Microplastic aging alters the adsorption-desorption behaviors of sulfamethoxazole in marine animals: A study in simulated biological liquids.

Antibiotics and microplastics (MPs) coexisting as unique environmental contaminants may cause unintended environmental issues. In this study, the adsorption-desorption behaviors of sulfamethoxazole (SMX) on both original and UV-aged MPs were examined. Polyhydroxyalkanoates (PHA) and polyethylene (PE), which represent degradable and refractory MPs, respectively, were chosen as two distinct types of MPs. Furthermore, simulated fish intestinal fluids (SFIF) and simulated mammalian stomach fluids (SMGF) were employed to evaluate the desorption behaviors of SMX from aged MPs. Our findings demonstrate that UV-aging altered the polarity, hydrophilicity, and structure of the MPs. Aged MPs showed a higher adsorption capacity than the original MPs and they have a higher desorption capacity than original MPs in simulated body fluids. PE has a higher SMX desorption capacity in SFIF and the opposite happened in SMGF. Our results highlight the importance of considering the different adsorption-desorption behaviors of antibiotics on MPs when evaluating their environmental impact.

P4HA2-mediated HIF-1α stabilization promotes erdafitinib-resistance in FGFR3-alteration bladder cancer.

Erdafitinib is a novel fibroblast growth factor receptor (FGFR) inhibitor that has shown great therapeutic promise for solid tumor patients with FGFR3 alterations, especially in urothelial carcinoma. However, the mechanisms of resistance to FGFR inhibitors remain poorly understood. In this study, we found Erdafitinib could kill cells by inducing incomplete autophagy and increasing intracellular reactive oxygen species levels. We have established an Erdafitinib-resistant cell line, RT-112-RS. whole transcriptome RNA sequencing (RNA-Seq) and Cytospace analysis performed on Erdafitinib-resistant RT-112-RS cells and parental RT-112 cells introduced P4HA2 as a linchpin to Erdafitinib resistance. The gain and loss of function study provided evidence for P4HA2 conferring such resistance in RT-112 cells. Furthermore, P4HA2 could stabilize the HIF-1α protein which then activated downstream target genes to reduce reactive oxygen species levels in bladder cancer. In turn, HIF-1α could directly bind to P4HA2 promoter, indicating a positive loop between P4HA2 and HIF-1α in bladder cancer. These results suggest a substantial role of P4HA2 in mediating acquired resistance to Erdafitinib and provide a potential target for bladder cancer treatment.

SGK2 promotes prostate cancer metastasis by inhibiting ferroptosis via upregulating GPX4.

Recent research has shown that ferroptosis, the iron-dependent accumulation of lipid peroxides that leads to cell death, suppresses cancer metastasis. However, the role of ferroptosis in prostate cancer metastasis has not been completely elucidated. In the current study, we identified the essential role of serum/glucocorticoid regulated kinase 2 (SGK2) in promoting prostate cancer metastasis by inhibiting ferroptosis. We found that the expression of SGK2 was higher in metastatic prostate cancer and predicted poor clinical outcomes. SGK2 knockdown inhibited the metastatic capacity of prostate cancer cells in vivo and in vitro, while SGK2 overexpression inhibited ferroptosis and facilitated prostate cancer metastasis by phosphorylating the Thr-24 and Ser-319 sites of forkhead box O1 (FOXO1). This process induced the translocation of FOXO1 from the nucleus to the cytoplasm, relieving the inhibitory effect of FOXO1 on glutathione peroxidase 4 (GPX4). These findings delineated a novel role of SGK2 in ferroptosis regulation of prostate cancer metastasis, identifying a new key pathway driving prostate cancer metastasis and potentially providing new treatment strategies for metastatic prostate cancer.

Distinct responses of Chlorella vulgaris upon combined exposure to microplastics and bivalent zinc.

