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Abstract Background Radiotherapy interruption (RTI) prolongs the overall total treatment time and leads to local control loss in many cancers, but it is unclear in esophageal cancer. We aimed to evaluate the influence of RTI on the overall survival (OS), progression-free survival (PFS), and local-regional recurrence-free survival (LRFS) of patients with esophageal cancer undergoing chemoradiotherapy. Methods A total of 299 patients with esophageal squamous cell carcinoma from 2017 to 2019 were retrospectively analyzed to investigate the effect of RTI on OS, PFS, and LRFS. The delayed time of radiotherapy interruption was calculated as the actual radiation treatment time minus the scheduled time. The univariate and multivariate analyses were performed by the COX proportional hazards regression models, and the survival analysis was performed through the Kaplan‒Meier method, and compared with the log-rank test. Results The 3-year OS, PFS, and LRFS rates were 53.0%, 42.0%, and 48.0%, respectively. The univariate and multivariate analyses showed that the delayed time > 3 days was an independent adverse prognostic factor for OS (HR = 1.68, 95% CI 1.10–2.55, p = 0.016), and LRFS (HR = 1.74, 95% CI 1.18–2.57, p = 0.006). The patient with a delayed time of > 3 days had poorer survival rates of OS, and LRFS than patients with a delayed time of ≤ 3 days (OS, p = 0.047; LRFS, p = 0.013), and the survival outcomes of patients with shorter delayed time (1–3 days) were slightly different from the patients without interruptions. The impact of delay time on PFS is not statistically significant, but the survival outcomes of the two groups were slightly different. Conclusion There was a significant correlation between delayed time and local control of esophageal cancer. The delayed time for more than 3 days might decrease the survival outcome, and increase the local recurrence risk.

Abstract Colorectal cancer (CRC) often necessitates cetuximab (an EGFR-targeting monoclonal antibody) for treatment. Despite its clinical utility, the specific operative mechanism of cetuximab remains elusive. This research investigated the influence of PLCB3, a potential CRC oncogene, on cetuximab treatment. We extracted differentially expressed genes from the GSE140973, the overlapping genes combined with 151 Wnt/β-Catenin signaling pathway-related genes were identified. Then, we conducted bioinformatics analysis to pinpoint the hub gene. Subsequently, we investigated the clinical expression characteristics of this hub gene, through cell experimental, scrutinized the impact of cetuximab and PLCB3 on CRC cellular progression. The study identified 26 overlapping genes. High expression of PLCB3, correlated with poorer prognosis. PLCB3 emerged as a significant oncogene associated with patient prognosis. In vitro tests revealed that cetuximab exerted a cytotoxic effect on CRC cells, with PLCB3 knockdown inhibiting CRC cell progression. Furthermore, cetuximab treatment led to a reduction in both β-catenin and PLCB3 expression, while simultaneously augmenting E-cadherin expression. These findings revealed PLCB3 promoted cetuximab inhibition on Wnt/β-catenin signaling. Finally, simultaneous application of cetuximab with a Wnt activator (IM12) and PLCB3 demonstrated inhibited CRC proliferation, migration, and invasion. The study emphasized the pivotal role of PLCB3 in CRC and its potential to enhance the efficacy of cetuximab treatment. Furthermore, cetuximab suppressed Wnt/β-catenin pathway to modulate PLCB3 expression, thus inhibiting colorectal cancer progression. This study offered fresh perspectives on cetuximab mechanism in CRC.

Concrete-filled steel tubular (CFST) Structures often face challenges with debonding during construction, which can markedly compromise the structural integrity. The hydration of concrete can generate significant heat during construction, making the infrared thermography as a potential method for the defect detection. However, effects of concrete hydration behavior, debonding size, and environmental factors on the infrared thermal imaging of CFST debonding remains unclear. This study conducted experiments using four different hydration heating rates and three debonding sizes to simulate debonding detection using infrared imaging during the hydration phase of CFST. The feasibility of the simulation approach was validated through pair-to-pair comparison, and multiple linear regression analysis was employed to evaluate the impact of these factors. The findings highlight that absolute temperature difference has the most significant impact on detection effectiveness regardless of interaction effects. In regression models without interaction, heating rate demonstrated the least impact, Whereas the model considering the interaction showed that the interaction effect of heating rate and debonding size showed a secondary effect. Further examination indicated that interaction effects decrease as heating rate and debonding size decrease.

