ABSTRACT
Alzheimer's disease (AD) represents the most widespread neurodegenerative disorder, distinguished by a gradual onset and slow progression, presenting a substantial challenge to global public health. The mitochondrial-associated membrane (MAMs) functions as a crucial center for signal transduction and material transport between mitochondria and the endoplasmic reticulum, playing a pivotal role in various pathological mechanisms of AD. The dysregulation of mitochondrial quality control systems is considered a fundamental factor in the development of AD, leading to mitochondrial dysfunction and subsequent neurodegenerative events. Recent studies have emphasized the role of MAMs in regulating mitochondrial quality control. This review will delve into the molecular mechanisms underlying the imbalance in mitochondrial quality control in AD and provide a comprehensive overview of the role of MAMs in regulating mitochondrial quality control.
Subject(s)
Alzheimer Disease , Mitochondria , Mitochondrial Membranes , Alzheimer Disease/metabolism , Humans , Mitochondria/metabolism , Animals , Mitochondrial Membranes/metabolism , Endoplasmic Reticulum/metabolismABSTRACT
Phosphohistidine (pHis) is a reversible protein post-translational modification (PTM) that is currently poorly understood. The P-N bond in pHis is heat and acid-sensitive, making it more challenging to study than the canonical phosphoamino acids pSer, pThr, and pTyr. As advancements in the development of tools to study pHis have been made, the roles of pHis in cells are slowly being revealed. To date, a handful of enzymes responsible for controlling this modification have been identified, including the histidine kinases NME1 and NME2, as well as the phosphohistidine phosphatases PHPT1, LHPP, and PGAM5. These tools have also identified the substrates of these enzymes, granting new insights into previously unknown regulatory mechanisms. Here, we discuss the cellular function of pHis and how it is regulated on known pHis-containing proteins, as well as cellular mechanisms that regulate the activity of the pHis kinases and phosphatases themselves. We further discuss the role of the pHis kinases and phosphatases as potential tumor promoters or suppressors. Finally, we give an overview of various tools and methods currently used to study pHis biology. Given their breadth of functions, unraveling the role of pHis in mammalian systems promises radical new insights into existing and unexplored areas of cell biology.
Subject(s)
Histidine , Humans , Phosphorylation , Histidine/metabolism , Histidine/analogs & derivatives , Animals , Phosphoric Monoester Hydrolases/metabolism , Protein Processing, Post-Translational , Protein Kinases/metabolism , Phosphoprotein Phosphatases/metabolism , Histidine Kinase/metabolism , Histidine Kinase/geneticsABSTRACT
Concerns over maternal and fetal drug exposures highlight the need for a better understanding of drug distribution into the fetus through the placental barrier. This study aimed to predict maternal and fetal drug disposition using physiologically based pharmacokinetic (PBPK) modeling. The detailed maternal-placental-fetal PBPK model within the Simcyp Simulator V20 was used to predict the maternal and fetoplacental exposure of cefazolin, cefuroxime, and amoxicillin during pregnancy and at delivery. The mechanistic dynamic model includes physiologic changes of the maternal, fetal, and placental parameters over the course of pregnancy. Placental kinetics were parametrized using permeability parameters determined from the physicochemical properties of these compounds. Then, the PBPK predictions were compared with the observed data. Fully bottom-up fetoplacental PBPK models were developed for cefuroxime, cefazolin, and amoxicillin without any parameter fitting. Predictions in nonpregnant subjects and in pregnant subjects fall within 2-fold of the observed values. Predictions matched observed pharmacokinetic data reported in nine maternal (five fetoplacental) studies for cefuroxime, 10 maternal (five fetoplacental) studies for cefazolin, and six maternal (two fetoplacental) studies for amoxicillin. Integration of the fetal and maternal system parameters within PBPK models, together with compound-related parameters used to calculate placental permeability, facilitates and extends the applications of the maternal-placental-fetal PBPK model. The developed model can also be used for designing clinical trials and prospectively used for maternal-fetal risk assessment after maternally administered drugs or unintended exposure to environmental toxicants. SIGNIFICANCE STATEMENT: This study investigates the performance of an integrated maternal-placental-fetal PBPK model to predict maternal and fetal tissue exposure of renally eliminated antibiotics that cross the placenta through a passive diffusion mechanism. The transplacental permeability clearance was predicted from the drug physicochemical properties. Results demonstrate that the PBPK approach can facilitate the prediction of maternal and fetal drug exposure simultaneously at any gestational age to support its use in the maternal-fetal exposure assessments.
