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SARS-CoV-2 emerged in late 2019 and resulted in the ongoing COVID-19 pandemic. Several animal models have been rapidly developed that recapitulate the asymptomatic to moderate disease spectrum. Now, there is a direct need for additional small animal models to study the pathogenesis of severe COVID-19 and for fast-tracked medical countermeasure development. Here, we show that transgenic mice expressing the human SARS-CoV-2 receptor (angiotensin-converting enzyme 2 [hACE2]) under a cytokeratin 18 promoter (K18) are susceptible to SARS-CoV-2 and that infection resulted in a dose-dependent lethal disease course. After inoculation with either 10 4 TCID 50 or 10 5 TCID 50 , the SARS-CoV-2 infection resulted in rapid weight loss in both groups and uniform lethality in the 10 5 TCID 50 group. High levels of viral RNA shedding were observed from the upper and lower respiratory tract and intermittent shedding was observed from the intestinal tract. Inoculation with SARS-CoV-2 resulted in upper and lower respiratory tract infection with high infectious virus titers in nasal turbinates, trachea and lungs. The observed interstitial pneumonia and pulmonary pathology, with SARS-CoV-2 replication evident in pneumocytes, were similar to that reported in severe cases of COVID-19. SARS-CoV-2 infection resulted in macrophage and lymphocyte infiltration in the lungs and upregulation of Th1 and proinflammatory cytokines/chemokines. Extrapulmonary replication of SARS-CoV-2 was observed in the cerebral cortex and hippocampus of several animals at 7 DPI but not at 3 DPI. The rapid inflammatory response and observed pathology bears resemblance to COVID-19. Additionally, we demonstrate that a mild disease course can be simulated by low dose infection with 10 2 TCID 50 SARS-CoV-2, resulting in minimal clinical manifestation and near uniform survival. Taken together, these data support future application of this model to studies of pathogenesis and medical countermeasure development.

Surgical site infection is one of the most severe complications of surgical treatments. However, the optimal procedure to prevent such infections remains uninvestigated. Ultraviolet radiation C (UVC) with a short wavelength has a high bactericidal effect; however, it is cytotoxic. Nonetheless, given that UVC with a wavelength of 222 nm reaches only the stratum corneum, it does not affect the skin cells. This study aimed to investigate the safety of 222-nm UVC irradiation and to examine its skin sterilization effect in healthy volunteers. This trial was conducted on 20 healthy volunteers. The back of the subject was irradiated with 222-nm UVC at 50-500 mJ/cm.sup.2, and the induced erythema (redness of skin) was evaluated. Subsequently, the back was irradiated with a maximum amount of UVC not causing erythema, and the skin swabs before and after the irradiation were cultured. The number of colonies formed after 24 hours was measured. In addition, cyclobutene pyrimidine dimer (CPD) as an indicator of DNA damage was measured using skin tissues of the nonirradiated and irradiated regions. All subjects experienced no erythema at all doses. The back of the subject was irradiated at 500 mJ/cm.sup.2, and the number of bacterial colonies in the skin swab culture was significantly decreased by 222-nm UVC irradiation. The CPD amount produced in the irradiated region was slightly but significantly higher than that of the non-irradiated region. A 222-nm UVC at 500 mJ/cm.sup.2 was a safe irradiation dose and possessed bactericidal effects. In the future, 222-nm UVC irradiation is expected to contribute to the prevention of perioperative infection.

Increased population necessitates an expansion of infrastructure and urbanization, resulting in growth in the construction industry. A rise in population also results in an increased plastic waste, globally. Recycling plastic waste is a global concern. Utilization of plastic waste in concrete can be an optimal solution from recycling perspective in construction industry. As environmental issues continue to grow, the development of predictive machine learning models is critical. Thus, this study aims to create modelling tools for estimating the compressive and tensile strengths of plastic concrete. For predicting the strength of concrete produced with plastic waste, this research integrates machine learning algorithms (individual and ensemble techniques), including bagging and adaptive boosting by including weak learners. For predicting the mechanical properties, 80 cylinders for compressive strength and 80 cylinders for split tensile strength were casted and tested with varying percentages of irradiated plastic waste, either as of cement or fine aggregate replacement. In addition, a thorough and reliable database, including 320 compressive strength tests and 320 split tensile strength tests, was generated from existing literature. Individual, bagging and adaptive boosting models of decision tree, multilayer perceptron neural network, and support vector machines were developed and compared with modified learner model of random forest. The results implied that individual model response was enriched by utilizing bagging and boosting learners. A random forest with a modified learner algorithm provided the robust performance of the models with coefficient correlation of 0.932 for compressive strength and 0.86 for split tensile strength with the least errors. Sensitivity analyses showed that tensile strength models were least sensitive to water and coarse aggregates, while cement, silica fume, coarse aggregate, and age have a substantial effect on compressive strength models. To minimize overfitting errors and corroborate the generalized modelling result, a cross-validation K-Fold technique was used. Machine learning algorithms are used to predict mechanical properties of plastic concrete to promote sustainability in construction industry.

