Intra- and peritumoral radiomics features based on multicenter automatic breast volume scanner for noninvasive and preoperative prediction of HER2 status in breast cancer: a model ensemble research.

The aim to investigate the predictive efficacy of automatic breast volume scanner (ABVS), clinical and serological features alone or in combination at model level for predicting HER2 status. The model weighted combination method was developed to identify HER2 status compared with single data source model method and feature combination method. 271 patients with invasive breast cancer were included in the retrospective study, of which 174 patients in our center were randomized into the training and validation sets, and 97 patients in the external center were as the test set. Radiomics features extracted from the ABVS-based tumor, peritumoral 3 mm region, and peritumoral 5 mm region and clinical features were used to construct the four types of the optimal single data source models, Tumor, R3mm, R5mm, and Clinical model, respectively. Then, the model weighted combination and feature combination methods were performed to optimize the combination models. The proposed weighted combination models in predicting HER2 status achieved better performance both in validation set and test set. For the validation set, the single data source model, the feature combination model, and the weighted combination model achieved the highest area under the curve (AUC) of 0.803 (95% confidence interval [CI] 0.660-947), 0.739 (CI 0.556,0.921), and 0.826 (95% CI 0.689,0.962), respectively; with the sensitivity and specificity were 100%, 62.5%; 81.8%, 66.7%; 90.9%,75.0%; respectively. For the test set, the single data source model, the feature combination model, and the weighted combination model attained the best AUC of 0.695 (95% CI 0.583, 0.807), 0.668 (95% CI 0.555,0.782), and 0.700 (95% CI 0.590,0.811), respectively; with the sensitivity and specificity were 86.1%, 41.9%; 61.1%, 71.0%; 86.1%, 41.9%; respectively. The model weighted combination was a better method to construct a combination model. The optimized weighted combination models composed of ABVS-based intratumoral and peritumoral radiomics features and clinical features may be potential biomarkers for the noninvasive and preoperative prediction of HER2 status in breast cancer.

Licraside as novel potent FXR agonist for relieving cholestasis: structure-based drug discovery and biological evaluation studies.

Cholestasis is a common clinical disease caused by a disorder in bile acids (BAs) homeostasis, which promotes its development. The Farnesoid X receptor (FXR) plays a critical role in regulating BAs homeostasis, making it an essential target for cholestasis treatment. Although several active FXR agonists have been identified, effective drugs for cholestasis are still lacking. To address this, a molecular docking-based virtual screening method was used to identify potential FXR agonists. A hierarchical screening strategy was employed to improve the screening accuracy, and six compounds were selected for further evaluation. Dual-luciferase reporter gene assay was used to demonstrate FXR activation by the screened compounds, and their cytotoxicity was then evaluated. Among the compounds, licraside showed the best performance and was selected for in vivo evaluation using an ANIT-induced cholestasis animal model. Results demonstrated that licraside significantly reduced biliary TBA, serum ALT, AST, GGT, ALP, TBIL, and TBA levels. Liver histopathological analysis showed that licraside also had a therapeutic effect on ANIT-induced liver injury. Overall, these findings suggest that licraside is an FXR agonist with potential therapeutic effects on cholestasis. This study provides valuable insights into the development of novel lead compounds from traditional Chinese medicine for cholestasis treatment.

Band engineering enhances the electrochemical properties by constructing TiO2 NRs-MoS2 NSFs flexible electrode.

Research and development of flexible electrodes with high performance are crucial to largely determine the performance of flexible lithium-ion batteries (FLIBs) to a large extent. In this work, a flexible anode (TiO2 NRs-MoS2 NSFs/CC) is rationally designed and successfully constructed, in which TiO2 nanorods arrays (NRs) vertically grown on CC as a supporting backbone for MoS2 nanosheets flowers (NSFs) to form a TiO2 NRs-MoS2 NSFs heterostructure. The backbone can not only serve as a mechanical support MoS2 and improve its electronic conductivity, but also limit the dissolution of polysulfides issue during cycling. The density functional theory (DFT) analysis manifests that the obvious interaction between O and S at the interface for the TiO2 NRs-MoS2 NSFs heterostructure changes the electronic structure and reduces the band gap of TiO2 NRs-MoS2 NSFs. The small band gap and high electron state at the Fermi level are both beneficial to the transport of electrons, enhancing the kinetics, and giving the long cycling stability at high density and excellent rate capacity. Furthermore, the assembled TiO2 NRs-MoS2 NSFs/CC//NCM622 full cell delivers superior rate capacity and good cycling stability. Meanwhile, the soft-packed cell shows good mechanical flexibility, which can be lighted up successfully and keep brightness when folding with different angles. This result illustrates that it is a highly potential strategy for constructing flexible electrodes with the controlled electronic structure through band engineering to not only improve the electrochemical performance, but also possibly meet the requirements of high-performance FLIBs.

