Search Results (75)

Background/Objectives: Ewing sarcoma (ES), a highly aggressive bone and soft tissue cancer occurring in children and young adults, is defined by the ETS fusion oncoprotein EWS::FLI1. Although event-free survival rates remain high in ES patients with localized disease, those with metastatic or relapsed disease face poor long-term survival odds. Topoisomerase 1 (TOP1) inhibitors are commonly used therapeutics in ES relapse regimens. Methods: In this work, we used a genome-wide CRISPR knockout library screen to identify the deletion of the TOP1 gene as a mechanism for resistance to topoisomerase 1 inhibitors. Using isogenic cell line models, we performed a high-throughput small-molecule screen to discover a small molecule, GNF-7, which had an IC50 that was 10-fold lower in TOP1-deficient cells when compared to the wild-type cells. Results: The characterization of GNF-7 demonstrated the molecule was highly active in the inhibition of CSK, p38α, EphA2, Lyn, and ZAK and specifically downregulated genes induced by the EWS::FLI1 fusion oncoprotein. Conclusions: Together, these results suggest that GNF-7 or small molecules with a similar kinase profile could be effective treatments for ES patients in combination with TOP1 inhibitors or for those patients who have developed resistance to TOP1 inhibitors. Full article

Background/Objectives: The increasing occurrence of carbapenem resistance A. baumannii (CRAB) has forced clinicians to seek out alternative options with activity against CRAB. CRAB with inactivated PBP7/8 has been shown to result in an increased outer membrane permeability and could serve as a potential new adjuvant target. Methods: Two isogenic clinical isolates of A. baumannii HUMC1 were utilized (WT and HUMC1 ΔPBP7/8). Static concentration time-kill assays were performed against both isolates with escalating exposures to antibiotics. The resulting data were modeled using the Monolix software suite to capture parameters related to bacterial killing and PBP7/8 synergism. The model results were used to prospectively simulate clinically relevant antibiotic dosing of three antibiotics under physiological conditions and were validated using a hollow-fiber infection model (HFIM). Results: Treatment with monotherapy or combination therapy resulted in concentration-dependent killing for both isolates. Bacterial killing was greater with HUMC1 ΔPBP7/8 for all tested antibiotic concentrations. The mean bacterial population reduction was 4.38 log₁₀ CFU/mL for HUMC1 and 5.38 log₁₀ CFU/mL for HUMC1ΔPBP7/8 knockout isolate. The final mechanism-based model demonstrated improved antibacterial activity with PBP7/8 inhibition through a decline in KC₅₀ values of 59.7% across the beta-lactams in the PBP7/8 knockout. HFIM observations that were retrospectively compared to the simulated model-predicted bacterial concentration time course showed our final model was able to appropriately capture changes in bacterial population within a dynamic HFIM scenario. Conclusions: The quantification of KC₅₀ decline and increase in effectiveness of previously sidelined antimicrobial therapies with PBP7/8 inhibition suggests PBP7/8 is a promising potential target for an antibacterial adjuvant. This lends further support to advance to next-stage studies for identifying compounds that specifically inhibit PBP7/8 activity. Full article

The decommissioning of the Zion Nuclear Power Plant (NPP) provided a unique opportunity to harvest and study service-aged reactor pressure vessel (RPV) beltline materials. This work, conducted through the U.S. Department of Energy’s Light Water Reactor Sustainability (LWRS) Program, aims to improve the understanding of radiation-induced embrittlement to support extended nuclear plant operations. Material segments containing the Linde 80 flux, wire heat 72105 (WF-70) beltline weld and the A533B Heat B7835-1 base metal, obtained from the intermediate shell region with a peak fluence of 0.7 × 10¹⁹ n/cm² (E > 1.0 MeV), were extracted, cut into blocks, and machined into test specimens for mechanical and microstructural characterization. The segmentation process involved oxy-propane torch-cutting, followed by precision machining using wire saws and electrical discharge machining (EDM). A chemical composition analysis confirmed the expected variations in alloying elements, with copper levels being notably higher in the weld metal. The harvested specimens enable a detailed evaluation of through-wall embrittlement gradients, a comparison with the existing surveillance data, and the validation of predictive embrittlement models. This study provides critical data for assessing long-term reactor vessel integrity, informing aging-management strategies, and supporting regulatory decisions to extend the life of nuclear plants. This article is a revised and expanded version of a paper entitled, “Current Status of the Characterization of RPV Materials Harvested from the Decommissioned Zion Unit 1 Nuclear Power Plant”, PVP2017-65090, which was accepted and presented at the ASME 2017 Pressure Vessels and Piping Conference, Waikoloa, HI, USA, 16–20 July 2017. Full article

