The power and the promise of synthetic lethality for clinical application in cancer treatment.

Synthetic lethality is a phenomenon wherein the simultaneous deficiency of two or more genes results in cell death, while the deficiency of any individual gene does not lead to cell death. In recent years, synthetic lethality has emerged as a significant topic in the field of targeted cancer therapy, with certain drugs based on this concept exhibiting promising outcomes in clinical trials. Nevertheless, the presence of tumor heterogeneity and the intricate DNA repair mechanisms pose challenges to the effective implementation of synthetic lethality. This review aims to explore the concepts, development, and ethical quandaries surrounding synthetic lethality. Additionally, it will provide an in-depth analysis of the clinical application and underlying mechanism of synthetic lethality.

The power and the promise of CAR-mediated cell immunotherapy for clinical application in pancreatic cancer.

BACKGROUND: Pancreatic cancer, referred to as the "monarch of malignancies," is a neoplastic growth mostly arising from the epithelial cells of the pancreatic duct and acinar cells. This particular neoplasm has a highly unfavorable prognosis due to its marked malignancy, inconspicuous initial manifestation, challenging early detection, rapid advancement, and limited survival duration. Cellular immunotherapy is the ex vivo culture and expansion of immune effector cells, granting them the capacity to selectively target malignant cells using specialized techniques. Subsequently, these modified cells are reintroduced into the patient's organism with the purpose of eradicating tumor cells and providing therapeutic intervention for cancer. PRESENT SITUATION: Presently, the primary cellular therapeutic modalities employed in the treatment of pancreatic cancer encompass CAR T-cell therapy, TCR T-cell therapy, NK-cell therapy, and CAR NK-cell therapy. AIM OF REVIEW: This review provides a concise overview of the mechanisms and primary targets associated with various cell therapies. Additionally, we will explore the prospective outlook of cell therapy in the context of treating pancreatic cancer.

The influence of motor learning methods on motor performance stability: The moderating effect of reinvestment propensity.

Different motor learning methods (explicit or analogy learning) show different effects on motor performance stability, and reinvestment propensity plays an important role in motor performance stability. This study aimed to explore whether reinvestment propensity, that is, movement self-consciousness (MS-C) and conscious motor processing (CMP) as two dimensions, played a moderating role in the relationship between motor learning methods and motor performance stability. A total of 78 participants were randomly assigned to either the explicit or analogy learning group and their reinvestment propensity was measured. We recorded the number of golf putt goals in both the practice phase and the test phases (including a retention test and a stress test). In the moderating analysis, participants' reinvestment propensity was the moderating variable, and the dependent variable was motor performance stability (i.e., the difference between the two test phases). Results showed that motor performance was significantly different between practicing blocks, which indicated that the motor performance of learners was gradually increasing. The significant interaction between learning methods and the test phase on motor performance was detected, suggesting under stress, analogy learning was more likely to maintain the stability of motor performance, while explicit learning impaired the stability of motor performance. The CMP played a significant moderating role in the relationship between motor learning methods and motor performance stability. The result indicated that for learners with low CMP, the motor performance stability of analogy learning was better than explicit learning, while there was no significant difference in the stability of motor performance between the two learning methods for learners with high reinvestment propensity. No significant evidence was found that MS-C played a moderating role in the relationship between motor learning methods and motor performance stability. These findings expand the theoretical framework of motor skill learning and provide theoretical support for motor performance stability.

KLK10/LIPH/PARD6B/SLC52A3 are promising molecular biomarkers for the prognosis of pancreatic cancer through a ceRNA network.

Pancreatic adenocarcinoma (PAAD) remains challenging to diagnose and treat clinically due to its difficult early diagnosis, low surgical resection rate, and high risk of postoperative recurrence and metastasis. SMAD4 is a classical mutated gene in pancreatic cancer and is lost in up to 60%-90 % of PAAD patients, and its mutation often predicts a poor prognosis and treatment resistance. In this study, based on the expression profile data in The Cancer Genome Atlas database, we identified a ceRNA network composed of 2 lncRNAs, 1 miRNA, and 4 mRNAs through differential expression analysis and survival prognosis analysis. Among them, high expression of KLK10/LIPH/PARD6B/SLC52A3 influenced the prognosis and overall survival of PAAD patients. We confirmed the high expression of these target genes in pancreatic tissue of pancreatic-specific SMAD4-deficient mice. In addition, immune infiltration analysis showed that the high expression of these target genes affects the tumor immune environment and contributes to the progression of PAAD. Abnormal overexpression of these target genes may be caused by hypermethylation. In conclusion, we found that KLK10/LIPH/PARD6B/SLC52A3 is a potential prognostic marker for PAAD based on a competing endogenous RNA-mediated mechanism and revealed the potential pathogenic mechanism by which deficient expression of SMAD4 promotes pancreatic cancer progression, which provides a new pathway and theoretical basis for targeted therapy or improved prognosis of pancreatic cancer. These data will help reveal potential therapeutic targets for pancreatic cancer and improve the prognosis of pancreatic cancer patients.