Subject(s)
Cefazolin , Cefuroxime , Amoxicillin , Cefazolin/pharmacokinetics , Cefuroxime/pharmacokinetics , Female , Humans , Maternal-Fetal Exchange/physiology , Models, Biological , Placenta , PregnancyABSTRACT
Type 2 diabetes (T2DM) is a well known risk factor for Alzheimer's disease. Mitochondria are the center of intracellular energy metabolism and the main source of reactive oxygen species. Mitochondrial dysfunction has been identified as a key factor in diabetes-associated brain alterations contributing to neurodegenerative events. Defective insulin signaling may act in concert with neurodegenerative mechanisms leading to abnormalities in mitochondrial structure and function. Mitochondrial dysfunction triggers neuronal energy exhaustion and oxidative stress, leading to brain neuronal damage and cognitive impairment. The normality of mitochondrial function is basically maintained by mitochondrial quality control mechanisms. In T2DM, defects in the mitochondrial quality control pathway in the brain have been found to lead to mitochondrial dysfunction and cognitive impairment. Here, we discuss the association of mitochondrial dysfunction with T2DM and cognitive impairment. We also review the molecular mechanisms of mitochondrial quality control and impacts of mitochondrial quality control on the progression of cognitive impairment in T2DM.
Subject(s)
Alzheimer Disease , Cognitive Dysfunction , Diabetes Mellitus, Type 2 , Alzheimer Disease/metabolism , Cognitive Dysfunction/metabolism , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/metabolism , Humans , Mitochondria/metabolism , Oxidative Stress/physiology , Reactive Oxygen Species/metabolismABSTRACT
A machine learning method was used to process a multiagent information database to study the spatial distribution characteristics of agglomerations of metal-related enterprises and to analyze the spatial and temporal differentiation characteristics of pollution reduction in metal-related enterprises. Based on the spatial distribution of enterprises and a simulation of their pollution reduction behaviors, the layout of 380 enterprises sample is optimized, and the direction of industrial transfer is planned to give full play to the pollution reduction effect of enterprise agglomeration. The results showed that (1) the metal-related enterprises in the Chang-Zhu-Tan urban agglomeration have obvious spatial heterogeneity and are mainly distributed in the district of Changsha, the Qingshuitang Industrial Zone, Liling city and the Qibaoshan Industrial Zone of Liuyang city, while the metal-related enterprises in Shaoshan city, Zhuzhou County and Liling city are scattered. (2) The pollution emission behaviors of enterprises differ in time and space, and the pollution concentrations are highest in industrial parks such as Qingshuitang and Zhubu Port. (3) There is an interactive relationship between the degree of enterprise agglomeration and the pollution reduction effect. The spatial positive coupling degree between the concentration of metal-related enterprises and the degree of metal-related pollution is significant, accounting for 94.96% of the study area. Low pollution-high agglomeration areas, high pollution-low agglomeration areas, high pollution-high agglomeration areas, and low pollution-low agglomeration area account for 1.01%, 4.03%, 2.87%, and 92.09% of the study area, respectively. Finally, based on the new development concept of dual circulation and the theory of a two-oriented society in the new era, the paper puts forward suggestions and policies for the sustainable development of industrial transfer.
