We estimated the size-resolved particle deposition rates for the ultrafine and submicrometer particles using a nonlinear regression method with unknown particle background concentrations during nonsourced period following a controlled sourced period in a well-mixed residential environment. A dynamic adjustment method in conjunction with the constant injection of tracer gas was used to maintain the air exchange rate at three target levels across the range of 0.61-1.24 air change per hour (ACH). Particle deposition was found to be highly size dependent with rates ranging from 0.68 ± 0.10 to 5.03 ± 0.20 h(-1) (mean ± s.e.). Our findings also suggest that the effect of air exchange on the particle deposition under enhanced air mixing was relatively small when compared to both the strong influence of size-dependent deposition mechanisms and the effects of mechanical air mixing by fans. Nonetheless, the significant association between air exchange and particle deposition rates for a few size categories indicated potential influence of air exchange on particle deposition. In the future, the proposed approach can be used to explore the separate or composite effects between air exchange and air mixing on particle deposition rates, which will contribute to improved assessment of human exposure to ultrafine and submicrometer particles.
This study proposes a numerical modeling method for the indoor environment with ceiling fans and upper-room ultraviolet germicidal irradiation (UR-UVGI) fixtures. The numerical modeling deployed steady-state Computational Fluid Dynamics (CFD) with a rotating reference frame to simulate the rotation of fan blades. CFD was validated with experimental data of velocity field and fraction of microorganism remaining at the exhaust diffuser. The fraction of microorganism remaining represented the ratio of the concentration of airborne microorganisms measured with UVGI turned on to the one measured with UVGI turned off. According to the validation results, the CFD model correctly reproduced the air movement induced by the rotation of ceiling fan. When the ambient ventilation rate was 2 ACH (air changes per hour) or 6 ACH, the CFD model accurately predicted the average vertical speeds in the section 2.44 m above the floor with the errors less than 10%, regardless of the ceiling fan's rotational direction or speed. In addition, the simulation results showed that the fraction of microorganism remaining increased with the ambient air exchange rate when the fan blew air downward with a rotational speed as high as 235 rpm, which corresponded with the experimental results. Furthermore, the simulation results accurately predicted the fraction of microorganism remaining when the ambient air exchange rate was 2 ACH. We conclude that this novel numerical model can reproduce the effects of ceiling fans and UR-UVGI fixtures on indoor environment, and should aid in the investigation of the impact of ceiling fans on UR-UVGI disinfection efficacy.
This study investigated the disinfection efficacy of the upper-room ultraviolet germicidal irradiation (UR-UVGI) system with ceiling fans. The investigation used the steady-state computational fluid dynamics (CFD) simulations to solve the rotation of ceiling fan with a rotating reference frame. Two ambient air exchange rates, 2 and 6 air changes per hour (ACH), and four downward fan rotational speeds, 0, 80, 150 and 235 rpm were considered. In addition, the passive scalar concentration simulations incorporated ultraviolet (UV) dose by two methods: one based on the total exposure time and average UV fluence rate, and another based on SVE3* (New Scale for Ventilation Efficiency 3), originally defined to evaluate the mean age of the air from an air supply opening. Overall, the CFD results enabled the evaluation of UR-UVGI disinfection efficacy using different indices, including the fraction of remaining microorganisms, equivalent air exchange rate, UR-UVGI effectiveness and tuberculosis infection probability by the Wells-Riley equation. The results indicated that air exchange rate was the decisive factor for determining UR-UVGI performance in disinfecting indoor air. Using a ceiling fan could also improve the performance in general. Furthermore, the results clarified the mechanism for the ceiling fan to influence UR-UVGI disinfection efficacy.