(2E)-1-(2,4,6-Trimethoxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one, a Chalcone Derivative, Promotes Apoptosis by Suppressing RAS-ERK and AKT/FOXO3a Pathways in Hepatocellular Carcinoma Cells.

BACKGROUND: Liver cancer is an extremely common cancer with the highest mortality rate and poor prognosis. Owing to their low systemic toxicity and few side effects, natural compounds may provide better therapeutic effects for patients. (2E)-1-(2,4,6-trimethoxyphenyl)-3-(4-chlorophenyl)prop-2-en-1-one (TMOCC), a chalcone derivative, exhibits cytotoxicity towards many tumor cells. However, the anticancer mechanism of TMOCC has not been elucidated in human hepatocellular carcinoma (HCC). METHODS: Cell Counting Kit-8 and colony formation assays were used to evaluate the effects of TMOCC on viability and proliferation. Mitochondrial transmembrane potential and flow cytometry assays were used to detect apoptosis. The expression levels of proteins related to apoptosis, the RAS-ERK and AKT/FOXO3a signaling pathways were assessed using western blot. Potential targets of TMOCC were detected using molecular docking analysis. RESULTS: TMOCC inhibited viability and proliferation, and induced the loss of mitochondrial transmembrane potential, apoptosis and DNA double-strand breaks in both HCC cells. The RAS-ERK and AKT/FOXO3a signaling pathways were suppressed by TMOCC. Finally, ERK1, PARP-1, and BAX were identified as potential targets of TMOCC. CONCLUSION: Taken together, our results show that TMOCC promotes apoptosis by suppressing the RAS-ERK and AKT/FOXO3a signaling pathways. TMOCC may be a potential multi-target compound that is effective against liver cancer.

Computational Insights into the Allosteric Modulation of a Phthalate-Degrading Hydrolase by Distal Mutations.

Phthalate esters (PAEs) are a ubiquitous kind of environmental endocrine that disrupt chemicals, causing environmental and health issues. EstJ6 is an effective phthalate-degrading hydrolase, and its mutant with a combination of three non-conservative distal mutations has an improved activity against PAEs with unknown molecular mechanisms. Herein, we attempt to fill the significant gap between distal mutations and the activity of this enzyme using computational approaches. We found that mutations resulted in a redistribution of the enzyme's preexisting conformational states and dynamic changes of key functional regions, especially the lid over the active site. The outward motion of the lid upon the mutations made it easier for substrates or products to enter or exit. Additionally, a stronger substrate binding affinity and conformational rearrangements of catalytic reaction-associated residues in the mutant, accompanied by the strengthened communication within the protein, could synergistically contribute to the elevated catalytic efficiency. Finally, an attempt was made to improve the thermostability of EstJ6 upon introducing a distal disulfide bond between residues A23 and A29, and the simulation results were as expected. Together, our work explored the allosteric effects caused by distal mutations, which could provide insights into the rational design of esterases for industrial applications in the future.

A Critical Review of Machine Learning Techniques on Thermoelectric Materials.

Thermoelectric (TE) materials can directly convert heat to electricity and vice versa and have broad application potential for solid-state power generation and refrigeration. Over the past few decades, efforts have been made to develop new TE materials with high performance. However, traditional experiments and simulations are expensive and time-consuming, limiting the development of new materials. Machine learning (ML) has been increasingly applied to study TE materials in recent years. This paper reviews the recent progress in ML-based TE material research. The application of ML in predicting and optimizing the properties of TE materials, including electrical and thermal transport properties and optimization of functional materials with targeted TE properties, is reviewed. Finally, future research directions are discussed.

High-Throughput Screening for Thermoelectric Semiconductors with Desired Conduction Types by Energy Positions of Band Edges.

