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Background: Lymph node status is a prominent prognostic factor for intrahepatic cholangiocarcinoma (ICC). However, the prognostic value of performing lymph node dissection (LND) in patients with clinical node-negative ICC remains controversial. The aim of this study was to evaluate the clinical value of LND on long-term outcomes in this subgroup of patients., Methods: We retrospectively analyzed patients who underwent radical liver resection for clinically node-negative ICC from three tertiary hepatobiliary centers. The propensity score matching analysis at 1:1 ratio based on clinicopathological data was conducted between patients with and without LND. Recurrence-free survival (RFS) and overall survival (OS) were compared in the matched cohort., Results: Among 303 patients who underwent radical liver resection for ICC, 48 patients with clinically positive nodes were excluded, and a total of 159 clinically node-negative ICC patients were finally eligible for the study, with 102 in the LND group and 57 in the non-LND group. After propensity score matching, two well-balanced groups of 51 patients each were analyzed. No significant difference of median RFS (12.0 vs. 10.0 months, P = 0.37) and median OS (22.0 vs. 26.0 months, P = 0.47) was observed between the LND and non-LND group. Also, LND was not identified as one of the independent risks for survival. Among 51 patients who received LND, 11 patients were with positive lymph nodes (lymph node metastasis (LNM) (+)) and presented significantly worse outcomes than those with LND (-). On the other hand, postoperative adjuvant therapy was the independent risk factor for both RFS (hazard ratio (HR): 0.623, 95% confidence interval (CI): 0.393 - 0.987, P = 0.044) and OS (HR: 0.585, 95% CI: 0.359 - 0.952, P = 0.031). Furthermore, postoperative adjuvant therapy was associated with prolonged survivals of non-LND patients (P = 0.02 for RFS and P = 0.03 for OS)., Conclusions: Based on the data, we found that LND did not significantly improve the prognosis of patients with clinically node-negative ICC. Postoperative adjuvant therapy was associated with prolonged survival of ICC patients, especially in non-LND individuals., Competing Interests: The authors declare that they have no conflict of interest., (Copyright 2024, Sha et al.)

Rapid accumulation of repair factors at DNA double-strand breaks (DSBs) is essential for DSB repair. Several factors involved in DSB repair have been found undergoing liquid-liquid phase separation (LLPS) at DSB sites to facilitate DNA repair. RNF168, a RING-type E3 ubiquitin ligase, catalyzes H2A.X ubiquitination for recruiting DNA repair factors. Yet, whether RNF168 undergoes LLPS at DSB sites remains unclear. Here, we identified K63-linked polyubiquitin-triggered RNF168 condensation which further promoted RNF168-mediated DSB repair. RNF168 formed liquid-like condensates upon irradiation in the nucleus while purified RNF168 protein also condensed in vitro. An intrinsically disordered region containing amino acids 460-550 was identified as the essential domain for RNF168 condensation. Interestingly, LLPS of RNF168 was significantly enhanced by K63-linked polyubiquitin chains, and LLPS largely enhanced the RNF168-mediated H2A.X ubiquitination, suggesting a positive feedback loop to facilitate RNF168 rapid accumulation and its catalytic activity. Functionally, LLPS deficiency of RNF168 resulted in delayed recruitment of 53BP1 and BRCA1 and subsequent impairment in DSB repair. Taken together, our finding demonstrates the pivotal effect of LLPS in RNF168-mediated DSB repair., Competing Interests: Competing interests statement:The authors declare no competing interest.

Twelve new austalide meroterpenoids ( 1 - 12 ) were isolated from the endophytic fungus Diaporthe sp. XC1211. Their structures were elucidated by extensive spectroscopic analysis. The absolute configurations of compounds 1 , 3 , 4 , and 6 were established by single-crystal X-ray diffraction, whereas those for the others were established by experimental electronic circular dichroism (ECD) data analysis. Compounds 1 - 12 represent a rare class of austalides with a 24α-CH 3 . Compounds 2 and 5 demonstrated potent proliferation inhibitory effects against LPS-induced B cells with IC 50 values of 6.7 (SI = 3.6) and 3.8 (SI > 13) μM, respectively. Compounds 2 and 5 decreased the secretion of IL-6 in LPS-induced B cells in a dose-dependent manner.

