Search

An approach is presented to employ two different types of converters in bridgeless configuration for supply side power factor enhancement of the system. The isolated single‐stage electric vehicle battery charger uses two different converters in a bridgeless configuration to extract the advantages of both converters for supply‐side power factor enhancement. For the negative and positive semi‐cycles of the supply voltage, the power factor‐enhanced asymmetrical alternating current–direct current converter utilises a fourth order single‐ended primary‐inductor converter and a second order buck‐boost converter, respectively. The use of single‐ended primary‐inductor converter and buck‐boost converter in bridgeless configuration reduces the net order of the system with respect to conventional bridgeless‐single‐ended primary‐inductor converter schemes. The buck‐boost converter also needs the supply‐side filter to eradicate the unwanted harmonics in the supply current which increases the order of the system. The usage of both converters presents many benefits like input inductance of the single‐ended primary‐inductor converter can be utilised as a filtering element with a capacitor for the buck‐boost converter. The anti‐parallel diode conduction operation of both switches facilitates the elimination of extra reverse feed diodes (generally used in bridgeless schemes). The single‐stage charger itself comes with the benefit of elimination of extra stages and thus the losses associated with it. The presented charger also witnesses the elimination of the rectifier due to usage of bridgeless configuration. The isolated single‐stage electric vehicle battery charger is also garnished with electrical isolation which adds to the safety standard of the system. To attain power factor enhancement, the asymmetrical alternating current–direct current converter functions in discontinuous current conduction mode in the present work. The elimination of extra‐stages (with respect to two stage charger), a filter, a rectifier, two extra reverse‐feeding diodes, one voltage sensor, one current sensor (with respect to continuous current conduction mode), and electrical isolation not only makes the system compact and safer but also makes the system cheaper. Elaborated mathematical modelling and stability analysis of the presented alternating current–direct current converter using a pole‐zero map and bode plot have been included in the article. The prototype and MATLAB/Simulink model of isolated single‐stage electric vehicle battery charger system with discontinuous current conduction mode control has been built and results of both prototype and MATLAB/Simulink are deployed to verify isolated single‐stage electric vehicle battery charger system's performance during dynamic and steady‐state conditions. [ABSTRACT FROM AUTHOR]

Autoimmune regulator (Aire) and TGF‐β signaling play important roles in central tolerance and peripheral tolerance, respectively, by eliminating or suppressing the activity of autoreactive T cells. We previously demonstrated that dnTGFβRII mice develop a defect in peripheral tolerance and a primary biliary cholangitis (PBC)‐like disease. We hypothesized that by introducing the Aire gene to this model, we would observe a more severe PBC phenotype. Interestingly, however, we demonstrated that, while dnTGFβRII Aire−/− mice do manifest key histological and serological features of autoimmune cholangitis, they also develop mild to moderate interface hepatitis and show high levels of alanine transaminase (ALT) and antinuclear antibodies (ANA), characteristics of autoimmune hepatitis (AIH). To further understand this unique phenotype, we performed RNA sequencing (RNA‐seq) and flow cytometry to explore the functional pathways and immune cell pathways in the liver of dnTGFβRII Aire−/− mice. Our data revealed enrichments of programmed cell death pathways and predominant CD8+ T cell infiltrates. Depleting CD8+ T cells using an anti‐CD8α antibody significantly alleviated hepatic inflammation and prolonged the life span of these mice. Finally, RNA‐seq data indicated the clonal expansion of hepatic CD8+ T cells. In conclusion, these mice developed an autoreactive CD8+ T‐cell‐mediated autoimmune cholangitis with concurrent hepatitis that exhibited key histological and serological features of the AIH‐PBC overlap syndrome, representing a novel model for the study of tolerance and autoimmune liver disease. © 2023 The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Summary: Dengue virus (DENV) infection is considered one of the most important mosquito‐borne diseases. It causes a spectrum of illness that could be due to qualitative and/or quantitative difference(s) of the natural killer (NK) cell responses during acute DENV infection. This view prompted us to perform a detailed phenotypic comparative characterization of NK cell subsets from DENV‐infected patients with dengue fever (DF), patients with dengue haemorrhagic fever (DHF) and healthy controls. The activation/differentiation molecules, CD69 and CD57 and a variety of tissue homing molecules were analysed on the CD56hi CD16− and CD56lo CD16+ NK cells. Although there was no increase in the frequency of the total NK cells during DENV infection compared with the healthy individuals, there was a significant increase in the frequency of the CD56hi CD16− subset and the frequency of CD69 expression by both NK cell subsets during the febrile phase of infection. We also found an increase in the frequencies of cells expressing CD69 and CD57 in the CD56lo CD16+ subset compared with those in the CD56hi CD16− subset. Moreover, although the CD56lo CD16+ subset contained a high frequency of cells expressing skin‐homing markers, the CD56hi CD16− subset contained a high frequency of cells expressing bone marrow and lymph node trafficking markers. Interestingly, no differences of these NK cell subsets were noted in samples from patients with DF versus those with DHF. These findings suggest that activation and differentiation and the patterns of tissue homing molecules of the two major NK cell subsets are different and that these might play a critical role in the immune response against acute DENV infection. [ABSTRACT FROM AUTHOR]

