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Background Cryptocaryon irritans is a fatal parasite for marine teleosts and causes severe economic loss for aquaculture. Galvanized materials have shown efficacy in controlling this parasite infestation through the release of zinc ions to induce oxidative stress. Methods In this study, the resistance mechanism in C. irritans against oxidative stress induced by zinc ions was investigated. Untargeted metabolomics analysis was used to determine metabolic regulation in C. irritans in response to zinc ion treatment by the immersion of protomonts in ZnSO 4 solution at a sublethal dose (20 μmol). Eight differential metabolites were selected to assess the efficacy of defense against zinc ion stimulation in protomonts of C. irritans . Furthermore, the mRNA relative levels of glutathione metabolism-associated enzymes were measured in protomonts following treatment with ZnSO 4 solution at sublethal dose. Results The results showed that zinc ion exposure disrupted amino acid metabolism, carbohydrate metabolism, lipid metabolism, and nucleotide metabolism in C. irritans . Four antioxidants, namely ascorbate, S-hexyl-glutathione, syringic acid, and ubiquinone-1, were significantly increased in the Zn group ( P  < 0.01), while the glutathione metabolism pathway was enhanced. The encystment rate of C. irritans was significantly higher in the ascorbate and methionine treatment ( P  < 0.05) groups. Additionally, at 24 h post-zinc ion exposure, the relative mRNA level of glutathione reductase ( GR ) was increased significantly ( P  < 0.01). On the contrary, the relative mRNA levels of glutathione S-transferase ( GT ) and phospholipid-hydroperoxide glutathione peroxidase ( GP x) were significantly decreased ( P  < 0.05), thus indicating that the generation of reduced glutathione was enhanced. Conclusions These results revealed that glutathione metabolism in C. irritans contributes to oxidative stress resistance from zinc ions, and could be a potential drug target for controlling C. irritans infection. Graphical Abstract

Background. Remnant gastric cancer (RGC) is a rare malignant tumor with poor prognosis. There is no universally accepted prognostic model for RGC. Methods. We analyzed data for 253 RGC patients who underwent radical gastrectomy from 6 centers. The prognosis prediction performances of the AJCC7th and AJCC8th TNM staging systems and the TRM staging system for RGC patients were evaluated. Web-based prediction models based on independent prognostic factors were developed to predict the survival of the RGC patients. External validation was performed using a cohort of 49 Chinese patients. Results. The predictive abilities of the AJCC8th and TRM staging systems were no better than those of the AJCC7th staging system (c-index: AJCC7th vs. AJCC8th vs. TRM, 0.743 vs. 0.732 vs. 0.744; P>0.05). Within each staging system, the survival of the two adjacent stages was not well discriminated (P>0.05). Multivariate analysis showed that age, tumor size, T stage, and N stage were independent prognostic factors. Based on the above variables, we developed 3 web-based prediction models, which were superior to the AJCC7th staging system in their discriminatory ability (c-index), predictive homogeneity (likelihood ratio chi-square), predictive accuracy (AIC, BIC), and model stability (time-dependent ROC curves). External validation showed predictable accuracies of 0.780, 0.822, and 0.700, respectively, in predicting overall survival, disease-specific survival, and disease-free survival. Conclusions. The AJCC TNM staging system and the TRM staging system did not enable good distinction among the RGC patients. We have developed and validated visual web-based prediction models that are superior to these staging systems.

The present study was designed to evaluate the dynamic survival and recurrence of remnant gastric cancer (RGC) after radical resection and to provide a reference for the development of personalized follow‐up strategies. A total of 298 patients were analyzed for their 3‐year conditional overall survival (COS3), 3‐year conditional disease‐specific survival (CDSS3), corresponding recurrence and pattern changes, and associated risk factors. The 5‐year overall survival (OS) and the 5‐year disease‐specific survival (DSS) of the entire cohort were 41.2% and 45.8%, respectively. The COS3 and CDDS3 of RGC patients who survived for 5 years were 84.0% and 89.8%, respectively. The conditional survival in patients with unfavorable prognostic characteristics showed greater growth over time than in those with favorable prognostic characteristics (eg, COS3, ≥T3: 46.4%‐83.0%, Δ36.6% vs ≤T2: 82.4%‐85.7%, Δ3.3%; P < 0.001). Most recurrences (93.5%) occurred in the first 3 years after surgery. The American Joint Committee on Cancer (AJCC) stage was the only factor that affected recurrence. Time‐dependent Cox regression showed that for both OS and DSS, after 4 years of survival, the common prognostic factors that were initially judged lost their ability to predict survival (P > 0.05). Time‐dependent logistic regression analysis showed that the AJCC stage independently affected recurrence within 2 years after surgery (P < 0.05). A postoperative follow‐up model was developed for RGC patients. In conclusion, patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages, which may affect the design of future clinical trials. Patients with RGC usually have a high likelihood of death or recurrence within 3 years after radical surgery. We developed a postoperative follow‐up model for RGC patients of different stages.

