Giant enhancement of fluorescence resonance energy transfer based on nanoporous gold with small amount of residual silver.

Fluorescence resonance energy transfer (FRET) was found strongly enhanced by plasmon resonance. In this work, Nanoporous Gold with small amount of residual silver was used to form nanoporous gold/organic molecular layer compound with PSS and PAH. The ratio of its specific gold and silver content is achieved by controlling the time of its dealloying. Layered films of polyelectrolyte multilayers were assembled between the donor-acceptor pairs and NPG films to control distance. The maximum of FRET enhancement of 80-fold on the fluorescence intensity between the donor-acceptor pairs (CFP-YFP) is observed at a distance of ∼10.5 nm from the NPG film. This Nanoporous Gold with small amount of residual silver not only enhanced FRET 4-fold more than nanoporous gold of only gold content almost, but also effectively realized the regulation of FRET enhancement. The ability to precisely measure and regulate the enhancement of FRET enables the rational selection of plasmonic nanotransducer dimensions for the particular biosensing application.

Exploring the causal relationship between asthma in the metabolic syndrome: a Mendelian randomization study.

Background Previous observational studies have indicated a potential association between metabolic syndrome (MetS) and asthma, though the causal nature of this connection is still uncertain. Our study used Mendelian randomization (MR) to examine the causal relationship between metabolic syndrome (MetS) and its components with asthma.Methods This study utilized single nucleotide polymorphisms (SNPs) related to MetS and its components, sourced from publicly available genome-wide association studies (GWAS) data, in combination with asthma data from the FinnGen database. Statistical analyses were conducted using the inverse variance weighting method (IVW), MR-Egger, and weighted median method. The robustness of the findings was confirmed through various sensitivity analyses.Results The IVW analysis indicated that MetS was associated with an increased risk of asthma (OR = 1.0781, 95% CI = 1.0255-1.1333, P = 0.0032). Among the components of MetS, waist circumference (WC) showed a strong association with asthma (OR = 1.4777, 95% CI = 1.3412-1.6281, P = 2.8707 × 10-15). Conversely, high-density lipoprotein cholesterol (HDL-C) was found to be inversely related to the risk of asthma (OR = 0.9186, 95% CI = 0.8669-0.9734, P = 0.0041).Conclusion The findings of this study support that MetS and its specific components, particularly abdominal obesity, are linked to a higher risk of asthma, while HDL-C might offer protective effects against asthma. These findings provide a foundation both for further research and possible therapeutic interventions.

PCK1 attenuates tumor stemness via activating the Hippo signaling pathway in hepatocellular carcinoma.

Liver cancer stem cells were found to rely on glycolysis as the preferred metabolic program. Phosphoenolpyruvate carboxylase 1 (PCK1), a gluconeogenic metabolic enzyme, is down-regulated in hepatocellular carcinoma and is closely related to poor prognosis. The oncogenesis and progression of tumors are closely related to cancer stem cells. It is not completely clear whether the PCK1 deficiency increases the stemness of hepatoma cells and promotes the oncogenesis of hepatocellular carcinoma. Herein, the results showed that PCK1 inhibited the self-renewal property of hepatoma cells, reduced the mRNA level of cancer stem cell markers, and inhibited tumorigenesis. Moreover, PCK1 increased the sensitivity of hepatocellular carcinoma cells to sorafenib. Furthermore, we found that PCK1 activated the Hippo pathway by enhancing the phosphorylation of YAP and inhibiting its nuclear translocation. Verteporfin reduced the stemness of hepatoma cells and promoted the pro-apoptotic effect of sorafenib. Thus, combined treatment with verteporfin and sorafenib may be a potential anti-tumor strategy in hepatocellular carcinoma.

O-GlcNAcylation of E3 ubiquitin ligase SKP2 promotes hepatocellular carcinoma proliferation.

