Myeloid-Derived Suppressor Cells in Murine Retrovirus-Induced AIDS Inhibit T- and B-Cell Responses In Vitro That Are Used To Define the Immunodeficiency

Myeloid-derived suppressor cells (MDSCs) have been characterized in several disease settings, especially in many tumor systems. Compared to their involvement in tumor microenvironments, however, MDSCs have been less well studied in their responses to infectious disease processes, in particular to retroviruses that induce immunodeficiency. Here, we demonstrate for the first time the development of a highly immunosuppressive MDSC population that is dependent on infection by the LP-BM5 retrovirus, which causes murine acquired immunodeficiency. These MDSCs express a cell surface marker signature (CD11b Gr-1 Ly6C ) characteristic of monocyte-type MDSCs. Such MDSCs profoundly inhibit immune responsiveness by a cell dose- and substan- tially inducible nitric oxide synthase (iNOS)-dependent mechanism that is independent of arginase activity, PD-1–PD-L1 ex- pression, and interleukin 10 (IL-10) production. These MDSCs display levels of immunosuppressive function in parallel with the extent of disease in LP-BM5-infected wild-type (w.t.) versus knockout mouse strains that are differentially susceptible to patho- genesis. These MDSCs suppressed not only T-cell but also B-cell responses, which are an understudied target for MDSC inhibi- tion. The MDSC immunosuppression of B-cell responses was confirmed by the use of purified B responder cells, multiple B-cell stimuli, and independent assays measuring B-cell expansion. Retroviral load measurements indicated that the suppressive Ly6Glow/ Ly6C CD11b -enriched MDSC subset was positive for LP-BM5, albeit at a significantly lower level than that of non- fractionated splenocytes from LP-BM5-infected mice. These results, including the strong direct MDSC inhibition of B-cell re- sponsiveness, are novel for murine retrovirus-induced immunosuppression and, as this broadly suppressive function mirrors that of the LP-BM5-induced disease syndrome, support a possible pathogenic effector role for these retrovirus-induced MDSCs

Adoptive Transfer of Polyclonal and Cloned Cytolytic T Lymphocytes (CTL) Specific for Mouse AIDS-associated Tumors is Effective in Preserving CTL Responses: A Measure of Protection Against LP-BM5 Retrovirus-induced Immunodeficiency.

Cytolytic T lymphocytes (CTL) can be raised against C57BL/6 B-cell lymphomas from mice with LP-BM5 murine leukemia virus-induced AIDS (MAIDS). Adoptive transfer of polyclonal anti-MAIDS tumor CTL or two CTL clones specific for the B6-1710 MAIDS lymphoma caused preservation of major histocompatibility complex-restricted and allogeneic CTL responses, which may be interpreted as indices of protection from LP-BM5 murine leukemia virus-induced immunodeficiency

Selective Involvement of the Checkpoint Regulator VISTA in Suppression of B-Cell, but Not T-Cell, Responsiveness by Monocytic Myeloid-Derived Suppressor Cells from Mice Infected with an Immunodeficiency-Causing Retrovirus

Inhibition of T-cell responses in tumor microenvironments by myeloid-derived suppressor cells (MDSCs) is widely accepted. We demonstrated augmentation of monocytic MDSCs whose suppression of not only T-cell, but also B-cell, responsiveness paralleled the immunodeficiency during LP-BM5 retrovirus infection. MDSCs inhibited T cells by inducible nitric oxide synthase (iNOS)/nitric oxide (NO), but uniquely, inhibition of B cells was ~50% dependent each on iNOS/NO and the MDSC-expressed negative-checkpoint regulator VISTA. Blockade with a combination of iNOS/NO and VISTA caused additive or synergistic abrogation of MDSC-mediated suppression of B-cell responsiveness

The CD154/CD40 Interaction Required for Retrovirus-Induced Murine Immunodeficiency Syndrome Is Not Mediated by Upregulation of the CD80/CD86 Costimulatory Molecules

C57BL/6 (B6) mice infected with LP-BM5 retroviruses develop disease, including an immunodeficiency similar to AIDS. This disease, murine AIDS (MAIDS), is inhibited by in vivo anti-CD154 monoclonal antibody treatment. The similar levels of insusceptibility of CD40−/− and CD154−/− B6 mice indicate that CD154/CD40 molecular interactions are required for MAIDS. CD4+ T and B cells, respectively, provide the CD154 and CD40 expression needed for MAIDS induction. Here, the required CD154/CD40 interaction is shown to be independent of CD80 and CD86 expression: CD80/CD86−/− B6 mice develop MAIDS after LP-BM5 infection

Cytolytic T Lymphocytes Specific for Tumors and Infected Cells from Mice with a Retrovirus-induced Immunodeficiency Syndrome.