The conduction type of semiconductors is vitally important in many fields (e.g., photovoltaics, transistors, and thermoelectrics), but so far, there is no effective and simple indicator to quickly judge or predict the conduction type of various semiconductors. In this work, based on the relationship between the formation energy of charged defect and the Fermi level, we propose a simple and low-cost strategy for high-throughput screening the potential n-type or p-type semiconductors from the material database by using energy positions of band edges as indicators. As a case study, we validate this strategy in searching potential n-type thermoelectric materials from copper (Cu)-containing metal chalcogenides. A new promising thermoelectric material, CuIn5Se8, with potential intrinsic n-type conduction, is successfully screened from 407 Cu-containing metal chalcogenides and validated in the subsequent experiments. Upon doping iodine in CuIn5Se8, a peak thermoelectric figure of merit zT of 0.84 is obtained at 850 K. Beyond thermoelectrics, the strategy proposed in this study also sheds light on the new material development with desired conduction types in photovoltaics, transistors, and other fields.

Understanding the Allosteric Modulation of PTH1R by a Negative Allosteric Modulator.

The parathyroid hormone type 1 receptor (PTH1R) acts as a canonical class B G protein-coupled receptor, regulating crucial functions including calcium homeostasis and bone formation. The identification and development of PTH1R non-peptide allosteric modulators have obtained widespread attention. It has been found that a negative allosteric modulator (NAM) could inhibit the activation of PTH1R, but the implied mechanism remains unclear. Herein, extensive molecular dynamics simulations together with multiple analytical approaches are utilized to unravel the mechanism of PTH1R allosteric inhibition. The results suggest that the binding of NAM destabilizes the structure of the PTH1R-PTH-spep/qpep (the C terminus of Gs/Gq proteins) complexes. Moreover, the presence of NAM weakens the binding of PTH/peps (spep and qpep) and PTH1R. The intra- and inter-molecular couplings are also weakened in PTH1R upon NAM binding. Interestingly, compared with our previous study of the positive allosteric effects induced by extracellular Ca2+, the enhanced correlation between the PTH and G-protein binding sites is significantly reduced by the replacement of this negative allosteric regulator. Our findings might contribute to the development of new therapeutic agents for diseases caused by the abnormal activation of PTH1R.

Materials informatics platform with three dimensional structures, workflow and thermoelectric applications.

Since the proposal of the "Materials Genome Initiative", several material databases have emerged and advanced many materials fields. In this work, we present the Materials Informatics Platform with Three-Dimensional Structures (MIP-3d). More than 80,000 structural entries, mainly from the inorganic crystal structural database, are included in MIP-3d. Density functional theory calculations are carried out for over 30,000 entries in the database, which contain the relaxed crystal structures, density of states, and band structures. The calculation of the equations of state and sound velocities is performed for over 12,000 entries. Notably, for entries with band gap values larger than 0.3 eV, the band degeneracies for the valence band maxima and the conduction band minima are analysed. The electrical transport properties for approximately 4,400 entries are also calculated and presented in MIP-3d under the constant electron-phonon coupling approximation. The calculations of the band degeneracies and electrical transport properties make MIP-3d a database specifically designed for thermoelectric applications.

Conformational dynamics is critical for the allosteric inhibition of cGAS upon acetyl-mimic mutations.

Detection of cytosolic dsDNA by cyclic GMP-AMP synthase (cGAS) is critical for the immune system to sense and fight against infection, but chronic activation of cGAS by self-DNA leads to autoimmune diseases without effective treatment yet. It was found that acetylation on either Lys384, Lys394, or Lys414 could inhibit the catalytic production of cGAMP by cGAS, and further suppressed self-DNA-induced autoimmunity. However, the implied mechanism remains unclear. Here, extensive molecular dynamics simulations combined with multiple analytical approaches were employed to uncover the allosteric inhibition mechanisms by using the K-to-Q mutations to mimic acetylation. Results suggested that the exterior loops contributed most to the conformational dynamics of cGAS, and two concerted intrinsic motions were observed: the inward/outward or twisting movement for the outer appendage of lobe 1 and the open/closed swing of the active-site loops. Mutations slightly affected the binding of dsDNA and cGAMP. The shift of the conformational sampling of the active-site loops or residues around cGAMP upon mutation might potentially explain the inhibition of cGAS activity. Moreover, the intra- and inter-molecular coupling was weakened upon mutations more or less but via distinct pathways. Hence, conformational dynamics play a vital role in the allosteric inhibition of cGAS upon the studied acetyl-mimic mutations. As the studied acetyl-mimic mutations are located at either the inter-lobe or inter-molecular interfaces, hence except for acetylation, our findings might help the development of new therapeutics against autoimmune diseases due to abnormal cGAS activation by designing inter-lobe or intermolecular allosteric inhibitors.