Subject(s)
Environmental Pollution , Industry , China , Cities , Metals , Sustainable DevelopmentABSTRACT
BACKGROUND: To investigate the clinical feasibility of preoperative routine clinical dynamic Gd-EOB-DTPA-enhanced MRI alone to predict post-hepatectomy liver failure (PHLF) in patients with hepatocellular carcinoma (HCC). METHODS: 116 patients with HCC who underwent liver resection in Southwest Hospital from 2014 through 2017 were selected in this retrospective cohort study. The remnant function (RF) of the liver RFUR and RFRE15 were calculated by the sum of the uptake rate (UR) or relative enhancement at 15 min (RE15) from dynamic Gd-EOB-DTPA-enhanced MR images in the remnant liver regions, and standardized by standard liver volume (SLV) to generate sRFUR (standardized RFUR) and sRFRE15 (standardized RFRE15). Student's t test or Mann-Whitney U test, logistic regression, and ROC analyses were used to test the associations of preoperative RFUR, sRFUR, RFRE15, sRFRE15, the remnant liver volume (RLV)/SLV, ICG retention rate at 15 min (ICG R15) and sRFICG-K [ICG clearance rate (ICG-K) × RLV/SLV] with PHLF. RESULTS: 28 patients were found to have PHLF, who showed lower RFUR, sRFUR, RFRE15, sRFRE15, RLV/SLV, sRFICG-K, and higher ICG R15 than patients without PHLF (p < 0.001 for all). After adjusting for clinical parameters, RFUR (p = 0.001), sRFUR (p = 0.001), RFRE15 (p = 0.002), or sRFRE15 (p = 0.003) was found to be independently significant indicator in multivariable logistic regression, respectively. RFUR (0.882) and sRFUR (0.882) had larger AUCs than RLV/SLV (0.731, p = 0.008; p = 0.005), ICG R15 (0.765, p = 0.039; p = 0.044) and sRFICG-K (0.767, p = 0.031; p = 0.023). RFRE15 (0.845) and sRFRE15 (0.839) had larger AUCs than RLV/SLV (0.731, p = 0.027; p = 0.025). CONCLUSIONS: The remnant liver function parameters preoperatively estimated from a routine clinical dynamic Gd-EOB-DTPA-enhanced MRI protocol can predict PHLF in patients with HCC, and may be better predictors than conventional methods.
Subject(s)
Carcinoma, Hepatocellular , Liver Neoplasms , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/surgery , Contrast Media , Gadolinium DTPA , Humans , Liver/diagnostic imaging , Liver Function Tests , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/surgery , Magnetic Resonance Imaging , Retrospective StudiesABSTRACT
BACKGROUND: The relationship between dietary and drinking water habits and oral health are still unclear. We aimed at evaluating the association of dietary and drinking water habits with number of teeth in the elderly adults. METHODS: We conducted a longitudinal study based on the Chinese Longitudinal Healthy Longevity Survey from 1998 to 2018. The data of dietary and drinking water habits at baseline were collected using a questionnaire. The number of teeth at baseline and follow-up was collected for each subject. We used the linear mixed-effect model to analyze the associations of dietary habits and drinking water sources with tooth number. RESULTS: Among 19,896 participants at baseline, the mean age of the participants was 83.87 years, with the average number of natural teeth of 9.37, 8.26, 8.38, 8.68, 4.05, 1.92, 1.12, 2.20 for the first to eighth waves of survey. Compared with subjects drinking tap water, 1.036 (95 % CI: -1.206, -0.865), 0.880 (95 % CI: -1.122, -0.637) and 1.331 (95 % CI: -1.715, -0.947) fewer natural teeth were reported for those drinking well, surface water and spring at baseline survey. Compared with participants with rice intake as the staple food, those with wheat intake (ß = -0.684; 95 % CI: -0.865, -0.503) tended to have fewer natural teeth. Compared with participants with fresh fruit intake almost every day, those with quite often intake of fresh fruit tended to have fewer teeth with a significant dose-response trend (Ptrend <0.001). Similar decreased trend for number of teeth was also indicated for increased frequency of vegetable intake (Ptrend <0.001). Fewer number of teeth was found for subjects with less frequency of meat and fish intakes. CONCLUSIONS: The study suggested that drinking well, surface water, and spring, intakes of wheat as staple food, as well as less frequency of fresh fruit, vegetable, meat and fish intakes were associated with significantly fewer number of teeth in the Chinese elderly population.
Subject(s)
Drinking Water , Aged , Aged, 80 and over , Animals , China/epidemiology , Diet , Habits , Humans , Longitudinal StudiesABSTRACT
The NME (Non-metastatic) family members, also known as NDPKs (nucleoside diphosphate kinases), were originally identified and studied for their nucleoside diphosphate kinase activities. This family of kinases is extremely well conserved through evolution, being found in prokaryotes and eukaryotes, but also diverges enough to create a range of complexity, with homologous members having distinct functions in cells. In addition to nucleoside diphosphate kinase activity, some family members are reported to possess protein-histidine kinase activity, which, because of the lability of phosphohistidine, has been difficult to study due to the experimental challenges and lack of molecular tools. However, over the past few years, new methods to investigate this unstable modification and histidine kinase activity have been reported and scientific interest in this area is growing rapidly. This review presents a global overview of our current knowledge of the NME family and histidine phosphorylation, highlighting the underappreciated protein-histidine kinase activity of NME family members, specifically in human cells. In parallel, information about the structural and functional aspects of the NME family, and the knowns and unknowns of histidine kinase involvement in cell signaling are summarized.