Background Pertussis toxin ( PTX) blocks GPCR signaling resulting in the inhibition of chemotaxis/cell adhesion. It was reasoned that inhibition of cell trafficking may be an approach to prevent HIV/ SIV transmission. Methods In this study, PTX in HEC gel was applied to the vaginal wall of monkeys that were then challenged intravaginally with SIVmac251. Results Results of these studies showed that 2 of 4 animals were resistant to infection. Furthermore, infection was correlated with a marked increase in the plasma and cervicovaginal lavage levels of select chemokines and cytokines. Conclusions Results from this preliminary feasibility study dictate that further studies that include a larger number of animals are required to optimize this protocol and establish the efficacy of this approach. In addition, such future studies will provide important information on the role of specific chemokines that play a role in lymphocyte trafficking within the genital tract and serve as additional therapeutic targets. [ABSTRACT FROM AUTHOR]

Varying susceptibility during menstrual cycling could be a factor for S(H) IV infection risk in female rhesus macaques. We retrospectively determined vaginal SIV infection time points relative to the menstrual cycle in a group of rhesus macaques (n=11) enrolled in an HIV transmission trial. Eight of nine rhesus macaques became infected around menstruation time. [ABSTRACT FROM AUTHOR]

The article discusses various reports published within the issue, including one by W. Ian Lipkin on the impact of emerging technologies on the discovery of new infectious agents, one by Betty A. Wu-Hsieh on the primary infection model of dengue hemorrhage and demonstrates the involvement of endothelial cells and TNF alpha producing macrophages, and one by Eva Harris on the role of antibody-dependent enhancement in dengue virus infection.

Viremia is one of the features of dengue virus infection among the flaviviruses. Dengue virus infection results in a spectrum of clinical symptoms, ranging from undifferentiated flu-like illness, mild dengue fever, to dengue hemorrhagic fever (DHF)/dengue shock syndrome (DSS), a life-threatening illness. Several mechanisms have been hypothesized based primarily on data collected from post-acute clinical phase to account for DHF/DSS. Lack of a suitable animal model for DHF/DSS has hindered progress in defining the etiology of DHF/DSS. Levels of circulating dengue virus have been well-correlated to severe dengue disease. However, the cell lineage(s) serving as a primary target for the source of viremia are largely unknown. Results from in vivo and in vitro pilot studies using molecular and more advanced technologies reveal that dengue virus appears to be associated with platelets and the megakaryocytic lineage. The observation may partially explain the dysfunction of platelets observed in dengue affected patients. [ABSTRACT FROM AUTHOR]

Abstract: Aim: Peripartum cardiomyopathy (PPCM) is characterized by acute onset of heart failure of unknown aetiology. We aimed to identify mechanisms involved in initiation and progression of the disease. Methods and results: Serum markers related to cardiac function, apoptosis, oxidative stress, remodelling, inflammation and the nursing hormone prolactin were analyzed in PPCM patients and healthy controls. The kinetics of these markers were compared between patients who improved cardiac function (IMP) and those patients who did not improve (NIMP), over 6 months follow-up. All patients received ACE-inhibitors, beta-blockers and diuretics. Baseline levels of TGF-beta-1 were significantly lower, MMP-9 and VEGF were not different; all other markers were significantly higher in PPCM compared with controls. Only baseline NT-proBNP levels were higher in NIMP compared with IMP. After 6 months, NT-proBNP, oxLDL and IFN-γ were significantly lower in IMP and the decrease in oxLDL, IFN-γ and prolactin was significant in IMP but not in NIMP. Significant correlations were observed between the kinetics of NT-proBNP, oxLDL, prolactin and IFN-γ in PPCM patients. Conclusion: Baseline NT-proBNP and the failure to decrease oxLDL, IFN-γ and prolactin are associated with poor outcome in PPCM, suggesting a potential role of these factors in the pathophysiology of PPCM and for risk stratification of PPCM patients. [Copyright &y& Elsevier]