Microplastics (MPs) and heavy metals are ubiquitous pollutants in the aquatic environment. In this study, the sorption behavior of two typical MPs (PVC and PE) to bivalent zinc ions (Zn(II)) and their combined toxic effects on Chlorella vulgaris were systemically studied. The growth inhibition rate, the activities of photosynthesis and antioxidant enzymes (SOD and CAT), the cell membrane integrity and the cell apoptosis rate were employed to evaluate the toxicity. Our result showed that PVC and PE have different adsorption capacities for Zn(II), and the combined exposure to Zn(II) and MPs had distinct patterns on the inhibition of the cell growth and induction of oxidative stress. Under our experimental concentrations, PE and Zn(II) showed a synergistic effect, while PVC and Zn(II) exhibited an antagonistic effect. Finally, an action mechanism was proposed to explain the experimental phenomena. This study demonstrated that flow cytometry can be a powerful tool to study the toxic effect of MP composites, and MPs can not only allow a free ride for the water contaminants, but also remarkably alter their toxic effects on phytoplankton. These effects deserve further consideration during evaluation of ecological risks of MPs in the water environment.

Polybrominated diphenyl ethers as hitchhikers on microplastics: Sorption behaviors and combined toxicities to Epinephelus moara.

Emerging pollutants, such as microplastics (MPs) and polybrominated diphenyl ethers (PBDEs) may pose a serious threat to human health and ecological safety. However, little is known about the MP-mediated PBDEs exposures and their combined toxicities towards farmed fishes. This study investigated the sorption behaviors of two typical PBDEs (BDE-47 and BDE-209) to MPs of different polymer types (PE, PS, PHA and PHB), and examined their combined toxic effects on grouper (Epinephelus moara) by determining the change of oxidative stress markers and comparing gene expression difference through high-throughput sequencing. Our results demonstrated that the sorption of PBDEs on MPs were polymer type-dependent and the sorption capacities were in the order of PHA>PHB>PS>PE. The combined exposures of MPs and PBDEs led to more severe disturbance on the oxidative system compared with individual exposure. The activity of superoxide dismutase (SOD) and the content of glutathione were decreased, while the activity of catalase (CAT) and the content of malondialdehyde were increased. The disorder of oxidative system can influence the growth of groupers. High-throughput sequencing confirmed that pathways of ferroptosis, IL-17 and PPAR expressed differently under combined exposure of MPs and BDE-47. IL-17 pathway related genes were inhibited, while genes in PPAR pathway were upregulated. The combined exposure brought more severe effect on grouper's gene expression compared with individual exposure. GPX-related genes and CAT gene in the liver were up-regulated, while SOD-related genes were down-regulated. Our results demonstrated that the combined toxicity of MPs and PBDEs can pose a non-neglectable threat to aquaculture development and food safety, and gained a primary insight into the potential risk of MPs to farmed fishes.

Suppression of the Electrical Crosstalk of Planar-Type High-Density InGaAs Detectors with a Guard Hole.

The resolution of InGaAs FPA detectors is degraded by the electrical crosstalk, which is especially severe in high-density FPAs. We propose a guard-hole structure to suppress the electrical crosstalk in a planar-type 640 × 512 15 µm InGaAs short wavelength infrared FPA detector. For comparison, the frequently used guard ring is also prepared according to the same processing. The calculation results show that the electrical crosstalk with a guard hole is suppressed from 13.4% to 4.5%, reducing by 66%, while the electrical crosstalk with a guard ring is suppressed to 0.4%. Furthermore, we discuss the effects of the guard ring and the guard hole on the dark current, quantum efficiency, and detectivity. Experimental results show the detector with a guard-hole structure has higher performance compared with the detector with a guard-ring structure, the dark current density is reduced by 60%, the QE is increased by 64.5%, and the detectivity is increased by 1.36 times, respectively. The guard-hole structure provides a novel suppression method for the electrical crosstalk of high-density InGaAs detectors.

CircCEMIP promotes anoikis-resistance by enhancing protective autophagy in prostate cancer cells.

BACKGROUND: Circular RNAs (circRNAs) are essential participants in the development and progression of various malignant tumors. Previous studies have shown that cell migration-inducing protein (CEMIP) accelerates prostate cancer (PCa) anoikis resistance (AR) by activating autophagy. This study focused on the effect of circCEMIP on PCa metastasis. METHODS: This study gradually revealed the role of circ_0004585 in PCa anoikis resistance via quantitative real-time PCR (qRT-PCR) analysis, western blotting, pull-down assays, and dual fluorescence reporter assays. RESULTS: Functionally, circ_0004585 promoted PCa cells invasion and metastasis both in vitro and in vivo. Mechanistically, circ_0004585 directly interacted with miR-1248 to upregulate target gene expression. Furthermore, target prediction and dual-luciferase reporter assays identified transmembrane 9 superfamily member 4 (TM9SF4) as a potential miR-1248 target. Pathway analysis revealed that TM9SF4 activated autophagy to promote PCa cells anoikis resistance via mTOR phosphorylation. CONCLUSIONS: These results demonstrated that circ_0004585 played an oncogenic role during PCa invasion and metastasis by targeting the miR-1248/TM9SF4 axis while providing new insight into therapeutic strategy development for metastatic PCa.

