Growth inhibition and ultrastructural alterations induced by Δ24(25)-sterol methyltransferase inhibitors in Candida spp. isolates, including non-albicans organisms

<p>Abstract</p> <p>Background</p> <p>Although <it>Candida </it>species are commensal microorganisms, they can cause many invasive fungal infections. In addition, antifungal resistance can contribute to failure of treatment.</p> <p>The purpose of this study was to evaluate the antifungal activity of inhibitors of Δ²⁴⁽²⁵⁾-sterol methyltransferase (24-SMTI), 20-piperidin-2-yl-5α-pregnan-3β-20(R)-diol (AZA), and 24(R,S),25-epiminolanosterol (EIL), against clinical isolates of <it>Candida </it>spp., analysing the ultrastructural changes.</p> <p>Results</p> <p>AZA and EIL were found to be potent growth inhibitors of <it>Candida </it>spp. isolates. The median MIC₅₀was 0.5 μg.ml^-1for AZA and 2 μg.ml^-1for EIL, and the MIC₉₀was 2 μg.ml^-1for both compounds. All strains used in this study were susceptible to amphotericin B; however, some isolates were fluconazole- and itraconazole-resistant. Most of the azole-resistant isolates were <it>Candida </it>non-<it>albicans </it>(CNA) species, but several of them, such as <it>C. guilliermondii, C. zeylanoides</it>, and <it>C. lipolytica</it>, were susceptible to 24-SMTI, indicating a lack of cross-resistance. Reference strain <it>C. krusei </it>(ATCC 6258, FLC-resistant) was consistently susceptible to AZA, although not to EIL. The fungicidal activity of 24-SMTI was particularly high against CNA isolates. Treatment with sub-inhibitory concentrations of AZA and EIL induced several ultrastructural alterations, including changes in the cell-wall shape and thickness, a pronounced disconnection between the cell wall and cytoplasm with an electron-lucent zone between them, mitochondrial swelling, and the presence of electron-dense vacuoles. Fluorescence microscopy analyses indicated an accumulation of lipid bodies and alterations in the cell cycle of the yeasts. The selectivity of 24-SMTI for fungal cells versus mammalian cells was assessed by the sulforhodamine B viability assay.</p> <p>Conclusion</p> <p>Taken together, these results suggest that inhibition of 24-SMT may be a novel approach to control <it>Candida </it>spp. infections, including those caused by azole-resistant strains.</p

TLR2 expression is increased in rosacea and stimulates enhanced serine protease production by keratinocytes.

A diverse environment challenges skin to maintain temperature, hydration, and electrolyte balance while also maintaining normal immunological function. Rosacea is a common skin disease that manifests unique inflammatory responses to normal environmental stimuli. We hypothesized that abnormal function of innate immune pattern recognition could explain the enhanced sensitivity of patients with rosacea, and observed that the epidermis of patients with rosacea expressed higher amounts of Toll-like receptor 2 (TLR2) than normal patients. Increased expression of TLR2 was not seen in other inflammatory skin disorders such as atopic dermatitis or psoriasis. Overexpression of TLR2 on keratinocytes, treatment with TLR2 ligands, and analysis of TLR2-deficient mice resulted in a calcium-dependent release of kallikrein 5 from keratinocytes, a critical protease involved in the pathogenesis of rosacea. These observations show that abnormal TLR2 function may explain enhanced inflammatory responses to environmental stimuli and can act as a critical element in the pathogenesis of rosacea

Three-body dN interaction in the analysis of the 12C(pol_d,d') reaction at 270 MeV

We have measured the cross sections and analyzing powers Ay and Ayy for the elastic and inelastic scattering of deuterons from the 0+(g.s.), 2+(4.44 MeV), 3-(9.64 MeV), 1+(12.71 MeV), and 2-(18.3 MeV) states in 12C at an incident energy of 270 MeV. The data are compared with microscopic distorted-wave impulse approximation calculations where the projectile-nucleon effective interactionis taken from the three-nucleon t-matrix given by rigorous Faddeev calculations presently available at intermediate energies. The agreement between theory and data compares well with that for the (p,p') reactions at comparable incident energies/nucleon.Comment: 17 pages, 3 Postscript figure

