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BackgroundEsketamine, the first Food and Drug Administration-approved fast-acting antidepressant, has limited use because of its addictive properties. Although the combination of dextromethorphan and bupropion partially addresses the limitations of esketamine, concerns remain regarding neurologic side effects related to dextromethorphan metabolites, and seizure risks associated with high-dose bupropion. SAL0114, a novel formulation combining deuterated dextromethorphan (in which hydrogen atoms are replaced with deuterium) with bupropion, seeks to enhance dextromethorphan stability through deuteration of its metabolic sites. This approach is expected to increase antidepressant efficacy, reduce metabolite-induced safety issues, and allow for lower bupropion dosages.MethodsRadioligand competition binding assays were used to evaluate the impact of deuterium substitution on the in vitro activity of dextromethorphan and its metabolite, dextrorphan. In vitro hepatic microsomal stability and in vivo mouse pharmacokinetic assays were performed to assess the effects of deuteration on dextromethorphan stability. Two mouse models of behavioral despair were used to determine the antidepressant and synergistic effects of deuterated dextromethorphan and bupropion. Additionally, a reserpine-induced hypothermia rat model and an ammonia-induced cough mouse model were used to assess the in vivo effects from a pathological perspective.ResultsDeuterated dextromethorphan maintained the same in vitro activity as dextromethorphan while exhibiting twice the metabolic stability both in vitro and in vivo. Combination with bupropion further improved its in vivo stability, increasing the exposure by 2.4 times. The combination demonstrated efficacy and synergistic effects in all tested animal models, showing superior efficacy compared with the dextromethorphan-bupropion combination.ConclusionDeuteration improved dextromethorphan metabolic stability without altering its in vitro activity. Bupropion enhanced this stability and synergistically boosted the antidepressant effect by increasing deuterated dextromethorphan exposure in vivo. This enhanced metabolic stability suggests a reduction in dextromethorphan metabolites associated with clinical neurological side effects. Consequently, SAL0114 is hypothesized to offer improved efficacy and safety compared with the non-deuterated combination, potentially allowing for lower bupropion dosages. Further clinical studies are required to confirm these preclinical findings.

PurposeThe present study aimed to further examine the factor structure and measurement invariance of the UDRQ among a sample of Hungarian university students.MethodsFirstly, the factor structure of the UDRQ was examined among 837 Hungarian university students. Specifically, two measurement models (first-order model and second-order model) were constructed and compared. Secondly, the internal consistency reliability of the UDRQ was examined. Thirdly, measurement invariance of the UDRQ was evaluated across genders. Finally, measurement invariance of the UDRQ was evaluated across two different samples.ResultsIt was found that the first-order model outperformed the second-order model and better represented the factor structure of the UDRQ subscales. Results of Cronbach’s alpha and Composite Reliability suggested that the internal consistency reliabilities of the two UDRQ subscales were satisfactory. Measurement invariance analysis revealed that the UDRQ measurement model was strict invariant across genders and samples.ConclusionThe findings of the present study indicated that the UDRQ displayed satisfactory reliability and validity and could be used to assess demands and resources of Hungarian university students.

The usage of cheap crude H2 in proton-exchange membrane fuel cells (PEMFCs) is still unrealistic to date, due to the suffering of the current Pt based nano-catalysts from impurities such as CO in anode. Recently, synergistic active sites between single atom (SA) and nanoparticle (NP) have been found to be promising for overcoming the poisoning problem. However, lengthening the nanoparticle-single atom (SA–NP) interface, i.e., constructing high density synergistic active sites, remains highly challenging. Herein, we present a new strategy based on molecular fusion strategy to create abundant SA–NP interfaces, with high density SA–NP interfaces created on a two dimensional nitrogen doped carbon nanosheets (Ir-SACs&NPs/NC). Owing to the abundance of SA–NP interface sites, the catalyst was empowered with a high tolerance towards up to 1000 ​ppm CO in H2 feed. These findings provide guidelines for the design and construction of active and anti-poisoning catalysts for PEMFC anode.

