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Radiation attenuated sporozoite (RAS), a whole‐parasite vaccine approach, provides sterile protection against malaria. However, RAS immunization does not confer protection for long, and that has been correlated with the waning parasite–induced memory CD8+ T‐cell responses. Interestingly, an intermittent infectious (wild type) sporozoite challenge to the RAS‐vaccinated mice lengthened the protection period from 6 to 18 months. Herein, we have studied the changes induced by the infectious sporozoites in RAS‐induced memory CD8+ T cells for conferring lengthened protection. We observed that the infectious sporozoite challenge boosted the frequency of foreign antigen–experienced memory CD8+ T cells. In those CD8+ T cells, it has reduced the Annexin‐V reactivity, raised Bcl‐2 expression, and also more cells undergo homeostatic proliferation (Ki‐67+). It has also scaled down the frequency of Nur77 and CX3CR1 high expressing cells in those memory CD8+ T‐cell populations which we further correlated with better survival signals. [ABSTRACT FROM AUTHOR]

Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8+ T cell memory responses to LS infection. It is reported that CD8α+ dendritic cells (DCs) are involved in the induction of LS-specific CD8+ T cells following RAS or genetically attenuated parasite (GAP) vaccination. In this study, we demonstrate that CD8α+ DCs respond differently to infectious sporozoite or RAS inoculation. The higher accumulation and activation of CD8α+ DCs was seen in the liver in response to infectious sporozoite 72 h postinoculation and found to be associated with higher expression of chemokines (CCL-20 and CCL-21) and type I interferon response via toll-like receptor signaling in liver. Moreover, the infectious sporozoites were found to induce qualitative changes in terms of the increased MHCII expression as well as costimulatory molecules including CD40 on the CD8α+ DCs compared to RAS inoculation. We have also found that infectious sporozoite challenge increased CD40L-expressing CD4+ T cells, which could help CD8+ T cells in the liver through "licensing" of the antigen-presenting cells. Our results suggest that infectious sporozoite challenge to prior RAS immunized mice modulates the CD8α+ DCs, which might be shaping the fate of memory CD8+ T cells against Plasmodium LS infection. [ABSTRACT FROM AUTHOR]

A two-dimensional steady-state model of a catalytic plate reactor for diesel steam reforming is developed. Heat is provided indirectly to endothermic reforming sites by flue gas from a SOFC tail-gas burner. Two experimentally validated kinetic models on diesel reforming on platinum (Pt) catalyst were implemented for a comparative study; the model of Parmar et al., Fuel. 2010;89(6):1212-1220 for a Pt/Al2O3 and the model of Shi et al., International Journal of Hydrogen Energy. 2009;34(18):7666-7675 for a Pt/Gd-CeO2 (GDC). The kinetic models were compared for: species concentration, approach to equilibrium, gas hourly space velocity and effectiveness factor. Cocurrent flow arrangement between the reforming and the flue gas channels showed better heat transfer compared to counter-current flow arrangement. The comparison between the two kinetic models showed that different supports play significant role in the final design of a reactor. The study also determined that initial 20% of the plate reactor has high diffusion limitation suggesting to use graded catalyst to optimize the plate reactor performance. © 2016 American Institute of Chemical Engineers AIChE J, 63: 1102-1113, 2017 [ABSTRACT FROM AUTHOR]

Abstract: Kinetics of autothermal reforming (ATR) of tetradecane on Pt–Al2O3 catalyst over the temperature range 750–900°C is investigated. Experimental results obtained from NETL (US-DOE) are used for model parameter estimation and validation. Two Langmuir–Hinshelwood–Hougen–Watson (LHHW) type rate models are developed and subjected to parameter estimation and model discrimination. LHHW model in which hydrocarbon is adsorbed on the catalyst surface as alkyl intermediate species by scission of C–H bond gave physically meaningful parameters. Parameters are estimated by using generalized reduced gradient method in spreadsheet and sequential quadratic programming in Matlab. The estimated parameters for the selected model are thermodynamically consistent. The developed kinetic model could capture the experimental behavior of the process and could predict the outlet composition within 25% error. [Copyright &y& Elsevier]