Circ_0004087 interaction with SND1 promotes docetaxel resistance in prostate cancer by boosting the mitosis error correction mechanism.

BACKGROUND: Acquisition of the chemoresistance to docetaxel (DTX), a microtubule-targeting agent, has been a huge obstacle in treatment for metastatic castration-resistant prostate cancer (mCRPC). Recently, strategies targeting the mitosis error correction mechanism including chromosomal passenger complex (CPC) were reported to reverse the resistance to microtubule-targeting anticancer agents. Meanwhile, accumulating evidence indicated the important roles of circRNAs in DTX resistance of prostate cancer (PCa). However, whether circRNAs could regulate DTX chemosensitivity by affecting the mitosis error correction mechanism remains unclear. METHODS: Expression patterns of circ_0004087 and BUB1 were determined through mining the public circRNA datasets and performing western blot and qRT-PCR assays. Agarose gel electrophoresis, Sanger sequencing, and RNase R treatment were conducted to examine the circular characteristics of circ_0004087. CircRNA pull-down, mass spectrometry analysis, Co-IP, and dual-luciferase reporter assays were performed to uncover the interaction among circ_0004087, SND1, and MYB. The effects of circ_0004087 and BUB1 on docetaxel-based chemotherapy were explored by flow cytometry and in vivo drug studies upon xenografted tumor model. RESULTS: In the present study, we revealed the profound interaction between a novel circRNA, circ_0004087, and the mitosis error correction mechanism. Mechanistically, circ_0004087 binding with transcriptional coactivator SND1 could stimulate the transactivation of MYB and enhance the expression of downstream target BUB1. In turn, elevated BUB1 expression further recruited CPC to centromeres and guaranteed the error-free mitosis of PCa cells. Biologically, the overexpression of circ_0004087 conferred while the knockdown impaired DTX resistance in PCa cells. CONCLUSIONS: Our study uncovered the crucial role of circ_0004087/SND1/MYB/BUB1 axis in modulating the error mitosis correction mechanism and DTX chemoresistance, suggesting that circ_0004087 may serve as a valuable prognostic biomarker and a potential therapeutic target in DTX-resistant PCa patients.

Identification of ISG15 and ZFP36 as novel hypoxia- and immune-related gene signatures contributing to a new perspective for the treatment of prostate cancer by bioinformatics and experimental verification.

BACKGROUND: Prostatic cancer (PCa) is one of the most common malignant tumors in men worldwide. Emerging evidence indicates significance of hypoxia and immunity in PCa invasion and metastasis. This study aimed to develop a hypoxia- and immune-related gene risk signature and explore the molecular mechanisms to formulate a better prognostic tool for PCa patients. METHODS: The hypoxia and immune scores of all PCa patients in The Cancer Genome Atlas (TCGA) dataset were calculated via the maximally selected rank statistics method and the ESTIMATE algorithm. From common genes identified overlapping hypoxia- and immune-related differentially expressed genes (DE-HRGs and DE-IRGs), a hypoxia- and immune-related gene risk signature was developed utilizing univariate and multivariate Cox regression analyses, and validated in the Memorial Sloan Kettering Cancer Centre (MSKCC) database. The immune cell infiltration level of PCa samples were evaluated with ssGSEA algorithm. Differential expression of prognostic genes was evidenced by immunohistochemistry and western blot (WB) in paired PCa samples. Expression levels of these genes and their variations under regular and hypoxic conditions were examined in cell lines. The functional effects of the prognostic gene on PCa cells were examined by wound healing and transwell assays. RESULTS: A hypoxia- and immune-related gene risk signature constructed by ISG15 and ZFP36 displays significant predictive potency, with higher risk score representing worse survival. A nomogram based on independent prognostic factors including the risk score and Gleason score exhibited excellent clinical value in the survival prediction of PCa. Infiltration levels of eosinophils, neutrophils, Tcm, Tem, TFH, Th1 cells, and Th17 cells were significantly lower in the high-risk group. Conversely, aDC, pDC, T helper cells, and Tregs were significantly higher. Additionally, the two prognostic genes were closely correlated with the tumor-infiltrating immune cell subset in PCa progression. RT-qPCR and WB presented higher and lower expression of ISG15 and ZFP36 in PCa cells, respectively. They were correspondingly increased and decreased in PCa cells under hypoxic conditions. Wound healing and transwell assays showed that over-expression of ISG15 promoted the migration and invasion of PCa cells. CONCLUSION: Our study identified a novel hypoxia- and immune-related gene signature, contributing a new perspective to the treatment of PCa.