Inoculum Sources of Puccinia striiformis f. sp. tritici for Stripe Rust Epidemics on the Eastern Coast of China.

Stripe rust, a fungal disease caused by Puccinia striiformis f. sp. tritici (Pst), is one of the most destructive diseases affecting wheat production areas worldwide. In recent years in China, wheat stripe rust has caused huge yield losses throughout the vast Huang-Huai-Hai region, including the eastern coast regions, especially Shandong province. The aim of the present study was to explore the population structure and potential inoculum sources of the pathogen in this region. A total of 234 Pst isolates in 2021 were collected and isolated from seven provinces and identified for virulence phenotypes using 19 Chinese differentials and for genotypes using 17 single-nucleotide polymorphism-based Kompetitive allele-specific PCR markers. The virulence phenotype tests identified predominant races CYR34 (18.0%) and CYR32 (16.0%) in Shandong, which were similar to the results in Henan province, also with the predominant races CYR34 (21.9%) and CYR32 (18.8%). Based on the virulence data of phenotyping, the Pst populations in Shandong, Hubei, and Henan were similar. The genotypic analysis revealed remarkable gene flows among the Shandong, Hubei, Henan, Yunnan, and Guizhou populations, showing a migration of Pst from the southwestern oversummering regions to Shandong through the winter spore production regions. Genetic structure analysis also indicated an additional migration route from the northwestern oversummering regions through winter spore production regions to Shandong. The results are useful for understanding stripe rust epidemiology in the eastern coast region and improving control of the disease throughout the country.

Synergistic enhancement of chemisorption and catalytic conversion in lithium-sulfur batteries via Co3Fe7/Co5.47N separator mediator.

Lithium-sulfur batteries (LSBs) show considerable potential in next-generation high performance batteries, but the heavy shuttle effect and sluggish redox kinetics of polysulfide hinder their further applications. In this paper, to address these shortcomings of LSBs, Co3Fe7/Co5.47N heterostructure were prepared and constructed from their Fe-Co Prussian blue analogue precursors under the condition of high temperature pyrolysis. The obtained Co3Fe7/Co5.47N display excellent immobilization-diffusion-conversion performance for polysulfides by synergistic effect in successfully hindering the shuttle effect of polysulfides. When the Co3Fe7/Co5.47N heterostructure were applied to modify the commercial polypropylene (PP) separator, the batteries displayed fantastic rate capacity and cycling stability. Specifically, the Co3Fe7/Co5.47N-PP batteries exhibit an extremely satisfactory initial specific capacity of 1430 m Ah/g at 0.5C, wonderful rate capacity of around 780 m Ah/g at 3C and superior per cycle decaying rate of 0.08 % for 500 cycles at 0.5C. When the current density reaches to 2C, the batteries still exhibit 501 m Ah/g after 900 cycles with 0.015 % per cycle decay rate. Besides, even in the high loading of sulfur (3.0 mg cm-2) at 0.5C, the superior cycling stability (0.075 % per cycle decay rate after 200 cycles) and high specific capacity (741 mAh/g after 200 cycles) can still be performed. Thus, this work provides a facile method for high-powered and long-life Li-S batteries with eminent entrapping-conversion processes of polysulfides.

Effect of preoperative moderate-dose statin and duration on acute kidney injury after cardiac surgery: a retrospective cohort study.