LP-BM5 retrovirus complex-infected C57BL/6 mice develop immunodeficiency, somewhat analogous to AIDS, termed murine AIDS (MAIDS). After secondary stimulation with syngeneic B-cell lymphomas from LP-BM5-infected mice, C57BL/6 mice produced vigorous CD8+ cytotoxic T lymphocytes specific for MAIDS-associated tumors. An anti-LP-BM5 specificity was suggested because spleen and lymph node cells from LP-BM5-infected mice served as target cells in competition assays, and cells from LP-BM5, but not ecotropic, virus-infected mice functioned as secondary in vitro stimulators to generate cytotoxic T lymphocytes to MAIDS tumors

Profiles of Coronary Artery Disease Risk in Cardiac Patients: Actual versus Perceived

PURPOSE: To describe interrelations and differences between actual vs. perceived cardiac risk in a cohort of coronary artery disease (CAD) patients. METHODS: 33 females (HT: 164 cm, WT: 80kg) and 67 males (HT: 179 cm, WT: 93kg) with documented CAD completed a questionnaire designed to assess CAD risk perception. They also underwent assessments for all ACSM risk factors. Five-point Likert scale responses to the question “Compared to other persons of your own age and sex, how would you rate your risk of ever having a heart attack?” were used to quantify CAD risk perception. To quantify actual risk, the number of ACSM risk markers for each subject was tabulated. It should be noted that, since all of the subjects had active CAD, they were all at high risk. Tabulations and Likert scale responses were compared using Chi-square analysis or Fisher’s Exact test with significance accepted at p\u3c0.05. To assess risk perception accuracy, Chi-square analysis with pre-determined expected cell count percentages was used. RESULTS: When compared to diagnosis driven expected frequencies of risk perception being higher or much higher (75% and 25% respectively), patients responses were only 30% and 11% respectively (Chi-square=19696.9, p\u3c.0001). Also, as the number of actual ACSM risk markers increased for each patient, no increase in patient risk perception was found (Chi-square=40.2, p=0.29). Factors associated with accurate perception include age, resting ECG status, and number of bypass grafts. Factors that were not accurately included in risk perception include family history, waist circumference, number and type of angioplasties, smoking, having had a heart attack, number of additional structural cardiac abnormalities present, the presence of arrhythmias, elevated blood lipids and blood glucose, and elevated systolic and diastolic blood pressures. CONCLUSION: Although substantial differences in number and type of actual cardiac risk exist in a cohort of cardiac patients, individual perception of these risks is not accurate in the majority of cases

Social networks in public and community housing: the impact on employment outcomes

Author version made available here in accordance with publisher copyright policy.This article seeks to examine some of the ways in which social networks may contribute to employment outcomes for community and public housing tenants. There is a body of literature that explores the relationship between social networks and employment outcomes, and a separate literature on the relationship between housing and social networks (which is largely concerned with homeowners). However, there has been little research that links all three aspects, especially in relation to social housing. This provides a starting point for this research, which involved interviews with housing organisation staff and focus groups with tenants in two case study areas in metropolitan Adelaide, South Australia. This article reports on the findings through examining the way in which housing tenure may affect social network formation, and considering the ways that these networks can impact on job attainment. It is concluded that, overall, those in community housing appeared to fare better, in terms of employment-conducive networks, than those in public housing. This finding is related not just to the management of the housing, but also to the broader issues of stigma, area-level deprivation and intergenerational unemployment

Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups

CITATION: Van der Westhuyzen, A. E. et al. 2020. Synthesis of pyrrolocarbazoles with N-substituted alkynyl-, alkylcyano- and alkylhydroxyl-groups. Arkivoc, v:129-147, doi:10.24820/ark.5550190.p011.412.The original publication is available at https://www.arkat-usa.orgDue to their involvement in almost all stages of cellular life, kinase biomolecular catalysts have been linked to cancer development and, thus, remain attractive drug targets for cancer therapeutics. 6-(3ꞌ-Hydroxypropyl)-, 6-(2ꞌ-hydroxyethyl)-, 6-(2ꞌ-propynyl)- and 6-(3ꞌ-propanenitrile)-pyrrolo[3,4-c]carbazole-1,3(2H,6H)-diones were synthesized as potential small molecule EGFR kinase inhibitors. The pyrrolocarbazole compounds were synthesized by way of a Diels-Alder approach involving N-alkylated 2-vinyl-1H-indole and maleimide as starting materials followed by aromatization with MnO2.Publisher's versio

Notes on Dynamics of an External Cavity Semiconductor Lasers

Dynamics of external cavity semiconductor lasers is known to be a complex and uncontrollable phenomenon. Due to the lack of experimental studies on the nature of the external cavity semiconductor lasers, there is a need to theoretically clarify laser dynamics. The stability of laser dynamics in the present paper, is analyzed through plotting the Lyapunov exponent spectra, bifurcation diagrams, phase portrait and electric field intensity time series. The analysis is preformed with respect to applied feedback phase $C_p$, feedback strength $\eta$ and the pump current of the laser. The main argument of the paper is to show that the laser dynamics can not be accounted for through simply a bifurcation diagram and single-control parameter. The comparison of the obtained results provides a very detailed picture of the qualitative changes in laser dynamics.Comment: 7 pages, 34 figure

GABB : A global dataset of alpine breeding birds and their ecological traits

Alpine ecosystems represent varied climates and vegetation structures globally, with the potential to support rich and functionally diverse avian communities. High mountain habitats and species are under significant threat from climate change and other anthropogenic factors. Yet, no global database of alpine birds exists, with most mountain systems lacking basic information on species breeding in alpine habitats, their status and trends, or potential cryptic diversity (i.e., sub-species distributions). To address these critical knowledge gaps, we combined published literature, regional monitoring schemes, and expert knowledge from often inaccessible, data-deficient mountain ranges to develop a global list of alpine breeding bird species with their associated distributions and select ecological traits. This dataset compiles alpine breeding records for 1,310 birds, representing 12.0% of extant species and covering all major mountain regions across each continent, excluding Antarctica. The Global Alpine Breeding Bird dataset (GABB) is an essential resource for research on the ecological and evolutionary factors shaping alpine communities, as well as documenting the value of these high elevation, climate-sensitive habitats for conserving biodiversity.Peer reviewe