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An imbalance in lymphatic fluid, whether it is caused by generation, transport, outflow, or dysfunctional vessels, can lead to lymphedema; however, the exact pathogenesis of this disease remains unclear. To explore the mechanism, we focused on the association among TRPML1, aquaporin-3 (AQP3), and aquaporin-5 (AQP5) in human lymphatic endothelial cells (HLECs). We explored the role of TRPML1 in altering the permeability of HLECs in lymphedema. Meanwhile, we constructed a disease model using gene-knockout mice to observe the effect of TRPML1 on inflammation and fibrosis in lymphedema sites. Our results indicate that TRPML1 not only regulates the localization of AQP3, -5 to the cell membrane but also increases HLEC permeability, disrupts lymphatic fluid transport, and mediates the development of chronic inflammation at the site of lymphedema. Our study suggests that TRPML1 is a precipitating factor in lymphedema. Our findings improve the understanding of TRPML1 and aquaporins in secondary lymphedema, providing valuable insights for future research. [ABSTRACT FROM AUTHOR]

Despite a growing body of research indicating a link between fasting glucose levels and mortality, the relationship between fasting glucose and all-cause and cancer mortality remains inconsistent. In this study, we used Cox regression and restricted cubic spline models to analyze the association and dose-response relationship between fasting plasma glucose levels and all-cause and cancer mortality in a retrospective cohort based on data from the 2015 health check-ups of residents in Quzhou City. After a mean follow-up of 5.31 years for 148,755 study participants, 10,345 deaths occurred, with an all-cause mortality density of 131.09/10,000 person-years, of which 2,845 were cancer deaths, with a cancer mortality density of 36.05/10,000 person-years. There was a "J" shaped dose-response relationship between fasting plasma glucose levels and all-cause and cancer mortality. Relative to normal fasting glucose (NFG), the risk of all-cause mortality (HRs and 95% CIs) in the impaired fasting glucose (IFG) and diabetes mellitus (DM) groups was 1.11 (1.06, 1.16) and 1.43 (1.35, 1.52), respectively, and the risk of cancer mortality in the DM group was 1.22 (1.09, 1.37). In this cohort study, we found that fasting plasma glucose levels were significantly associated with the risk of all-cause and cancer mortality. [ABSTRACT FROM AUTHOR]

Psoriasis is an inflammatory skin disease that relapses frequently. Keratinocyte apoptosis dysregulation plays a crucial role in the pathological mechanisms of psoriasis. PANoptosis is a process with intermolecular interaction among pyroptosis, apoptosis, and necroptosis. The mechanism of PANoptosis in the occurrence and development of psoriasis is still unclear. Here we present a novel approach by identifying PANoptosis-related signatures (PANoptosis-sig) from skin tissue of psoriasis patients and healthy controls on transcriptional and protein levels. Five PANoptosis-sig (TYMP, S100A8, S100A9, NAMPT, LCN2) were identified. Enrichment analysis showed they were mainly enriched in response to leukocyte aggregation, leukocyte migration, chronic inflammatory response and IL−17 signaling pathway. Single cell transcriptome analysis showed TYMP and NAMPT were expressed in almost all cell populations, while LCN2, S100A8 and S100A9 were significantly highly expressed in keratinocyte. We then constructed predictive and diagnostic models with the PANoptosis-sig and evaluated their performance. Finally, unsupervised consensus clustering analysis was conducted to ascertain psoriasis molecular subtypes by the PANoptosis-sig. The psoriasis cohort was divided into two distinct subtypes. Immune landscape showed that the stromal score of cluster 1 was significantly higher than cluster 2, while the immune and estimate scores of cluster 2 were expressively higher than cluster 1. Cluster 1 exhibited high expression of Plasma cells, Tregs and Mast cells resting, while cluster 2 showed high expression of T cells, Macrophages M1, Dendritic cells activated, and Neutrophils in immune infiltration analysis. And cluster 2 was more sensitive to immune checkpoints. In conclusion, our findings revealed potential biomarkers and therapeutic targets for the prevention, diagnosis, and treatment of psoriasis, enhancing our understanding of the molecular mechanisms underlying PANoptosis. [ABSTRACT FROM AUTHOR]