Recombinant immunotoxins, consisting of single-chain variable fragments (scFv) genetically fused to polypeptide toxins, represent potentially effective candidates for cancer therapeutics. We evaluated the affinity of various anti-Her2/neu scFv fused to recombinant gelonin (rGel) and its effect on antitumor efficacy and off-target toxicity. A series of rGel-based immunotoxins were created from the human anti-Her2/neu scFv C6.5 and various affinity mutants (designated ML3-9, MH3-B1, and B1D3) with affinities ranging from 10(-8) to 10(-11) mol/L. Against Her2/neu-overexpressing tumor cells, immunotoxins with increasing affinity displayed improved internalization and enhanced autophagic cytotoxicity. Targeting indices were highest for the highest affinity B1D3/rGel construct. However, the addition of free Her2/neu extracellular domain (ECD) significantly reduced the cytotoxicity of B1D3/rGel because of immune complex formation. In contrast, ECD addition had little impact on the lower affinity constructs in vitro. In vivo studies against established BT474 M1 xenografts showed growth suppression by all immunotoxins. Surprisingly, therapy with the B1D3-rGel induced significant liver toxicity because of immune complex formation with shed Her2/neu antigen in circulation. The MH3-B1/rGel construct with intermediate affinity showed effective tumor growth inhibition without inducing hepatotoxicity or complex formation. These findings show that while high-affinity constructs can be potent antitumor agents, they may also be associated with mistargeting through the facile formation of complexes with soluble antigen leading to significant off-target toxicity. Constructs composed of intermediate-affinity antibodies are also potent agents that are more resistant to immune complex formation. Therefore, affinity is an exceptionally important consideration when evaluating the design and efficacy of targeted therapeutics.
Antibody drugs are widely used in cancer therapy, but conditions to maximize tumor penetration and efficacy have yet to be fully elucidated. In this study, we investigated the impact of antibody binding affinity on tumor targeting and penetration with affinity variants that recognize the same epitope. Specifically, we compared four derivatives of the C6.5 monoclonal antibody (mAb), which recognizes the same HER2 epitope (monovalent K(D) values ranging from 270 to 0.56 nmol/L). Moderate affinity was associated with the highest tumor accumulation at 24 and 120 hours after intravenous injection, whereas high affinity was found to produce the lowest tumor accumulation. Highest affinity mAbs were confined to the perivascular space of tumors with an average penetration of 20.4 ± 7.5 ?m from tumor blood vessels. Conversely, lowest affinity mAbs exhibited a broader distribution pattern with an average penetration of 84.8 ± 12.8 ?m. In vitro internalization assays revealed that antibody internalization and catabolism generally increased with affinity, plateauing once the rate of HER2 internalization exceeded the rate of antibody dissociation. Effects of internalization and catabolism on tumor targeting were further examined using antibodies of moderate (C6.5) or high-affinity (trastuzumab), labeled with residualizing ((111)In-labeled) or nonresidualizing ((125)I-labeled) radioisotopes. Significant amounts of antibody of both affinities were degraded by tumors in vivo. Furthermore, moderate- to high-affinity mAbs targeting the same HER2 epitope with monovalent affinity above 23 nmol/L had equal tumor accumulation of residualizing radiolabel over 120 hours. Results indicated equal tumor exposure, suggesting that mAb penetration and retention in tumors reflected affinity-based differences in tumor catabolism. Together, these results suggest that high-density, rapidly internalizing antigens subject high-affinity antibodies to greater internalization and degradation, thereby limiting their penetration of tumors. In contrast, lower-affinity antibodies penetrate tumors more effectively when rates of antibody-antigen dissociation are higher than those of antigen internalization. Together, our findings offer insights into how to optimize the ability of therapeutic antibodies to penetrate tumors.
GATA-3 and c-Myb are core elements of a transcriptionally active complex essential for human Th2 cell development and maintenance. We report herein mechanistic details concerning the role of these transcription factors in human peripheral blood Th2 cell development. Silencing c-Myb in normal human naive CD4(+) cells under Th2 cell-promoting conditions blocked up-regulation of GATA-3 and interleukin-4, and in effector/memory CD4(+) T cells, decreased expression of GATA-3 and Th2 cytokines. In primary T cells, c-Myb allows GATA-3 to autoactivate its own expression, an event that requires the direct interaction of c-Myb and GATA-3 on their respective binding sites in promoter of GATA-3. Immunoprecipitation revealed that the c-Myb/GATA-3 complex contained Menin and mixed lineage leukemia (MLL). MLL recruitment into the c-Myb-GATA-3-Menin complex was associated with the formation Th2 memory cells. That MLL-driven epigenetic changes were mechanistically important for this transition was suggested by the fact that silencing c-Myb significantly decreased the methylation of histone H3K4 and the acetylation of histone H3K9 at the GATA-3 locus in developing Th2 and CD4(+) effector/memory cells. Therefore, c-Myb, GATA-3, and Menin form a core transcription complex that regulates GATA-3 expression and, with the recruitment of MLL, Th2 cell maturation in primary human peripheral blood T cells.