Strong dusty bursts of star formation in galaxies falling into the cluster RXJ0152.7-1357

We have observed the cluster RX J0152.7-1357 (z$\sim$0.83) at 24$\mu$m with the Multiband Imaging Photometer for Spitzer (MIPS). We detected twenty-two sources associated with spectroscopically confirmed cluster members, while ten more have photometric redshifts compatible with membership. Two of the 32 likely cluster members contain obvious active nuclei while the others are associated with dusty star formation. The median IR-determined star formation rate among the remaining galaxies is estimated at 22 M$_\odot$$$yr$^{-1}$, significantly higher than in previous estimates from optical data. Most of the MIR-emitting galaxies also have optical emission lines, but a few do not and hence have completely hidden bursts of star formation or AGN activity. An excess of MIR-emitting galaxies is seen in the cluster in comparison to the field at the same redshift. The MIR cluster members are more associated with previously detected infalling late type galaxies rather than triggered by the ongoing merging of bigger X-ray clumps. Rough estimates also show that ram pressure may not be capable of stripping the gas away from cluster outskirt galaxies but it may disturb the gas enough to trigger the star formation activity. Harassment can also play a role if for example these galaxies belong to poor galaxy groups. Thus, bursts of star formation occur in the cluster environment and could also help consume the galaxy gas content in addition to ram pressure, harassment or galaxy-galaxy strong interactions.Comment: 12 pages, 6 figures, accepted for publication in ApJ. A full resolution version and fig.2 are available at http://mips.as.arizona.edu/~dmarci

Preparation and Characterization of Covalently Binding of Rat Anti-human IgG Monolayer on Thiol-Modified Gold Surface

The 16-mercaptohexadecanoic acid (MHA) film and rat anti-human IgG protein monolayer were fabricated on gold substrates using self-assembled monolayer (SAM) method. The surface properties of the bare gold substrate, the MHA film and the protein monolayer were characterized by contact angle measurements, atomic force microscopy (AFM), grazing incidence X-ray diffraction (GIXRD) method and X-ray photoelectron spectroscopy, respectively. The contact angles of the MHA film and the protein monolayer were 18° and 12°, respectively, all being hydrophilic. AFM images show dissimilar topographic nanostructures between different surfaces, and the thickness of the MHA film and the protein monolayer was estimated to be 1.51 and 5.53 nm, respectively. The GIXRD 2θ degrees of the MHA film and the protein monolayer ranged from 0° to 15°, significantly smaller than that of the bare gold surface, but the MHA film and the protein monolayer displayed very different profiles and distributions of their diffraction peaks. Moreover, the spectra of binding energy measured from these different surfaces could be well fitted with either Au4f, S2p or N1s, respectively. Taken together, these results indicate that MHA film and protein monolayer were successfully formed with homogeneous surfaces, and thus demonstrate that the SAM method is a reliable technique for fabricating protein monolayer

Proanthocyanidins polymeric tannin from Stryphnodendron adstringens are active against Candida albicans biofilms