Background and purpose: GLP-1 receptor agonists are clinically utilized for type 2 diabetes and obesity. In vitro and in vivo preclinical studies were performed to assess the druggability of a novel small molecule GLP-1 receptor biased agonist SAL0112. Experimental approach: The HTRF assay, FLIPR assay, TR-FRET assay, and PathHunter assay were utilized for in vitro studies. Liver transporter tests were conducted using the HEK293-OATP1B1 and HEK293-OATP1B3 cell lines. In vitro stability assessments of various species and in vivo PK studies in rodents were performed. A model of type 2 diabetes and obesity induced by a high-energy diet in transgenic C57BL/6 mice expressing the human GLP-1 receptor gene was conducted. Principal results: SAL0112 demonstrated high potency and selectivity in activating the Gαs pathway of the GLP-1 receptor, with no observed desensitization. SAL0112 demonstrated greater stability in human and rat liver microsomes compared to Danuglipron. In vivo PK studies revealed higher absorption of SAL0112 in rats. SAL0112 displayed a significantly lower potential for DDI on liver transporters compared to Danuglipron. SAL0112 led to significant reductions in body weight (P

Fully renewable oxygen barrier thermoplastic starch (TPS)/sugar alcohol blown films were innovatively prepared by blending proper loadings of Erythritol (ET), Sorbitol (ST), and Lactitol (LT) and supercritical carbon dioxide (scC[O.sub.2]) assistance. The oxygen transmission rate (OTR) values of the properly prepared scC[O.sub.2]TP[S.sub.x]ETy, scC[O.sub.2]TP[S.sub.x]S[T.sub.y], and scC[O.sub.2]TP[S.sub.x]L[T.sub.y] films reduced to 4.3, 6.6, and 12.5 [cm.sup.3]/[m.sup.2]*day*atm, which are about 5-28 times smaller than those of the conventional TPS films reported in the literature. The free-volume-cavity characteristics (FVCC) and OTR detected for TP[S.sub.x]E[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]E[T.sub.y]), TP[S.sub.x]S[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]S[T.sub.y]), and TP[S.sub.x]L[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]L[T.sub.y]) films diminished to a minimum, as their ET, ST and LT loadings came near an optimal value. Slightly smaller OTR and FVCC values were detected for scC[O.sub.2]TP[S.sub.x]E[T.sub.y], scC[O.sub.2]TP[S.sub.x]S[T.sub.y] and scC[O.sub.2]TP[S.sub.x]L[T.sub.y] films than those of corresponding TP[S.sub.x]E[T.sub.y], TP[S.sub.x]S[T.sub.y], and TP[S.sub.x]L[T.sub.y] films prepared without scC[O.sub.2]-assistance. The smallest OTR and FVCC detected for the properly prepared TP[S.sub.x]E[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]E[T.sub.y]), TP[S.sub.x]S[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]S[T.sub.y]), and TP[S.sub.x]L[T.sub.y] (or scC[O.sub.2]TP[S.sub.x]L[T.sub.y]) films diminished with decreasing sugar alcohol's molecular weight. An essential result is that the OTR of the properly prepared scC[O.sub.2]TP[S.sub.x]E[T.sub.y] film was merely 4.3 [cm.sup.3]/[m.sup.2]*day*atm, which is small enough to meet the demand of high oxygen barrier packaging application. Dynamic molecular relaxations detected for these films disclosed that ET, ST, and LT were compatible with TPS, as their loads were [less than or equal to] the optimum value. The distinctly reduced OTR and FVCC for these properly prepared films are partially attributed to the reinforced molecular interactions between sugar alcohol and TPS's hydroxyl groups when they were prepared with scC[O.sub.2]assistance, optimal sugar alcohol loading, and/or smaller sugar alcohol's molecular weight. Highlights * High oxygen barrier thermoplastic starch/sugar alcohol blown films were prepared. * The lowest oxygen transmission rate of the renewable film was 4.3 [cm.sup.3]/ [m.sup.2]*day*atm. * This oxygen transmission rate is qualified for high oxygen barrier application. * Boosted oxygen barrier property was ascribed to the reduced free volume values. KEYWORDS erythritol, free-volume-cavity characteristics, lactitol, oxygen transmission rate, scC[O.sub.2]assisted thermoplastic starch, sorbitol, 1 | INTRODUCTION The contamination problem for nonbiodegradable petroleum-derived waste plastics has turned out to be a harsh challenge to our environment for the last tens of years. (1-7) Petroleum-derived [...]