Whole sporozoite vaccine (WSV) is shown to induce sterile protection that targets Plasmodium liver-stage infection. There are many underlying issues associated with induction of effective sterile protracted protection. In this study, we have addressed how the alterations in successive vaccine regimen could possibly affect the induction of sterile protection. We have demonstrated that the pattern of vaccination with RAS (radiation attenuated sporozoites) induces varying degrees of protection among B6 mice. Animals receiving four successive doses generated 100% sterile protection. However, three successive doses, though with the same parasite inoculum as four doses, could induce sterile protection in ∼50% mice. Interestingly, mice immunized with the same 3 doses, but with longer gap, could not survive the challenge. We demonstrate that degree of protection correlates with the frequencies of IFN-γ + and multifunctional (IFN-γ + CD107a + ) CD8 + T EM cells present in liver. The failure to achieve protective threshold frequency of these cells in liver might make the host more vulnerable to parasite infection during infectious sporozoite challenge. [ABSTRACT FROM AUTHOR]

Introduction: Staphylococcus aureus bacteremia (SAB) is a life-threatening infection particularly involving methicillin-resistant S. aureus (MRSA). In contrast to resolving MRSA bacteremia (RB), persistent MRSA bacteremia (PB) blood cultures remain positive despite appropriate antibiotic treatment. Host immune responses distinguishing PB vs. RB outcomes are poorly understood. Here, integrated transcriptomic, IL-10 cytokine levels, and genomic analyses sought to identify signatures differentiating PB vs. RB outcomes., Methods: Whole-blood transcriptomes of propensity-matched PB (n=28) versus RB (n=30) patients treated with vancomycin were compared in one independent training patient cohort. Gene expression (GE) modules were analyzed and prioritized relative to host IL-10 cytokine levels and DNA methyltransferase-3A ( DNMT3A ) genotype., Results: Differential expression of T and B lymphocyte gene expression early in MRSA bacteremia discriminated RB from PB outcomes. Significant increases in effector T and B cell signaling pathways correlated with RB, lower IL-10 cytokine levels and DNMT3A heterozygous A/C genotype. Importantly, a second PB and RB patient cohort analyzed in a masked manner demonstrated high predictive accuracy of differential signatures., Discussion: Collectively, the present findings indicate that human PB involves dysregulated immunity characterized by impaired T and B cell responses associated with excessive IL-10 expression in context of the DNMT3A A/A genotype. These findings reveal distinct immunologic programs in PB vs. RB outcomes, enable future studies to define mechanisms by which host and/or pathogen drive differential signatures and may accelerate prediction of PB outcomes. Such prognostic assessment of host risk could significantly enhance early anti-infective interventions to avert PB and improve patient outcomes., Competing Interests: VGF reports Grant/Research Support: MedImmune, Cerexa/Forest/Actavis/Allergan, Pfizer, Advanced Liquid Logics, Theravance, Novartis, Cubist/Merck; Medical Biosurfaces; Locus; Affinergy; Contrafect; Karius; Genentech, Regeneron, BasileaPaid Consultant: Pfizer, Novartis Galderma, Novadigm, Durata, Debiopharm, Genentech, Achaogen, Affinium, Medicines Co., Cerexa, Tetraphase, Trius, MedImmune, Bayer, Theravance, Cubist, Basilea, Affinergy, Janssen, xBiotech, Contrafect, Regeneron, Basilea, Destiny. Membership: Merck Co-Chair V710 Vaccine. Educational fees: Green Cross, Cubist, Cerexa, Durata, Theravance; Debiopharm. Royalties: UpToDate. MRY is a founder and shareholder of NovaDigm Therapeutics, Inc., which develops vaccines and immunotherapeutics targeting multi-drug-resistant pathogens, including S. aureus. He has received research funding from the U.S. National Institutes of Health and the U.S. Department of Defense and has received honoraria for educational activities or consultation from Alexion/AstraZeneca, Genentech-Roche and Horizon/Amgen. EFR is on the board of Federation of Clinical Immunology Societies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2024 Parmar, Pickering, Ahn, Rossetti, Gjertson, Ruffin, Chan, Fowler, Yeaman, Reed and MRSA Systems Immunology Group.)