BACKGROUND: The impact of preoperative statin use on postoperative acute kidney injury (AKI) is uncertain. We aimed to examine the association of statin therapy before cardiac surgery with postoperative AKI. METHODS: The retrospective cohort study consisted of 1581 patients undergoing cardiac surgery. Postoperative AKI were identified by the modified KDIGO definition. Propensity-score matching was employed to control for selection bias, and logistic regression was used to control for confounders. Subgroup and interaction analyses were performed to evaluate the robustness of the findings. RESULTS: The overall incidence of postoperative AKI and severe AKI were 42.19% and 12.27%, respectively. Preoperative moderate-dose statin was significantly associated with a reduced incidence of postoperative AKI (28.9% vs 43.0%, OR (95%CI): 0.54 (0.38, 0.77), p < 0.001) and severe AKI (6.9% vs 13.7%, OR (95%CI): 0.46 (0.26, 0.83), p = 0.009). The beneficial effect on postoperative AKI persisted after adjusting for major confounding factors (OR (95%CI): 0.47 (0.34, 0.66)). Decreased risk of postoperative AKI was observed in patients with preoperative statin duration of 7 ∼ 14 days (OR (95%CI): 0.41 (0.25, 0.65)) and over 14 days (OR (95%CI): 0.43 (0.28, 0.65)), but not in those with preoperative statin duration of <7 days. Similar favorable effects were noted in most subgroup patients, except for those with high-risk factors such as diabetes mellitus, previous congestive cardiac failure, arrhythmia, preoperative ACEI/ARB, aortic cross-clamping or IABP. CONCLUSION: Preoperative moderate-dose statin was significantly related to a decreased risk of postoperative AKI, especially in patients who received statins for a longer duration. Further large-scale multicenter randomized controlled trials are needed to ascertain the impact of statin dose, duration, and timing on postoperative AKI in cardiac surgery patients.

NAT10 Promotes Malignant Progression of Lung Cancer via the NF-κB Signaling Pathway.

BACKGROUND: NAT10 (N-acetyltransferase 10) is a newly identified novel acetyltransferase. Abnormal expression of NAT10 is associated with several human disorders, including cancer, autoimmune diseases, and cardiovascular disease. This study aimed to investigate the role of NAT10 in promoting lung cancer malignant progression through the NF-κB (nuclear factor κB) signaling pathway. METHODS: Cells lines BEAS-2B, NCI-H524, A549, PC-9, NCI-H23, and NCI-H258 were cultured for identification. Western blotting and PCR assays determined gene expression within the sample cells. Cellular functionality was assayed using CCK8 (Cell Counting Kit-8), Dual-Luciferase Reporter, and Colony formating. RESULTS: The PCR assay and Western blotting showed a significant elevation of NAT10 levels within tumor tissues compared to paraneoplastic tissues (p < 0.05). Specifically, NAT10 only affected the expression and content of RelA/p65 in lung cancer. Analysis from the TCGA (The Cancer Genome Atlas) database indicated that elevated expression levels of NAT10 in tumors can be a good prognostic indicator for lung cancer patients. The CCK8 assay showed that the knockdown of NAT10 significantly suppressed the A549 cells' progression rate (p < 0.05). The colony formation assays further confirmed that the overexpression of NAT10 significantly increased the generation of clones in the NCI-H524 cells (p < 0.05). The proliferation rate influenced by the overexpression of NAT10 was inhibited by blocking the NF-κB signaling pathway (p < 0.05). Dual-luciferase reporter gene assay results revealed NAT10's potential in promoting the NF-κB signaling pathway's activity in lung cancer. Immunohistochemical staining underscored a strong link between NAT10 protein expression and the NF-κB signaling pathway in lung cancer tissues. CONCLUSIONS: NAT10's expression is significantly upregulated in tumor tissues, supported by PCR results. NAT10 plays a role in the development and proliferation of lung cancer cells and can activate the NF-κB signaling pathway in lung cancer. Hence, NAT10's regulation of the NF-κB signaling pathway is critical in the malignant proliferation of lung cancer.

Interpretable machine learning models for early prediction of acute kidney injury after cardiac surgery.