Subject(s)
Histidine/metabolism , NM23 Nucleoside Diphosphate Kinases/metabolism , Amino Acid Sequence , Animals , Biocatalysis , Humans , NM23 Nucleoside Diphosphate Kinases/chemistry , Phosphorylation , Structure-Activity RelationshipABSTRACT
In order to integrate resource consumption, environmental damage and ecological benefits into the evaluation system of social and economic development, and practice the green concept of "Lucid waters and lush mountains are invaluable assets", this research was based on the Green GDP and Gross Ecosystem Product accounting to develop comprehensive accounting indicators for Gross Economic-Ecological Product (GEEP). At the same time, the 2016 GEEP of 31 provinces in China is calculated. The results show that: 1) GEEP is a comprehensive ecological-economic accounting system based on weak sustainable development theory and welfare economics. GEEP follows the principle of GDP accounting and carries out value accounting for the final products of ecological and economic systems. Based on GDP, GEEP considers the ecological-environmental damage caused by human beings in economic product activities and the benefits of the ecological system to the economic system. 2) In 2016, China's GEEP was 126.6 trillion RMB, 1.6 times of GDP, among them, the cost of pollution damage was 2.1 trillion RMB, the ecological degradation cost was 0.69 trillion RMB, and the ecosystem regulating service was 51.4 trillion RMB. 3) The regional Gini coefficient based on GEEP was 0.44, which was 0.07 smaller than the regional Gini coefficient calculated based on GDP in 2016, thus GEEP accounting would benefit to shrink regional disparity. 4) Compared GEEP ranking with GDP ranking of all provinces, GEEP rankings in Inner Mongolia, Heilongjiang, Yunnan, Qinghai and Tibet have increased by more than 10 ranks compared with GDP, and Beijing, Shanghai, Tianjin, Hebei and Shaanxi, their GEEP ranking compared with the GDP ranking has descending more than 10 places.
Subject(s)
Economic Development , Ecosystem , Beijing , China , Humans , TibetABSTRACT
To investigate the effect of salidroside on the proteomics of erythrocyte membrane in high altitude erythrocytosis(HAPC) rats, in order to explore the mechanism of salidroside in improving HAPC based on the proteomics analysis. First, HPAC rat models were established, and 16 rats were randomly divided into HAPC model group and salidroside(100 mg·kg~(-1)) treatment group(8 rats per group). Saline was administered to the HAPC model group, while salidroside treatment group was given 100 mg·kg~(-1) salidroside once a day. After continuous oral administration with salidroside for 40 days(once a day), blood was collected from the femoral artery to obtain total red blood cell membrane proteins. Two-dimensional electrophoresis was used to separate total proteins. The two-dimensional electrophoresis of erythrocyte membrane proteins was analyzed before and after salidroside intervention, and the proteins with significant differences were identified by mass spectrometry. Finally, biological functions were analyzed using bioinformatics. A two-dimensional electrophoresis method was used to establish a protein expression profile with a high resolution and reproducibility of erythrocyte membranes in HAPC rats. Salidroside treatment significantly changed 18 protein spots in the 2-DE map of erythrocyte membranes, of which 13 proteins were up-regulated and 5 proteins were down-regulated. Eight differential proteins were successfully identified by mass spectrometry. Moreover, bioinformatics analysis found that these differential proteins were involved in such biological processes as oxidative stress, redox, and peroxisome pathway, which are mainly associated with peroxisome and MAPK signaling pathways. Therefore, salidroside could significantly change the expressions of erythrocyte membrane proteins in HAPC rats. Eight differential proteins were identified by a proteomic-based approach. The differential proteins were involved in such biological processes as oxidative stress, redox, peroxisome pathway.