Here, we will present recently peer-reviewed results to showcase the advanced multimodal imaging capabilities developed to study irradiated materials at the Pacific Northwest National Laboratory. Irradiated cladding samples selected to support the tritium science and technology program will be used as an example to demonstrate the multimodal imaging capabilities.

Radiotherapy (RT), the major anti-cancer modality for more than half of cancer patients after diagnosis, has the advantage of local tumor control with relatively less systematic side effects comparing to chemotherapy. However, the efficacy of RT is limited by acquired tumor resistance leading to the risks of relapse and metastasis. To further enhance the efficacy of RT, with the renaissances of targeted immunotherapy (TIT), increasing interests are raised on RT combined with TIT including cancer vaccines, T-cell therapy, and antibody-based immune checkpoint blockers (ICB) such as anti-CTLA-4 and anti-PD1/PD-L1. In achieving a significant synergy between RT and TIT, the dynamics of radiation-induced response in tumor cells and stromal cells, especially the cross-talk between tumor cells and immune cells in the irradiated tumor microenvironment (ITME) as highlighted in recent literature are to be elucidated. The abscopal effect refereeing the RT-induced priming function outside of ITME could be compromised by the immune-suppressive factors such as CD47 and PD-L1 on tumor cells and Treg induced or enhanced in the ITME. Cell surface receptors temporally or permanently induced and bioactive elements released from dead cells could serve antigenic source (radiation-associated antigenic proteins, RAAPs) to the host and have functions in immune regulation on the tumor. This review is attempted to summarize a cluster of factors that are inducible by radiation and targetable by antibodies, or have potential to be immune regulators to synergize tumor control with RT. Further characterization of immune regulators in ITME will deepen our understanding of the interplay among immune regulators in ITME and discover new effective targets for the combined modality with RT and TIT.

Purpose To identify key dosimetric parameters that have close associations with tumor treatment response and body weight change in SFRT treatments with a large range of spatial-fractionation scale at dose rates of several Gy/min. Methods Six study arms using uniform tumor radiation, half-tumor radiation, 2mm beam array radiation, 0.3mm minibeam radiation, and an untreated arm were used. All treatments were delivered on a 320kV x-ray irradiator. Forty-two female Fischer 344 rats with fibrosarcoma tumor allografts were used. Dosimetric parameters studied are peak dose and width, valley dose and width, peak-to-valley-dose-ratio (PVDR), volumetric average dose, percentage volume directly irradiated, and tumor- and normal-tissue EUD. Animal survival, tumor volume change, and body weight change (indicative of treatment toxicity) are tested for association with the dosimetric parameters using linear regression and Cox Proportional Hazards models. Results The dosimetric parameters most closely associated with tumor response are tumor EUD (R.sup.2 = 0.7923, F-stat = 15.26*; z-test = -4.07***), valley (minimum) dose (R.sup.2 = 0.7636, F-stat = 12.92*; z-test = -4.338***), and percentage tumor directly irradiated (R.sup.2 = 0.7153, F-stat = 10.05*; z-test = -3.837***) per the linear regression and Cox Proportional Hazards models, respectively. Tumor response is linearly proportional to valley (minimum) doses and tumor EUD. Average dose (R.sup.2 = 0.2745, F-stat = 1.514 (no sig.); z-test = -2.811**) and peak dose (R.sup.2 = 0.04472, F-stat = 0.6874 (not sig.); z-test = -0.786 (not sig.)) show the weakest associations to tumor response. Only the uniform radiation arm did not gain body weight post-radiation, indicative of treatment toxicity; however, body weight change in general shows weak association with all dosimetric parameters except for valley (minimum) dose (R.sup.2 = 0.3814, F-stat = 13.56**), valley width (R.sup.2 = 0.2853, F-stat = 8.783**), and peak width (R.sup.2 = 0.2759, F-stat = 8.382**). Conclusions For a single-fraction SFRT at conventional dose rates, valley, not peak, dose is closely associated with tumor treatment response and thus should be used for treatment prescription. Tumor EUD, valley (minimum) dose, and percentage tumor directly irradiated are the top three dosimetric parameters that exhibited close associations with tumor response.