GCdiscrimination: identification of gastric cancer based on a milliliter of blood.

Gastric cancer (GC) continues to be one of the major causes of cancer deaths worldwide. Meanwhile, liquid biopsies have received extensive attention in the screening and detection of cancer along with better understanding and clinical practice of biomarkers. In this work, 58 routine blood biochemical indices were tentatively used as integrated markers, which further expanded the scope of liquid biopsies and a discrimination system for GC consisting of 17 top-ranked indices, elaborated by random forest method was constructed to assist in preliminary assessment prior to histological and gastroscopic diagnosis based on the test data of a total of 2951 samples. The selected indices are composed of eight routine blood indices (MO%, IG#, IG%, EO%, P-LCR, RDW-SD, HCT and RDW-CV) and nine blood biochemical indices (TP, AMY, GLO, CK, CHO, CK-MB, TG, ALB and γ-GGT). The system presented a robust classification performance, which can quickly distinguish GC from other stomach diseases, different cancers and healthy people with sensitivity, specificity, total accuracy and area under the curve of 0.9067, 0.9216, 0.9138 and 0.9720 for the cross-validation set, respectively. Besides, this system can not only provide an innovative strategy to facilitate rapid and real-time GC identification, but also reveal the remote correlation between GC and these routine blood biochemical parameters, which helped to unravel the hidden association of these parameters with GC and serve as the basis for subsequent studies of the clinical value in prevention program and surveillance management for GC. The identification system, called GC discrimination, is now available online at http://lishuyan.lzu.edu.cn/GC/.

Farnesoid X Receptor as a Promising Therapeutic Target for Nonalcoholic Fatty Liver Disease (NAFLD) and the Current Development of Its Agonists.

Nonalcoholic fatty liver disease (NAFLD) comprises a group of clinical syndromes characterized by excessive fat deposition in liver cells. Owing to its increasing incidence, NAFLD has becomea pertinent global health problem as well as an important contributor to the fatality rate of liver and metabolic diseases. Farnesoid X receptor (FXR) has emerged as a new target in the treatment of NAFLD, and related drugs are being reported. This review provides an overview of the structure and function of FXR, along with its important regulatory roles in bile acid metabolism and lipid metabolism. The review also highlights the clinical application of FXR and the progress on basic research related to FXR modulators in NAFLD treatment. Identifying potent FXR modulators, structure-based virtual screening strategy, and the development of new drugs to regulate the allosteric pathway of FXR activity have become effective approaches for the study of novel ligand, which can expand the therapeutic applications of novel FXR agonists. Identification of potential FXR modulators may help elucidate the physiological effects of FXR and provide new opportunities for targeting FXR for metabolic diseases.

Discovery of potential Toxoplasma gondii CDPK1 inhibitors with new scaffolds based on the combination of QSAR and scaffold-hopping method with in vitro validation.

To discover drugs for toxoplasmosis with less side-effects and less probability to get drug resistance is eagerly appealed for pregnant women, infant or immunocompromised patients. In this work, using TgCDPK1 as drug target, we design a method to discover new inhibitors for CDPK1 as potential drug lead for toxoplasmosis with novel scaffolds based on the combination of 2D/3D-QSAR and scaffold-hopping methods. All the binding sites of the potential inhibitors were checked by docking method, and only the ones that docked to the most conserved sites of TgCDPK1, which make them have less probability to get drug resistance, were remained. As a result, 10 potential inhibitors within two new scaffolds were discovered for TgCDPK1 with experimentally verified inhibitory activities in micromole level. The discovery of these inhibitors may contribute to the drug development for toxoplasmosis. Besides, the pipeline which is composed in this work as the combination of QSAR and scaffold-hopping is simple, easy to repeat for researchers without need of in-depth knowledge of pharmacology to get inhibitors with novel scaffolds, which will accelerate the procedure of drug discovery and contribute to the drug repurposing study.