Subject(s)
Polycythemia , Altitude , Animals , Erythrocytes , Glucosides , Phenols , Proteomics , Rats , Reproducibility of ResultsABSTRACT
The aim of the present study was to predict the effect of inter-individual and inter-ethnic human kinetic variation on the sensitivity towards acute liver toxicity of lasiocarpine in the Chinese and the Caucasian population, and to derive chemical specific adjustment factors (CSAFs) by integrating variation in the in vitro kinetic constants Vmax and Km, physiologically based kinetic (PBK) modelling and Monte Carlo simulation. CSAFs were derived covering the 90th and 99th percentile of the population distribution of pyrrole glutathione adduct (7-GS-DHP) formation, reflecting bioactivation. The results revealed that in the Chinese population, as compared to the Caucasian population, the predicted 7-GS-DHP formation at the geometric mean, the 90th and the 99th percentile were 2.1-, 3.3- and 4.3-fold lower respectively. The CSAFs obtained using the 99th percentile values were 8.3, 17.0 and 19.5 in the Chinese, the Caucasian population and the two populations combined, respectively, while the CSAFs were generally 3.0-fold lower at the 90th percentile. These results indicate that when considering the formation of 7-GS-DHP the Caucasian population may be more sensitive towards acute liver toxicity of lasiocarpine, and further point out that the default safety factor of 3.16 for inter-individual human kinetic differences may not be sufficiently protective. Altogether, the results obtained demonstrate that integrating PBK modelling with Monte Carlo simulations using human in vitro data is a powerful strategy to quantify inter-individual variations in kinetics, and can be used to refine the human risk assessment of pyrrolizidine alkaloids.
Subject(s)
Asian People , Chemical and Drug Induced Liver Injury/etiology , Models, Biological , Pyrrolizidine Alkaloids/pharmacokinetics , White People , Animals , Chemical and Drug Induced Liver Injury/ethnology , Computer Simulation , Glutathione/chemistry , Humans , Male , Microsomes, Liver/drug effects , Microsomes, Liver/metabolism , Monte Carlo Method , Pyrrolizidine Alkaloids/toxicity , Risk Assessment/methodsABSTRACT
Lasiocarpine and riddelliine are pyrrolizidine alkaloids (PAs) known to cause liver toxicity. The aim of this study was to predict the inter-species and inter-ethnic human differences in acute liver toxicity of lasiocarpine and riddelliine using physiologically based kinetic (PBK) modelling based reverse dosimetry of in vitro toxicity data. The concentration-response curves of in vitro cytotoxicity of lasiocarpine and riddelliine defined in pooled human hepatocytes were translated to in vivo dose-response curves by PBK models developed using kinetic data obtained from incubations with pooled tissue fractions from Chinese and Caucasian individuals, providing PBK models for the average Chinese and average Caucasian, respectively. From the predicted in vivo dose-response curves, the benchmark dose lower and upper confidence limits for 5% effect (BMDL5 and BMDU5) were derived and subsequently compared to those previously obtained in rat to evaluate inter-species differences. The inter-species differences amounted to 2.0-fold for lasiocarpine and 8.2-fold for riddelliine with humans being more sensitive than rats. The inter-ethnic human differences varied 2.0-fold for lasiocarpine and 5.0-fold for riddelliine with the average Caucasian being more sensitive than the average Chinese. In conclusion, the present study provides the proof-of-principle to predict inter-species and inter-ethnic differences in in vivo liver toxicity for PAs by an alternative testing strategy integrating in vitro cytotoxicity data with PBK modelling-based reverse dosimetry.
