Changes in Mood States and Biomarkers During Peginterferon and Ribavirin Treatment of Chronic Hepatitis C

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/74953/1/j.1572-0241.2008.02106.x.pd

Land systems as surrogates for biodiversity in conservation planning

Environmental surrogates (land classes) for the distribution of biodiversity are increasingly being used for conservation planning. However; data that demonstrate coincident patterns in land classes and biodiversity are limited. We ask the overall question, "Are land systems effective surrogates for the spatial configuration of biodiversity for conservation planning?" and we address three specific questions: (1) Do different land systems represent different biological assemblages.? (2) Do biological assemblages on the same land system remain similar with increasing geographic separation? and (3) Do biological assemblages on the same land system remain similar with increasing land system isolation? Vascular plants, invertebrates, and microbiota were surveyed from 24 sites in four land systems in and northwest New South Wales, Australia. Within each land system, sites were located to give a hierarchy of inter-site distances, and land systems were classified as either "low isolation" (large and continuous) or "high isolation" (small patches interspersed among other land systems). Each type of land system supported components of biodiversity either not found, or found infrequently, on other land systems, suggesting that land systems function as surrogates for biodiversity, and that conservation-area networks representing land-system diversity will also represent biological diversity. However, the majority of taxa were found on more than one land-system type, suggesting that a large proportion of the plant, arthropod, and microbial biodiversity may be characterized by widespread species with low fidelity to particular land systems. Significant relationships between geographic distance among sites and differences among assemblages were revealed for all taxa except the microbiota. Therefore, as sites on the same land system were located farther apart, the assemblages at those sites became more different. This finding strongly suggests that conservation planning based on land-system diversity should also sample the geographic range occupied by each land system. Land-system isolation was not revealed to be a significant Source of variation in assemblage composition. Our research finds support for environmental surrogates for biodiversity in conservation planning, specifically the use of land systems and similarly derived land classifications. However, the need for explicit modeling of geographic distance in conservation planning is clearly indicated

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

Interaction of melittin with a human lymphoblastoid cell line, HMy2.

We have examined the cytolytic effects of the membrane-active peptide, melittin, on a human lymphoblastoid cell line (HMy2) in the context of the use of melittin as the toxic component of an immunotoxin. The toxicity of melittin for HMy2 cells was linear over the concentration range 0.875–3.5 μM. Increased incubation times failed to result in significant cell death at concentrations of melittin below 0.875 μM. Kinetic analysis revealed that the cytolytic activity of melittin was independent of time of exposure beyond 90 min. Flow cytometric analysis of HMy2 cells incubated with FITC-labeled melittin demonstrated that the cells could incorporate up to 2.5 3 105 FITC-melittin molecules per cell with no reduction in viability. Extrapolation of this data indicates that 106 melittin molecules per cell are required for maximum cytotoxicity to HMy2 cells. Further analysis of HMy2 cells that incorporated melittin, but that remained viable, revealed that these cells were able to reduce the number of melittin molecules per cell over time. The data indicate a potential threshold value for the number of melittin molecules that may be required to be delivered to the cell surface in the form of an immunotoxin if effective selective cell death is to be achieved

Cell membrane changes induced by the cytolytic peptie, melittin, are detectable by 90 degree laser scatter

The 90 light scatter parameter of the flow cytometer was used to observe changes in the membrane of human lymphoblastoid cells (HMy2) as a result of the action of the cytolytic peptide, melittin. There was a rapid and concentrationdependent increase in 90 light scatter after incubation of the cells with melittin, with the level of 90 light scatter reaching a maximum after 2 min. Even after all the cells were killed, as determined by ethidium bromide incorporation, the 90 light scatter continued to increase. Further, the 90 light scatter changes were temper- memature dependent. The data are consistent with the formation of lipid vesicles, either attached to the cell membrane or intracellular, as confirmed by electron microscopy of cells treated with melittin. The results demonstrate the use of the flow cytometer to detect changes in the integrity of the cell membrane

Cytokines and cross-linking of sIgM augment PMA-induced activation of human leukaemic CD5+ B cells

Purified leukaemic CD5+ B cells obtained from patients with B cell chronic lymphocytic leukaemia (B-CLL) undergo activation and differentiation following in vitro stimulation with optimal concentrations of the phorbol ester PMA. This paper examines the ability of exogenous cytokines, anti-Ig antibodies, or combinations of these, to enhance or replace the activation signal provided by PMA to different populations of leukaemic B cells. Proliferation induced by PMA was enhanced 2–20-fold when the cells were co-cultured with either anti-Ig, IL-2, IL-4. IL-I3. IFN- or TNF-. Moreover, the combination of anti-Ig. PMA and any one of the above cytokines further enhanced proliferation. Anti-Ig and exogenous cytokines were also capable of inducing proliferation in leukaemic B cells cultured with a non-mitogenic concentration of PMA. When taken together with the finding that IL-2, IL-4, IL-13, IFN- and TNF-a prevent in vitro apoptosis of leukaemic CD5+ B cells, the results presented here suggest that these cytokines, in conjunction with signals delivered via sig, may play a role in the proliferation of leukaemic B cells in vivo and. consequently, the pathogenesis of B-CLL