The isoflavone calycosin-7-O-β-d-glucopyranoside (CG) is a principal constituent of Astragalus membranaceus (AR) and has been reported to inhibit osteoclast development in vitro and bone loss in vivo. The aim of this study was to investigate the osteogenic effects of CG and its underlying mechanism in ST2 cells. The results show that exposure of cells to CG in osteogenic differentiation medium increases ALP activity, osteocalcin (Ocal) mRNA expression and the osteoblastic mineralization process. Mechanistically, CG treatment increased the expression of bone morphogenetic protein 2 (BMP-2), p-Smad 1/5/8, β-catenin and Runx2, all of which are regulators of the BMP- or wingless-type MMTV integration site family (WNT)/β-catenin-signaling pathways. Moreover, the osteogenic effects of CG were inhibited by Noggin and DKK-1 which are classical inhibitors of the BMP and WNT/β-catenin-signaling pathways, respectively. Taken together, the results indicate that CG promotes the osteoblastic differentiation of ST2 cells through regulating the BMP/WNT signaling pathways. On this basis, CG may be a useful lead compound for improving the treatment of bone-decreasing diseases and enhancing bone regeneration.

19F electron-nuclear double resonance (ENDOR) has emerged as an attractive method for determining distance distributions in biomolecules in the range of 0.7–2 nm, which is not easily accessible by pulsed electron dipolar spectroscopy. The 19F ENDOR approach relies on spin labeling, and in this work, we compare various labels' performance. Four protein variants of GB1 and ubiquitin bearing fluorinated residues were labeled at the same site with nitroxide and trityl radicals and a Gd(III) chelate. Additionally, a double-histidine variant of GB1 was labeled with a Cu(II) nitrilotriacetic acid chelate. ENDOR measurements were carried out at W-band (95 GHz) where 19F signals are well separated from 1H signals. Differences in sensitivity were observed, with Gd(III) chelates providing the highest signal-to-noise ratio. The new trityl label, OXMA, devoid of methyl groups, exhibited a sufficiently long phase memory time to provide an acceptable sensitivity. However, the longer tether of this label effectively reduces the maximum accessible distance between the 19F and the Cα of the spin-labeling site. The nitroxide and Cu(II) labels provide valuable additional geometric insights via orientation selection. Prediction of electron–nuclear distances based on the known structures of the proteins were the closest to the experimental values for Gd(III) labels, and distances obtained for Cu(II) labeled GB1 are in good agreement with previously published NMR results. Overall, our results offer valuable guidance for selecting optimal spin labels for 19F ENDOR distance measurement in proteins. [ABSTRACT FROM AUTHOR]

Machining processes have been widely employed in the modern manufacturing industry to transform raw materials into final products, and they are of great importance in improving the environmental impact and production efficiency of this industry. The selection of appropriate machining process parameters can effectively improve the environmental impact and production efficiency of a process. However, most existing studies on the optimization of these parameters have targeted optimization techniques or modeling methods, and have seldom taken into consideration the adaptability of the machining process. Thus, they suffer from poor generalization and flexibility in actual deployment. Based on this, a generic optimization framework based on the end-to-end evolutionary algorithm was proposed in this study, which can be adapted to various machining optimization problems, to guide the operators in selecting the best parameters in an automated way. Firstly, a modeling framework was introduced to guide the operators to develop optimization objectives. Subsequently, a flexible optimization algorithm was employed to generate Pareto front solutions. Finally, the CRITIC-TOPSIS method was employed to provide a final solution from the different Pareto solutions generated. Experiments were conducted on a milling machine to demonstrate the effectiveness and advantages of the proposed method. The results showed that the proposed method is flexible and applicable for the optimization of the different machining steps and objectives. [ABSTRACT FROM AUTHOR]