OBJECTIVE: Postoperative acute kidney injury (PO-AKI) is a common complication after cardiac surgery. We aimed to evaluate whether machine learning algorithms could significantly improve the risk prediction of PO-AKI. METHODS: The retrospective cohort study included 2310 adult patients undergoing cardiac surgery in a tertiary teaching hospital, China. Postoperative AKI and severe AKI were identified by the modified KDIGO definition. The sample was randomly divided into a derivation set and a validation set based on a ratio of 4:1. Exploiting conventional logistic regression (LR) and five ML algorithms including decision tree, random forest, gradient boosting classifier (GBC), Gaussian Naive Bayes and multilayer perceptron, we developed and validated the prediction models of PO-AKI. We implemented the interpretation of models using SHapley Additive exPlanation (SHAP) analysis. RESULTS: Postoperative AKI and severe AKI occurred in 1020 (44.2%) and 286 (12.4%) patients, respectively. Compared with the five ML models, LR model for PO-AKI exhibited the largest AUC (0.812, 95%CI: 0.756, 0.860, all P < 0.05), sensitivity (0.774, 95%CI: 0.719, 0.813), accuracy (0.753, 95%CI: 0.719, 0.781) and Youden index (0.513, 95%CI: 0.451, 0.573). Regarding severe AKI, GBC algorithm showed a significantly higher AUC than the other four ML models (all P < 0.05). Although no significant difference (P = 0.173) was observed in AUCs between GBC (0.86, 95%CI: 0.808, 0.902) and conventional logistic regression (0.803, 95%CI: 0.746, 0.852), GBC achieved greater sensitivity, accuracy and Youden index than conventional LR. Notably, SHAP analyses showed that preoperative serum creatinine, hyperlipidemia, lipid-lowering agents and assisted ventilation time were consistently among the top five important predictors for both postoperative AKI and severe AKI. CONCLUSION: Logistic regression and GBC algorithm demonstrated moderate to good discrimination and superior performance in predicting PO-AKI and severe AKI, respectively. Interpretation of the models identified the key contributors to the predictions, which could potentially inform clinical interventions.

Case report: Short-term efficacy and changes in 18F-FDG-PET with acute multi-target stimulation in spinocerebellar ataxia type 3 (SCA3/MJD).

Objective: Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease (MJD), is a rare neurodegenerative disease for which there is no specific treatment. Very few cases have been treated with single-target deep brain stimulation (DBS), and the results were not satisfactory. We applied multi-target DBS to an SCA3/MJD patient and performed positron emission computed tomography (PET) before and after DBS to explore the short-term clinical therapeutic effect. Materials and methods: A 26-year-old right-hand-dominant female with a family history of SCA3/MJD suffered from cerebellar ataxia and dystonia. Genetic testing indicated an expanded CAG trinucleotide repeat in the ATXN3 gene and a diagnosis of SCA3/MJD. Conservative treatment had no obvious effect; therefore, leads were implanted in the bilateral dentate nucleus (DN) and the globus pallidus internus (GPi) and connected to an external stimulation device. The treatment effect was evaluated in a double-blind, randomized protocol in five phases (over a total of 15 days): no stimulation, GPi, DN, or sham stimulation, and combined GPi and DN stimulation. 18F-fluoro-2-deoxy-d-glucose and dopamine transporter PET, Scale for the Assessment and Rating of Ataxia, Fahn-Tolosa-Marin Clinical Rating Scale for Tremor (FTM), Burke-Fahn-Marsden Dystonia Rating Scale (BFMDRS), and SF-36 quality of life scores were compared before and after DBS. Results: The Total Scale for the Assessment and Rating of Ataxia scores improved by ~42% (from 24 to 14). The BFMDRS movement scores improved by ~30% (from 40.5 to 28.5). The BFMDRS disability scores improved by ~12.5% (from 16 to 14). Daily living activities were not noticeably improved. Compared with the findings in pre-DBS imaging, 18F-fluoro-2-deoxy-d-glucose uptake increased in the cerebellum, while according to dopamine transporter imaging, there were no significant differences in the bilateral caudate nucleus and putamen. Conclusion: Multi-target acute stimulation (DN DBS and GPi DBS) in SCA3/MJD can mildly improve cerebellar ataxia and dystonia and increase cerebellar metabolism.

Modified separators boost polysulfides adsorption-catalysis in lithium-sulfur batteries from Ni@Co hetero-nanocrystals into CNT-porous carbon dual frameworks.

