The role of CD8 T cells in controlling Mycobacterium tuberculosis infections in mice was confirmed by comparing the levels of growth of the organism in control, major histocompatibility complex class II knockout, and athymic mice and by transferring T-cell populations into athymic mice. By using donor mice which were incapable of making gamma interferon (IFN-γ), it was shown that IFN-γ production was essential for CD8 cell mediation of protective immunity against M. tuberculosis.

Excipients, considered “inactive ingredients,” are a major component of formulated drugs and play key roles in their pharmacokinetics. Despite their pervasiveness, whether they are active on any targets has not been systematically explored. We computed the likelihood that approved excipients would bind to molecular targets. Testing in vitro revealed 25 excipient activities, ranging from low-nanomolar to high-micromolar concentration. Another 109 activities were identified by testing against clinical safety targets. In cellular models, five excipients had fingerprints predictive of system-level toxicity. Exposures of seven excipients were investigated, and in certain populations, two of these may reach levels of in vitro target potency, including brain and gut exposure of thimerosal and its major metabolite, which had dopamine D3 receptor dissociation constant Kd values of 320 and 210 nM, respectively. Although most excipients deserve their status as inert, many approved excipients may directly modulate physiologically relevant targets.

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Cationic liposomes enhanced the rate of transduction of target cells with retroviral vectors. The greatest effect was seen with the formulation DC-Chol/DOPE, which gave a 20-fold increase in initial transduction rate. This allowed an efficiency of transduction after brief exposure of target cells to virus plus liposome that could be achieved only after extensive exposure to virus alone. Enhancement with DC-Chol/DOPE was optimal when stable virion-liposome complexes were preformed. The transduction rate for complexed virus, as for virus used alone or with the polycation Polybrene, showed first-order dependence on virus concentration. Cationic liposomes, but not Polybrene, were able to mediate envelope-independent transduction, but optimal efficiency required envelope-receptor interaction. When virus complexed with DC-Chol/DOPE was used to transduce human mesothelioma xenografts, transduction was enhanced four- to fivefold compared to that for virus alone. Since the efficacy of gene therapy is dependent on the number of cells modified, which is in turn dependent upon the balance between transduction and biological clearance of the vector, the ability of cationic liposomes to form stable complexes with retroviral vectors and enhance their rate of infection is likely to be important for in vivo application.

Snml'rlaryThe gene encoding a highly immunogenic mycobacterial heat-shock protein (hsp65) was transfected into the murine macrophage tumor cell line J774. The resulting hsp65-expressing cells 0774-hsp65) were no longer able to produce tumors in syngeneic mice. This loss of tumorigenicity was not mediated through T cells since the transfected cells did not produce tumors in atbymic mice. If mice are :first immunized with the J774-hsp65 cells and then challenged with the parent J774 cells, the mice do not develop tumors, indicating that the presence of the mycobacterial hsp65 protein greatly enhances immunological recognition of unique structures expressed by the parent tumor cells. This is further confirmed by the demonstration in vitro of T cells derived from J774-hsp65-immunized mice that are cytotoxic for the parent J774 cells. The results provide the basis for a novel strategy for enhancing the immunological recognition and decreasing the tumorigenicity of transformed cells.

Puberty represents an independent risk of the development of microalbuminuria in diabetes. This findings suggests that the endocrine changes of puberty lead to an accelerated process of early kidney damage in diabetes. In pediatric diabetes care, screening for microalbuminuria is needed soon after the onset of puberty.

In intensively used landscapes biodiversity is often restricted to fragmented habitats. Exploring the biodiversity potential of habitat fragments is essential in order to reveal their complementary role in maintaining landscape-scale biodiversity. We investigated the conservation potential of dry grassland fragments in the Great Hungarian Plain, i.e. patch-like habitats on ancient burial mounds and linear-shaped habitats in verges, and compared them to continuous grasslands. We focused on plant taxonomic diversity, species richness of specialists, generalists and weeds, and the phylogenetic diversity conserved in the habitats. Verges meshing the landscape are characterised by a small core area and high level of disturbance. Their species pool was more similar to grasslands than mounds due to the lack of dispersal limitations. They held high species richness of weeds and generalists and only few specialists. Verges preserved only a small proportion of the evolutionary history of specialists, which were evenly distributed between the clades. Isolated mounds are characterised by a small area, a high level of environmental heterogeneity, and a low level of disturbance. Steep slopes of species accumulation curves suggest that high environmental heterogeneity likely contributes to the high species richness of specialists on mounds. Mounds preserved the same amount of phylogenetic diversity represented by the branch-lengths as grasslands. Abundance-weighted evolutionary distinctiveness of specialists was more clustered in these habitats due to the special habitat conditions. For the protection of specialists in transformed landscapes it is essential to focus efforts on preserving both patch-like and linear grassland fragments containing additional components of biodiversity.

Incubation of bovine neutrophils with antigen-stimulated mononuclear cell supernatant (lymphokine) caused an inhibition of neutrophil migration and an enhancement of the neutrophils' ability to adhere to plastic, reduce nitroblue tetrazolium, ingest Staphylococcus aureus, and mediate antibody-dependent cell-mediated cytotoxicity (ADCC) against chicken erythrocytes. Lymphokine-treated neutrophils also became cytotoxic for chicken, turkey and human erythrocytes in the absence of specific antibody but were not cytotoxic for bovine erythrocytes. The increase in antibody-independent neutrophil cytotoxicity (AINC) was not due to direct cytotoxic activity of the lymphokine or to a stable, soluble mediator released by the neutrophils. Enhancement of AINC, but not ADCC, required RNA and protein synthesis by the neutrophil. These results indicate that several aspects of neutrophil function can be altered by products secreted by antigen-stimulated mononuclear cells and that neutrophils can be induced to recognize and to have increased cytotoxic activity toward heterologous erythrocytes.