be defined or not by visual objects (simple square outlines). We find an attentional benefit at the spatiotopic location of the cue only when the object (the placeholder) has been continuously present at that location. We conclude that the presence of an object at the attended location is a critical factor for the maintenance of spatial constancy of attention across eye movements, a finding that helps to reconcile previous conflicting results

Evidence for a nuclear compartment of transcription and splicing located at chromosome domain boundaries

The nuclear topography of splicing snRNPs, mRNA transcripts and chromosome domains in various mammalian cell types are described. The visualization of splicing snRNPs, defined by the Sm antigen, and coiled bodies, revealed distinctly different distribution patterns in these cell types. Heat shock experiments confirmed that the distribution patterns also depend on physiological parameters. Using a combination of fluorescencein situ hybridization and immunodetection protocols, individual chromosome domains were visualized simultaneously with the Sm antigen or the transcript of an integrated human papilloma virus genome. Three-dimensional analysis of fluorescence-stained target regions was performed by confocal laser scanning microscopy. RNA transcripts and components of the splicing machinery were found to be generally excluded from the interior of the territories occupied by the individual chromosomes. Based on these findings we present a model for the functional compartmentalization of the cell nucleus. According to this model the space between chromosome domains, including the surface areas of these domains, defines a three-dimensional network-like compartment, termed the interchromosome domain (ICD) compartment, in which transcription and splicing of mRNA occurs

Bianchi Type-II String Cosmological Models in Normal Gauge for Lyra's Manifold with Constant Deceleration Parameter

The present study deals with a spatially homogeneous and anisotropic Bianchi-II cosmological models representing massive strings in normal gauge for Lyra's manifold by applying the variation law for generalized Hubble's parameter that yields a constant value of deceleration parameter. The variation law for Hubble's parameter generates two types of solutions for the average scale factor, one is of power-law type and other is of the exponential form. Using these two forms, Einstein's modified field equations are solved separately that correspond to expanding singular and non-singular models of the universe respectively. The energy-momentum tensor for such string as formulated by Letelier (1983) is used to construct massive string cosmological models for which we assume that the expansion ($\theta$) in the model is proportional to the component $\sigma^{1}_{~1}$ of the shear tensor $\sigma^{j}_{i}$. This condition leads to $A = (BC)^{m}$, where A, B and C are the metric coefficients and m is proportionality constant. Our models are in accelerating phase which is consistent to the recent observations. It has been found that the displacement vector $\beta$ behaves like cosmological term $\Lambda$ in the normal gauge treatment and the solutions are consistent with recent observations of SNe Ia. It has been found that massive strings dominate in the decelerating universe whereas strings dominate in the accelerating universe. Some physical and geometric behaviour of these models are also discussed.Comment: 24 pages, 10 figure