To better inform the public about ambient air quality and associated health risks and prevent cardiovascular and chronic respiratory diseases in Macau, the local government authorities apply the Air Quality Index (AQI) for air quality management within its jurisdiction. The application of AQI requires first determining the sub-indices for several pollutants, including respirable suspended particulates (PM₁₀), fine suspended particulates (PM_2.5), nitrogen dioxide (NO₂), ozone (O₃), sulfur dioxide (SO₂), and carbon monoxide (CO). Accurate prediction of AQI is crucial in providing early warnings to the public before pollution episodes occur. To improve AQI prediction accuracy, deep learning methods such as artificial neural networks (ANNs) and long short-term memory (LSTM) models were applied to forecast the six pollutants commonly found in the AQI. The data for this study was accessed from the Macau High-Density Residential Air Quality Monitoring Station (AQMS), which is located in an area with high traffic and high population density near a 24 h land border-crossing facility connecting Zhuhai and Macau. The novelty of this work lies in its potential to enhance operational AQI forecasting for Macau. The ANN and LSTM models were run five times, with average pollutant forecasts obtained for each model. Results demonstrated that both models accurately predicted pollutant concentrations of the upcoming 24 h, with PM₁₀ and CO showing the highest predictive accuracy, reflected in high Pearson Correlation Coefficient (PCC) between 0.84 and 0.87 and Kendall’s Tau Coefficient (KTC) between 0.66 and 0.70 values and low Mean Bias (MB) between 0.06 and 0.10, Mean Fractional Bias (MFB) between 0.09 and 0.11, Root Mean Square Error (RMSE) between 0.14 and 0.21, and Mean Absolute Error (MAE) between 0.11 and 0.17. Overall, the LSTM model consistently delivered the highest PCC (0.87) and KTC (0.70) values and the lowest MB (0.06), MFB (0.09), RMSE (0.14), and MAE (0.11) across all six pollutants, with the lowest SD (0.01), indicating greater precision and reliability. As a result, the study concludes that the LSTM model outperforms the ANN model in forecasting air pollutants in Macau, offering a more accurate and consistent prediction tool for local air quality management. Full article

Background/Objectives: Fluorescein angiography (FA) is essential for diagnosing and managing diabetic retinopathy (DR) and other retinal vascular diseases and has recently demonstrated potential as a quantitative tool for disease staging. The advent of ultra-widefield (UWF) FA, allowing visualization of the peripheral retina, enhances this potential. Retinal hypoperfusion is a critical risk factor for proliferative DR, yet quantifying it reliably remains a challenge. Methods: This study evaluates the efficacy of the Michigan grid method, a software-based grading system, in detecting retinal hypoperfusion compared to the traditional freehand method. Retinal UWF fluorescein angiograms were obtained from 50 patients, including 10 with healthy retinae and 40 with non-proliferative DR. Two independent, masked graders quantified hypoperfusion in each image using two methods: freehand annotation and a new Michigan grid method. Results: Using the Michigan grid method, Grader 1 identified more ungradable segments, while Grader 2 identified more perfused and nonperfused segments. Cohen’s weighted kappa indicated substantial agreement, which was slightly higher for the entire retina (0.711) compared to the central retinal area (0.686). The Michigan grid method shows comparable or slightly improved inter-rater reliability compared to the freehand method. Conclusions: This study demonstrates a new Michigan grid method for the evaluation of FA for hypoperfusion while highlighting ongoing challenges in achieving consistent and objective retinal nonperfusion assessment, underscoring the need for further refinement and the potential integration of automated approaches. Full article