Influenza virus has been found to persist in the environment for hours to days, allowing for secondary transmission of influenza via inanimate objects known as fomites. We evaluated the efficacy of heat and moisture for the decontamination of surfaces for the purpose of preventing of the spread of influenza. Aqueous suspensions of influenza A virus were deposited onto stainless steel coupons, allowed to dry under ambient conditions, and exposed to temperatures of 55 degrees C, 60 degrees C, or 65 degrees C and relative humidity (RH) of 25%, 50%, or 75% for up to 1 h. Quantitative virus assays were performed on the solution used to wash the viruses from these coupons, and results were compared with the solution used to wash coupons treated similarly but left under ambient conditions. Inactivation of influenza virus on surfaces increased with increasing temperature, RH, and exposure time. Reductions of greater than 5 logs of influenza virus on surfaces were achieved at temperatures of 60 and 65 degrees C, exposure times of 30 and 60 min, and RH of 50 and 75%. Our data also suggest that absolute humidity is a better predictor of surface inactivation than RH and allows the prediction of survival using two parameters rather than three. Modest amounts of heat and adequate moisture can provide effective disinfection of surfaces while not harming surfaces, electrical systems, or mechanical components, leaving no harmful residues behind after treatment and requiring a relatively short amount of time.
Many factors contribute to successful tumor targeting by antibodies. Besides properties of the tumor tissue and general antibody pharmacology, a relationship exists between an antibody and its antigen that can shape penetration, catabolism, specificity, and efficacy. The affinity and avidity of the binding interactions play critical roles in these dynamics. In this work, we review the principles that guide models predicting tumor penetration and cellular internalization while providing a critical overview of studies aimed at experimentally determining the specific role of affinity and avidity in these processes. One should gain the perspective that binding affinity can, in part, dictate the localization of antibodies in tumors, leading to high concentrations in the perivascular space or low concentrations diffused throughout the tumor. These patterns can be simply due to the diminution of available dose by binding antigen and are complicated by internalization and degradation stemming from slow rates of dissociation. As opposed to the trend of simply increasing affinity to increase efficacy, novel strategies that increase avidity and broaden specificity have made significant progress in tumor targeting.
Surfaces in congregate settings, such as vehicles used for mass transportation, can become contaminated with infectious microorganisms and facilitate disease transmission. We disinfected surfaces contaminated with H1N1 influenza viruses using hydrogen peroxide (HP) vapor at concentrations below 100 ppm and triethylene glycol (TEG)-saturated air containing 2 ppm of TEG at 25 degrees C.
The person-to-person transmission of influenza virus, especially in the event of a pandemic caused by a highly virulent strain of influenza, such as H5N1 avian influenza, is of great concern due to widespread mortality and morbidity. The consequences of seasonal influenza are also substantial. Because airborne transmission appears to play a role in the spread of influenza, public health interventions should focus on preventing or interrupting this process. Air disinfection via upper-room 254-nm germicidal UV (UV-C) light in public buildings may be able to reduce influenza transmission via the airborne route. We characterized the susceptibility of influenza A virus (H1N1, PR-8) aerosols to UV-C light using a benchtop chamber equipped with a UVC exposure window. We evaluated virus susceptibility to UV-C doses ranging from 4 to 12 J/m(2) at three relative humidity levels (25, 50, and 75%). Our data show that the Z values (susceptibility factors) were higher (more susceptible) to UV-C than what has been reported previously. Furthermore, dose-response plots showed that influenza virus susceptibility increases with decreasing relative humidity. This work provides an essential scientific basis for designing and utilizing effective upper-room UV-C light installations for the prevention of the airborne transmission of influenza by characterizing its susceptibility to UV-C.
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