Herein, Mg/Al-loaded sludge-based biochar was prepared via electro-assisted impregnation. The structure and chemical analysis of modified sludge-based biochar (MgSBC-0.5(@Al) showed that the material was loaded with MgO and Al2O3. The specific surface area of MgSBC-0.5(@Al) was 11.27 times higher than that of unmodified sludge-based biochar (SBC). The simultaneous adsorption performance of MgSBC-0.5(@Al for ammonia nitrogen (NH4+–N) and phosphate phosphorus (PO43−–P) was studied. The maximum adsorption capacities of MgSBC-0.5(@Al for NH4+–N and PO43−–P at 298 K were 65.19 and 92.10 mg·g−1, respectively, 4.45 and 6.28 times higher than those of SBC. The external and internal elemental compositions of the modified and unmodified biochar specimens were quantitatively characterized using inductively coupled plasma mass spectrometry, X-ray photoelectron spectroscopy, and X-ray fluorescence spectrometry. The results emphasized the importance of Mg-loading for NH4+–N and PO43−–P capture. MgO was mainly loaded on the surface of biochar, enabling adsorption through chemical reactions. Analysis showed that the adsorption of NH4+–N and PO43−–P on the modified biochar proceeded simultaneously through multiple mechanisms. Particularly, the adsorption of NH4+–N and PO43−–P occurred through the precipitation of struvite and physical adsorption, with PO43−–P also adsorbed through the formation of MgHPO4 and CaHPO4. Other data indicated that Al, Ca, and Fe had a trapping effect on the adsorbate. Importantly, the biochar after adsorption could be used as a soil amendment. [ABSTRACT FROM AUTHOR]

In this paper, we applied an analytical framework called "city cooperation intention → city relationship network → regional economic resilience," while considering the concept of externality as a measure of city cooperation intention, to draw insights from the perspectives of city relationships, biological evolution, and evolutionary economy. The evaluation system we developed focuses on the impact of inherent city culture on the inter-city relationship network, using variables such as knowledge spillover effect, technology symbiosis index, and market structure. We also incorporated innovation, resilience, and regeneration as determinants of regional economic resilience, building upon previous research findings. By applying structural force theory and a three-dimensional coordinate method, we analyzed the correlation between the relationship network and regional economic resilience, established a model to illustrate how the relationship network influences regional economic resilience, and described the course of action taken by the "three factors" of the relationship network on regional economic resilience. Ultimately, the aim of this study is to uncover the mechanism through which the inter-city relationship network affects regional economic resilience, with implications for healthy city design. [ABSTRACT FROM AUTHOR]

As essential components of human society, buildings serve a multitude of functions and significance. Convolutional Neural Network (CNN) has made remarkable progress in the task of building extraction from detailed satellite imagery, owing to the potent capability to capture local information. However, CNN performs suboptimal in extracting larger buildings. Conversely, Transformer has excelled in capturing global information through self-attention mechanisms but are less effective in capturing local information compared to CNN, resulting in suboptimal performance in extracting smaller buildings. Therefore, we have designed the hybrid model STransU2Net, which combines meticulously designed Transformer and CNN to extract buildings of various sizes. In detail, we designed a Bottleneck Pooling Block (BPB) to replace the conventional Max Pooling layer during the downsampling phase, aiming to enhance the extraction of edge information. Furthermore, we devised the Channel And Spatial Attention Block (CSAB) to enhance the target location information during the encoding and decoding stages. Additionally, we added a Swin Transformer Block (STB) at the skip connection location to enhance the model's global modeling ability. Finally, we empirically assessed the performance of STransU2Net on both the Aerial imagery and Satellite II datasets, The IoU achieved state-of-the-art results with 91.04% and 59.09%, respectively, outperforming other models. [ABSTRACT FROM AUTHOR]

5-Fluorouracil (5-FU) is widely used in the treatment of gastric cancer, and the emergence of drug resistance and toxic effects has limited its application. Therefore, there is an urgent need for safe and effective novel drugs or new therapies. β-Ionone (BI) is found in vegetables and fruits and possesses an inhibitory proliferation of tumor cells in vitro and in vivo. In this study, we investigated whether BI could enhance the inhibitory effects of 5-FU on the proliferation of gastric adenocarcinoma cells and the growth of gastric cancer cell xenografts in a mouse model. The effects of BI and 5-FU alone or their combination on the cell viability, apoptosis, and mitochondrial membrane potential, the cell cycle, and its related proteins—Cyclin D1, and CDK4 as well as PCNA and GSK-3β were evaluated in SGC-7901 cells and MKN45 cells by MTT, MB, flow cytometry and Western blot. In addition, the effects of BI and 5-FU alone or their combination on the growth of SGC-7901 cell xenografts in nude mice were investigated. The results showed that BI significantly enhanced the sensitivity of gastric adenocarcinoma cells to 5-FU in vitro and in vivo, i.e. proliferation inhibited, apoptosis induced and GSK-3β protein activated. Therefore, our results suggest that BI increases the antitumor effect of 5-FU on gastric adenocarcinoma cells, at least partly from an activated GSK-3β signaling pathway. [ABSTRACT FROM AUTHOR]

