A Time-Varying Mixture Integer-Valued Threshold Autoregressive Process Driven by Explanatory Variables.

In this paper, a time-varying first-order mixture integer-valued threshold autoregressive process driven by explanatory variables is introduced. The basic probabilistic and statistical properties of this model are studied in depth. We proceed to derive estimators using the conditional least squares (CLS) and conditional maximum likelihood (CML) methods, while also establishing the asymptotic properties of the CLS estimator. Furthermore, we employed the CLS and CML score functions to infer the threshold parameter. Additionally, three test statistics to detect the existence of the piecewise structure and explanatory variables were utilized. To support our findings, we conducted simulation studies and applied our model to two applications concerning the daily stock trading volumes of VOW.

Cerebellum drives functional dysfunctions in restless leg syndrome.

OBJECTIVE: Restless legs syndrome (RLS) has serious effects on patients' sleep quality, physical and mental health. However, the pathophysiological mechanisms of RLS remain unclear. This study utilized both static and dynamic functional activity and connectivity analyses approaches as well as effective connectivity analysis to reveal the neurophysiological basis of RLS. METHODS: The resting-state functional MRI (rs-fMRI) data from 32 patients with RLS and 33 age-, and gender-matched healthy control (HC) were collected. Dynamic and static amplitude of low frequency fluctuation (ALFF), functional connectivity (FC), and Granger causality analysis (GCA) were employed to reveal the abnormal functional activities and couplings in patients with RLS. RESULTS: RLS patients showed over-activities in left parahippocampus and right cerebellum, hyper-connectivities of right cerebellum with left basal ganglia, left postcentral gyrus and right precentral gyrus, and enhanced effective connectivity from right cerebellum to left postcentral gyrus compared to HC. CONCLUSIONS: Abnormal cerebellum-basal ganglia-sensorimotor cortex circuit may be the underlying neuropathological basis of RLS. Our findings highlight the important role of right cerebellum in the onset of RLS and suggest right cerebellum may be a potential target for precision therapy.

Coordination Mechanism and Bio-Evidence: Reactive γ-Ketoenal Intermediated Hepatotoxicity of Psoralen and Isopsoralen Based on Computer Approach and Bioassay.

Psoralen and isopsoralen are secondary plant metabolites found in many fruits, vegetables, and medicinal herbs. Psoralen-containing plants (Psoralea corylifolia L.) have been reported to cause hepatotoxicity. Herein, we found that psoralen and isopsoralen were oxidized by CYP450s to reactive furanoepoxide or γ-ketoenal intermediates, causing a mechanism-based inhibition of CYP3A4. Furthermore, in GSH-depleted mice, the hepatotoxicity of these reactive metabolites has been demonstrated by pre-treatment with a well-known GSH synthesis inhibitor, L-buthionine-S, Rsulfoxinine (BSO). Moreover, a molecular docking simulation of the present study was undertaken to understand the coordination reaction that plays a significant role in the combination of unstable intermediates and CYP3A4. These results suggested that psoralen and isopsoralen are modest hepatotoxic agents, as their reactive metabolites could be deactivated by H2O and GSH in the liver, which partly contributes to the ingestion of psoralen-containing fruits and vegetables being safe.

Sector mapping method for 3D detached retina visualization.

A new sphere-mapping algorithm called sector mapping is introduced to map sector images to the sphere of an eyeball. The proposed sector-mapping algorithm is evaluated and compared with the plane-mapping algorithm adopted in previous work. A simulation that maps an image of concentric circles to the sphere of the eyeball and an analysis of the difference in distance between neighboring points in a plane and sector were used to compare the two mapping algorithms. A three-dimensional model of a whole retina with clear retinal detachment was generated using the Visualization Toolkit software. A comparison of the mapping results shows that the central part of the retina near the optic disc is stretched and its edges are compressed when the plane-mapping algorithm is used. A better mapping result is obtained by the sector-mapping algorithm than by the plane-mapping algorithm in both the simulation results and real clinical retinal detachment three-dimensional reconstruction.

The mechanism and risk factors of clopidogrel-induced liver injury.