Subject(s)
Hazardous Substances/toxicity , Liver/drug effects , Pyrrolizidine Alkaloids/toxicity , Toxicity Tests/methods , Animals , Computer Simulation , Hepatocytes , Humans , Kinetics , Liver/metabolism , Microsomes, Liver , Models, Biological , RatsABSTRACT
Interleukin 17 expression is increased in children with Hirschsprung disease, which is characterized by intestinal inflammation. This study designed to exploit the characteristics of intestinal inflammation and examine the correlation of interleukin 17 in this process of hypoganglionosis model established by benzalkonium chloride treatment. Colon sections from female rats were treated with benzalkonium chloride to induce hypoganglionosis or with saline alone as a sham control. C-reactive protein and tumor necrosis factor-É were used as markers of inflammation. Expression of C-reactive protein, tumor necrosis factor-É, and interleukin 17 was assessed in colon tissue and blood serum on days 7, 14 and 21 after treatment. The correlation between C-reactive protein, tumor necrosis factor-É, and interleukin 17 expression was estimated using the Spearman's rank-correlation coefficient. C-reactive protein, tumor necrosis factor-É, and interleukin 17 were strongly expressed in submucosa and mucosa layers and serum from treated animals. The expression of C-reactive protein, tumor necrosis factor-É, and interleukin 17 maintained the highest level at Day 21. Only C-reactive protein and tumor necrosis factor-É expression was increased in control animals and only on day 7. Spearman's rank correlation coefficient was significant in C-reactive protein, tumor necrosis factor-É, and interleukin 17â¯at Day 7, 14 and 21. Concomitant upregulation of C-reactive protein, tumor necrosis factor-É, and interleukin 17 and significant positive correlations between C-reactive protein, tumor necrosis factor-É, and interleukin 17 may imply that interleukin 17 is involved in spatio-temporal inflammation induced by benzalkonium chloride.
Subject(s)
Hirschsprung Disease/pathology , Inflammation/pathology , Interleukin-17/metabolism , Intestines/pathology , Animals , Benzalkonium Compounds , C-Reactive Protein/metabolism , Disease Models, Animal , Female , Hirschsprung Disease/blood , Inflammation/blood , Interleukin-17/blood , Rats, Sprague-Dawley , Tumor Necrosis Factor-alpha/blood , Tumor Necrosis Factor-alpha/metabolismABSTRACT
PURPOSE: To propose a simple method to correct vascular input function (VIF) due to inflow effects and to test whether the proposed method can provide more accurate VIFs for improved pharmacokinetic modeling. METHODS: A spoiled gradient echo sequence-based inflow quantification and contrast agent concentration correction method was proposed. Simulations were conducted to illustrate improvement in the accuracy of VIF estimation and pharmacokinetic fitting. Animal studies with dynamic contrast-enhanced MR scans were conducted before, 1 week after, and 2 weeks after portal vein embolization (PVE) was performed in the left portal circulation of pigs. The proposed method was applied to correct the VIFs for model fitting. Pharmacokinetic parameters fitted using corrected and uncorrected VIFs were compared between different lobes and visits. RESULTS: Simulation results demonstrated that the proposed method can improve accuracy of VIF estimation and pharmacokinetic fitting. In animal study results, pharmacokinetic fitting using corrected VIFs demonstrated changes in perfusion consistent with changes expected after PVE, whereas the perfusion estimates derived by uncorrected VIFs showed no significant changes. CONCLUSION: The proposed correction method improves accuracy of VIFs and therefore provides more precise pharmacokinetic fitting. This method may be promising in improving the reliability of perfusion quantification. Magn Reson Med 79:3093-3102, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Subject(s)
Contrast Media/pharmacokinetics , Image Processing, Computer-Assisted/methods , Liver/diagnostic imaging , Magnetic Resonance Imaging/methods , Animals , Female , Liver/blood supply , Liver/metabolism , Phantoms, Imaging , SwineABSTRACT
PURPOSE: To propose a simultaneous acquisition sequence for improved hepatic pharmacokinetics quantification accuracy (SAHA) method for liver dynamic contrast-enhanced MRI. METHODS: The proposed SAHA simultaneously acquired high temporal-resolution 2D images for vascular input function extraction using Cartesian sampling and 3D large-coverage high spatial-resolution liver dynamic contrast-enhanced images using golden angle stack-of-stars acquisition in an interleaved way. Simulations were conducted to investigate the accuracy of SAHA in pharmacokinetic analysis. A healthy volunteer and three patients with cirrhosis or hepatocellular carcinoma were included in the study to investigate the feasibility of SAHA in vivo. RESULTS: Simulation studies showed that SAHA can provide closer results to the true values and lower root mean square error of estimated pharmacokinetic parameters in all of the tested scenarios. The in vivo scans of subjects provided fair image quality of both 2D images for arterial input function and portal venous input function and 3D whole liver images. The in vivo fitting results showed that the perfusion parameters of healthy liver were significantly different from those of cirrhotic liver and HCC. CONCLUSIONS: The proposed SAHA can provide improved accuracy in pharmacokinetic modeling and is feasible in human liver dynamic contrast-enhanced MRI, suggesting that SAHA is a potential tool for liver dynamic contrast-enhanced MRI. Magn Reson Med 79:2629-2641, 2018. © 2017 International Society for Magnetic Resonance in Medicine.