The recombinant vesicular stomatitis virus-Zaire Ebolavirus envelope glycoprotein vaccine (rVSVΔG-ZEBOV-GP) was highly effective against Ebola virus disease in a ring vaccination trial conducted during the 2014–2016 outbreak in Guinea and is licensed by regulatory agencies including US FDA, EMA, and prequalified by WHO. Vaccination studies in a nonhuman primate (NHP) model guided initial dose selection for clinical trial evaluation. We summarize two dose-ranging studies with the clinical-grade rVSVΔG-ZEBOV-GP vaccine candidate to assess the impact of dose level on immune responses and efficacy in an NHP Ebola virus (EBOV) challenge model. Forty-six cynomolgus macaques were vaccinated with a wide range of rVSVΔG-ZEBOV-GP doses and challenged 42 days later intramuscularly with 1000 pfu EBOV. Vaccination with rVSVΔG-ZEBOV-GP induced relatively high levels of EBOV-specific IgG and neutralizing antibodies, measured using the same validated assays as used in rVSVΔG-ZEBOV-GP clinical trials. Similar responses were observed across dose groups from 1 × 10⁸ to 1 × 10² pfu. A single vaccination conferred 98% protection from lethal intramuscular EBOV challenge across all dose groups. These results demonstrate that robust antibody titers are induced in NHPs across a wide range of rVSVΔG-ZEBOV-GP vaccine doses, correlating with high levels of protection against death from EBOV challenge. Full article

Background/Objectives: Whole-food plant-based diets (WFPBDs) are beneficial in managing hypertension in the general population but have not been well studied in chronic kidney disease (CKD), potentially due to concerns about hyperkalemia. We hypothesized that individuals with CKD 3 or 4 attending a 15-day WFPBD education program would achieve lower blood pressure compared to those who did not, without an increased risk of hyperkalemia. Methods: This was a pilot trial of 40 subjects with mild-to-moderate CKD and hypertension but without diabetes or proteinuria from a single academic center. The subjects were randomized to the 15-day education program or the control group. The changes in blood pressure, serum potassium, and other anthropometric and biochemical values were assessed. Results: Systolic blood pressure decreased from the baseline to day 15 in the intervention group by 8 mm Hg and increased in the control group by 2.7 mm Hg, although the difference in the blood pressure change did not reach statistical significance (p = 0.12). Diastolic blood pressure was not different between the two groups. Potassium changed by 0.01 mEq/L in the intervention group and −0.07 mEq/L in the control group (p = 0.52). The intervention subjects had significant decreases in body mass (−3.0 vs. −0.12 kg, p < 0.0001), total cholesterol (−39.4 vs. −5.0 mg/dL, p < 0.0001), low-density lipoprotein (−28.4 vs. −0.6 mg/dL, p < 0.0001), and high-density lipoprotein (−8.6 vs. −0.4 mg/dL, p = 0.006) compared to the controls. The changes in albumin and phosphorus were not different between the two groups. Conclusions: The subjects with mild-to-moderate CKD attending a 15-day WFPBD education program had a non-statistically significant reduction in systolic blood pressure without an increased risk of hyperkalemia compared to those who did not attend. The intervention subjects achieved significantly greater reductions in body mass and cholesterol without adverse effects on albumin or phosphorus. Larger and longer-duration trials using this approach in a diverse group of CKD patients are warranted. Full article

The COllaborative Carbon Column Observing Network has become a reliable source of high-quality ground-based remote sensing network data that provide column-averaged dry-air mole fractions of carbon dioxide (XCO₂), methane (XCH₄), and carbon monoxide (XCO). The fiducial reference measurements of these gases from the COCCON complement the TCCON and NDACC-IRWG data. This study shows the application of COCCON data for the validation of existing greenhouse gas satellite products. This study includes the validation of XCH₄ and XCO products from the European Copernicus Sentinel-5 Precursor (S5P) mission, XCO₂ products from the American Orbiting Carbon Observatory-2 (OCO-2) mission, and XCO₂ and XCH₄ products from the Japanese Greenhouse gases Observing SATellite (GOSAT). A total of 27 datasets contributed to this study; some of these were collected in the framework of campaign activities and covered only a short time period. In addition, several permanent stations provided long-term observations. The random uncertainties in the validation results, specifically for S5P with a lot of coincidences pairs, are found to be similar to the comparison with the TCCON. The comparison results of OCO-2 land nadir and land glint observation modes to the COCCON on a global scale, despite limited coincidences, are very promising. The stations can, therefore, expand on the coverage of the already existing ground-based reference remote sensing sites from the TCCON and the NDACC network. The COCCON data can be used for future satellite and model validation studies and carbon cycle studies. Full article