ATBdiscrimination: An in Silico Tool for Identification of Active Tuberculosis Disease Based on Routine Blood Test and T-SPOT.TB Detection Results.

Tuberculosis remains one of the deadliest infectious diseases worldwide. Only 5-15% of people infected with Mycobacterium tuberculosis develop active TB disease (ATB), while others remain latently infected (LTBI) during their lifetime, which has a completely different clinical treatment schedule. However, most current clinical diagnostic methods are based on the immune response of M. tuberculosis infections and cannot distinguish ATB from LTBIs. Thus, the rapid diagnosis of active or latent tuberculosis infections remains a serious challenge for clinicians. In this work, based on the test data of a total of 478 patients, 36 blood biochemical data were specially included with T-SPOT.TB detection results which are all from routine clinical practice as commercially available. Then a discrimination method to detect ATB infections was successfully developed based on these data by the random forest algorithm. This method presents a robust classification performance with AUC as 0.9256 and 0.8731 for the cross-validation set and the external validation set, respectively. This work suggests an innovative strategy for identification of ATB disease from a single drop of blood with advantages of being timely, efficient, and economical. It also provides valuable information for the comprehensive understanding of TB with deep associations between TB infection and routine blood test data. The web server of this identification method, called ATBdiscrimination, is now available online at http://lishuyan.lzu.edu.cn/ATB/ATBdiscrimination.html .

The alterations of bile acids in rats with high-fat diet/streptozotocin-induced type 2 diabetes and their negative effects on glucose metabolism.

PURPOSE: Bile acids (BAs) as a kind of endogenous and signaling molecules altered under the circumstance of T2DM, which could impact on the relevant pathways to further affect the glucose metabolism and insulin secretion and might be associated with the T2DM development and restoration. However, the potential mechanisms still need more various and multifaceted studies. Here, we explored the alterations of BAs features and their mechanisms, and discussed the potential effects of the altered BAs on the glucose metabolic disorder via the relevant signaling pathways. MAIN METHODS: The high-fat diet (HFD) feeding combining with injection of low-dose streptozotocin (STZ) was employed for inducing the T2DM rat model. Based on that, we investigated the alterations of the concentrations and compositions of BAs and their mechanisms, and explored the effects of the altered BAs on the glucose metabolic disorder via farnesoid X receptor (Fxr) and G protein-coupled bile acid receptor (Tgr5)-mediated pathways. KEY FINDINGS: In rats with T2DM, the BAs in rats with T2DM exhibited characteristic alterations, especially the increased ratio of 12α-OH to non-12α-OH BAs in serum, which could be ascribed to the up-regulated Cyp8b1 mRNA expression ratio in the liver. Moreover, Additionally, the altered BAs had negative effects on glucose metabolic disorder via inhibiting the Trg5/Fxr-mediated pathways in colon, liver and pancreas in rats with T2DM. SIGNIFICANCE: BAs in rats with T2DM exhibited the characteristic alterations, which could provide a cue for searching biomarkers of the T2DM diagnosis, and the altered BAs might aggravate the glucose metabolic disorder.

High-Throughput Screening for Advanced Thermoelectric Materials: Diamond-Like ABX2 Compounds.

High-throughput (HTP) calculations are a highly promising direction for the discovery of novel functional materials. Here we use an HTP framework to investigate the electronic structures and p-type thermoelectric properties of the ABX2 compounds with diamond-like structures. We show application of HTP both to identify compounds and also to identify underlying trends. A total of 65 entries out of 84 908 in the Materials Informatics Platform are selected for this study. The electronic structures and chemical-bonding analyses reveal that there exists a general conductive network consisting of the anion X sublattice, which dominates the electrical transport properties of the compounds. Electrical and thermal transport properties of the 41 pnictide and chalcogenide compounds with sufficient band gaps are studied. Pnictide compounds have relatively smaller Seebeck coefficients than the chalcogenide compounds. This is due to the smaller effective masses around the valence band maxima. The electrical conductivities and power factors, however, are better in pnictide compounds. This is because pnictide compounds have high electronic group velocities and electronic relaxation times. Combined with the predictions of lattice thermal conductivities based on the Slack model, 12 novel p-type and n-type ABX2 materials with high ZT values are predicted.