Aim： To investigate the effects of piperine, a major pungent alkaloid present in Piper nigrum and Piper Iongum, on the tumor growth and metastasis of mouse 4T1 mammary carcinoma in vitro and in vivo, and elucidate the underlying mechanisms. Methods： Growth of 4T1 cells was assessed using MTIassay. Apoptosis and cell cycle of 4T1 cells were evaluated with flow cytometry, and the related proteins were examined using Western blotting. Real-time quantitative PCR was applied to detect the expression of matrix metalloproteinases （MMPs）. A highly malignant, spontaneously metastasizing 4T1 mouse mammary carcinoma model was used to evaluate the in vivo antitumor activity. Piperine was injected into tumors every 3 d for 3 times. Results： Piperine （35-280 pmol/L） inhibited the growth of 4T1 cells in time- and dose-dependent manners （the IC5o values were 105±1.08 and 78.52±1.06 pmol/L, respectively, at 48 and 72 h）. Treatment of 4T1 cells with piperine （70-280 pmol/L） dose-dependently induced apoptosis of 4T1 cells, accompanying activation of caspase 3. The cells treated with piperine （140 and 280 pmol/L） significantly increased the percentage of cells in G2/M phase with a reduction in the expression of cyclin BI. Piperine （140 and 280 pmol/L） significantly decreased the expression of MMP-9 and MMP-13, and inhibited 4T1 cell migration in vitro. Injection of piperine （2.5 and 5 mg/kg） dose-dependently suppressed the primary 4T1 tumor growth and injection of piperine （5 mg/kg） significantly inhibited the lung metastasis. Conclusion： These results demonstrated that piperine is an effective antitumor compound in vitro and in vivo, and has the potential to be developed as a new anticancer drug.

In a community-based study, the relationship between age and human prostate size was investigated in a population of men between the ages of 40 and 70 years to determine the normal prostate increase curve equation. One thousand male volunteers were randomly recruited from the Shanghai community, and the length, width, height, volume of the transition zone （TZ） and the whole prostates were measured by transrectal ultrasound （TRUS）. Each volunteer was evaluated bythe International Prostate Symptom Score （IPSS）. Among those who completed the examination, the mean prostate parameters were all positively associated with increased age. There were statistically significant differences between each age group （P〈O.05）. The mean transition zone volume （TZV） had a higher increase rate with age than the mean total prostate volume （TPV）, indicating that the enlargement of the TZ contributed the most to the increase in TPV. While all prostate parameters were positively correlated with the IPSS, the strongest correlation was associated with the TZ length （TZL） and TZV. The growth curve equations for prostate width, height and length were also positively associated with increasing

CD133 and Notch1 double-positive GSCs were preferentially located along Jagged1-expressing white matter tracts, which exhibited a demyelinated phenotype. The NOTCH1–SOX9–SOX2 positive-feedback loop controls GSC invasion along white matter tracts.

Water-dispersed CdSe/Bi2Se3 core/shell QDs with a photothermal conversion coefficient of 27.09% have been synthesized by a cation exchange reaction. The microstructure and crystal structure of the QDs, which were confirmed by TEM and XRD, showed that partial cation exchange occurred inside the CdSe QDs. Two main mechanisms are responsible for the excellent photothermal conversion： inhibition of radiative recombination of carriers due to the formation of type-II semiconductor heterostructures, and the large surface-to-volume ratio of the QDs. Photothermal conversion experiments indicated that the CdSe/Bi2Se3 QDs showed high photothermal conversion efficiency and excellent NIR photostability.