Subject(s)
Contrast Media/pharmacokinetics , Image Interpretation, Computer-Assisted/methods , Liver/diagnostic imaging , Liver/metabolism , Adult , Algorithms , Carcinoma, Hepatocellular/diagnostic imaging , Carcinoma, Hepatocellular/metabolism , Humans , Liver Neoplasms/diagnostic imaging , Liver Neoplasms/metabolism , Magnetic Resonance Imaging/methods , Male , Middle Aged , Phantoms, ImagingABSTRACT
Cyclophilin 40 (Cyp40) is a member of the immunophilin family that acts as a peptidyl-prolyl-isomerase enzyme and binds to the heat shock protein 90 (Hsp90). Its structure comprises an N-terminal cyclophilin domain and a C-terminal tetratricopeptide (TPR) domain. Cyp40 is overexpressed in prostate cancer and certain T-cell lymphomas. The groove for Hsp90 binding on the TPR domain includes residues Lys227 and Lys308, referred to as the carboxylate clamp, and is essential for Cyp40-Hsp90 binding. In this study, the effect of two mutations, K227A and K308A, and their combinative mutant was investigated by performing a total of 5.76 µs of all-atom molecular dynamics (MD) simulations in explicit solvent. All simulations, except the K308A mutant, were found to adopt two distinct (extended or compact) conformers defined by different cyclophilin-TPR interdomain distances. The K308A mutant was only observed in the extended form which is observed in the Cyp40 X-ray structure. The wild-type, K227A, and combined mutant also showed bimodal distributions. The experimental melting temperature, Tm, values of the mutants correlate with the degree of compactness with the K308A extended mutant having a marginally lower melting temperature. Another novel measure of compactness determined from the MD data, the "coordination shell volume," also shows a direct correlation with Tm. In addition, the MD simulations show an allosteric effect with the mutations in the remote TPR domain having a pronounced effect on the molecular motions of the enzymatic cyclophilin domain which helps rationalise the experimentally observed increase in enzyme activity measured for all three mutations.
Subject(s)
Cyclophilins/chemistry , Point Mutation/genetics , Peptidyl-Prolyl Isomerase F , Cyclophilins/genetics , Humans , Molecular Dynamics Simulation , Protein Conformation , Protein Domains/genetics , Thermodynamics , Transition TemperatureABSTRACT
This study investigated the total concentrations and bioaccessibility of heavy metals in edible tissues and trophic levels of 12 marine organism species in the South China Sea. The results were used to estimate health risks to humans. Of the heavy metals detected, nickel (Ni) was present at the highest concentrations, followed in descending, order by iron (Fe), zinc (Zn), manganese (Mn), chromium (Cr), copper (Cu), cadmium (Cd) and lead (Pb). Cd had the highest percentage bioaccessibility (61.91%). There were no correlations between log-transformed total metal concentrations and trophic level values, nor between log-transformed bioaccessibility metal concentrations and trophic level values. This indicates there is no biomagnification among these trace metals. The carcinogenic risk probabilities for Pb and Cr to urban and rural residents were below the acceptable level (< 1â¯× 10-4). The target hazard quotient (THQ) value for each metal and the total THQ values for all metals studied indicated no significant risk of non-carcinogenic effects to urban and rural residents from consuming marine organisms from the South China Sea.
