A Bimetallic Polymerization Network for Effective Increase in Labile Iron Pool and Robust Activation of cGAS/STING Induces Ferroptosis-Based Tumor Immunotherapy.

Due to the inherent low immunogenicity and immunosuppressive tumor microenvironment (TME) of malignant cancers, the clinical efficacy and application of tumor immunotherapy have been limited. Herein, a bimetallic drug-gene co-loading network (Cu/ZIF-8@U-104@siNFS1-HA) is developed that increased the intracellular labile iron pool (LIP) and enhanced the weakly acidic TME by co-suppressing the dual enzymatic activities of carbonic anhydrase IX (CA IX) and cysteine desulfurylase (NFS1), inducing a safe and efficient initial tumor immunogenic ferroptosis. During this process, Cu2+ is responsively released to deplete glutathione (GSH) and reduce the enzyme activity of glutathione peroxidase 4 (GPX4), achieving the co-inhibition of the three enzymes and further inducing lipid peroxidation (LPO). Additionally, the reactive oxygen species (ROS) storm in target cells promoted the generation of large numbers of double-stranded DNA breaks. The presence of Zn2+ substantially increased the expression of cGAS/STING, which cooperated with ferroptosis to strengthen the immunogenic cell death (ICD) response and remodel the immunosuppressive TME. In brief, Cu/ZIF-8@U-104@siNFS1-HA linked ferroptosis with immunotherapy through multiple pathways, including the increase in LIP, regulation of pH, depletion of GSH/GPX4, and activation of STING, effectively inhibiting cancer growth and metastasis.

Wastewater reuse and energy saving require a more decentralized urban wastewater system? Evidence from multi-objective optimal design at the city scale.

Decentralization is recognized as an emerging solution for a more sustainable urban wastewater system (UWS) for the future. However, the debate of centralization vs. decentralization at the system's planning stage remains unresolved, mainly due to the complexity of the system's spatial structure and the multiple design objectives, such as water reuse and energy conservation. This paper presents the Sustainable Urban Wastewater System Generator (SUWStor) as a tool to address this issue. Integrating a graph representation of the system structure and the ant colony algorithm, SUWStor can produce Pareto optimal solutions for system design under three objectives: minimizing the capital cost, minimizing the operational energy consumption, and maximizing the water reuse capacity. The model is used for system design in a 100-square-km new city, the Xiong'an New District in China. Compared to the solution based on human experience, the model can reduce the system's capital cost by 7% and the operational energy in the pipe network by 26%, while maintaining the water reuse capacity at 100%. With this model, the relation between the optimal system layout and the choice over different design objectives can be discussed for any given area. In our case study, the optimal capacity of WWTPs for the lowest-cost solution is 48,000 m3 per day, leading to a total number of WWTPs of 5. As the water reuse level increases to maximum, the optimal capacity reduces to 15,000 m3 per day, where the number of WWTPs is 16. The model is also able to perform significantly better than the locally optimized results, in which only the WWTP locations are fixed at their optimal values. This demonstrates the importance of a global optimization model in designing the integrated UWS.

The structure design of integrated urban drainage systems: A view of robust optimization.

Rapid urbanization puts a lot of pressure on urban water pollution from point and non-point sources, calling for the practical, specific, and integrated management of urban drainage systems (UDS). The structural design of an integrated UDS is essential for highly complex and uncertain urban water management. In this study, we developed a multi-objective robust optimization model to explore the optimal structures of UDS considering system uncertainty. We applied this model to City B, northern China, to illustrate its effectiveness. The results show that the model can produce optimal designs with a more robust performance in terms of structural uncertainty. When the uncertainty degree ranges from 5% to 20%, a considerable extra cost (increased by 1.10-2.68 times) is required to improve the robustness of UDS. With the increase in structural uncertainty, the fraction of the cost invested in the stormwater subsystem increased from 10.2% to 27.2%. The findings showed that stormwater management is efficient in coping with system uncertainty. The research results promote an understanding of robust urban drainage systems.

Exploring the structural factors of resilience in urban drainage systems: a large-scale stochastic computational experiment.