CEMIP promotes extracellular matrix-detached prostate cancer cell survival by inhibiting ferroptosis.

Cells detached from the extracellular matrix (ECM) can trigger different modes of cell death, and the survival of ECM-detached cells is one of the prerequisites for the metastatic cascade. Ferroptosis, a form of iron-dependent programmed cell death, has recently been found to be involved in matrix-detached cancer cells. However, the molecular mechanisms by which ECM-detached cells escape ferroptosis are not fully understood. Here, we observed that cell migration-inducing protein (CEMIP) upregulation facilitates ferroptosis resistance during ECM detachment by promoting cystine uptake in prostate cancer (PCa) cells. Meanwhile, silencing CEMIP causes it to lose its ability to promote cystine uptake and inhibit ferroptosis. Mechanistically, the interaction of CEMIP with inositol 1,4,5-trisphosphate receptor type 3 (ITPR3) modulates calcium ion (Ca2+ ) leakage from the endoplasmic reticulum, activating calcium/calmodulin-dependent protein kinase II (CaMKII), which further facilitates nuclear factor erythroid 2-related factor 2 (NRF2) phosphorylation and nuclear localization, leading to elevated transcription of solute carrier family 7 member 11 (SLC7A11), a glutamate/cystine antiporter, in PCa cells. Our findings delineate a novel role of CEMIP in ferroptosis resistance during ECM detachment and provide new insights into therapeutic strategies for metastatic PCa.

Quinoline-Based Photolabile Protection Strategy Facilitates Efficient Protein Assembly.

Native chemical ligation (NCL) provides a powerful solution to assemble proteins with precise chemical features, which enables a detailed investigation of the protein structure-function relationship. As an extension to NCL, the discovery of desulfurization and expressed protein ligation (EPL) techniques has greatly expanded the efficient access to large or challenging protein sequences via chemical ligations. Despite its superior reliability, the NCL-desulfurization protocol requires orthogonal protection strategies to allow selective desulfurization in the presence of native Cys, which is crucial to its synthetic application. In contrast to traditional thiol protecting groups, photolabile protecting groups (PPGs), which are removed upon irradiation, simplify protein assembly and therefore provide minimal perturbation to the peptide scaffold. However, current PPG strategies are mainly limited to nitro-benzyl derivatives, which are incompatible with NCL-desulfurization. Herein, we present for the first time that quinoline-based PPG for cysteine can facilitate various ligation strategies, including iterative NCL and EPL-desulfurization methods. 7-(Piperazin-1-yl)-2-(methyl)quinolinyl (PPZQ) caging of multiple cysteine residues within the protein sequence can be readily introduced via late-stage modification, while the traceless removal of PPZQ is highly efficient via photolysis in an aqueous buffer. In addition, the PPZQ group is compatible with radical desulfurization. The efficiency of this strategy has been highlighted by the synthesis of γ-synuclein and phosphorylated cystatin-S via one-pot iterative ligation and EPL-desulfurization methods. Besides, successful sextuple protection and deprotection of the expressed Interleukin-34 fragment demonstrate the great potential of this strategy in protein caging/uncaging investigations.

ATF4/CEMIP/PKCα promotes anoikis resistance by enhancing protective autophagy in prostate cancer cells.