In this manuscript, nickel/cobalt bimetallic nanocrystals confining into three-dimensional interpenetrating dual-carbon conductive structure (NiCo@C/CNTs) were successfully manufactured by annealing its core-shell structure (Ni-ZIF-67@ZIF-8) precursor under the high temperature. The results presented that the bimetallic nickel and cobalt nanocrystals with superior catalytic activity could quickly convert solid Li2S/Li2S2into soluble LiPSs and effectively decrease the energy barrier. While the hierarchical CNT-porous carbon dual frameworks can provide quick electron/ion transport because of their large specific surface area and the exposure of enough active sites. When used as the separator modifier for lithium sulfur batteries, the battery properties were significantly improved with high specific capacity, outstanding rate capability, and long-term cycle stability. Specifically, its initial specific capacity can achieve to 1038.51 mAh g-1 at 0.5C. At the high rate of 3C, it still delivers satisfactory discharge capacity of 555 mAhg-1 and the capacity decay rate is only 0.065% per cycle after 1000 cycles at 1C. Furthermore, even exposed to heavy sulfur loading (3.61 mg/cm2), they still maintain promising cycle stability. Therefore, such kinds of MOFs derivative with powerful chemical immobilization and catalytic conversion for polysulfides provides a novel guidance for the modification separator and the potential application in the field of high-performance Li-S batteries.

Resting-state functional magnetic resonance imaging study comparing tremor-dominant and postural instability/gait difficulty subtypes of Parkinson's disease.

PURPOSE: The symptom-specific intrinsic neural mechanisms underlying Parkinson's disease (PD) subtypes (tremor dominant [TD] and postural instability gait difficulty [PIGD]) remain unclarified. We examined spontaneous brain activity patterns in TD and PIGD. MATERIAL AND METHODS: We included 49 patients with PD (21 with TD/28 with PIGD) and 32 healthy controls (HCs) in this study. We conducted analysis of variance and post-hoc analyses of the amplitude of low-frequency fluctuation (ALFF) and regional homogeneity (ReHo) values of the three groups, with age, sex, and gray matter volume as covariates, and a relationship analysis of the ALFF and ReHo values with clinical variables. RESULTS: In comparison with HCs, PIGD PD patients had increased ALFF values in the right middle occipital gyrus and left superior occipital gyrus and decreased values primarily in the bilateral inferior frontal gyrus (triangular part). TD PD patients had lower ALFF values in the right inferior frontal gyrus (triangular part) and left insula. In comparison to TD PD patients, PIGD PD patients had higher ALFF values in the left middle occipital gyrus and left superior occipital gyrus. In contrast to HCs, TD PD patients demonstrated a reduction of ReHo values in the left middle temporal gyrus, and PIGD patients showed a decrease of ReHo values in the left inferior temporal gyrus. CONCLUSION: ALFF values increased in the occipital gyrus of the PIGD PD patients, thus providing evidence of a compensatory mechanism of altered motor function in comparison with the TD PD patients.

Characterization of Monoclonal Antibodies to Measure Cell Surface Protein Levels of Human Interferon-Lambda Receptor 1.

Type III interferons (IFN-lambdas, IFN-λs) are important antiviral cytokines that can also modulate immune responses by acting through a heterodimeric receptor composed of the specific and limited expressed IFN-λR1 chain and the ubiquitous IL-10R2 chain, which is shared with IL-10 family cytokines. Conflicting data have been reported regarding which cells express the IFN-λR1 subunit and directly respond to IFN-λs. This is, in part, owing to transcript levels of the IFN-λR1 gene, IFNLR1, not always correlating with cell surface protein levels. In this study, we tested a panel of novel monoclonal antibodies (mAbs) that specifically recognize human IFN-λR1. Initially, antigen specificity was confirmed by enzyme-linked immunosorbent assay (ELISA), from which a subset of antibodies was selected for additional flow cytometry and neutralization assays. We further characterized two antibodies based on their strong ELISA binding activity (HLR1 and HLR14) and found only HLR14 could reliably detect cell surface IFN-λR1 protein on a variety of cell lines by flow cytometry. HLR14 could also detect IFN-λR1 protein on certain primary human blood cells, including plasmacytoid dendritic cells and B cells from peripheral blood. Availability of the HLR14 mAb will enable the quantification of IFN-λR1 protein levels on cells and better characterization of the cell specificity of the IFN-λ response.

A demonstration based on multi-omics transcriptome sequencing data revealed disulfidptosis heterogeneity within the tumor microenvironment of esophageal squamous cell carcinoma.