In vivo binding of mouse IgG via polyreactive surface IgM abrogates progressive lymphocytosis in prolymphocytic leukemia

Surface IgM expressed by malignant CD5+ B-cells from patients with B-chronic lymphocytic leukemia (B-CLL) has previously been shown to bind mouse Ig in what appears to be an example of polyreactive antigen-binding activity. This report demonstrates the in vitro and in vivo binding of mouse Ig to the surface of malignant B-cells from a patient with B-cell prolymphocytic leukemia (B-PLL). In vitro studies showed that K121, a mouse monoclonal antibody, bound to the B-PLL cells via the same low-affinity binding interaction demonstrated to occur between mouse Ig and surface IgM expressed by B-CLL cells rather than in the conventional sense against a specific antigen via its antigen-binding site. With the view to using this phenomenon to target malignant B-cells, it was important to determine whether the lowaffinity interaction also occurred in vivo. Infusions of K121 totalling 286 mg were administered to a B-PLL patient over 7 days. Binding of K121 to circulating B-PLL cells was demonstrable after the administration of 36 mg of antibody and was preceded by the appearance of free antibody in the serum. Throughout the period of the infusion, the rapid rise in the peripheral blood white cell count normally observed after leukopheresis was abrogated. However, the count rose markedly after cessation of the antibody infusion in parallel with a decrease in both free and cell-bound K121. There were no observable side effects and no host immune response to either species specific or idiotypic determinants on the mouse Ig was detected. The in vivo binding of mouse Ig together with the previous in vitro data suggest the potential for a novel targeting mechanism using a region of the mouse Ig molecule to target polyreactive Ig expressed by malignant cells in B-CLL and B-PLL

Phorbol ester activates CD5+ leukaemic B cells via a T cell-independent mechanism

B cell chronic lymphocytic leukaemia (B-CLL) is characterized by the proliferation and accumulation of slgM + COS + lymphocytes that fail to progress to the final stages of B cell development. Stimulation of unfractionated PBL from three patients with B-CLL with the phorbol ester PMA and the mitogens PHA and PWM resulted in significant increases in cell proliferation. RNA synthesis and IgM secretion when compared to unstimulated cell populations. PMA was the most potent mducer of IgM secretion and this occurred irrespective of the presence of residual T cells. PMA-induced proliferation and RNA synthesis was also independent of T cells. However, in the presence of T cells, these parameters of cellular activation were enhanced during in vitro culture. Thus. the inductive ability of PMA on CD5+ CLL B cells was independent of T cells. In contrast. activation and differentiatIOn of the malignant CD5+ B cells into IgM-secreting cells following culture with mitogens did not occur in the absence of T cells

Interleukin- 10 Inhibits the In vitro proliferation of human activated leukemic CDS B-Cells

B-cell chronic lymphocytic leukemia (B-CLL) is characterised by the proliferation and accumulation of sIgM+/CDS\u27 B-cells that fail to progress to the final stages of B-cell development. Despite their developmental arrest, leukemic CD5\u27 B-cells can undergo proliferation in vitro in the presence of different activators including phorbol esters, antibodies to cell surface antigens and human cytokines. Interleukin-I0 (IL-10) has recently been found to inhibit CLL Bcell function in vitro by inducing apoptosis and down-regulating expression of bcl-2. Here, we examined the effect of IL- 10 on proliferation, RNA synthesis, immunoglobulin (IgM) secretion and viability of leukemic CDS B-cells induced by activation with the phorbol ester PMA, alone or in combination with anti-Ig. IL-I0 reduced PMA and PMA/anti-Ig induced proliferation and RNA synthesis by 50430% and 1540% respectively. Although proliferation and RNA synthesis induced by PMA/anti-Ig could be enhanced by the addition of IL-2, IL-4, IL-13, IFN-y or TNF-a, the presence of these cytokines failed to abrogate the IL-lomediated inhibition of leukemic CD5+ B-cell activation. In contrast to the effects on proliferation and RNA synthesis, IL-10 did not inhibit IgM secretion, and had only a minimal effect on the viability of activated cells. Our results indicate that IL-10 inhibits proliferation of leukemic CD5\u27 B-cells by a mechanism distinct from induction of apoptosis and support the proposal for the utilisation of IL-10 in the therapy of B-CLL