Discovery of High-Performance Thermoelectric Chalcogenides through Reliable High-Throughput Material Screening.

High-throughput (HTP) material design is an emerging field and has been proved to be powerful in the prediction of novel functional materials. In this work, an HTP effort has been carried out for thermoelectric chalcogenides with diamond-like structures on the newly established Materials Informatics Platform (MIP). Specifically, the relaxation time is evaluated by a reliable yet efficient method, which greatly improves the accuracy of HTP electrical transport calculations. The results show that all the compounds may have power factors over 10 µW/cm·K2 if fully optimized. A new series of diamond-like chalcogenides with an atomic ratio of 1:2:4 possess relatively higher electrical transport properties among all the compounds investigated. One particular compound, CdIn2Te4, and its variations have been verified experimentally with a peak ZT over 1.0. Further analysis reveals the existence of general conductive networks and the similar Pisarenko relations under the same anion sublattice, and the transport distribution function is found to be a good indicator for the power factors for the compounds investigated. This work demonstrates a successful case study in HTP material screening.

The ileum-liver Farnesoid X Receptor signaling axis mediates the compensatory mechanism of 17α-ethynylestradiol-induced cholestasis via increasing hepatic biosynthesis of chenodeoxycholic acids in rats.

BACKGROUND AND PURPOSE: Estrogen-induced intrahepatic cholestasis is one of the most common pathogenic factors for liver diseases in clinic. It is, however, regrettable that effective medical therapies to ameliorate or reverse this cholestasis are limited. Fortunately, the novel insights now allow us to target crucial transporters, enzymes and their regulatory pathways therapeutically by restoring disrupted bile acids (BAs) transport and signaling thus ameliorating cholestasis. Additionally, it has been found that a compensatory effect could have been developed under the condition of estrogen-induced in cholestasis. Hence, exploring the molecular mechanism of the adaptive changes counteracting the cholestasis would be one of the approaches for development of new therapeutic targets. METHODS: Parameters of BAs in different specimens, mRNA expressions of transporters, enzymes and farnesoid X receptor (Fxr) signaling pathways that relate to BAs homeostasis in liver and ileum were measured in rats with 7-day and 14-day 17α-ethynylestradiol (EE)-induced cholestasis, and the molecular docking and HepaRG cells studies for verification were also evaluated. KEY RESULTS: It has been found that the depression of "ileal Fxr-Fgf15 (fibroblast growth factor 15)-hepatic Cyp7a1 pathway" in coordinated with activation of "hepatic Fxr-Shp (small heterodimer partner)-Cyp8b1 pathway" as well as up-regulation of Cyp27a1 expression synergistically promoting the hepatic biosynthesis of chenodeoxycholic acids (CDCAs) that are the potent agonists of Fxr, contribute to the Bsep up-regulation mediated the bile flow restoration to alleviate the cholestasis. CONCLUSION: These findings suggest that the adaptive regulation of Fxr-mediated ileum-liver signaling axis on Cyp7a1/Cyp8b1 might be the potentially novel targets for amelioration or treatment of estrogen-induced cholestasis, and we expect that this study would be of great value to provide a cue for patients with estrogen-induced cholestasis.

The influences of cholecystectomy on the circadian rhythms of bile acids as well as the enterohepatic transporters and enzymes systems in mice.