Abstract Background Epoxide hydrolase can regioselectively catalyze the oxirane ring-opening hydrolysis of rac-epoxides producing the corresponding chiral diols. In our laboratory, a gene named pveh1 encoding an EH from Phaseolus vulgaris was cloned. Although the directed modification of PvEH1 was carried out, the mutant PvEH1Y3 showed a limited degree of enantioconvergence towards racemic (rac-) m-chlorostyrene oxide (mCSO). Results PvEH1 and PvEH1Y3 were combinatively subjected to laboratory evolution to further enhance the enantioconvergence of PvEH1Y3 towards rac-mCSO. Firstly, the substrate-binding pocket of PvEH1 was identified using a CAVER 3.0 software, and divided into three zones. After all residues in zones 1 and 3 were subjected to leucine scanning, two E. coli transformants, E. coli/pveh1 Y149L and /pveh1 P184L, were selected, by which rac-mCSO was transformed into (R)-m-chlorophenyl-1,2-ethanediol (mCPED) having 55.1% and 27.2% ee p. Secondly, two saturation mutagenesis libraries, E. coli/pveh1 Y149X and /pveh1 P184X (X: any one of 20 residues) were created at sites Y149 and P184 of PvEH1. Among all transformants, both E. coli/pveh1 Y149L (65.8% α S and 55.1% ee p) and /pveh1 P184W (66.6% α S and 59.8% ee p) possessed the highest enantioconvergences. Finally, the combinatorial mutagenesis was conducted by replacements of both Y149L and P184W in PvEH1Y3, constructing E. coli/pveh1 Y3Z2, whose α S reached 97.5%, higher than that (75.3%) of E. coli/pveh1 Y3. In addition, the enantioconvergent hydrolysis of 20 mM rac-mCSO was performed by E. coli/pveh1 Y3Z2, giving (R)-mCPED with 95.2% ee p and 97.2% yield. Conclusions In summary, the enantioconvergence of PvEH1Y3Z2 was successfully improved by laboratory evolution, which was based on the study of substrate-binding pocket by leucine scanning. Our present work introduced an effective strategy for the directed modification of enantioconvergence of PvEH1.

Deflectable nose control is a new trajectory correction method. In this paper, the aerodynamic and trajectory characteristics of a typical mortar projectile with a deflectable nose are investigated with respect to its flight conditions. Using the method of wind tunnel testing, the aerodynamic coefficients of four kinds of mortar models were measured under the conditions of different angles of attack from −10° to 10° and Mach numbers from 0.3 to 0.9. Based on the aerodynamic coefficients, the trajectory ranges at different nose deflection angles and times were calculated. Furthermore, a trajectory optimization was performed by reducing the static margin. The results and discussions show that the nose deflection provided limited lift, while the pitching moment varied significantly. The mortar obtained the extended flight range and trajectory correction ability with nose deflection. Keywords: Nose deflection, Aerodynamic characteristics, Wind tunnel test, Trajectory simulation

Abstract The X-chromosome linked inhibitor of apoptosis (XIAP) is a multidomain metalloprotein involved in caspase inhibition and in copper homeostasis. It contains three zinc-binding baculoviral IAP repeats (BIR) domains, which are responsible for caspase interaction. Recently, it has been suggested that the BIR domains can bind copper, however high resolution data on such interaction is missing. Here we characterize by NMR the structural properties of BIR1 in solution, and the effects of its interaction with copper both in vitro and in physiological environments. BIR1 is dimeric in solution, consistent with the X-ray structure. Cysteine 12, located in the unfolded N-terminal region, has a remarkably low redox potential, and is prone to oxidation even in reducing physiological environments. Interaction of BIR1 with copper(II) results in the oxidation of cysteine 12, with the formation of either an intermolecular disulfide bond between two BIR1 molecules or a mixed disulfide bond with glutathione, whereas the zinc binding site is not affected by the interaction.

Store-operated calcium entry (SOCE) is elicited by the interaction of oligomerized STIM1 with plasma membrane Orai channels. Here, the authors show that this process is regulated by calmodulin, which binds STIM1 and disassembles the STIM1-Orai1 complex and STIM1 oligomers.