Objectives: We sought to investigate the visual function, retinal features, and genotype–phenotype correlations of an Australian cohort of RPGR carriers. Methods: In this cross-sectional study, we evaluated RPGR carriers seen in Melbourne and Perth between 2013 and 2023 and healthy women seen between 2022 and 2023 in Melbourne. Visual acuity tests, fundus-tracked microperimetry, and retinal imaging were performed. RPGR carriers were classified into four retinal phenotypes (normal, radial, focal pigmentary retinopathy, and male pattern phenotype) and compared against healthy controls. Genotype–phenotype relationships in the RPGR carriers were investigated. Results: Thirty-five female RPGR carriers and thirty healthy controls were included in this study. The median ages were 40 and 48.5 years for RPGR carriers and controls, respectively (p = 0.26). Most RPGR carriers (89%) had a genetic diagnosis. Best-corrected visual acuity (BCVA), low luminance visual acuity, retinal sensitivity, central inner retinal thickness (IRT, 1°), and photoreceptor complex (PRC) thickness across the central 1–7° of the retina differed between phenotypes of RPGR carriers. On average, RPGR carriers with ORF15 variants (n = 25 carriers) had reduced LLVA, a greater IRT at 1°, and thinner PRC thickness at 7° from the fovea (all p < 0.05) compared to those with exon 1–14 variants. Conclusions: Female RPGR carriers with severe retinal phenotypes had significantly decreased visual function and changes in retinal structure in comparison to both the controls and carriers with mild retinal disease. BCVA, LLVA, retinal sensitivity, and retinal thickness are biomarkers for detecting retinal disease in RPGR carriers. The genetic variant alone did not influence retinal phenotype; however, RPGR carriers with ORF15 variants exhibited reduced retinal and visual measurements compared to those with exon 1–14 variants. Full article

Tree nuts are rich in nutrients, and global production and consumption have doubled during the last decade. However, nuts have a range of quality defects that must be detected and removed during post-harvest processing. Tree nuts can develop hidden internal discoloration, and current sorting methods are prone to subjectivity and human error. Therefore, non-destructive, real-time methods to evaluate internal nut quality are needed. This study explored the potential for VNIR (400–1000 nm) hyperspectral imaging to classify brown center disorder in macadamias. This study compared the accuracy of classifiers developed using images of kernels imaged in face-up and face-down orientations. Classification accuracy was excellent using face-up (>97.9%) and face-down (>94%) images using ensemble and linear discriminate models before and after wavelength selection. Combining images to form a pooled dataset also provided high accuracy (>90%) using artificial neural network and support vector machine models. Overall, HSI has great potential for commercial application in nut processing to detect internal brown centers using images of the outside kernel surface in the VNIR range. This technology will allow rapid and non-destructive evaluation of intact nut products that can then be marketed as a high-quality, defect-free product, compared with traditional methods that rely heavily on representative sub-sampling. Full article

Modular construction is emerging into the limelight in the construction industry as one of the front-running modern methods of construction, facilitating multiple benefits, including improved productivity. Meanwhile, Circular Economy (CE) principles are also becoming prominent in the Building Construction Industry (BCI), which is infamous for its prodigious resource consumption and waste generation. In essence, the basic concepts of modular construction and CE share some commonalities in their fundamental design principles, such as standardisation, simplification, prefabrication, and mobility. Hence, exploring ways of synergising circularity and modularity in the design stage with a Whole Life Cycle (WLC) of value creation and retention is beneficial. By conducting a thorough literature review, supported by expert interviews and brainstorming sessions, followed by a case study, the concept of Design for Circular Manufacturing and Assembly (DfCMA) was proposed to deliver circularity and modularity synergistically in circularity-oriented modular construction. This novel conceptualisation of DfCMA is envisaged to be a value-adding original theoretical contribution of this paper. Furthermore, the findings are expected to add value to the BCI by proposing a way forward to synergise circularity and modularity to contribute substantially towards an efficient circular built environment. Full article

Immunotherapies, including checkpoint inhibitor antibodies, have precipitated significant improvements in clinical outcomes for melanoma. However, approximately half of patients do not benefit from approved treatments. Additionally, apart from Tebentafusp, which is approved for the treatment of uveal melanoma, there is a lack of immunotherapies directly focused on melanoma cells. This is partly due to few available targets, especially those expressed on the cancer cell surface. Chondroitin sulfate proteoglycan 4 (CSPG4) is a cell surface molecule overexpressed in human melanoma, with restricted distribution and low expression in non-malignant tissues and involved in several cancer-promoting and dissemination pathways. Here, we summarize the current understanding of the expression and functional significance of CSPG4 in health and melanoma, and we outline immunotherapeutic strategies. These include monoclonal antibodies, antibody–drug conjugates (ADCs), chimeric-antigen receptor (CAR) T cells, and other strategies such as anti-idiotypic and mimotope vaccines to raise immune responses against CSPG4-expressing melanomas. Several showed promising functions in preclinical models of melanoma, yet few have reached clinical testing, and none are approved for therapeutic use. Obstacles preventing that progress include limited knowledge of CSPG4 function in human cancer and a lack of in vivo models that adequately represent patient immune responses and human melanoma biology. Despite several challenges, immunotherapy directed to CSPG4-expressing melanoma harbors significant potential to transform the treatment landscape. Full article