BACKGROUND: It is of great concern to identify prognostic signatures for the prediction and prediction of esophageal squamous cell carcinoma (ESCC), which is the lethal pathological type of malignancy. METHOD: Bulk RNA sequencing and scRNA-seq data were retrieved from GSE53624, GSE53622, and GSE188900. Disulfidptosis-related differentially expressed genes (DEGs) were identified between disulfidptosis-high score and disulfidptosis-low score groups. Functional annotation of DEGs were analyzed by Gene Ontology (GO). Consistent clustering and co-expression modules were analyzed, and then constructed a risk score model via multivariate Cox regression analysis. Immune infiltration and immunotherapy response analyses were conducted based on risk score. qRT-PCR, colony formation assay, and flow cytometry analysis were conducted in KYSE-150 and TE-1 cell lines. RESULTS: Seven genes (CD96, CXCL13, IL2RG, LY96, TPK1, ACAP1, and SOX17) were selected as marker genes. CD96 and SOX17 are independent prognostic signatures for ESCC patients, with a significant correlation with infiltrated immune cells. ESCC patients had worse response to nivolumab in the high-risk group. Through cellular experiments, we found that CD96 expression was associated with apoptosis and cell cycle ESCC cells. CONCLUSION: In a word, the risk score based on disulfidptosis is associated with prognosis and the immune microenvironment, which may direct immunotherapy of ESCC. The key gene of risk score, namely CD96, plays a role in proliferation and apoptosis in ESCC. We offer an insight into the exploration of the genomic etiology of ESCC for its clinical management.

Trait Mindfulness and Problematic Smartphone Use in Chinese Early Adolescent: The Multiple Mediating Roles of Negative Affectivity and Fear of Missing Out.

This study used a cross-sectional study design to investigate whether the mindfulness trait was a protective factor against problematic smartphone use (PSPU) of early adolescents, and whether negative affectivity and fear of missing out (FoMO) mediated this relationship. The study selected a sample of middle school students (N = 517, 46.03% males, Mage = 13.81, SD = 1.40) in China. The results of the structural equation modelling indicated that (a) mindfulness significantly and negatively predicted PSPU, (b) FoMO played a mediating role between mindfulness and PSPU, (c) negative affectivity (including depression and anxiety) played a mediating role between mindfulness and PSPU, but loneliness did not, and (d) negative affectivity and FoMO played a chain-mediated role, and depression, anxiety, and loneliness played a chain-mediated role with FoMO between mindfulness and PSPU. We discuss the possibility that high levels of mindfulness in early adolescents may reduce the short-term effects of problematic smartphone use by reducing negative emotions and FoMO and relate our results to an emphasis on the role of enhanced mindfulness in long-term internal self-regulation and well-being. Findings have implications for individuals and schools for PSPU prevention and intervention.

Prevalence and management of hypertension in Central China: a cross-sectional survey.

OBJECTIVE: We aimed to assess hypertension prevalence and management in Central China. METHODS: In this cross-sectional study conducted from February 2019 to February 2020, we applied stratified multistage random sampling to investigate residents aged 35 to 75 years in Dancheng county of Zhoukou city and Xincai county of Zhumadian city, both in Central China. RESULTS: We enrolled 63,940 participants in this survey. A total of 43.6% (95% confidence interval [CI]: 43.2-44.0) of participants had hypertension. Of these, 49.3% (95% CI: 48.7-49.9) were aware of their diagnosis, 36.5% (95% CI: 35.9-37.1) took antihypertensive medication, and 14.3% (95% CI: 13.9-14.7) had their blood pressure under control. Only 31.4% of hypertensive people receiving antihypertensive treatment had achieved control. The hypertension prevalence was lower in urban areas than in rural areas, with higher rates of awareness, treatment, and control. Among subgroups, rural men had the highest prevalence of hypertension. Prevalence, awareness, and treatment rates all increased with age, except for control rates, which declined in the 65- to 75-year-old group. CONCLUSIONS: People in Central China have a high hypertension prevalence but low rates of awareness, treatment, and control. Great effort is needed to improve the prevention and management of hypertension in this region.

Discovery of 2-(isoxazol-5-yl)phenyl 3,4-dihydroxybenzoate as a potential inhibitor for the Wnt/ß-catenin pathway.