Phenotypic and functional studies of the programmed death-1 (PD-1) molecule on CD4+ and CD8+ T cells were performed on peripheral blood mononuclear cells from uninfected and simian immunodeficiency virus (SIV)-infected rhesus macaques. These data demonstrated a rapid upregulation of PD-1 expression on tetramer-positive CD8+ T cells from MamuA.01+ SIV-infected macaques upon infection. Upregulation of PD-1 on total CD8+ T cells was not detectable. In contrast, CD4+ T-cell PD-1 expression was markedly higher in total CD4+ T cells during chronic, but not acute, infection and there was a correlation between the level of PD-1 expression on naive and central memory CD4+ T cells and the levels of viral loads. Such association was emphasized further by a marked decrease of PD-1 expression on tetramer-positive CD8 T cells as well as on CD4+ T cells on longitudinal samples collected before and after the initiation of antiretroviral therapy and downregulation of viral replication in vivo. Cloning of PD-1 and its two ligands from several non-human primate species demonstrated > 95% conservation for PD-1 and PD-L2 and only about 91% homology for PD-L1. Functional studies using soluble recombinant PD-1 protein or PD-1–immunoglobulin G fusion proteins induced marked increases in the SIV-specific proliferative responses of both CD4+ and CD8+ T cells from rhesus macaques. The results of these studies serve as a foundation for future in vivo trials of the use of rMamu-PD-1 to potentially enhance and/or restore antiviral immune responses in vivo. [ABSTRACT FROM AUTHOR]

The purpose of this review is to provide an overview of the spectrum of autoimmune responses that we have so far characterized in the simian immunodeficiency virus (SIV)-infected disease susceptible rhesus macaques, the potential role of the lymphopenic state for the generation of the autoimmune response and the important new finding that such autoimmune response in fact can serve to provide both clinical benefit and clinical disease depending on the stage of the disease and the nature of the host proteins that are recognized during this process. [ABSTRACT FROM AUTHOR]

The absence of suitable mouse models has represented a major drawback in our understanding of early events leading to the development of primary biliary cirrhosis (PBC). The recent report of not one, but three mouse models, each with distinctive features resembling PBC, represents a major advance in PBC research and generates novel experimental perspectives. The dnTGFβRII mouse, the IL-2Rα–/– mouse and the NOD.c3c4 mouse are all characterized by different genetic backgrounds and modifications, nonetheless all develop characteristic lymphocytic biliary infiltrates and specific antimitochondrial antibody response. Each model reflects characteristics of PBC in association with unique phenotypic differences. These three distinct models will allow a better understanding of the specific genetics involved in breaking of tolerance and progression of disease, in association with the possible definition of novel therapeutic approaches. [ABSTRACT FROM AUTHOR]

Background Our lab has previously shown that adoptive transfer of in vitro expanded autologous purified polyclonal CD4+ T cells using anti-CD3/CD28 coated beads induced antiviral responses capable of controlling simian immunodeficiency virus (SIV) replication in vivo. Results Expansion on anti-CD3/28 coated beads was found to induce a true polyclonal expansion as CFSE labeled cells uniformly showed dilution of the dye over several days of culture, in contrast to aliquots of the same cells subjected to mitogen stimulation. Of interest was the finding that CD4+ T cells collected before and during early chronic SIV infection or AIDS stage did not show any or only modest differences in proliferative response or expansion kinetics. The reason for such excellent expansion properties was analyzed by the quantitation of telomerase activity in aliquots of expanding CD4+ T cells from sample collected at various times post-infection. First, anti-CD3/28 expanded CD4+ T cells exhibited telomerase levels 2- to 20-fold higher than the starting population of CD4+ T cells. Moreover, while telomerase activity in ex vivo tested CD4+ T cells was found to decrease following SIV infection and disease progression, anti-CD3/28 expansion appeared to restore significant levels of telomerase activity as no difference was noted in telomerase expression between CD4+ T cells expanded from samples collected before or during the chronic SIV infection. When such expanded and CFSE labeled T cells were autologously transferred to monkeys, evidence for extended survival in vivo was provided as CFSE labeled cells were detected to relatively high levels in blood and spleen at 1 week post-infection. Conclusion In summary, the data suggest that anti-CD3/28 mediated expansion of CD4+ T cells retains its immunotherapeutic potential not only during the early stages of lentiviral infection but also at more advanced stages of disease. [ABSTRACT FROM AUTHOR]