Exposure to ionizing radiation, a physical treatment that inactivates live tumor cells, has been extensively applied to enhance the antitumor responses induced by cancer cell vaccines in both animal research and human clinical trials. However, the mechanisms by which irradiated cells function as immunogenic tumor vaccines and induce effective antitumor responses have not been fully explored. Here, we demonstrate that oxidized mitochondrial DNA (mtDNA) and stimulator of interferon genes (STING) signaling play a key roles in the enhanced antitumor effect achieved with an irradiated tumor cell vaccine. Elevations in ROS and oxidized mtDNA 8-OHG content could be induced in irradiated tumor cells. Oxidized mtDNA derived from irradiated tumor cells gained access to the cytosol of dendritic cells (DCs). Oxidized mtDNA, as a DAMP or adjuvant, activated the STING-TBK1-IRF3-IFN-β pathway in DCs, which subsequently cross-presented irradiated tumor cell-derived antigens to CD8+ T cells and elicited antitumor immunity. The results of our study provide insight into the mechanism by which an irradiated cell vaccine mediates antitumor immunity, which may have implications for new strategies to improve the efficacy of irradiated vaccines.

Combination of the sterile insect technique with the incompatible insect technique is considered to be a safe approach to control Aedes albopictus populations in the absence of an accurate and scalable sex separation system or genetic sexing strain. Our previous study has shown that the triple Wolbachia-infected Ae. albopictus strain (wAlbA, wAlbB and wPip) was suitable for mass rearing and females could be completely sterilized as pupae with a radiation dose of at least 28 Gy. However, whether this radiation dose can influence the mating competitiveness of the triple infected males was still unknown. In this study we aimed to evaluate the effects of irradiation on the male mating competitiveness of the triple infected strain under laboratory and semi-field conditions. The results herein indicate that irradiation with a lower, female-sterilizing dose has no negative impact on the longevity of triple infected males while a reduced lifespan was observed in the wild type males (wAlbA and wAlbB) irradiated with a higher male-sterilizing dose, in small cages. At different sterile: fertile release ratios in small cages, triple-infected males induced 39.8, 81.6 and 87.8% sterility in a wild type female population at 1:1, 5:1 and 10:1 release ratios, respectively, relative to a fertile control population. Similarly, irradiated triple infected males induced 31.3, 70.5 and 89.3% sterility at 1:1, 5:1 and 10:1 release ratios, respectively, again relative to the fertile control. Under semi-field conditions at a 5:1 release ratio, relative to wild type males, the mean male mating competitiveness index of 28 Gy irradiated triple-infected males was significantly higher than 35 Gy irradiated wild type males, while triple infected males showed no difference in mean mating competitiveness to either irradiated triple-infected or irradiated wild type males. An unexpected difference was also observed in the relative male mating competitiveness of the triple infected strain after irradiation at 28 Gy dose in small vs large cages, with a higher male mating competitiveness index calculated from results of experiments in the large cages. Based on these results, we consider that the male mating performance of the triple infected strain after irradiation at 28 Gy, a dose required for complete female sterility and the avoidance of population replacement, is approximately equal to that of the wild type males under semi-field conditions. Though field evaluation is required, this suggests that the triple infected strain is suitable for irradiation and release as part of a combined SIT-IIT approach to Ae. albopictus control.

Purpose Graft choice in primary anterior cruciate ligament (ACL) reconstruction remains controversial. The use of allograft has risen exponentially in recent years with the attraction of absent donor site morbidity, reduced surgical time and reliable graft size. However, the published evidence examining their clinical effectiveness over autograft tendons has been unclear. The aim of this paper is to provide a current review of the clinical evidence available to help guide surgeons through the decision-making process for the use of allografts in primary ACL reconstruction. Methods The literature in relation to allograft healing, storage, sterilisation, differences in surgical technique and rehabilitation have been reviewed in addition to recent comparative studies and all clinical systematic reviews and meta-analyses. Results Early reviews have indicated a higher risk of failure with allografts due to association with irradiation for sterilisation and where rehabilitation programs and post-operative loading may ignore the slower incorporation of allografts. More recent analysis indicates a similar low failure rate for allograft and autograft methods of reconstruction when using non-irradiated allografts that have not undergone chemically processing and where rehabilitation has been slower. However, inferior outcomes with allografts have been reported in young (< 25 years) highly active patients, and also when irradiated or chemically processed grafts are used. Conclusion When considering use of allografts in primary ACL reconstruction, use of irradiation, chemical processing and rehabilitation programs suited to autograft are important negative factors. Allografts, when used for primary ACL reconstruction, should be fresh frozen and non-irradiated. Quantification of the risk of use of allograft in the young requires further evaluation. Levels of evidence III.