The N-terminal Phosphodegron Targets TAZ/WWTR1 Protein for SCF β-TrCP -dependent Degradation in Response to Phosphatidylinositol 3-Kinase Inhibition

The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as WWTR1) is a transcription co-activator acting downstream of the Hippo pathway, and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by large tumor suppressor (LATS)-dependent phosphorylation, leading to cytoplasmic retention and ubiquitin-dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study, we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT-dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ, and the phosphorylated TAZ binds to β-TrCP subunit of the SCFβ-TrCP E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling

Fault Spread and Recovery Strategy of Urban Rail Transit System Based on Complex Network

Urban rail transit plays a pivotal role in the overall urban transportation system, serving as a preferred mode of travel for a growing number of people in recent years. However, the occurrence of station failures due to emergencies is an inevitable challenge that can significantly impact the entire transit system. This has led to an increased demand for improved operational resilience and recovery mechanisms within urban rail transit systems. Addressing how to effectively suppress fault spread and swiftly recover the system post-failure has become a pressing issue.In this research, we utilized metro network data obtained from Gaode map and employed complex network theory to establish a network topology model. The study focused on investigating the fault spread dynamics within the metro network, both in scenarios without recovery and with recovery measures in place. The goal was to understand the underlying patterns and laws governing fault propagation in urban rail transit systems. By analyzing the data and modeling recovery strategies, we aimed to contribute insights into mitigating the impact of failures and enhancing the overall reliability of urban rail transit systems.The research concludes with a simulation of four distinct recovery strategies, providing a comparative analysis of their effectiveness. These findings are crucial for urban planners, transit authorities, and policymakers in developing strategies to minimize the impact of emergencies on urban rail transit, ensuring a resilient and efficient transportation system for the growing urban population

Isolation and characterization of a marine bacterium Vibrio diabolicus strain L2-2 capable of biotransforming sulfonamides

Sulfonamides (SAs) have attracted much attention because of their high detection rates in natural water. In this study, a marine bacterium Vibrio diabolicus strain L2-2 was isolated which could metabolize 9 SAs to a different extent. Compared with SAs and their analogs, SAs with N-oxides of heterocyclic structure were easier to be transformed to their N-4-acetylated metabolites or their isoxazole ring rearrangement isomers by strain L2-2. And, gene vdnatA and vdnatG were likely to be the key genes in SAs acetylation process, which might code Arylamine N-acetyltransferase. The biotransformation rates of sulfathiazole(STZ), sulfamonomethoxine(SMT), sulfadiazine (SDZ), sulfamethoxazole(SMX) and sulfisoxazole(SIX) could reach 29.39 +/- 5.63, 24.97 +/- 4.45, 79.41 +/- 4.05, 64.64 +/- 1.71, 32.82 +/- 4.46% in 6 days, respectively. Besides, the overall optimal conditions for SAs biotransformation were less than 100 mg/L for total SAs in neutral or weakly alkaline medium with the salinity of 10-20%o and additional nutrients like glucose, sucrose or glycerine. Furthermore, toxicity was demonstrated to be significantly reduced after biotransformation. Together, this study introduced a strategy to use V. diabolicus strain L2-2 to realize simultaneous removal and detoxification of multiple SAs in freshwater and seawater, and revealed SAs removal pathways and relevant molecular mechanism

Exposure to microplastics reduces the bioaccumulation of sulfamethoxazole but enhances its effects on gut microbiota and the antibiotic resistome of mice

Microplastics (MPs) have aroused a global health concern and their coexistence with antibiotics is inevitable. However, how MPs would affect the bioaccumulation and risks of antibiotics in humans remains poorly understood. Here a mouse model was used, and through dietary exposure, we observed that while the relative distributions of sulfamethoxazole (SMX) in tissues were relatively stable, MPs significantly reduced the bioaccumulation of SMX in mice tissues (liver, lung, spleen, heart and kidney). Notably, while SMX and MPs showed a differential effect, MPs could exacerbate the effects of SMX on gut microbiota and antibiotic resistance gene (ARG) profile, with the relative abundances of sulfonamide resistance genes and multidrug genes being significantly increased. We further identified that shifts in gut microbiota contributed to the changes in ARG profiles in mice. Combined, our results demonstrate that MPs reduced the bioaccumulation of SMX, but they enhanced its effects on gut microbiota and the antibiotic resistome of mice, indicating they might have high risks to humans

Methylparaben toxicity and its removal by microalgae Chlorella vulgaris and Phaeodactylum tricornutum

The widespread occurrence of methylparaben (MPB) has aroused great concern due to its weak estrogenic endocrine-disrupting property and potential toxic effects. However, the degradation potential and pathway of MPB by microalgae have rarely been reported. Here, microalgae Chlorella vulgaris and Phaeodactylum tricornutum were used to investigate their responses, degradation potential and mechanisms towards MPB. MPB showed low -dose stimulation (by 86.02 +/- 0.07% at 1 mg/L) and high-dose inhibition (by 60.17 +/- 0.05% at 80 mg/L) to-wards the growth of C. vulgaris, while showed inhibition for P. tricornutum (by 6.99 +/- 0.05%-20.14 +/- 0.19%). The degradation efficiencies and rates of MPB were higher in C. vulgaris (100%, 1.66 +/- 0.54-5.60 +/- 0.86 day-1) than in P. tricornutum (4.3-34.2%, 0.04 +/- 0.01-0.08 +/- 0.00 day -1), which could be explained by the signifi-cantly higher extracellular enzyme activity and more fluctuation of the protein ratio for C. vulgaris, indicating a higher ability of C. vulgaris to adapt to pollutant stress. Biodegradation was the main removal mechanism of MPB for both the two microalgae. Furthermore, two different degradation pathways of MPB by the two microalgae were proposed. MPB could be mineralized and completely detoxified by C. vulgaris. Overall, this study provides novel insights into MPB degradation by microalgae and strategies for simultaneous biodegradation and detox-ification of MPB in the environment

Genome-wide association analyses in Han Chinese identify two new susceptibility loci for amyotrophic lateral sclerosis

10.1038/ng.2627Nature Genetics456697-700NGEN