Therapy of Mycobacterium avium complex infections in beige mice with streptomycin encapsulated in sterically stabilized liposomes

Mycobacterium avium complex (MAC) causes serious opportunistic infections in AIDS patients. Previous studies with MAC-infected beige mice have indicated that weekly administration of liposome-encapsulated streptomycin can reduce significantly the CFU in the liver and spleen. We examined whether streptomycin encapsulated in recently developed sterically stabilized liposomes with prolonged circulation times would have a therapeutic effect in this animal model. Two liposome types with prolonged circulation (polyethyleneglycol-distearoylphosphatidylethanolamine [PEG-DSPE]- distearoylphosphatidylcholine [DSPC]-cholesterol [chol] or phosphatidylinositol [PI]-DSPC-chol) and conventional liposomes (phosphatidylglycerol [PG]-phosphatidylcholine [PC]-chol) encapsulating streptomycin and administered twice weekly were bactericidal to MAC strain 101 in the spleen when the level of infection after treatment was compared with the level of infection before treatment. PI-DSPC-chol and PG-PC-chol liposomes encapsulating streptomycin were bactericidal in the liver. Although PG-PC-chol or PEG-DSPE-DSPE-chol liposomes encapsulating streptomycin were not bactericidal in the lungs, they reduced the level of MAC infection by more than 3 orders of magnitude compared with the level of MAC infection in untreated controls

Fusion activity and inactivation of influenza virus: Kinetics of low pH-induced fusion with cultured cells

The kinetics of fusion of influenza virus (A/PR/8/34) with human promyelocytic leukaemia (HL-60), human T lymphocytic leukaemia (CEM) and murine lymphoma (S49) cells were investigated. Fusion was demonstrated by electron microscopy, and monitored by fluorescence dequenching of octadecylrhodamine incorporated in the virus membrane. Rapid fusion was induced upon mild acidification of the medium. At pH 5, all virus particles were capable of fusing with the cells. The initial rate and the extent of fusion were maximal between pH 4.9 and 5.2 and declined sharply below and above this range. The rate constants of adhesion of influenza virus to cells or erythrocyte ghosts were large, indicating a diffusion-controlled process. The rate constants of fusion of the virus with cells were smaller than those found previously for fusion with various liposomes. Although preincubation of the virus at acidic pH in the absence of target membranes almost completely inactivated the virus in its ability to fuse with erythrocyte ghosts, it reduced the extent of fusion with cultured cells by only 20 to 40%. Kinetic analysis of fusion revealed a mode of inactivation of the virus bound to erythrocyte ghosts or suspension cells, below pH 5.4, different from that of the virus preincubated at low pH without target membranes

Dust and Metal Column Densities in Gamma-Ray Burst Host Galaxies

In this paper we present the results from the analysis of a sample of 28 gamma-ray burst (GRB) afterglow spectral energy distributions, spanning the X-ray through to near-infrared wavelengths. This is the largest sample of GRB afterglow spectral energy distributions thus far studied, providing a strong handle on the optical depth distribution of soft X-ray absorption and dust-extinction systems in GRB host galaxies. We detect an absorption system within the GRB host galaxy in 79% of the sample, and an extinction system in 71% of the sample, and find the Small Magellanic Cloud (SMC) extinction law to provide an acceptable fit to the host galaxy extinction profile for the majority of cases, consistent with previous findings. The range in the soft X-ray absorption to dust-extinction ratio, N_{H,X}/Av, in GRB host galaxies spans almost two orders of magnitude, and the typical ratios are significantly larger than those of the Magellanic Clouds or Milky Way. Although dust destruction could be a cause, at least in part, for the large N_{H,X}/Av ratios, the good fit provided by the SMC extinction law for the majority of our sample suggests that there is an abundance of small dust grains in the GRB environment, which we would expect to have been destroyed if dust destruction were responsible for the large N_{H,X}/Av ratios. Instead, our analysis suggests that the distribution of N_{H,X}/Av in GRB host galaxies may be mostly intrinsic to these galaxies, and this is further substantiated by evidence for a strong negative correlation between N_{H,X}/Av and metallicity for a subsample of GRB hosts with known metallicity. Furthermore, we find the N_{H,X}/Av ratio and metallicity for this subsample of GRBs to be comparable to the relation found in other more metal-rich galaxies.Comment: 23 pages, 10 figures, accepted for publication in MNRA

Quo vadis, cold molecules? - Editorial review

We give a snapshot of the rapidly developing field of ultracold polar molecules abd walk the reader through the papers appearing in this topical issue

Thermal Stability of the Human Immunodeficiency Virus Type 1 (HIV-1) Receptors, CD4 and CXCR4, Reconstituted in Proteoliposomes

BACKGROUND: The entry of human immunodeficiency virus (HIV-1) into host cells involves the interaction of the viral exterior envelope glycoprotein, gp120, and receptors on the target cell. The HIV-1 receptors are CD4 and one of two chemokine receptors, CCR5 or CXCR4. METHODOLOGY/PRINCIPAL FINDINGS: We created proteoliposomes that contain CD4, the primary HIV-1 receptor, and one of the coreceptors, CXCR4. Antibodies against CD4 and CXCR4 specifically bound the proteoliposomes. CXCL12, the natural ligand for CXCR4, and the small-molecule CXCR4 antagonist, AMD3100, bound the proteoliposomes with affinities close to those associated with the binding of these molecules to cells expressing CXCR4 and CD4. The HIV-1 gp120 exterior envelope glycoprotein bound tightly to proteoliposomes expressing only CD4 and, in the presence of soluble CD4, bound weakly to proteoliposomes expressing only CXCR4. The thermal stability of CD4 and CXCR4 inserted into liposomes was examined. Thermal denaturation of CXCR4 followed second-order kinetics, with an activation energy (E(a)) of 269 kJ/mol (64.3 kcal/mol) and an inactivation temperature (T(i)) of 56°C. Thermal inactivation of CD4 exhibited a reaction order of 1.3, an E(a) of 278 kJ/mol (66.5 kcal/mol), and a T(i) of 52.2°C. The second-order denaturation kinetics of CXCR4 is unusual among G protein-coupled receptors, and may result from dimeric interactions between CXCR4 molecules. CONCLUSIONS/SIGNIFICANCE: Our studies with proteoliposomes containing the native HIV-1 receptors allowed an examination of the binding of biologically important ligands and revealed the higher-order denaturation kinetics of these receptors. CD4/CXCR4-proteoliposomes may be useful for the study of virus-target cell interactions and for the identification of inhibitors