More than 30% of acute myeloid leukemia (AML) patients possess activating mutations in the receptor tyrosine kinase FMS-like tyrosine kinase 3 or FLT3. A small-molecule inhibitor of FLT3 (known as quizartinib or AC220) that is currently in clinical trials appears promising for the treatment of AML. Here, we report the co-crystal structure of the kinase domain of FLT3 in complex with quizartinib. FLT3 with quizartinib bound adopts an "Abl-like" inactive conformation with the activation loop stabilized in the "DFG-out" orientation and folded back onto the kinase domain. This conformation is similar to that observed for the uncomplexed intracellular domain of FLT3 as well as for related receptor tyrosine kinases, except for a localized induced fit in the activation loop. The co-crystal structure reveals the interactions between quizartinib and the active site of FLT3 that are key for achieving its high potency against both wild-type FLT3 as well as a FLT3 variant observed in many AML patients. This co-complex further provides a structural rationale for quizartinib-resistance mutations.

Physical capital stock is the basic indicator of macroeconomic empirical studies and also an important manifestation of macroeconomic activity capacity. When measuring China's provincial physical capital stock by the perpetual inventory method, the treatment for the depreciation rate and the initial physical capital stock in the existing literature has some defects in reflecting the economic performance. The purpose of this paper is to build the most reliable and reasonable statistical series of China's provincial physical capital stock. We establish a measurement formula in form of the variable depreciation rate and improve the treatment for the depreciation rate and the initial physical capital stock. For the depreciation rate, we measure the benchmark depreciation rate of physical capital and determine the variable depreciation rate according to the economic growth rate, which makes the variable depreciation rate reflect the economic growth. For the initial physical capital stock, we measure the initial physical capital stock according to the capital output ratio, which makes the initial physical capital stock reflect the economic aggregate. Based on these improvements, we measure China's provincial physical capital stock from 1952 to 2022 by the perpetual inventory method. Through analyzing the measurement results, we have a more distinct insight into the temporal and spatial characteristics of China's provincial physical capital stock: The growth rate of physical capital stock at the provincial level has slowed in spite of remaining high; The eastern region is much higher than the central and western regions. According to these two characteristics, it is suggested that policymakers need to improve market mechanisms and adjust investment policies to promote a benign profile of economic growth and a regional optimization of capital formation. [ABSTRACT FROM AUTHOR]

This paper investigates the effect of Chinese outward foreign direct investment (FDI) on youth unemployment in sub-Saharan Africa (SSA) by using a modified labour demand model to identify the investment sources that are helpful for reducing youth unemployment in the region. The model is applied to a panel of 42 countries for the period 2003–2021 using random-effect, and generalized method of moment (GMM) estimators for robustness check. Our results suggest that Chinese FDI has direct short-term reducing effect on youth unemployment in SSA. The direction of China's capital investment to infrastructure development and other labour-intensive activities leads to immediate reduction in youth unemployment. However, overtime, due to absence of linkages with domestic firms, and thus lack of demand effects, Chinese FDI becomes insignificant for employment creation. Our results also indicate that Other FDI does not lead to significant reduction in youth unemployment both currently and overtime. Our analysis gives partial support to the argument that the impact of Chinese FDI may differ from those of developed countries. Finally, we could not find evidence that the effect of FDI on employment depends on host country human capital and institutional quality. Several specifications of the empirical model are tested, and explanations are provided for the results. Policy implications are highlighted, especially the need to attract more job absorbing FDI and improve domestic absorptive capacity. [ABSTRACT FROM AUTHOR]

Background: Existing research has demonstrated links between airborne particulate matter and ulcerative colitis (UC) onset. Through Mendelian randomization, this study aims to further delineate the causal association between specific types of airborne particulates and UC. Methods: A two-sample Mendelian randomization analysis was undertaken to investigate the causality between airborne particulate matter and UC. Genetic datasets for both airborne particulates and UC were derived from accessible genome-wide association studies (GWAS). We employed a range of MR techniques, such as inverse variance weighted (IVW), weighted median, MR-Egger, and Wald Ratio, to validate the causality. In addition, sensitivity assessments were executed to ensure result reliability. Results: The data indicate a probable positive correlation between PM2.5 exposure and UC risk (OR: 3.6; 95% CI: [1.2–11.3]; P = 0.026). The statistical strength for causal determination via the IVW approach stood at 0.87, with a Type I error rate set at 0.025. Assessments using Cochran's Q test, MR-Egger intercept, MR-PRESSO, and leave-one-out sensitivity analyses did not identify notable heterogeneity, pleiotropy, or biases in the overall relationship between PM2.5 and UC. Furthermore, the MR-Steiger assessment indicated that PM2.5 exposure level determinants predominantly affect UC vulnerability. Conclusion: The findings underscore the potential involvement of PM2.5 in UC pathogenesis. [ABSTRACT FROM AUTHOR]