CONTEXT AND OBJECTIVE: Clopidogrel (CLP) is a prodrug which is widely used as a platelet aggregation inhibitor. Hepatotoxicity is rare but a potentially serious adverse reaction that is associated with CLP. Thiophene in CLP (the thienopyridine derivative) is a group that is easily oxidated by cytochrome P450 enzymes (CYP450s) to generate reactive metabolites (RMs), it may be implicated in the mechanism of CLP-induced hepatotoxicity. CYP2C19 and CYP2B6 are important CYP450s involved in the metabolism and activation of CLP, and the aim of this study is to investigate whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced liver injury. METHOD: Primary rat hepatocytes are applied to evaluate the hepatotoxicity of CLP. Glutathione-depleted mouse model is used to evaluate whether this toxicity of CLP is metabolized by CYP450s. We also used HepG2 cells co-incubated with recombinant CYP2B6 and CYP2C19 enzymes to further assess whether the metabolites of CYP2C19 and CYP2B6 are associated with the CLP-induced hepatocellular toxicity. RESULT: CLP in high dose (100 µM and 300 µM) showed cytotoxicity in primary rat hepatocytes assay. Administration of CLP with l-buthionine-S, R-sulfoxinine (BSO) for seven days enhanced the liver injury of CLP. The level of ALT, AST and TBIL in plasma increased significantly, and the histopathological results showed the obvious liver injury; Pretreatment of 1-aminobenzotriazole, a nonspecific inhibitor of CYP450s, suppressed CLP-induced hepatotoxicity; CLP showed a dose-dependent toxicity in HepG2/CYP2C19 enzyme and HepG2/CYP2B6 enzyme models. CONCLUSION: High activities of CYP2C19 and CYP2B6 are the risk factors for hepatocellular toxicity of CLP.

Mechanism-based inhibition of CYPs and RMs-induced hepatoxicity by rutaecarpine.

1. Rutaecarpine, a quinolone alkaloid isolated from the unripe fruit of Evodia rutaecarpa, is one of the main active components used in a variety of clinical applications, including the treatment of hypertension and arrhythmia. However, its hepatotoxicity has also been reported in recent years. 2. Reactive metabolites (RMs) play a vital role in drug-induced liver injury. Rutaecarpine has a secondary amine structure that may be activated to RMs. The aim of the study was to investigate the inhibition of rutaecarpine on CYPs and explore the possible relationship between RMs and potential hepatotoxicity. 3. A cell counting kit-8 cytotoxicity assay indicated that rutaecarpine can decrease the primary rat hepatocyte viability, increase lactate dehydrogenase and reactive oxygen species, reduce JC-1, and cause cell stress and membrane damage. The indexes were significantly restored by adding ABT, an inhibitor of CYPs. A cocktail assay showed that CYP1A2, CYP2C9, CYP2C19, CYP2E1 and CYP3A4 can be inhibited by rutaecarpine in human liver microsomes. The IC50 values of CYP1A2 with and without NADPH were 2.2 and 7.4 µM, respectively, which presented a 3.3 shift. The results from a metabolic assay indicated that three mono-hydroxylated metabolites and two di-hydroxylated metabolites were identified and two GSH conjugates were also trapped. 4. Rutaecarpine can inhibit the activities of CYPs and exhibit a potential mechanism-based inhibition on CYP1A2. RMs may cause herb-drug interactions, providing important information for predicting drug-induced hepatotoxicity.

Reactive metabolite activation by CYP2C19-mediated rhein hepatotoxicity.

1. Rhein, an active ingredient in the root of rhubarb, is used for its beneficial effects in a variety of clinical applications including the treatment of osteoarthritis and diabetic nephropathy. However, its hepatotoxicity has been reported in recent years. Rhein belongs to the conjugate structure which could be activated to reactive metabolites (RMs) inducing side-effects. This study is to explore the relationship between RMs and hepatotoxicity. 2. Based on the early detection of RMs, we have established a series of key technologies to research rhein hepatotoxicity mechanism: IC50 shift experiments and reduced glutathione (GSH) trapping experiment are adopted to identify RMs. The model of low activity of CYP450 enzymes (CYPs) in primary rat hepatocyte is constructed to analyze the relationship between the primary metabolic enzyme and hepatotoxicity of rhein better. 3. The IC50 shift value for CYP2C19 is 1.989, it suggests that CYP2C19 could activate rhein to RM. The structure of RM is epoxide intermediate. Besides, it is found that CYP2C19 is a primary metabolic enzyme for rhein. In the cytotoxicity assay, it is reported that rhein could cause mitochondrial dysfunction. Furthermore, mitochondrial membrane potential (Δψm) and AST levels could be restored by adding inhibitor of CYP2C19 together with rhein, which further shows that CYP2C19 could mediate the hepatotoxicity of rhein. 4. We put forward the possible mechanism that reactive metabolite activation by CYP2C19 mediated rhein hepatotoxicity, it provides important information on predicting in vivo drug-induced liver injury (DILI).