The focus of infrastructure design and management has turned from a reliability-based approach to a resilience-based one. Resilience is a system's ability to maintain its function and minimize failure consequences when faced with exceptional conditions. This study carries out a large-scale computational experiment to study how resilience is affected by system's structure in a combined sewer system. We build a stochastic generation model, involving a random sampling of facility locations and a graph-based random walk sampling algorithm to generate various layouts of pipelines. The performance of these virtual systems are assessed in the Storm Water Management Model. We apply statistical techniques on these samples to study the relation between resilience and system structure. Results show that the number of combined sewer overflow (CSO) outfalls is a more important factor of resilience compared to the number of wastewater treatment plants (WWTPs). Some locations are found more preferable for WWTP or CSO outfall placement, while adding WWTPs or outfalls at other locations might even lower the system's resilience. Size of the sub-catchments of the CSO outfalls also affects resilience. Although this effect is statistically significant, the extent is not remarkable compared to other factors. We further study the structural features of the cost-effective systems. The highest achievable resilience level increases as the number of CSO outfalls decreases and so does system's cost. This results from the difference in CSO quantity, therefore this dilemma can be cut off by end-of-pipe storage or treatment which specifically tackles CSO. The conclusion of this study provides an insight into the structural factors of combined sewer systems' resilience and can provide guidance for system's planning.

Clinical significance of 3D reconstruction of arteriovenous malformation using digital subtraction angiography and its modification with CT information in stereotactic radiosurgery.

PURPOSE: A three-dimensional (3D) reconstruction method of arteriovenous malformation (AVM) nidus from digital subtraction angiography (DSA) in combination with CT and/or MRI was developed, and its usefulness was evaluated in this study. MATERIALS AND METHODS: The contour of the AVM nidus was delineated on two orthogonal projected DSA images. First, the volume and center of the AVM nidus were calculated in a classic DSA plan using three maximal lengths of the nidus in three perpendicular directions, assuming that the nidus had a prolate ellipsoid shape. Second, in the 3D-DSA plan, the contours of the AVM nidus on the two orthogonal projected DSA images were segmented to be compatible with the slice thickness of the CT image. Assuming that each segment of the nidus has an ellipsoid pillar shape, the volume and center of each segment were calculated. The volume and 3D shape of the nidus were calculated by 3D reconstruction in the 3D-DSA plan. Third, in the CT-DSA plan, the contour based on the segmented DSA was superimposed on the corresponding transaxial CT image slice by slice. The cylindrical shape of the nidus in the transaxial image was modified using the enhanced CT images in the CT-DSA plan. These three planning methods were compared using dose-volume statistics from real patients' data. Eighteen patients with intracranial AVMs in different brain locations who had been treated by radiosurgery were the subjects of this study. To examine the visibility (validity) of the nidus on the CT image, the "nidus" was delineated on an enhanced CT image without DSA superposition in the CT plan and compared with the CT-DSA plan. RESULTS: The variance in the distance between coordinates determined by the CT plan and those determined by the classic DSA plan was significantly larger than the variance in the CT-DSA plan (p < 0.0001 for lateral, AP, and craniocaudal directions). The difference in the variance was not reduced by the addition of MRI (p < 0.0001 for each direction). The mean volume +/- SD of the nidus calculated was 5.9 +/- 8.0 cm(3) in the classic DSA plan, 4.0 +/- 5.6 cm(3) in the 3D-DSA plan, and 3.6 +/- 5.2 cm(3) in the CT-DSA plan. The 3D-DSA plan significantly reduced the mean nidus volume 31.8% +/- 12.7% from the classic DSA plan (p = 0.0054). The CT-DSA plan further significantly reduced the volume 9.8% +/- 8.8% from the 3D-DSA plan (p = 0.0021). The mean overlapping volume of the nidus between the CT plan and CT-DSA plan was 2.6 +/- 4.3 cm(3) (range 0.17-18.9), corresponding to 63.7% +/- 19.2% (range 11.4-85.3%) of the volume in the CT-DSA plan. CONCLUSIONS: The superposition of the segmented DSA information on CT was shown to be an important tool to determine the precise shape of the nidus and is suggested to be useful to reduce partial occlusion of the AVM or radiation complications in radiosurgery.