A Novel Tropically Stable Oral Amphotericin B Formulation (iCo-010) Exhibits Efficacy against Visceral Leishmaniasis in a Murine Model

Visceral leishmaniasis (VL) is a systemic form of a vector-borne parasitic disease caused by obligate intra-macrophage protozoa of the genus Leishmania. VL is always fatal in humans if left untreated and treatment options are limited. Amphotericin B (AmB), a polyene antibiotic, is the most active antileishmanial agent that currently exists. Liposomal AmB (AmBisome) is used as first-line treatment in developed countries [1], [7], [8], [9], [10]; however, the requisite parenteral administration and the high cost of the liposomal formulation prevents this treatment from reaching the majority of patients in developing nations [3]. A stable, efficacious oral treatment for VL that is able to withstand the rigors of tropical climates would overcome many of the current barriers to treatment that exist in countries with large VL-infected patient populations. In this study we have developed an oral formulation of AmB that is stable in tropical conditions and exhibits significant antileshimanial activity in mice

γ-Tubulin 2 Nucleates Microtubules and Is Downregulated in Mouse Early Embryogenesis

γ-Tubulin is the key protein for microtubule nucleation. Duplication of the γ-tubulin gene occurred several times during evolution, and in mammals γ-tubulin genes encode proteins which share ∼97% sequence identity. Previous analysis of Tubg1 and Tubg2 knock-out mice has suggested that γ-tubulins are not functionally equivalent. Tubg1 knock-out mice died at the blastocyst stage, whereas Tubg2 knock-out mice developed normally and were fertile. It was proposed that γ-tubulin 1 represents ubiquitous γ-tubulin, while γ-tubulin 2 may have some specific functions and cannot substitute for γ-tubulin 1 deficiency in blastocysts. The molecular basis of the suggested functional difference between γ-tubulins remains unknown. Here we show that exogenous γ-tubulin 2 is targeted to centrosomes and interacts with γ-tubulin complex proteins 2 and 4. Depletion of γ-tubulin 1 by RNAi in U2OS cells causes impaired microtubule nucleation and metaphase arrest. Wild-type phenotype in γ-tubulin 1-depleted cells is restored by expression of exogenous mouse or human γ-tubulin 2. Further, we show at both mRNA and protein levels using RT-qPCR and 2D-PAGE, respectively, that in contrast to Tubg1, the Tubg2 expression is dramatically reduced in mouse blastocysts. This indicates that γ-tubulin 2 cannot rescue γ-tubulin 1 deficiency in knock-out blastocysts, owing to its very low amount. The combined data suggest that γ-tubulin 2 is able to nucleate microtubules and substitute for γ-tubulin 1. We propose that mammalian γ-tubulins are functionally redundant with respect to the nucleation activity

Isospin effects on two-particle correlation functions in E/A=61 MeV Ar-36+Sn-112,Sn-124 reactions

Small-angle, two-particle correlation functions have been measured for Ar-36+Sn-112,Sn-124 collisions at E/A=61 MeV. Total momentum gated neutron-proton (np) and proton-proton (pp) correlations are stronger for the Sn-124 target. Some of the correlation functions for particle pairs involving deuterons or tritons (nd, pt, and nt) also show a dependence on the isospin of the emitting source

Calibration of a neutron time-of-flight multidetector system for an intensity interferometry experiment

We present the details of an experiment on light particle interferometry. In particular, we focus on a time-of-flight technique which uses a cyclotron RF signal as a start and a liquid scintillator time signal as a stop, to measure neutron energy in the range of En approximate to 1.8-150 MeV. This dynamic range (up to 300 ns) is much larger than the beam bunch separation (54 ns) of the AGOR cyclotron (KVI). However, the problem of a short burst period is overcome by using the time information obtained from a fast projectile fragment phoswich detector. The complete analysis procedure to extract the final neutron kinetic energy spectra, is discussed. (C) 2003 Elsevier B.V. All rights reserved

Growth and water relations of field-grown Valencia orange trees under long-term partial rootzone drying

Climate, soil water potential (SWP), leaf relative water content (RWC), stem water potential (WPstem), stomatal conductance (gs), trunk, shoot and fruit growth of 'Valencia' orange trees were monitored during five consecutive seasons (2007â2012) to study water status and growth responses to irrigation placement or volume. 48 adult trees were exposed to conventional irrigation (CI, 100% of crop evapotranspiration on both sides of the rootzone), partial rootzone drying (PRD, 50% of CI water only on one alternated side of the rootzone) and continuous deficit irrigation (DI, 50% of CI water on both sides of the rootzone). Reducing irrigation volumes by 55% (DI) over CI increased leaf water deficit by 27% and reduced 'Valencia' fruit growth by 15% but not shoot or trunk growth. Similar water savings by PRD did not induce significant growth reductions. Differences in fruit growth rates determined 17% yield reduction in DI but not PRD trees. If we consider integrals of data across each season, PRD induced milder soil and leaf water deficit than DI but similar stomatal conductance. Tree daily water consumption (Etree) estimated from daily leaf transpiration was significantly lower in PRD and DI than in CI. Fruit growth efficiency (growth rate per unit Etree) was similar in all irrigation treatments, while shoot growth efficiency was higher in PRD than in CI. In PRD, an increased shoot growth efficiency rather than fruit growth efficiency is most likely due to water and assimilates being diverted from fruit to shoot growth under high VPD conditions. Although these results show good evidence of an irrigation placement effect inducing an advantage of the PRD strategy in 'Valencia' orange in terms of milder soil and leaf water deficit and more sustainable fruit growth compared to DI, PRD did not induce any significant advantage in terms of final yield over a simple reduction of irrigation volumes