Up-regulation on cytochromes P450 in rat mediated by total alkaloid extract from Corydalis yanhusuo.

BACKGROUND: Yanhusuo (Corydalis yanhusuo W.T. Wang; YHS), is a well-known traditional Chinese herbal medicine, has been used in China for treating pain including chest pain, epigastric pain, and dysmenorrhea. Its alkaloid ingredients including tetrahydropalmatine are reported to inhibit cytochromes P450 (CYPs) activity in vitro. The present study is aimed to assess the potential of total alkaloid extract (TAE) from YHS to effect the activity and mRNA levels of five cytochromes P450 (CYPs) in rat. METHODS: Rats were administered TAE from YHS (0, 6, 30, and 150 mg/kg, daily) for 14 days, alanine aminotransferase (ALT) levels in serum were assayed, and hematoxylin and eosin-stained sections of the liver were prepared for light microscopy. The effects of TAE on five CYPs activity and mRNA levels were quantitated by cocktail probe drugs using a rapid chromatography/tandem mass spectrometry (LC-MS/MS) method and reverse transcription-polymerase chain reaction (RT-PCR), respectively. RESULTS: In general, serum ALT levels showed no significant changes, and the histopathology appeared largely normal compared with that in the control rats. At 30 and 150 mg/kg TAE dosages, an increase in liver CYP2E1 and CYP3A1 enzyme activity were observed. Moreover, the mRNA levels of CYP2E1 and CYP3A1 in the rat liver, lung, and intestine were significantly up-regulated with TAE from 6 and 30 mg/kg, respectively. Furthermore, treatment with TAE (150 mg/kg) enhanced the activities and the mRNA levels of CYP1A2 and CYP2C11 in rats. However, the activity or mRNA level of CYP2D1 remained unchanged. CONCLUSIONS: These results suggest that TAE-induced CYPs activity in the rat liver results from the elevated mRNA levels of CYPs. Co-administration of prescriptions containing YHS should consider a potential herb (drug)-drug interaction mediated by the induction of CYP2E1 and CYP3A1 enzymes.

A novel method of obtaining 3D images of detached retina.

We describe a new method of obtaining three-dimensional (3D) images of detached retina. Twelve-slice photos of the partial retina were obtained according to the twelve positions on a clock face. Twelve sections were then cut from these photos and joined together. Each sector was resized to match nearby sectors and the complete retinal picture was then created. A sphere mapping algorithm was used to map the two-dimensional (2D) picture to a sphere, which was then used to simulate the actual eyeball. Finally, a 3D image of the entire retina with a clearly visible detached section was created by the Visualization Toolkit (VTK).

A study on the reference electrode standardization technique for a realistic head model.

One oldest technical problem in EEG practice is the effect of an active reference on EEG recording, and it is especially important for identifying the temporal information of EEG recordings. To solve this problem, a reference electrode standardization technique (REST) has been proposed for a concentric three-sphere head model. REST, based on an equivalent distributed source model, reconstructs the potential with a reference at infinity from the potential with a scalp point reference or with the average reference. In this paper, investigated was the REST for a realistic head model. The results of simulation studies show that the potential reconstruction for the realistic head model is more sensitive to noise than that for the concentric three-sphere head model, so a regularized inverse by truncated singular value decomposition was introduced. The results confirm that REST is still an efficient method even for a realistic head model especially for the most important superficial cortex region.

A radial-basis function based surface Laplacian estimate for a realistic head model.

Scalp surface Laplacian (SL) is widely used to enhance spatial resolution and sensitivity for electroencephalograph (EEG) recordings. In this paper, a radial-basis function (RBF) based surface Laplacian (RBFL) estimate is proposed for realistic head model, in which RBF is used as basis function to interpolate the surface of a head model and the surface potentials. The efficiency of RBFL was confirmed through a comparative study to the global realistic geometry spline Laplacian (GSL) with both simulation studies and human visual evoked potential. The simulations include both feasibility in a 3-concentric sphere head model and influence of head model noise and potential noise, effects of border source and sources separation distance in a realistic head model. All the comparisons show RBFL can provide comparatively better results than GSL and hence RBFL provide another efficient method for high-resolution EEG mapping.