Bile acids (BAs), the most important endogenous and signaling molecules regulate the target transporters and enzymes at transcriptional level, participate in a wide variety of processes throughout the entire gastrointestinal tract to orchestrate homeostasis in vivo. BAs and their metabolism and transportation appear to follow the clear circadian rhythms, and they are recently proposed also as the potential chronobiological signals that can affect the molecular clock mechanism. Cholecystectomy are believed to affect the circadian rhythms of BAs and the relevant enterohepatic transporters and enzymes systems and their regulatory signaling pathways, for the reason that the circadian cycle of gallbladder filling and emptying play a pivotal role in controlling the flow of bile into the intestine and the enterohepatic circulation of BAs. Here, in the present study, the circadian rhythms about BAs concentration and composition and the mRNA expression of genes involved in BAs transportation, metabolism and regulation in liver and ileum of mice with or without gallbladder were evaluated. As a result, it has been found that, mice with gallbladder exhibited significant and distinct circadian oscillations in BAs concentration, mRNA expression of enterohepatic transporters and enzymes systems and farnesoid X receptor-mediated regulatory pathways both in liver and ileum during gallbladder emptying period (1:00 AM and 1:00 PM), despite food was restricted during these periods; the circadian rhythmicity of BAs pool and hepatic and ileal BAs diminished but the BAs composition had no significant alteration in liver and ileum after cholecystectomy as compared with sham-operated mice; in parallel to the alteration of BAs levels in liver and ileum after cholecystectomy, the day/night circadian oscillations in the mRNA expression of the relevant transporting and metabolic genes and the farnesoid X receptor signaling pathway-mediated â€Å“intestine-liver†regulatory axis also shifted. In conclusion, the BAs concentration and the corresponding genes exhibit significant circadian rhythms in mice with gallbladder, and the circadian oscillations of most of the investigation factors are flattened and altered following by cholecystectomy, which could mainly ascribe to the disappearance of the filling and emptying cycle of gallbladder and might result in pathological states or drug chronopharmacology alternation. We expect that this study would provide a cue for patients with cholecystectomy. ABBREVIATIONS: Asbt: apical sodium-dependent bile acids transporter; AUC24h: area under the 24-hour BA concentration time curve; BAs: bile acids; Bsep: bile salt export pump; ß-MCA: ß-muricholic acid; CA: cholic acid; CDCA: chenodeoxycholic acid; Cyp3a11: cytochrome P450 3a11 (human CYP3A4); Cyp7a1: cholesterol 7α-hydroxylase cytochrome P450 7a1; DCA: deoxycholic acid; Fxr: farnesoid X receptor; Fgf15: fibroblast growth factor 15; G-: glycine conjugated bile acid; HDCA: hyodesoxycholic acid; LCA: lithocholic acid; Mrp2: multidrug resistance-associated protein 2; NDCA: demethylation deoxycholic acid; Ntcp: Na+-taurocholate co-transporting polypeptide; Oatp2: organic anion transporting polypeptide 2; Ostα/ß: heterodimeric organic solute transporters alpha and beta; Shp: small heterodimer partner; T-: taurine conjugated bile acid; UDCA: ursodeoxycholic acid.

Association between coronary artery atherosclerosis and plasma glucose levels assessed by dual-source computed tomography.

BACKGROUND: To assess the association between coronary artery atherosclerosis (CAA) and plasma glucose parameters in a randomly selected cohort of asymptomatic, community-dwelling, Chinese adults by dual-source computed tomography (DSCT). METHODS: We randomly selected participants and classified them into three groups based on their plasma glucose levels: normal glucose regulation (NGR), pre-diabetes, and diabetes mellitus (DM). The participants underwent DSCT, and those identified with CAA were divided into four groups according to the severity of their coronary artery stenosis. We analyzed the composition of plaques in all coronary artery segments according to the American Heart Association's (AHA) guidelines. We compared the severity of coronary artery stenosis and the plaque composition with plasma glucose parameters among participants. RESULTS: Out of a total of 335 participants, 118 were found to have CAA. The prevalence of CAA was highest (P value for trend =0.031) in the diabetic group (67.7%) followed by the pre-diabetic group (35.1%) then the NGR group (27.7%). Both calcified and mixed plaques were found in the coronary arteries of the diabetic group while mixed and non-calcified plaques predominated in the pre-diabetic and the NGR groups. When data from all subjects with CAA were analyzed, blood glucose parameters, fasting plasma glucose (FPG), 2-hr postprandial plasma glucose (PPG), and hemoglobin A1c (HbA1c), exhibited a positive correlation with the severity of coronary stenosis (P<0.05). Multivariable logistic regression models indicated a significantly higher risk of CAA among the diabetic patients. Triglyceride levels were positively correlated with the blood glucose parameters among the three groups while LDL-C was elevated in the DM group but not in the pre-diabetic group compared to the NGR group. CONCLUSIONS: The severity of CAA exhibited a direct correlation with the blood glucose parameters, FPG, PPG, and HbA1c. DSCT can accurately detect the presence and distribution of CAA in asymptomatic, community-dwelling subjects. DSCT is a useful screening tool for coronary artery disease (CAD).