The Module-0 Demonstrator is a single-phase 600 kg liquid argon time projection chamber operated as a prototype for the DUNE liquid argon near detector. Based on the ArgonCube design concept, Module-0 features a novel 80k-channel pixelated charge readout and advanced high-coverage photon detection system. In this paper, we present an analysis of an eight-day data set consisting of 25 million cosmic ray events collected in the spring of 2021. We use this sample to demonstrate the imaging performance of the charge and light readout systems as well as the signal correlations between the two. We also report argon purity and detector uniformity measurements and provide comparisons to detector simulations. Full article

With emerging genetic association studies, new genes and pathways are revealed as causative factors in the development of Parkinson’s disease (PD). However, many of these PD genes are poorly characterized in terms of their function, subcellular localization, and interaction with other components in cellular pathways. This represents a major obstacle towards a better understanding of the molecular causes of PD, with deeper molecular studies often hindered by a lack of high-quality, validated antibodies for detecting the corresponding proteins of interest. In this study, we leveraged the nanoluciferase-derived LgBiT-HiBiT system by generating a cohort of tagged PD genes in both induced pluripotent stem cells (iPSCs) and iPSC-derived neuronal cells. To promote luminescence signals within cells, a master iPSC line was generated, in which LgBiT expression is under the control of a doxycycline-inducible promoter. LgBiT could bind to HiBiT when present either alone or when tagged onto different PD-associated proteins encoded by the genes GBA1, GPNMB, LRRK2, PINK1, PRKN, SNCA, VPS13C, and VPS35. Several HiBiT-tagged proteins could already generate luminescence in iPSCs in response to the doxycycline induction of LgBiT, with the enzyme glucosylceramidase beta 1 (GCase), encoded by GBA1, being one such example. Moreover, the GCase chaperone ambroxol elicited an increase in the luminescence signal in HiBiT-tagged GBA1 cells, correlating with an increase in the levels of GCase in dopaminergic cells. Taken together, we have developed and validated a Doxycycline-inducible luminescence system to serve as a sensitive assay for the quantification, localization, and activity of HiBiT-tagged PD-associated proteins with reliable sensitivity and efficiency. Full article

This review explores the concept of futility timeouts and the use of traumatic brain injury (TBI) as an independent predictor of the futility of resuscitation efforts in severely bleeding trauma patients. The national blood supply shortage has been exacerbated by the lingering influence of the COVID-19 pandemic on the number of blood donors available, as well as by the adoption of balanced hemostatic resuscitation protocols (such as the increasing use of 1:1:1 packed red blood cells, plasma, and platelets) with and without early whole blood resuscitation. This has underscored the urgent need for reliable predictors of futile resuscitation (FR). As a result, clinical, radiologic, and laboratory bedside markers have emerged which can accurately predict FR in patients with severe trauma-induced hemorrhage, such as the Suspension of Transfusion and Other Procedures (STOP) criteria. However, the STOP criteria do not include markers for TBI severity or transfusion cut points despite these patients requiring large quantities of blood components in the STOP criteria validation cohort. Yet, guidelines for neuroprognosticating patients with TBI can require up to 72 h, which makes them less useful in the minutes and hours following initial presentation. We examine the impact of TBI on bleeding trauma patients, with a focus on those with coagulopathies associated with TBI. This review categorizes TBI into isolated TBI (iTBI), hemorrhagic isolated TBI (hiTBI), and polytraumatic TBI (ptTBI). Through an analysis of bedside parameters (such as the proposed STOP criteria), coagulation assays, markers for TBI severity, and transfusion cut points as markers of futilty, we suggest amendments to current guidelines and the development of more precise algorithms that incorporate prognostic indicators of severe TBI as an independent parameter for the early prediction of FR so as to optimize blood product allocation. Full article