The survival of cancer cells after detaching from the extracellular matrix (ECM) is essential for the metastatic cascade. The programmed cell death after detachment is known as anoikis, acting as a metastasis barrier. However, the most aggressive cancer cells escape anoikis and other cell death patterns to initiate the metastatic cascade. This study revealed the role of cell migration-inducing protein (CEMIP) in autophagy modulation and anoikis resistance during ECM detachment. CEMIP amplification during ECM detachment resulted in protective autophagy induction via a mechanism dependent on the dissociation of the B-cell lymphoma-2 (Bcl-2)/Beclin1 complex. Additional investigation revealed that acting transcription factor 4 (ATF4) triggered CEMIP transcription and enhanced protein kinase C alpha (PKCα) membrane translocation, which regulated the serine70 phosphorylation of Bcl-2, while the subsequent dissociation of the Bcl-2/Beclin1 complex led to autophagy. Therefore, CEMIP antagonization attenuated metastasis formation in vivo. In conclusion, inhibiting CEMIP-mediated protective autophagy may provide a therapeutic strategy for metastatic prostate cancer (PCa). This study delineates a novel role of CEMIP in anoikis resistance and provides new insight into seeking therapeutic strategies for metastatic PCa.

Impacts of Micro- and Nanoplastics on Photosynthesis Activities of Photoautotrophs: A Mini-Review.

The accumulation of micro- and nanoplastics (MNPs) has attracted immense global attention due to their adverse effects on the environment. Photosynthesis, an interface between non-living matter and living organisms, is very important for both energy flow and material circulation on our planet. Increasing evidence indicates that MNPs can pose direct or indirect stress effects on photoautotrophs, however, our knowledge about them is still limited. The purposes of this mini-review are (1) to review the latest literature of the impacts of MNPs on photosynthesis activities and summarize diverse impacts of MNPs on photosynthesis activities of different photoautotrophs (green plants, microalgae, and cyanobacteria); (2) to discuss the potential action mechanisms in both aquatic and terrestrial environments; and (3) various factors contributing toward these impacts. Additionally, this review provides key future research directions for both researchers and policymakers to better understand and alleviate the environmental impacts of MNPs on our planet.

Identification of Survival and Therapeutic Response-Related Ferroptosis Regulators in Bladder Cancer through Data Mining and Experimental Validation.

Ferroptosis has been reported to regulate tumorigenesis, metastasis, drug resistance and the immune response. However, the potential roles of ferroptosis regulators in the advancement of bladder cancer remain to be explored. We systematically evaluated the multidimensional alteration landscape of ferroptosis regulators in bladder cancer and checked if their expression correlated with the ferroptosis index. We used least absolute shrinkage and selection operator regression to form a signature consisting of seven ferroptosis regulator. We confirmed the signature's prognostic and predictive accuracy with five independent datasets. A nomogram was built to predict the overall survival and risk of death of patients. The relative expression of the genes involved in the signature was also clarified by real-time quantitative PCR. We found the risk score was related to tumor progression and antitumor immunity-related pathways. Moreover, there existed negative association between the relative antitumor immune cell infiltration level and the risk score, and higher tumor mutation burden was found in the group of lower risk score. We used The Tumor Immune Dysfunction and Exclusion database and IMvigor210 cohort having immunotherapy efficacy results to confirm the prediction function of the risk score. Furthermore, the ferroptosis regulator signature could also reflect the chemotherapy sensitivity of bladder cancer.

Scoring System Based on RNA Modification Writer-Related Genes to Predict Overall Survival and Therapeutic Response in Bladder Cancer.

Introduction: It's widely reported the "writer" enzymes mediated RNA adenosine modifications which is known as a crucial mechanism of epigenetic regulation in development of tumor and the immunologic response in many kinds of cancers. However, the potential roles of these writer genes in the progression of bladder cancer (BLCA) remain unclear. Materials and Methods: We comprehensively described the alterations of 26 RNA modification writer genes in BLCA from the genetic and transcriptional fields and identified writer-related genes from four independent datasets. Utilizing least absolute shrinkage and selection operator (LASSO) regression and multivariate Cox regression, we constructed a ten writer-related gene signature. After that, we confirmed the predictive and prognostic value of this signature on another six independent datasets and established a nomogram to forecast the overall survival (OS) and mortality odds of BLCA patients clinically. Results: The writer-related genes signature showed good performance in predicting the OS for BLCA patients. Moreover, the writer-related gene signature was related to EMT-related pathways and immune characteristics. Furthermore, the immune cell infiltration levels of CD8 T cells, cytotoxic cells, M1/2 macrophage cells and tumor mutation burden might be able to predict which patients will benefit from immunotherapy. This could also be reflected by the writer-related gene signature. Conclusions: This signature might play an important role in precision individualized immunotherapy. The present work highlights the crucial clinical implications of RNA modifications and may help developing individualized therapeutic strategies for patients with BLCA.