Carnosic acid could disrupt the ß-catenin/BCL9 protein-protein interaction and inhibit ß-catenin dependent transcription, thereby reduce the incidence of colorectal cancer induced by abnormal activation of Wnt/ß-catenin signalling pathway. However, its activity was weak (IC50 for SW480: 28.2 ± 2.05 µM) and total synthesis was difficult. During the structural simplification of natural products, S0 was revealed to be the basic pharmacophore of carnosic acid. Subsequent structural optimization of S0 led to the discovery of S11 as a possible anticancer agent with prominent proliferation inhibition effect (IC50 for SW480: 9.56 ± 0.91 µM) and best selectivity index (SI = 3.0) against Wnt hyperactive cancer cells. Futher mechanism investigation through TOP/FOP dual luciferase reporter assay, immunofluorescence, co-immunoprecipitation, microscale thermophoresis, downstream oncoprotein expression and cell apoptosis showed that compound S11 could significantly inhibit the proliferation of SW480 cells via obvioudsly decreasing the nucleus translocation of ß-catenin and effectively disrupting ß-catenin/BCL9 protein-protein interaction. Additionally, cell migration, molecule docking, in vitro stability and solubility assays were also conducted. Overall, S11 was worthy of in-depth study as a potential inhibitor for the Wnt/ß-catenin pathway and its discovery also proved that the structural simplification of natural products was still one of the effective methods to find new lead compounds or candidate drugs.

Facile fabrication of highly dispersed Pd catalyst on nanoporous chitosan and its application in environmental catalysis.

With the development of society, the problem of environmental pollution is becoming increasingly serious, such as the typical pollution of nitro compounds or dyes in wastewater. An effective strategy to remove these organic pollutants is catalytic conversion, including converting them into more chemically valuable compounds. Herein, a nanoporous chitosan microsphere derived from seafood waste resources of chitin was constructed via sol-gel method, which was used as supports to successfully fabricate a highly dispersed Pd nano-catalyst (mean diameter ~ 1.8 nm) via a facile way based on its interconnected nanoporous structure and rich functional -OH/-NH2 groups. The synthetic catalyst was applied to the hydrogenation of toxic nitro compounds, which could efficiently and selectively catalyze the conversion of nitro compounds. The catalyst was also used for the degradation of some representative dyes, which also showed good activity and stability, suggesting potential of applications in green environmental governance.

Understanding Human Behaviors and Injury Factors in Underground Mines using Data Analytics.

This study aims to understand human behaviors and associated injury causing factors in underground mines using data analytics of historical mining data. Decision tree and association rule were used to provide a statistical analysis of leading factors of hazards in underground mines. Based on the results, we were able to explore hazard feature identification using image feature recognition aiming to provide real-time monitoring for miners to secure healthy and safety operation via wearable computing.

A voxel-level brain-wide association study of cortisol at 8 a.m.: Evidence from Cushing's disease.

Cortisol, the end product of the hypothalamic-pituitary-adrenal axis, regulates cognitive function and emotion processing. Cushing's disease, which is characterized by a unique excess of cortisol upon clinical diagnosis, serve as an excellent in vivo "hyperexpression" model to investigate the neurobiological mechanisms of cortisol in the human brain. Previous studies have shown the association between cortisol and functional connectivity within an a priori brain network. However, the whole-brain connectivity pattern that accompanies endogenous cortisol variation is still unclear, as are its associated genetic underpinnings. Here, using resting-state functional magnetic resonance imaging in 112 subjects (60 patients with Cushing's disease and 52 healthy subjects), we performed a voxel-level brain-wide association analysis to investigate the functional connectivity pattern associated with a wide variation in cortisol levels at 8 a.m. The results showed that the regions associated with cortisol as of 8 a.m. were primarily distributed in brain functional hubs involved in self-referential processing, such as the medial prefrontal cortex, anterior and posterior cingulate cortex, and caudate. We also found that regions in the middle temporal, inferior parietal and ventrolateral prefrontal cortex, which is important for social communication tasks, and in the visual and supplementary motor cortex, which is involved in primary sensorimotor perception, were adversely affected by excessive cortisol. The connectivity between these regions was also significantly correlated with neuropsychiatric profiles, such anxiety and depression. Finally, combined neuroimaging and transcriptome analysis showed that functional cortisol-sensitive brain variations were significantly coupled to regional expression of glucocorticoid and mineralocorticoid receptors. These findings reveal cortisol-biased functional signatures in the human brain and shed light on the transcriptional regulation constraints on the cortisol-related brain network.