[Objective] Runoff changes under the combined influence of climate change and human activities. Exploring the temporal and spatial evolution of runoff and its causes has important guiding significance for the scientific operation of reservoirs and the sustainable use of water resources. [Methods] Based on the meteorological and hydrological data of the Wanzhou section of the Three Gorges Reservoir Area from 1960 to 2019, Mann-Kendall trend test, Pettitt mutation analysis and wavelet analysis were used to analyze the spatial and temporal evolution characteristics of runoff before and after the impoundment in the Three Gorges Reservoir Area. Finally, two Budyko hydrothermal coupling equilibrium equations were used to quantitatively calculate the influence rate of climate change and human activities on runoff change. [Results] (1) The annual runoff in the study area showed a significant downward trend (|z|>2.58), with the inflection point appearing in 2003 (the impoundment year of the Three Gorges Reservoir Area), after which the annual distribution was more uniform. (2) Compared to the period before impoundment, the contribution rates of climate change and human activities to the reduction of annual runoff in the study area after impoundment were 27.9% to 29.2% and 70.8% to 72.1%, respectively. (3) Human activities primarily influence the annual runoff of the basin by altering the type of land use and the construction of water conservation projects. [Conclusion] This study quantitatively describes the impact of human activities on runoff changes, and provides the oretical support for the next stage of water resources management in the Three Gorges Reservoir Area.

Abstract B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb–defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb–defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb–defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage–associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb–defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

Abstract Purpose To explore the predictive potential of intratumoral and multiregion peritumoral radiomics features extracted from multiparametric MRI for predicting pathological differentiation in hepatocellular carcinoma (HCC) patients. Methods A total of 265 patients with 277 HCCs (training cohort n = 193, validation cohort n = 84) who underwent preoperative MRI were retrospectively analyzed. The risk factors identified through stepwise regression analysis were utilized to construct a clinical model. Radiomics models based on MRI (arterial phase, portal venous phase, delayed phase) across various regions (entire tumor, Peri_5mm, Peri_10mm, Peri_20mm) were developed using the LASSO approach. The features obtained from the intratumoral region and the optimal peritumoral region were combined to design the IntraPeri fusion model. Model performance was assessed using the area under the curve (AUC). Results Larger size, non-smooth margins, and mosaic architecture were risk factors for poorly differentiated HCC (pHCC). The clinical model achieved AUCs of 0.77 and 0.73 in the training and validation cohorts, respectively, while the intratumoral model achieved corresponding AUC values of 0.92 and 0.82. The Peri_10mm model demonstrated superior performance to the Peri_5mm and Peri_20mm models, with AUC values of 0.87 vs. 0.84 vs. 0.73 in the training cohort and 0.80 vs. 0.77 vs. 0.68 in the validation cohort, respectively. The IntraPeri model exhibited remarkable AUC values of 0.95 and 0.86 in predicting pHCC in the training and validation cohorts, respectively. Conclusions Our study highlights the potential of a multiparametric MRI-based radiomic model that integrates intratumoral and peritumoral features as a tool for predicting HCC differentiation. Critical relevance statement Both clinical and multiparametric MRI-based radiomic models, particularly the intratumoral radiomic model, are non-invasive tools for predicting HCC differentiation. Importantly, the IntraPeri fusion model exhibited remarkable predictiveness for individualized HCC differentiation. Key points • Both the intratumoral radiomics model and clinical features were useful for predicting HCC differentiation. • The Peri_10mm radiomics model demonstrated better diagnostic ability than other peritumoral region-based models. • The IntraPeri radiomics fusion model outperformed the other models for predicting HCC differentiation. Graphical Abstract