O-linked-ß-N-acetylglucosamine (O-GlcNAc) modification (O-GlcNAcylation) and ubiquitination are critical posttranslational modifications that regulate tumor development and progression. The continuous progression of the cell cycle is the fundamental cause of tumor proliferation. S-phase kinase-associated protein 2 (SKP2), an important E3 ubiquitin ligase, assumes a pivotal function in the regulation of the cell cycle. However, it is still unclear whether SKP2 is an effector of O-GlcNAcylation that affects tumor progression. In this study, we found that SKP2 interacted with O-GlcNAc transferase (OGT) and was highly O-GlcNAcylated in hepatocellular carcinoma (HCC). Mechanistically, the O-GlcNAcylation at Ser34 stabilized SKP2 by reducing its ubiquitination and degradation mediated by APC-CDH1. Moreover, the O-GlcNAcylation of SKP2 enhanced its binding ability with SKP1, thereby enhancing its ubiquitin ligase function. Consequently, SKP2 facilitated the transition from the G1-S phase of the cell cycle by promoting the ubiquitin degradation of cell cycle-dependent kinase inhibitors p27 and p21. Additionally, targeting the O-GlcNAcylation of SKP2 significantly suppressed the proliferation of HCC. Altogether, our findings reveal that O-GlcNAcylation, a novel posttranslational modification of SKP2, plays a crucial role in promoting HCC proliferation, and targeting the O-GlcNAcylation of SKP2 may become a new therapeutic strategy to impede the progression of HCC.

EGR1 suppresses HCC growth and aerobic glycolysis by transcriptionally downregulating PFKL.

BACKGROUND: Hepatocellular Carcinoma (HCC) is a matter of great global public health importance; however, its current therapeutic effectiveness is deemed inadequate, and the range of therapeutic targets is limited. The aim of this study was to identify early growth response 1 (EGR1) as a transcription factor target in HCC and to explore its role and assess the potential of gene therapy utilizing EGR1 for the management of HCC. METHODS: In this study, both in vitro and in vivo assays were employed to examine the impact of EGR1 on the growth of HCC. The mouse HCC model and human organoid assay were utilized to assess the potential of EGR1 as a gene therapy for HCC. Additionally, the molecular mechanism underlying the regulation of gene expression and the suppression of HCC growth by EGR1 was investigated. RESULTS: The results of our investigation revealed a notable decrease in the expression of EGR1 in HCC. The decrease in EGR1 expression promoted the multiplication of HCC cells and the growth of xenografted tumors. On the other hand, the excessive expression of EGR1 hindered the proliferation of HCC cells and repressed the development of xenografted tumors. Furthermore, the efficacy of EGR1 gene therapy was validated using in vivo mouse HCC models and in vitro human hepatoma organoid models, thereby providing additional substantiation for the anti-cancer role of EGR1 in HCC. The mechanistic analysis demonstrated that EGR1 interacted with the promoter region of phosphofructokinase-1, liver type (PFKL), leading to the repression of PFKL gene expression and consequent inhibition of PFKL-mediated aerobic glycolysis. Moreover, the sensitivity of HCC cells and xenografted tumors to sorafenib was found to be increased by EGR1. CONCLUSION: Our findings suggest that EGR1 possesses therapeutic potential as a tumor suppressor gene in HCC, and that EGR1 gene therapy may offer benefits for HCC patients.

Ultrafast laser state active controlling based on anisotropic quasi-1D material.

Laser state active controlling is challenging under the influence of inherent loss and other nonlinear effects in ultrafast systems. Seeking an extension of degree of freedom in optical devices based on low-dimensional materials may be a way forward. Herein, the anisotropic quasi-one-dimensional layered material Ta2PdS6 was utilized as a saturable absorber to modulate the nonlinear parameters effectively in an ultrafast system by polarization-dependent absorption. The polarization-sensitive nonlinear optical response facilitates the Ta2PdS6-based mode-lock laser to sustain two types of laser states, i.e., conventional soliton and noise-like pulse. The laser state was switchable in the single fiber laser with a mechanism revealed by numerical simulation. Digital coding was further demonstrated in this platform by employing the laser as a codable light source. This work proposed an approach for ultrafast laser state active controlling with low-dimensional material, which offers a new avenue for constructing tunable on-fiber devices.

Diagnostic value of chemiluminescence for urinary lipoarabinomannan antigen assay in active tuberculosis: insights from a retrospective study.