KAT2A-mediated AR translocation into nucleus promotes abiraterone-resistance in castration-resistant prostate cancer.

Abiraterone, a novel androgen synthesis inhibitor, has been approved for castration-resistant prostate cancer (CRPC) treatment. However, most patients eventually acquire resistance to this agent, and the underlying mechanisms related to this resistance remain largely unelucidated. Lysine acetyltransferase 2 A (KAT2A) has been reported to enhance transcriptional activity for certain histone or non-histone proteins through the acetylation and post-translational modification of the androgen receptor (AR). Therefore, we hypothesised that KAT2A might play a critical role in the resistance of prostate tumours to hormonal treatment. In this study, we found that KAT2A expression was increased in abiraterone-resistant prostate cancer C4-2 cells (C4-2-AbiR). Consistently, elevated expression of KAT2A was observed in patients with prostate cancer exhibiting high-grade disease or biochemical recurrence following radical prostatectomy, as well as in those with poor clinical survival outcomes. Moreover, KAT2A knockdown partially re-sensitised C4-2-AbiR cells to abiraterone, whereas KAT2A overexpression promoted abiraterone resistance in parental C4-2 cells. Consistent with this finding, KAT2A knockdown rescued abiraterone sensitivity and inhibited the proliferation of C4-2-AbiR cells in a mouse model. Mechanistically, KAT2A directly acetylated the hinge region of the AR, and induced AR translocation from the cytoplasm to the nucleus, resulting in increased transcriptional activity of the AR-targeted gene prostate specific antigen (PSA) leading to resistance to the inhibitory effect of abiraterone on proliferation. Taken together, our findings demonstrate a substantial role for KAT2A in the regulation of post-translational modifications in AR affecting CRPC development, suggesting that targeting KAT2A might be a potential strategy for CRPC treatment.

A vertically configured photocatalytic-microbial fuel cell for electricity generation and gaseous toluene degradation.

A vertically configured photocatalytic-microbial fuel cell (photo-MFC) is developed by combining a nanodiamond-decorated ZnO (ZnO/ND) photocathode with a bioanode. The system can effectively couple the light energy with bioenergy to enhance the degradation of volatile organic compounds (VOCs) and boost electricity output. Results show that the composite system exhibits increased performance for toluene removal (60.65%), higher than those of individual parts (ZnO/ND-photocatalysis: 37.16%, MFC: 17.81%). Furthermore, its electrochemical performance is dramatically increased. The peak power density of 120 mW/m2 and the current density of 1.07 A/m2 are generated under light illumination, which are about 1.57-fold and 1.37-fold higher than that under dark (76 mW/m2, 0.78 A/m2), respectively. Microbial community analysis demonstrates Proteobacteria and Firmicute are dominant phyla, implying they play important roles on accelerating the extracellular-electron transfer and toluene degradation. In addition, the underlying mechanism for toluene degradation in the photo-MFC system is preliminary explored. Our results suggest that the photo-MFC has great potential for simultaneous treatment of VOCs with energy recovery.

Modification of N-terminal α-amine of proteins via biomimetic ortho-quinone-mediated oxidation.

Naturally abundant quinones are important molecules, which play essential roles in various biological processes due to their reduction potential. In contrast to their universality, the investigation of reactions between quinones and proteins remains sparse. Herein, we report the development of a convenient strategy to protein modification via a biomimetic quinone-mediated oxidation at the N-terminus. By exploiting unique reactivity of an ortho-quinone reagent, the α-amine of protein N-terminus is oxidized to generate aldo or keto handle for orthogonal conjugation. The applications have been demonstrated using a range of proteins, including myoglobin, ubiquitin and small ubiquitin-related modifier 2 (SUMO2). The effect of this method is further highlighted via the preparation of a series of 17 macrophage inflammatory protein 1ß (MIP-1ß) analogs, followed by preliminary anti-HIV activity and cell viability assays, respectively. This method offers an efficient and complementary approach to existing strategies for N-terminal modification of proteins.