Abstract Two-dimensional (2D) covalent organic frameworks (COFs) and their derivatives have been widely applied as electrocatalysts owing to their unique nanoscale pore configurations, stable periodic structures, abundant coordination sites and high surface area. This work aims to construct a non-thermodynamically stable Pt-N2 coordination active site by electrochemically modifying platinum (Pt) single atoms into a fully conjugated 2D COF as conductive agent-free and pyrolysis-free electrocatalyst for the hydrogen evolution reaction (HER). In addition to maximizing atomic utilization, single-atom catalysts with definite structures can be used to investigate catalytic mechanisms and structure-activity relationships. In this work, in-situ characterizations and theoretical calculations reveal that a nitrogen-rich graphene analogue COF not only exhibits a favorable metal-support effect for Pt, adjusting the binding energy between Pt sites to H* intermediates by forming unique Pt-N2 instead of the typical Pt-N4 coordination environment, but also enhances electron transport ability and structural stability, showing both conductivity and stability in acidic environments.

Introduction: Ovarian cancer is the most malignant gynecological tumor. Previous studies have demonstrated that chimeric antigen receptor (CAR)-engineered NK-92 cells targeting folate receptor α (αFR) (NK-92-αFR-CAR) can specifically kill αFR-positive ovarian cancer cells. However, the migration barrier restricts antitumor effects of CAR-engineered cells. Objectives: To elucidate the mechanism by which NK-92-αFR-CAR cells induce the secretion of chemokine CXCL10 during killing ovarian cancer cells. It is speculated that NK-92-αFR-CAR-CXCR3A can target αFR and have chemotaxis of CXCL10, and they may have stronger killing effect of ovarian cancer. Methods: Study the mechanism of CXCL10 expression strongly induced by TNF-α and IFN-γ combined stimulation in ovarian cancer cells. Construct the fourth generation of NK-92-αFR-CAR-CXCR3A cells, which were co-expressed CXCR3A and αFR-CAR. Evaluate the killing and migration effects of NK-92-αFR-CAR-CXCR3A in vitro and in vivo. Results: RNA sequencing (RNA-seq) first revealed that the expression level of the chemokine CXCL10 was most significantly increased in ovarian cancer cells co-cultured with NK-92-αFR-CAR. Secondly, cytokine stimulation experiments confirmed that IFN-γ and TNF-α secreted by NK-92-αFR-CAR synergistically induced high CXCL10 expression in ovarian cancer cells. Further signaling pathway experiments showed that IFN-γ and TNF-α enhanced the activation level of the IFN-γ-IFNGR-JAK1/2-STAT1-CXCL10 signaling axis. Cytotoxicity experiments showed that NK-92-αFR-CAR-CXCR3A cells could not only efficiently kill αFR-positive ovarian cancer cells in vitro but also secrete IFN-γ and TNF-α. Higher migration than that of NK-92-αFR-CAR was detected in NK-92-αFR-CAR-CXCR3A using transwell assay. NK-92-αFR-CAR-CXCR3A effectively killed tumor cells in different mouse xenograft models of ovarian cancer and increased infiltration into tumor tissue. Conclusion: This study confirmed that IFN-γ and TNF-α secreted by αFR-CAR-engineered NK cells can synergistically induce high expression of CXCL10 in ovarian cancer cells and constructed self-driving αFR-CAR-engineered NK cells that can break through migration barriers based on CXCL10, which may provide a new therapeutic weapon for ovarian cancer.

ABSTRACTConsumers have begun to move their attention away from product functioning and toward value probably extracted from items. Companies have begun to use customer service systems (CSS) in response to this trend, which are business models that give clients with not solitary tangible items as well as intangible facilities. Even with substantial investigation on Smart CSS frameworks, rare of this frameworks considered customers active data producers actively creating data for the Smart CSS. Furthermore, the majority of them offered a generic remedy rather than a personalized one. To classify customer service systems, performance metrics, such as precision, accuracy, F1-score, Recall (Sensitivity), Specificity, Error rate, Computation time, and RoC are considered. The performance of AETGCN-NGOA-CSS approach attains 19.11%, 24.12% and 28.13% high specificity, 24.93%, 23.04%, and 9.51% lower computation time, 15.2%, 25.45% and 13.91% higher ROC and 8.45%, 20.98%, and 27.55% higher accuracy compared with existing methods, such as developing personalized recommendation system in smart product service system depend on unsupervised learning model (CSS-BERT), Cognitive Decision-Making approaches in Data-driven Retail Intelligence: Consumer Sentiments, Choices, Shopping Behaviors (CSS-CDMA), e-Commerce Online Intelligent Customer Service System under Fuzzy Control (CSS-FFNN), respectively.