Subject(s)
Aquatic Organisms/metabolism , Food Chain , Metals, Heavy/analysis , Water Pollutants, Chemical/analysis , Cadmium/analysis , Cadmium/metabolism , Cadmium/toxicity , China , Chromium/analysis , Chromium/metabolism , Chromium/toxicity , Copper/analysis , Copper/metabolism , Copper/toxicity , Environmental Monitoring/methods , Humans , Iron/analysis , Iron/metabolism , Iron/toxicity , Manganese/analysis , Manganese/metabolism , Manganese/toxicity , Metals, Heavy/metabolism , Metals, Heavy/toxicity , Nickel/analysis , Nickel/metabolism , Nickel/toxicity , Risk Assessment , Water Pollutants, Chemical/metabolism , Water Pollutants, Chemical/toxicity , Zinc/analysis , Zinc/metabolism , Zinc/toxicityABSTRACT
INTRODUCTION: The purpose of this study was to evaluate the two-body wear resistances of natural enamel and four dental materials in vitro. METHODS: The testing machine was modified to form a type of pin-on-disk wear test apparatus. Four dental material specimens (Au-Pd alloy, Ag-Pd alloy, FiltekTMP60 and FiltekTMZ350 composite resins) and enamel were used as the pins, and a steatite ceramic grinding wheel was used as the abrasive counter face. The wear volume loss and the rigidity value was measured. The worn surface and the element analysis of the debris were analyzed. RESULT: The wear volume loss of Au-Pd alloy and its steatite antagonists were the nearest to those of the dental enamel. SEM microphotographs showed that, the main wear mechanism of the dental materials was abrasive and adhesive wear. CONCLUSIONS: Au-Pd alloy had good wear resistance and was more suitable for dental applications than other three dental materials.
Subject(s)
Composite Resins/pharmacology , Dental Enamel/metabolism , Dental Restoration Wear , Materials Testing/methods , Dental Alloys/pharmacology , Dental Materials/classification , Dental Materials/pharmacology , Humans , Surface PropertiesABSTRACT
PURPOSE: To propose a fast simultaneous noncontrast angiography and intraplaque hemorrhage (fSNAP) sequence for carotid artery imaging. METHODS: The proposed fSNAP sequence uses a low-resolution reference acquisition for phase-sensitive reconstruction to speed up the scan, and an inversion recovery acquisition with arbitrary k-space filling order to generate similar contrast to conventional SNAP. Four healthy volunteers and eight patients were recruited to test the performance of fSNAP in vivo. The lumen area quantification, muscle-blood CNR, IPH-blood CNR, lumen SNR, and standard deviation and intraplaque hemorrhage (IPH) detection accuracy were compared between fSNAP and SNAP. RESULTS: By using a low-resolution reference acquisition with 1/4 matrix size of the full-resolution reference scan, the scan time of fSNAP was 37.5% less than that of SNAP. A high agreement of lumen area measurement (ICC = 0.97, 95% CI: 0.96-0.99) and IPH detection (Kappa = 1) were found between fSNAP and SNAP. Also, no significant difference was found for muscle-blood CNR (P = 0.25), IPH-blood CNR (P = 0.35), lumen SNR (P = 0.60), and standard deviation (P = 0.46) between the two techniques. CONCLUSION: The feasibility of fSNAP was validated. fSNAP can improve the imaging efficiency with similar performance to SNAP on carotid artery imaging. Magn Reson Med 77:753-758, 2017. © 2016 International Society for Magnetic Resonance in Medicine.
Subject(s)
Carotid Arteries/diagnostic imaging , Carotid Stenosis/diagnostic imaging , Hemorrhage/diagnostic imaging , Image Interpretation, Computer-Assisted/methods , Magnetic Resonance Angiography/methods , Adult , Aged , Female , Humans , Male , Phantoms, Imaging , Young AdultABSTRACT
PURPOSE: To determine whether pharmacokinetic modeling parameters with different output assumptions of dynamic contrast-enhanced MRI (DCE-MRI) using Gd-EOB-DTPA correlate with serum-based liver function tests, and compare the goodness of fit of the different output assumptions. METHODS: A 6-min DCE-MRI protocol was performed in 38 patients. Four dual-input two-compartment models with different output assumptions and a published one-compartment model were used to calculate hepatic function parameters. The Akaike information criterion fitting error was used to evaluate the goodness of fit. Imaging-based hepatic function parameters were compared with blood chemistry using correlation with multiple comparison correction. RESULTS: The dual-input two-compartment model assuming venous flow equals arterial flow plus portal venous flow and no bile duct output better described the liver tissue enhancement with low fitting error and high correlation with blood chemistry. The relative uptake rate Kir derived from this model was found to be significantly correlated with direct bilirubin (r = -0.52, P = 0.015), prealbumin concentration (r = 0.58, P = 0.015), and prothrombin time (r = -0.51, P = 0.026). CONCLUSION: It is feasible to evaluate hepatic function by proper output assumptions. The relative uptake rate has the potential to serve as a biomarker of function. Magn Reson Med 78:1488-1495, 2017. © 2016 International Society for Magnetic Resonance in Medicine.