HIV-1 Tat suppresses gp120-specific T cell response in IL-10-dependent manner

A large number of multicomponent vaccine candidates are currently in clinical evaluation, many of which also include the HIV-1 Tat protein, an important regulatory protein of the virus. However, whether Tat, a known immune effector molecule with a well-conserved sequence among different HIV subtypes, affects the immune response to a coimmunogen is not well understood. In this study, using a bicistronic vector expressing both gp120 and Tat, we have analyzed the role of Tat in elicitation of the gp120-specific immune response. The T cell responses to gp120 were greatly diminished in mice coimmunized with Tat as compared with mice immunized with gp120 alone. This immunosuppressive activity of Tat was not confined to viral Ag only because it also suppressed the immune response of unrelated Ag. Analysis of the cytokine profile suggests that Tat induces IL-10 and since IL-10 has been demonstrated to have appreciable T cell inhibitory activity, it is plausible that IL-10 could be responsible for Tat-mediated immunosuppression. Finally, the immunosuppressive effect of Tat was not observed in IL-10-deficient mice, confirming the role of IL-10 in Tat-mediated immunosuppression. Thus, our results demonstrate for the first time that the immunosuppressive effect of Tat is mediated through IL-10 and suggests that Tat-induced IL-10-mediated immune suppression seems to cripple immune surveillance during HIV-1 infection.     

Controlled Comparison of Tetracycline and Furazolidone in Cholera

A controlled comparison of furazolidone and tetracycline in the treatment of cholera indicates that, in either dosage used, furazolidone reduced total stool volume by 50% and duration of diarrhoea by 40%. These results are comparable to those achieved with tetracycline, which was given in presently recommended dosage. Both furazolidone and tetracycline significantly reduced the rate of stool output within 18 to 24 hours of starting antibiotic treatment. Furazolidone was significantly less effective than tetracycline in rapidly and consistently terminating vibrio excretion. One convalescent carrier of cholera vibrios was identified among control patients; none was identified among patients treated with either tetracycline or furazolidone. All Vibrio cholerae strains tested were sensitive to tetracycline and furazolidone, but larger concentrations of the latter were required to achieve inhibition of growth. It is concluded that tetracycline remains the antibiotic of choice in cholera but that furazolidone would be a useful adjunct to cholera therapy when tetracycline is unobtainable or if strains of V. cholerae with clinically significant resistance to tetracycline should be encountered.     

Energy-minimized structures and MO levels of catalysts related to [RuO(hpsd)(bpy)] that competently hydroxylate benzene (hpsd(2-)=(2-hydroxyphenyl)salicyldiminato)

Two series of complexes with formal oxidation state assignments of {Ru^V(O²⁻)} have been examined by molecular mechanics and molecular orbital methods at the level of PM3 calculations in order to assess the origin of differences in the activity of these complexes in the conversion of benzene to phenol by oxygen transfer. The first series includes complexes of general formula [RuO(hpsd)(XY)]ⁿ⁺ with hpsd²⁻ (also known in the literature as amp²⁻)=(2-hydroxyphenyl)salicyldiminato; XY=bpy(2,2^′-bipyridine) and other py-X, wherein the second pyridyl group of bpy is changed to X=-CH₂N(CH₃)₂ (stronger σ-donor X), -CH₂P(CH₃)₂ (better π-acceptor X), -CO₂ ⁻ (weak π-donor X), -CH₂S⁻ (strong π-donor X), and -CH₂C(CH₃)₂ ⁻ (very strong σ-donor X).A second series of complexes, [RuO(TDL)(bpy)]ⁿ⁺ was also studied with TDL=(tridentate ligand) of the parent hpsd²⁻ (or amp²⁻); cpsd²⁻=(N-(2-carboxyphenyl)salicylaldiminato); cppc⁻=(N-2-carboxyphenylpyridine-2-carboxaldiminato); and hppc⁻=(2-hydroxyphenyl)2-pyridylcarboxaldiminato (or app⁻). Experimentally, the activity order based upon the percentage yields of oxygenated products for [RuO(TDL)(bpy)]ⁿ⁺ is as follows for TDL’s=hpsd²⁻ (91%) > cppc⁻ (87%) > cpsd²⁻ (84%) > hppc⁻ (80%). The rates approach toward saturation in reactivity as a function of the fractional positive charge on the apical O center: cppc⁻ (0.233) > hpsd²⁻ (0.166) > cpsd²⁻ (0.105) > hppc⁻ (0.041). The reactivity order follows chelate ring strain influences of the TDL, with 5,6-membered chelate rings; hpsd²⁻ and cppc⁻ > 6,6; cpsd²⁻ > 5,5; hppc⁻.It was determined that the general structures of these complexes are best described as pentagonal pyramidal (rather than pseudo-octahedral) with the RuO unit apical, the three donors of hpsd²⁻, cpsd²⁻, cppc⁻ or hppc⁻, and the two donors of XY ligands adopting a waffled arrangement around the Ru center as the remaining donors of the pentagonal set. The donor most trans to the apical RuO is approximately at 140°, rather than 180°. Ligands such as hpsd²⁻ (amp²⁻) are not retained in a single planar array, but rather with one of the aromatic donors turned upward to shield the approach of the RuO unit from one side. The ligand series [RuO(hpsd)(XY)]⁺ averages angles between adjacent atoms of the pentagonal set of 75.4° instead of a theoretical 72.0°; angles between the apical RuO and adjacent donors average 111° but with wide deviations (±30°) depending upon the donors of the TDL.Small changes in the donor atom positions, and in the capability of the “trans” donor’s σ-donor strength, and whether it is a π-acceptor or a π-donor, modulate the degree of mixing of ligand orbitals and the LUMO/SOMO energy gap which influences reactivity. The presence of a π-acceptor ligand provides the most destabilization of Ru-O π bonding, and this appears to be the best way to increase the activity of these catalysts toward oxidation of C₆H₆ to C₆H₅OH. Also, implicated in the activity of the catalysts is the need for two non-innocent phenolate donors that raise the energy of orbitals on the apical O atom. This increases the oxenoid character of the terminal O, and makes the insertion into a C-H bond more favored.     

On G-Efficiency of some Second Order Rotatable Designs

The effect of adding central points to a given design on the G-efficiency has been examined for certain classes of second order rotatable designs.