Glutamine synthetase (GS) catalyzes de novo synthesis of glutamine that facilitates cancer cell growth. In the liver, GS functions next to the urea cycle to remove ammonia waste. As a dysregulated urea cycle is implicated in cancer development, the impact of GS's ammonia clearance function has not been explored in cancer. Here, we show that oncogenic activation of β-catenin (encoded by CTNNB1) led to a decreased urea cycle and elevated ammonia waste burden. While β-catenin induced the expression of GS, which is thought to be cancer promoting, surprisingly, genetic ablation of hepatic GS accelerated the onset of liver tumors in several mouse models that involved β-catenin activation. Mechanistically, GS ablation exacerbated hyperammonemia and facilitated the production of glutamate-derived nonessential amino acids, which subsequently stimulated mechanistic target of rapamycin complex 1 (mTORC1). Pharmacological and genetic inhibition of mTORC1 and glutamic transaminases suppressed tumorigenesis facilitated by GS ablation. While patients with hepatocellular carcinoma, especially those with CTNNB1 mutations, have an overall defective urea cycle and increased expression of GS, there exists a subset of patients with low GS expression that is associated with mTORC1 hyperactivation. Therefore, GS-mediated ammonia clearance serves as a tumor-suppressing mechanism in livers that harbor β-catenin activation mutations and a compromised urea cycle.

Silty soil was widely used as filling soil materials for the replacement of expansive soil in cold regions. This paper presents a straightforward approach for the effects of wetting-drying-freezing-thawing cycles on mechanical behaviors of silty soil and expansive soil by laboratory tests. The results showed that the silty soil and expansive soil after 7th wetting-drying-freezing-thawing cycles presented the decreases of elastic modulus, failure strength, cohesion and angel of internal friction by 8.9 %∼12.0 %, 7.7 %∼9.0 %, 7.9 %, 4.5 % and 17.6 %∼37.0 %, 20.5 %∼29.4 %, 43.2 %, 13.0 %, respectively, indicating that wetting-drying-freezing-thawing cycles had little impact on mechanical property of silty soil and a great influence on that of expansive soil. Among them, the mechanical property attenuation ratio in the first three wetting-drying-freezing-thawing cycles accounted for over 90 % of the total. In the meantime, the micro-structure damage, surface crack characteristics and grain size distribution variations of expansive soil were all more significantly than these of silty soil exposed to wetting-drying-freezing-thawing cycles, which brought insight into the causes of the differences in mechanical properties for silty soil and expansive soil. It is found that the silty soil properties were more stable than expansive soil properties, and the silty soil is very effective for replacing the expansive soil below canal structures in cold regions.

BackgroundInferring directional connectivity of brain regions from functional magnetic resonance imaging (fMRI) data has been shown to provide additional insights into predicting mental disorders such as schizophrenia. However, existing research has focused on the magnitude data from complex-valued fMRI data without considering the informative phase data, thus ignoring potentially important information.MethodsWe propose a new complex-valued transfer entropy (CTE) method to measure causal links among brain regions in complex-valued fMRI data. We use the transfer entropy to model a general non-linear magnitude–magnitude and phase–phase directed connectivity and utilize partial transfer entropy to measure the complementary phase and magnitude effects on magnitude–phase and phase–magnitude causality. We also define the significance of the causality based on a statistical test and the shuffling strategy of the two complex-valued signals.ResultsSimulated results verified higher accuracy of CTE than four causal analysis methods, including a simplified complex-valued approach and three real-valued approaches. Using experimental fMRI data from schizophrenia and controls, CTE yields results consistent with previous findings but with more significant group differences. The proposed method detects new directed connectivity related to the right frontal parietal regions and achieves 10.2–20.9% higher SVM classification accuracy when inferring directed connectivity using anatomical automatic labeling (AAL) regions as features.ConclusionThe proposed CTE provides a new general method for fully detecting highly predictive directed connectivity from complex-valued fMRI data, with magnitude-only fMRI data as a specific case.