Background Our laboratory has previously shown that adoptive transfer of in vitro-expanded autologous purified polyclonal CD4+ T cells using anti-CD3/CD28-coated beads induced antiviral responses capable of controlling SIV replication in vivo. Methods As CD4+ T cells comprise several phenotypic and functional lineages, studies were carried out to optimize the in vitro culture conditions for maximal CD4+ T-cell expansion, survival and delineate the phenotype of these expanded CD4+ T cells to be linked to maximal clinical benefit. Results and Conclusions The results showed that whereas anti-monkey CD3 γ/ ℇ was able to induce T-cell proliferation and expansion in combination with antibodies against multiple co-stimulatory molecules, monkey CD3 ℇ cross reacting antibodies failed to induce proliferation of macaque CD4+ T cells. Among co-stimulatory signals, anti-CD28 stimulation was consistently superior to anti-4-1BB, CD27 or ICOS while the use of anti-CD154 failed to deliver a detectable proliferation signal. Increasing the relative anti-CD28 co-stimulatory signal relative to anti-CD3 provided a modest enhancement of expansion. Additional strategies for optimization included attempts to neutralize free radicals, enhancement of glucose uptake by T cells or addition of T-cell stimulatory cytokines. However, none of these strategies provided any detectable proliferative advantage. Addition of 10 autologous irradiated feeder cells/expanding T cell provided some enhancement of expansion; however, given the high numbers of T cell needed, this approach was deemed impractical and costly, and lower ratios of feeder to expanding T cells failed to provide such benefit. The most critical parameter for efficient expansion of purified CD4+ T cells from multiple monkeys was the optimization of space and culture conditions at culture inception. Finally, anti-CD3/28-expanded CD4+ T cells uniformly exhibited a central memory phenotype, absence of CCR5 expression, marked CXCR4 expression in vitro, low levels of caspase 3 but also of Bcl-2 expression. [ABSTRACT FROM AUTHOR]

The goal of this communication is to summarize the following-the types of autoimmune responses that have been characterized in human HIV-1 infection; the potential mechanisms that were initially thought to be the basis for such autoimmune responses; the prevalence and incidence of conventional autoimmune diseases with HIV-1 infection; the spectrum of autoimmune disorders following the institution of HAART and its associated mechanisms; the role of such autoimmunity in SIV-infected nonhuman primates; and the molecular basis for autoimmune responses, such as the role of exosomes in lentiviral disease. [ABSTRACT FROM AUTHOR]

The contribution of chronic immune stimulation on the progression of lentivirus-induced disease was evaluated in the SIVmac251 macaque model of AIDS. Following SIV inoculation, seroconversion and control of the acute viral replication phase, repeated immune stimulations with tetanus toxoid (TT), keyhole limpet hemocyanin (KLH) and allogeneic peripheral blood mononuclear cells (PBMC) were initiated in four monkeys. These animals showed a significant shortening of survival when compared with eight non-immune-stimulated control animals inoculated with the same route, dose and stock of SIVmac251 (median survival 9.5 months versus 17 months. P = 0.010). In addition, when the comparision was extended to another 22 control animals of different origin but inoculated by the same route with similar doses and stocks of SIVmac251, the difference in survival was still significant (9.5 versus 18 months, P = 0.003). This accelerated progression of symptomatic disease was not accompanied with significant increases in plasma viral loads, but suboptimal antibody responses to the immunizing antigens were noted, correlating with the length of survival. These findings may have implications for HIV-infected humans suffering from chronic infectious diseases. [ABSTRACT FROM AUTHOR]

Primary biliary cirrhosis (PBC) is an organ-specific autoimmune disease that predominantly affects women and is characterized by chronic progressive destruction of small intrahepatic bile ducts with portal inflammation and ultimately fibrosis. The serologic hallmark of PBC is the presence of antibodies to mictochondria, especially to the E2 component of the pyruvate dehydrogenase complex. The mechanisms by which (and if) such antibodies produce liver tissue injury are unknown. However, the presence of these antibodies has allowed detailed immunological definition of the antigenic epitopes, the nature of reactive autoantibodies and the characterization of T-cell responses. Several mechanisms may now be proposed regarding the immune-mediated bile duct damage in PBC, including the possible role of T-cell-mediated cytotoxicity and intracellular interaction between the IgA class of antimitochondrial antibodies and mitochondrial autoantigens. There are major questions which remain unanswered, including, of course, etiology, but also the reasons for female predominance, the absence of PBC in children, the relative inffectiveness of immunosuppressive drugs, and the specific role of mitochondrial antigens. The data so far provide suggestive evidence that PBC is a mucosal disease; this thesis provides a basis for discussion of etiology via the enterohepatic circulation of toxins and/or infection. [ABSTRACT FROM AUTHOR]

