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Abstract: 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 (MIC) 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 exhibit signals of granulocyte dysfunction, suppressed antigen presentation, and deviated lymphocyte polarization. In contrast, patients with resolving bacteremia 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 persistent versus resolving bacteremia 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.

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.

BackgroundCytomegalovirus (CMV) infection, either de novo or as reactivation after allotransplantation and chronic immunosuppression, is recognized to cause detrimental alloimmune effects, inclusive of higher susceptibility to graft rejection and substantive impact on chronic graft injury and reduced transplant survival. To obtain further insights into the evolution and pathogenesis of CMV infection in an immunocompromised host we evaluated changes in the circulating host proteome serially, before and after transplantation, and during and after CMV DNA replication (DNAemia), as measured by quantitative polymerase chain reaction (QPCR).MethodsLC-MS-based proteomics was conducted on 168 serially banked plasma samples, from 62 propensity score-matched kidney transplant recipients. Patients were stratified by CMV replication status into 31 with CMV DNAemia and 31 without CMV DNAemia. Patients had blood samples drawn at protocol times of 3- and 12-months post-transplant. Additionally, blood samples were also drawn before and 1 week and 1 month after detection of CMV DNAemia. Plasma proteins were analyzed using an LCMS 8060 triple quadrupole mass spectrometer. Further, public transcriptomic data on time matched PBMCs samples from the same patients was utilized to evaluate integrative pathways. Data analysis was conducted using R and Limma.ResultsSamples were segregated based on their proteomic profiles with respect to their CMV Dnaemia status. A subset of 17 plasma proteins was observed to predict the onset of CMV at 3 months post-transplant enriching platelet degranulation (FDR, 4.83E-06), acute inflammatory response (FDR, 0.0018), blood coagulation (FDR, 0.0018) pathways. An increase in many immune complex proteins were observed at CMV infection. Prior to DNAemia the plasma proteome showed changes in the anti-inflammatory adipokine vaspin (SERPINA12), copper binding protein ceruloplasmin (CP), complement activation (FDR = 0.03), and proteins enriched in the humoral (FDR = 0.01) and innate immune responses (FDR = 0.01).ConclusionPlasma proteomic and transcriptional perturbations impacting humoral and innate immune pathways are observed during CMV infection and provide biomarkers for CMV disease prediction and resolution. Further studies to understand the clinical impact of these pathways can help in the formulation of different types and duration of anti-viral therapies for the management of CMV infection in the immunocompromised host.

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28-CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28-CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

In the present study, lead-modified bismuth borovanadate glasses were synthesized using the conventional melt-quench technique, maintaining a fixed composition of (50 − x)V2O5–40B2O3–10Bi2O3–xPbO, where x ranged from 5 to 25 mol% in 5 mol% increments. To confirm the amorphous nature of the samples, X-ray diffraction was utilized. Several physical properties, including density (ρg) (3.55 to 4.41 g/cm3), molar volume (Vm) (47.21 to 39.83 cm3/mol), crystalline volume (Vc) (42.09 to 35.94 cm3/mol), and oxygen packing density (OPD) (80.49 to 75.32 g-atom/l), were examined and found to exhibit composition-dependent variations. Additionally, various other parameters were determined, including interionic distance (Ri) (1.16 to 0.65 cm−1), lead yield field (F) (0.38 to 1.21 cm−2), concentrations of Pb2+ ions (N) (ranging from 0.64 to 3.78 ions/cm3), and Polaron radius (Rp) (ranging from 4.68 to 2.60 cm−1). The analysis of DSC thermograms revealed a positive correlation between the concentration of lead oxide and the glass transition temperature (Tg), which varied from 254 to 295 ºC. This suggests an improvement in the thermal stability of the glass system with increasing lead oxide content. Structural investigations using infrared and Raman spectroscopy indicated that V2O5 served a dual role as a network former (with VO5 units) and as a modifier (with VO4 units). The presence of PbO and Bi2O3 as modifiers facilitated the transformation of BO3 units into BO4 units and the formation of diborovanadate ([B2V2O9]2−) groups and strong B–O–V linkages. The optical energy band gap (Eopt), determined through UV–visible spectroscopy, showed a consistent increase with the progressive incorporation of PbO. Both direct allowed (1.986 to 2.392 eV) and indirect allowed (1.582 to 2.087 eV) band gaps exhibited this rising trend. Furthermore, the prepared glasses demonstrated a high level of optical basicity (1.182 to 1.168), electronic polarizability (3.419 to 3.327) of oxide ions, third-order non-linear optical susceptibility (0.141 to 0.063 × 10–10 esu), and metallization criterion (0.281 to 0.323). These results suggest that the glasses prepared in this study have the potential for use in non-linear optical applications. [ABSTRACT FROM AUTHOR]

The goal of the current work is to identify the structural, magnetic, and optical properties of Gd-doped SnO2 nanoparticles and their potential use in the treatment of water contaminated with dye. These Gd-doped SnO2 (Gd = 0%, 0.5%, 1.5%, 3%, 5%) samples were prepared by the cost-effective sol–gel approach. XRD & FTIR were used to study structural properties and to confirm that the synthesized samples have single-phase crystalline nature. Using XRD Crystallite size have been calculated and found to be in the range 12.14–9.60 nm. Particle size obtained from HRTEM lying in the range 15.94–9.86 nm which was in well agreement with XRD. Raman, PL and XPS spectroscopy were utilized to investigate defects/oxygen vacancies in the lattice. Magnetic investigations indicate that the magnetic character of synthesized samples with maximum magnetization3.95 × 10–3 emu/g for Gd 5%. UV-DRS further showed that the band gap was reduced up to 5% Gd (Eg = 3.68 eV) in comparison to pure SnO2 (Eg = 3.81 eV) due to the formation of vacancy defects. In comparison to pure SnO2, Gd-doped SnO2 (Gd 5%) was found to have a maximum photodegradation efficiency of 95.64% in 60 min under UV irradiation for Rose Bengal dye. Henceforth, it can be concluded that SnO2 is a remarkable multifunctional material having uses in spintronic devices and as a catalyst in the degradation of organic dyes because of the improvement in the ferromagnetic character and enhancement in catalytic behavior on incorporation of rare-earth ions. [ABSTRACT FROM AUTHOR]

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]