Purpose: This study aimed to assess the efficacy of chemiluminescence-based urinary lipoarabinomannan (LAM) antigen assay as a diagnostic tool for identifying active tuberculosis. Methods: A retrospective study was conducted on 166 Tuberculosis (TB), 22 Non-Tuberculous Mycobacteria (NTM), 69 Non-TB cases, and 73 healthy controls from Zhangjiagang First Peoples Hospital between July 2022 and November 2022. Clinical and laboratory data were collected, including urine samples for LAM antigen detection, sputum samples and pleural effusion for GeneXpert, TB-DNA, and culture. Results: TB group exhibited a higher LAM positivity rate (P < 0.001). CD4 count and diabetes as independent factors influencing the diagnostic accuracy of LAM. The LAM assay showed a sensitivity of 50.6% and a specificity of 95.65%. Notably, LAM's sensitivity was superior to TB-DNA (50.60% vs. 38.16%, P < 0.05). LAM's PTB detection rate was 51.7%, superior to TB-DNA (P = 0.047). Moreover, in EPTB cases, the LAM detection rate was 42.11%, surpassing Gene Xpert (P = 0.042), as well as exceeding the detection rates of TB-DNA and sputum culture. Conclusion: LAM antigen detection using chemiluminescence has demonstrated outstanding clinical diagnostic value for active TB, especially in the diagnosis of extrapulmonary TB. The convenience of sample collection in this diagnostic approach allows for widespread application in the clinical diagnosis of active tuberculosis, particularly in cases of EPTB and sputum-negative patients.

Discovery of a Hidden Pocket beneath the NES Groove by Novel Noncovalent CRM1 Inhibitors.

Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold. Crystal structures of inhibitor-protein complexes revealed that one of the compounds, B28, utilized a deeply hidden protein interior cavity for binding. SAR analysis guided the development of several B28 derivatives with enhanced inhibition on nuclear export and growth of multiple cancer cell lines. This work may benefit the development of new CRM1-targeted therapies.

RGCC-mediated PLK1 activity drives breast cancer lung metastasis by phosphorylating AMPKα2 to activate oxidative phosphorylation and fatty acid oxidation.

BACKGROUND: More than 90% of the mortality of triple-negative breast cancer (TNBC) patients is attributed to cancer metastasis with organotropism. The lung is a frequent site of TNBC metastasis. However, the precise molecular mechanism for lung-specific metastasis of TNBC is not well understood. METHODS: RNA sequencing was performed to identify patterns of gene expression associated with lung metastatic behavior using 4T1-LM3, MBA-MB-231-LM3, and their parental cells (4T1-P, MBA-MB-231-P). Expressions of RGCC, called regulator of cell cycle or response gene to complement 32 protein, were detected in TNBC cells and tissues by qRT-PCR, western blotting, and immunohistochemistry. Kinase activity assay was performed to evaluate PLK1 kinase activity. The amount of phosphorylated AMP-activated protein kinase α2 (AMPKα2) was detected by immunoblotting. RGCC-mediated metabolism was determined by UHPLC system. Oxidative phosphorylation was evaluated by JC-1 staining and oxygen consumption rate (OCR) assay. Fatty acid oxidation assay was conducted to measure the status of RGCC-mediated fatty acid oxidation. NADPH and ROS levels were detected by well-established assays. The chemical sensitivity of cells was evaluated by CCK8 assay. RESULTS: RGCC is aberrantly upregulated in pulmonary metastatic cells. High level of RGCC is significantly related with lung metastasis in comparison with other organ metastases. RGCC can effectively promote kinase activity of PLK1, and the activated PLK1 phosphorylates AMPKα2 to facilitate TNBC lung metastasis. Mechanistically, the RGCC/PLK1/AMPKα2 signal axis increases oxidative phosphorylation of mitochondria to generate more energy, and promotes fatty acid oxidation to produce abundant NADPH. These metabolic changes contribute to sustaining redox homeostasis and preventing excessive accumulation of potentially detrimental ROS in metastatic tumor cells, thereby supporting TNBC cell survival and colonization during metastases. Importantly, targeting RGCC in combination with paclitaxel/carboplatin effectively suppresses pulmonary TNBC lung metastasis in a mouse model. CONCLUSIONS: RGCC overexpression is significantly associated with lung-specific metastasis of TNBC. RGCC activates AMPKα2 and downstream signaling through RGCC-driven PLK1 activity to facilitate TNBC lung metastasis. The study provides implications for RGCC-driven OXPHOS and fatty acid oxidation as important therapeutic targets for TNBC treatment.