Reports on the hematopoietic response to the exogenous administration of recombinant rhesus interleukin-3 (rrIL-3) or a combination of recombinant human granulocyte colony-stimulating factor (rhG-CSF)/erythropoietin (Epo)/thrombopoietin (Tpo) at two different stages of SIV infection. Impairment of bone marrow and peripheral blood responses to both rrIL-3 and rhG-CSF administration, as compared to historic controls; Decrease in the hematopoietic reserve and the response to various cytokines.

Background and Aims Materials and Methods Results Conclusions There is increased interest in utilizing dietary interventions to alter the progression of autoimmune diseases. These efforts are driven by associations of gut microbiota/metabolites with levels of short‐chain fatty acids (SCFAs). Propionate is a key SCFA that is commonly used as a food preservative and is endogenously generated by bacterial fermentation of non‐digestible carbohydrates in the gut. A thesis has suggested that a diet rich in propionate and other SCFAs can successfully modulate autoimmunity. Herein, we investigated the effect of long‐term administration of propionylated high‐amylose resistant starches (HAMSP) on the course of murine primary biliary cholangitis.Groups of female ARE‐Del mice were fed an HAMSP diet either before or after disease onset. A detailed immunobiological analysis was performed involving autoantibodies and rigorous T‐cell phenotyping, including enumeration of T‐cell subsets in the spleen, liver, intestinal intraepithelial lymphocytes and lamina propria by flow cytometry. Histopathological scores were used to assess the frequency and severity of liver inflammation and damage to hepatocytes and bile ducts.Our results demonstrate that a long‐term propionate‐yielding diet re‐populated the T‐cell pool with decreased naïve and central memory T‐cell subsets and an increase in the effector memory T cells in mice. Similarly, long‐term HAMSP intake reduced CD4+CD8+ double‐positive T cells in intraepithelial lymphocytes and the intestinal lamina propria. Critically, HAMSP consumption led to moderate‐to‐severe hepatocellular steatosis in ARE‐Del mice, independent of the stage of autoimmune cholangitis.Our data suggest that administration of HAMSP induces both regulatory and effector T cells. Furthermore, HAMSP administration resulted in hepatocellular steatosis. Given the interest in dietary modulation of autoimmunity and because propionate is widely used as a food preservative, these data have significant implications. This study also provides new insights into the immunological and pathological effects of chronic propionate exposure. [ABSTRACT FROM AUTHOR]

Isolated intraepithelial lymphocytes (IEL) and lamina propria lymphocytes (LPL) from jejunum of SIV infected animals were examined for alterations in basal cytokine expression by RT-PCR. Remarkable changes in IFNγ and IL-10 RNA levels were observed in IEL and LPL in SIV infection while IL-4 and IL-2 RNA levels remained unaltered In addition, the CD4+ and CD8+ LPL were examined for intracellular cytokine production following mit0genic activation by flowcytometry, Both CD4+ and CD8+ T lymphocytes in intestinal mucosa retained the potential to produce IFNγ in response to mitogenic stimulation in vitro, without a remarkable change in IL-4 production. The dominant IFNγ cytokine response could be one of the major contributing factors in SIV associated enteropathy. [ABSTRACT FROM AUTHOR]

Several human CC chemokines have been shown to inhibit HIV/ SIV infection in vitro, providing the rationale for their potential use in vivo. However, because of their inherent physiological effect, such chemokines are reasoned to be of limited therapeutic value due to potential side effects. The knowledge that amino terminus modified Or deleted human RANTES retains its receptor binding properties but loses its signaling properties has provided a means to use such modified chemokines in vivo for possible therapeutic benefits. In efforts to test the efficacy of such modified chemokines, our laboratory has cloned, sequenced, and prepared recombinant forms Of wild-type (wt) and amino-terminus modified rhesus macaque chemokines MIP-1α, MIP1β, and RANTES. These Sets of Chemokines were tested for their potential to inhibit SIV infection and induce signaling. The data showed that whereas wt chemokines retained both virus inhibitory and signaling functions, corresponding amino-terminus modified chemokines only showed vitals inhibitory effects without detectable signaling effects. Such reagents will be valuable for evaluation of their therapeutic potential in vivo, either alone or as adjuncts to other chemotherapeutic drugs. [ABSTRACT FROM AUTHOR]