Abstract\ud \ud Background\ud Biofilm formation is important in Candida albicans pathogenesis and constitutes a mechanism of antifungal resistance. Thus, we evaluated the effect of proanthocyanidins polymer-rich fractions from Stryphnodendron adstringens (fraction F2 and subfraction F2.4) against C. albicans biofilms.\ud \ud \ud Methods\ud Firstly, the antifungal activity of F2 and F2.4 against planktonic cells of Candida albicans (ATCC 10231) was determined using broth microdilution method. Anti-biofilm effect of F2 and F2.4 was evaluated during biofilm formation or on mature biofilm of C. albicans and compared with standard antifungals amphotericin B and fluconazole. Metabolic activity of sessile and dispersion cells from biofilms after antifungal treatments were measured using a tetrazolium reduction assay and the biofilm total biomass was quantified by crystal violet-based assay. Morphological alterations after treatments were observed using scanning electron microscopy.\ud \ud \ud Results\ud The anti-biofilm effect of F2 and F2.4 were comparable to standard antifungals (amphotericin B and fluconazole). F2 and F2.4 treatments reduced biofilm metabolic activity (in sessile and in dispersion cells) during biofilm formation, and in mature biofilms, unlike fluconazole, which only prevents the biofilm formation. Treatments with F2, F2.4 or fluconazole reduced biofilm biomass during biofilm formation, but not in mature biofilm. Amphotericin B presented higher inhibitory effect on biofilm formation and on mature biofilm of C. albicans. F2 and F2.4 treatments led to the appearance of dumbbell-shaped blastoconidia and of blastoconidia clusters in biofilms.\ud \ud \ud Conclusion\ud Proanthocyanidins polymer-rich fractions from S. adstringens successfully inhibited C. albicans planktonic growth and biofilm development, and they represent a potential new agent for the treatment of biofilm-associated candidiasis.This work was supported by Fundação de Amparo à Pesquisa\ud do Estado de São Paulo (FAPESP - Processo no. 2013/11232-0), Fundação\ud Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro\ud (FAPERJ), Coordenação de Aperfeiçoamento de Pessoal de Nível Superior\ud (CAPES), and Conselho Nacional de Desenvolvimento e Pesquisa (CNPq).\ud RLFL and TVMV are fellows of the CNPq

Thermal Conductivity of Carbon Nanotubes and their Polymer Nanocomposites: A Review

Thermally conductive polymer composites offer new possibilities for replacing metal parts in several applications, including power electronics, electric motors and generators, heat exchangers, etc., thanks to the polymer advantages such as light weight, corrosion resistance and ease of processing. Current interest to improve the thermal conductivity of polymers is focused on the selective addition of nanofillers with high thermal conductivity. Unusually high thermal conductivity makes carbon nanotube (CNT) the best promising candidate material for thermally conductive composites. However, the thermal conductivities of polymer/CNT nanocomposites are relatively low compared with expectations from the intrinsic thermal conductivity of CNTs. The challenge primarily comes from the large interfacial thermal resistance between the CNT and the surrounding polymer matrix, which hinders the transfer of phonon dominating heat conduction in polymer and CNT. This article reviews the status of worldwide research in the thermal conductivity of CNTs and their polymer nanocomposites. The dependence of thermal conductivity of nanotubes on the atomic structure, the tube size, the morphology, the defect and the purification is reviewed. The roles of particle/polymer and particle/particle interfaces on the thermal conductivity of polymer/CNT nanocomposites are discussed in detail, as well as the relationship between the thermal conductivity and the micro- and nano-structure of the composite

Candida tropicalis antifungal cross-resistance is related to different azole target (Erg11p) modifications

ABSTARCT: Candida tropicalis ranks between third and fourth among Candida species most commonly isolated from clinical specimens. Invasive candidiasis and candidemia are treated with amphotericin B or echinocandins as first-line therapy, with extended-spectrum triazoles as acceptable alternatives. Candida tropicalis is usually susceptible to all antifungal agents, although several azole drug-resistant clinical isolates are being reported. However, C. tropicalis resistant to amphotericin B is uncommon, and only a few strains have reliably demonstrated a high level of resistance to this agent. The resistance mechanisms operating in C. tropicalis strains isolated from clinical samples showing resistance to azole drugs alone or with amphotericin B cross-resistance were elucidated. Antifungal drug resistance was related to mutations of the azole target (Erg11p) with or without alterations of the ergosterol biosynthesis pathway. The antifungal drug resistance shown in vitro correlated very well with the results obtained in vivo using the model host Galleria mellonella. Using this panel of strains, the G. mellonella model system was validated as a simple, nonmammalian minihost model that can be used to study in vitro-in vivo correlation of antifungals in C. tropicalis. The development in C. tropicalis of antifungal drug resistance with different mechanisms during antifungal treatment has potential clinical impact and deserves specific prospective studies