Cellulase is essential for cellulose hydrolysis and is used across industries such as food, feed, textiles, biofuel, and biomass pretreatment. However, its utility is restricted by high temperatures and salt concentrations. This study identified a novel cellulase gene (named c5-cel4 ) from Ebinur Salt Lake in Xinjiang, China using metagenomic technology. Its amino acid sequence has a 90.97% similarity to the GH5 family cellulase of Microbulbifer litoralis (WP_250463697.1). The gene was expressed in Escherichia coli , and the recombinant protein, C5-CEL4, was purified via Ni-NTA affinity chromatography. C5-CEL4, secreted extracellularly (0.886 U/mL), revealed a protein size 14 KDa smaller than predicted, with mass spectrometry indicating a truncated C-terminal of 135 amino acid residues. Optimal activity was observed at 50 °C and pH 7.0, maintaining over 80% activity at 40–65 °C and 45–50 °C for 2 h. The enzyme’s half-life was 60 min at 55–60 °C, retaining over 90% activity after 24 h in pH 5.0–12.0 buffers. C5-CEL4 showed activity against CMC-Na, bagasse xylan, and beech xylan, with Kcat values of 98.20 s − 1 and 12.32 s − 1 for CMC-Na and bagasse xylan, respectively. It also hydrolyzed wheat bran and maize stalks into reducing sugars. Remarkably, C5-CEL4 exhibited high salt tolerance, maintaining 100% activity in 0.5 M-5.0 M NaCl and after 9 months in 5.0 M NaCl. It retained over 90% activity in ionic liquids (BMIM-Ac, EMIM-Cl, BMIM-BF4) at 50% concentration and showed resistance to heavy metal ions (Co 2+ , Cu 2+ , Ag + , Mn 2+ , Pb 2+ , and Ni 2+ ) and inhibitors (PMSF, DTT, Tween80, and SDS). In conclusion, C5-CEL4 is a robust cellulase with heat, alkali, salt, ionic liquid, and inhibitor resistance, alongside cellulase and xylanase activity, presenting significant potential for feed, food, and bioenergy applications.

Background Understanding the relationship between human evolution and environmental changes is the key to lifting the veil on human origin. The hypothesis that environmental changes triggered the divergence of humans from apes (ca. 9.3–6.5 million years ago, Ma) has been poorly tested because of limited continuous environmental data from fossil localities. Lufengpithecus (12.5-6.0 Ma) found on the southeastern margin of the Tibetan Plateau (SEMTP) across the ape–human split provides a good chance for testing this hypothesis. Results Here, we reconstructed the habitats of L . keiyuanensis (12.5–11.6 Ma) with comprehensive vegetation, climate, and potential food web data by palaeobotanical evidence, together with other multidisciplinary data and partly tested the environment-driven hypothesis by revealing the living conditions of Lufengpithecus . Conclusion A detailed comparison of hominoids on different continents reveals their behaviour and fate divergence across the ape–human split against the background of global climate change, i.e., the stable living conditions of SEMTP not only provided a so-called ‘refuge’ for arboreal Lufengpithecus but also acted as a ‘double-edged sword’, preventing their further evolution while vegetation shifts in East Africa probably stimulated the emergence of human bipedalism, and the intense climatic changes in Europe possibly prevented those hominoids from surviving that time interval. Our findings provide interesting insight into the environmental impacts on the behavioural evolution of hominoids.

DNA damage results in mutations and plays critical roles in cancer development, progression, and treatment. Targeting DNA damage response in cancers by inhibiting poly-(ADP-ribose) polymerases (PARPs) offers an important therapeutic strategy. However, the failure of PARP inhibitors to markedly benefit patients suggests the necessity for developing new strategies to improve their efficacy. Here, we show that the expression of cyclin-dependent kinase 4/6 (CDK4/6) complex members significantly correlates with mutations (as proxies of DNA damages), and that the combination of CDK4/6 and PARP inhibitors shows synergy in both RB-proficient and RB-deficient breast cancer cells. As PARPs constitute sensors of DNA damage and are broadly involved in multiple DNA repair pathways, we hypothesized that the combined inhibition of PARPs and DNA repair (or repair-related) pathways critical for cancer (DRPCC) should show synergy. To identify druggable candidate DRPCC(s), we analyzed the correlation between the genome-wide expression of individual genes and the mutations for 27 different cancer types, assessing 7146 exomes and over 1,500,000 somatic mutations. Pathway enrichment analyses of the top-ranked genes correlated with mutations indicated “cell cycle pathway” as the top candidate DRPCC. Additionally, among functional cell-cycle complexes, the CDK4/6 complex showed the most significant negative correlation with mutations, also suggesting that combined CDK4/6 and PARP inhibition might exhibit synergy. Furthermore, combination treatment showed synergy in not only RB-proficient but also RB-deficient breast cancer cells in a reactive oxygen species-dependent manner. These findings suggest a potential therapeutic strategy to improve the efficacy of PARP and CDK4/6 inhibitors in cancer treatment.