Quaternary ammonium compounds (QACs) are one type of widely used cationic biocide, and their usage amount is growing rapidly due to the flu and COVID-19 pandemic. Many QACs were released into the environment in or after the course of their use, and thus they were widely detected in water, sediment, soil, and other environmental media. QACs have stronger surface activity and non-specific biotoxicity, which poses a potential threat to the ecosystem. In this study, the environmental fate and potential toxicity of QACs were documented in terms of their migration and transformation process, biological toxicity effects, and the main mechanisms of bacterial resistance to QACs. Aerobic biodegradation was the main natural way of eliminating QACs in the environment, and the reaction was mainly initiated by the hydroxylation of C atoms at different positions of QACs and finally mineralized to CO 2 and H 2 O through decarboxylation, demethylation, and β-oxidation reaction. Toxicological studies showed that QACs at environmental concentrations could not pose acute toxicity to the selected biotas but threatened the growth and reproduction of aquatic organisms like Daphnia magna . Their toxicity effects depended on their molecular structure, the tested species, and the exposed durations. Additionally, our team first investigated the toxicity effects and mechanisms of QACs toward Microcystis aeruginosa , which showed that QACs depressed the algae growth through the denaturation of photosynthetic organelles, suppression of electron transport, and then induction of cell membrane damage. In the environment, the concentrations of QACs were always lower than their bactericidal concentrations, and their degradation could induce the formation of a concentration gradient, which facilitated microbes resistant to QACs. The known resistance mechanisms of bacteria to QACs mainly included the change in cell membrane structure and composition, formation of biofilm, overexpression of the efflux pump gene, and acquisition of resistance genes. Due to the similar targets and mechanisms, QACs could also induce the occurrence of antibiotic resistance, mainly through co-resistance and cross-resistance. Based on the existing data, future research should emphasize the toxicity effect and the potential QACs resistance mechanism of microorganisms in real environmental conditions.

The rapid recognition of DNA double-strand breaks (DSBs) by the MRE11/RAD50/NBS1 (MRN) complex is critical for the initiation of DNA damage response and DSB end resection. Here, we show that MRN complex interacting protein (MRNIP) forms liquid-like condensates to promote homologous recombination-mediated DSB repair. The intrinsically disordered region is essential for MRNIP condensate formation. Mechanically, the MRN complex is compartmentalized and concentrated into MRNIP condensates in the nucleus. After DSB formation, MRNIP condensates move to the damaged DNA rapidly to accelerate the binding of DSB by the concentrated MRN complex, therefore inducing the autophosphorylation of ATM and subsequent activation of DNA damage response signaling. Meanwhile, MRNIP condensates-enhanced MRN complex loading further promotes DSB end resection. In addition, data from xenograft models and clinical samples confirm a correlation between MRNIP and radioresistance. Together, these results reveal an important role of MRNIP phase separation in DSB response and the MRN complex-mediated DSB end resection., (© 2022. The Author(s).)

Introduction: Increasing evidence has indicated that LINC00680 represents an oncogenic factor in cancer; however, the mechanism by which LINC00680 contributes to breast cancer (BC) remains unknown. Methods: A dual-luciferase reporter assay was used to explore the relationship between LINC00680, miR-320b, and cyclin-dependent kinase 5 (CDKL5). A CCK-8 assay and transwell assay were utilized to evaluate the proliferation and invasion in docetaxel-resistant BC cells, respectively. Results: LINC00680 and CDKL5 protein levels were both upregulated when induced by different concentrations of docetaxel. LINC00680 knockdown decreased the expression level of drug resistance-related genes, proliferation, and invasion of BC cells. Bioinformatics prediction and dual-luciferase assays revealed that miR-320b targeted the 3 ' -unstranslated regions (UTR) of both LINC00680 and CDKL5, suggesting that the modulation of LINC00680 on CDKL5 occurred via sequestering miR-320b. Conclusion: Overall, this study highlights the important role of LINC00680 in docetaxel resistance through the miR-320b/CDKL5 pathway and provides a novel therapeutic strategy for BC drug resistance.

Objective: To evaluate the regulation efficacy of oral tangeretin on testosterone and cortisol in sprinters at winter training season. Methods: Twenty-four sprinters were paired and randomly divided into experimental group (EG) and control group (CG). During winter training season, EG were treated with 200 mg tangeretin by oral, and CG were treated with placebo for 4 weeks. Blood samples were collected on the first day of each week (T1, T2, T3, T4) and after the intervention (T5) to detect serum levels of testosterone, cortisol, superoxide dismutase (SOD), and adrenocorticotropic hormone (ACTH). The body composition was tested at T1 and T5. Results: After 4 weeks, ①the serum cortisol level of CG was increased, and the serum levels of testosterone and SOD were decreased significantly ( P ＜0.05). ②In EG, the serum levels of cortisoland ACTH were decreased significantly ( P ＜0.05, P ＜ 0.01), while the serum testosterone level was remained stable, and the level of SOD was increased slightly. ③The muscle mass of EG and CG were increases, but that of EG was increased higher than that of CG. Conclusion: Tangeretin reduces the oxidative stress response that caused by high-intensity exercise during winter training, which maintain the serum testosterone level and inhibit cortisol excessive secretion and promote muscle synthesis.