Methicillin-resistant Staphylococcus aureus (MRSA) bacteremia is a common and life-threatening infection that imposes up to 30% mortality even when appropriate therapy is used. Despite in vitro efficacy determined by minimum inhibitory concentration breakpoints, antibiotics often fail to resolve these infections in vivo, resulting in persistent MRSA bacteremia. Recently, several genetic, epigenetic, and proteomic correlates of persistent outcomes have been identified. However, the extent to which single variables or their composite patterns operate as independent predictors of outcome or reflect shared underlying mechanisms of persistence is unknown. To explore this question, we employed a tensor-based integration of host transcriptional and cytokine datasets across a well-characterized cohort of patients with persistent or resolving MRSA bacteremia outcomes. This method yielded high correlative accuracy with outcomes and immunologic signatures united by transcriptomic and cytokine datasets. Results reveal that patients with persistent MRSA bacteremia (PB) exhibit signals of granulocyte dysfunction, suppressed antigen presentation, and deviated lymphocyte polarization. In contrast, patients with resolving bacteremia (RB) heterogeneously exhibit correlates of robust antigen-presenting cell trafficking and enhanced neutrophil maturation corresponding to appropriate T lymphocyte polarization and B lymphocyte response. These results suggest that transcriptional and cytokine correlates of PB vs. RB outcomes are complex and may not be disclosed by conventional modeling. In this respect, a tensor-based integration approach may help to reveal consensus molecular and cellular mechanisms and their biological interpretation., (© The Author(s) 2024. Published by Oxford University Press on behalf of National Academy of Sciences.)

Radiation attenuated sporozoite (RAS), a whole-parasite vaccine approach, provides sterile protection against malaria. However, RAS immunization does not confer protection for long, and that has been correlated with the waning parasite-induced memory CD8 + T-cell responses. Interestingly, an intermittent infectious (wild type) sporozoite challenge to the RAS-vaccinated mice lengthened the protection period from 6 to 18 months. Herein, we have studied the changes induced by the infectious sporozoites in RAS-induced memory CD8 + T cells for conferring lengthened protection. We observed that the infectious sporozoite challenge boosted the frequency of foreign antigen-experienced memory CD8 + T cells. In those CD8 + T cells, it has reduced the Annexin-V reactivity, raised Bcl-2 expression, and also more cells undergo homeostatic proliferation (Ki-67 + ). It has also scaled down the frequency of Nur77 and CX3CR1 high expressing cells in those memory CD8 + T-cell populations which we further correlated with better survival signals., (© 2021 The Societies and John Wiley & Sons Australia, Ltd.)

Immunization with radiation-attenuated sporozoites (RAS) shown to confer complete sterile protection against Plasmodia liver-stage (LS) infection that lasts about 6 to 9 months in mice. We have found that the intermittent infectious sporozoite challenge to immune mice following RAS vaccination extends the longevity of sterile protection by maintaining CD8 + T cell memory responses to LS infection. It is reported that CD8α + dendritic cells (DCs) are involved in the induction of LS-specific CD8 + T cells following RAS or genetically attenuated parasite (GAP) vaccination. In this study, we demonstrate that CD8α + DCs respond differently to infectious sporozoite or RAS inoculation. The higher accumulation and activation of CD8α + DCs was seen in the liver in response to infectious sporozoite 72 h postinoculation and found to be associated with higher expression of chemokines (CCL-20 and CCL-21) and type I interferon response via toll-like receptor signaling in liver. Moreover, the infectious sporozoites were found to induce qualitative changes in terms of the increased MHCII expression as well as costimulatory molecules including CD40 on the CD8α + DCs compared to RAS inoculation. We have also found that infectious sporozoite challenge increased CD40L-expressing CD4 + T cells, which could help CD8 + T cells in the liver through "licensing" of the antigen-presenting cells. Our results suggest that infectious sporozoite challenge to prior RAS immunized mice modulates the CD8α + DCs, which might be shaping the fate of memory CD8 + T cells against Plasmodium LS infection.