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2.  GeneChip Expression Profiling Reveals the Alterations of Energy Metabolism Related Genes in Osteocytes under Large Gradient High Magnetic Fields 
PLoS ONE  2015;10(1):e0116359.
The diamagnetic levitation as a novel ground-based model for simulating a reduced gravity environment has recently been applied in life science research. In this study a specially designed superconducting magnet with a large gradient high magnetic field (LG-HMF), which can provide three apparent gravity levels (μ-g, 1-g, and 2-g), was used to simulate a space-like gravity environment. Osteocyte, as the most important mechanosensor in bone, takes a pivotal position in mediating the mechano-induced bone remodeling. In this study, the effects of LG-HMF on gene expression profiling of osteocyte-like cell line MLO-Y4 were investigated by Affymetrix DNA microarray. LG-HMF affected osteocyte gene expression profiling. Differentially expressed genes (DEGs) and data mining were further analyzed by using bioinfomatic tools, such as DAVID, iReport. 12 energy metabolism related genes (PFKL, AK4, ALDOC, COX7A1, STC1, ADM, CA9, CA12, P4HA1, APLN, GPR35 and GPR84) were further confirmed by real-time PCR. An integrated gene interaction network of 12 DEGs was constructed. Bio-data mining showed that genes involved in glucose metabolic process and apoptosis changed notablly. Our results demostrated that LG-HMF affected the expression of energy metabolism related genes in osteocyte. The identification of sensitive genes to special environments may provide some potential targets for preventing and treating bone loss or osteoporosis.
PMCID: PMC4312085  PMID: 25635858
3.  Identification and Cytotoxic Activities of Two New Trichothecenes and a New Cuparane-Type Sesquiterpenoid from the Cultures of the Mushroom Engleromyces goetzii 
Engleromyces goetzii is a traditional medicinal mushroom that is widely used to treat infection, inflammation and cancer in Tibet, Sichuan and Yunnan provinces of China. Two new trichothecenes, engleromycones A and B (1 and 2), one new cuparane-type sesquiterpenoid named infuscol F (11), eight known trichothecene analogs, sambucinol (3), 3-deoxysambucinol (4), trichothecolone (5), trichodermol (6), 8-deoxytrichothecin (7), trichothecin (8), trichothecinol B (9) and trichothecinol A (10), and one known cyclopentanoid sesquiterpene cyclonerodiol (12) were isolated from the cultures of E. goetzii. The new compounds were elucidated through spectroscopic analyses. The anticancer effects of trichothecenes 1–10 were examined in the HL-60, SMMC-7721, A549, MCF-7, and SW-480 human cancer cell lines using an MTT assay. Trichothecinol A (10) significantly inhibited the growth of MCF-7 cells, with an IC50 value of 0.006 µM, which was comparable to the cytotoxic activity of the positive control, paclitaxel, indicating that trichothecinol A (10) represents a potential anticancer agent.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0051-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4328002  PMID: 25633363
Engleromyces goetzii; Trichothecene; Engleromycone; Cuparane; Infuscol; Mycotoxin
4.  Identification and Cytotoxic Activities of Two New Trichothecenes and a New Cuparane-Type Sesquiterpenoid from the Cultures of the Mushroom Engleromyces goetzii 
Engleromyces goetzii is a traditional medicinal mushroom that is widely used to treat infection, inflammation and cancer in Tibet, Sichuan and Yunnan provinces of China. Two new trichothecenes, engleromycones A and B (1 and 2), one new cuparane-type sesquiterpenoid named infuscol F (11), eight known trichothecene analogs, sambucinol (3), 3-deoxysambucinol (4), trichothecolone (5), trichodermol (6), 8-deoxytrichothecin (7), trichothecin (8), trichothecinol B (9) and trichothecinol A (10), and one known cyclopentanoid sesquiterpene cyclonerodiol (12) were isolated from the cultures of E. goetzii. The new compounds were elucidated through spectroscopic analyses. The anticancer effects of trichothecenes 1–10 were examined in the HL-60, SMMC-7721, A549, MCF-7, and SW-480 human cancer cell lines using an MTT assay. Trichothecinol A (10) significantly inhibited the growth of MCF-7 cells, with an IC50 value of 0.006 µM, which was comparable to the cytotoxic activity of the positive control, paclitaxel, indicating that trichothecinol A (10) represents a potential anticancer agent.
Graphical Abstract
Electronic supplementary material
The online version of this article (doi:10.1007/s13659-014-0051-1) contains supplementary material, which is available to authorized users.
PMCID: PMC4328002  PMID: 25633363
Engleromyces goetzii; Trichothecene; Engleromycone; Cuparane; Infuscol; Mycotoxin
5.  An open-label, flexible-dose study of paliperidone extended-release in Chinese patients with first-onset psychosis 
Antipsychotic medications facilitate the improvement of psychotic symptoms in patients with first-episode psychosis. Paliperidone extended-release (pali-ER), an atypical antipsychotic, was assessed for efficacy and safety in Chinese patients with first-episode psychosis.
In this 8-week, open-label, single-arm, multicenter study, patients with first-episode psychosis (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria) and a Positive and Negative Syndrome Scale (PANSS) total score ≥70 were treated with flexible-dose pali-ER tablets (3–12 mg/day). The primary efficacy endpoint was the percentage of patients with an increase of ≥8 points in Personal and Social Performance (PSP) score from baseline to day 56 (8 weeks). Secondary endpoints included reduction in PANSS total score, improvement in Clinical Global Impression-Severity score, PSP score, Subjective Well-being under Neuroleptics Scale score, and relationship between duration of untreated psychosis and PANSS or PSP. Incidences of treatment-emergent adverse events were used to evaluate safety.
Overall, 283 of 294 patients (96%) achieved a ≥8-point increase in PSP (primary endpoint, analysis set). For the secondary efficacy endpoints, 284/306 patients (93%) had a ≥30% reduction in PANSS total score; 266/306 patients (87%) achieved a ≤3 Clinical Global Impression-Severity scale score, and 218/294 patients (74%) had a PSP score ≥71. The Subjective Well-being under Neuroleptics Scale score was improved from a baseline mean of 72.7 to 94.7 at endpoint. There was a negative correlation between duration of untreated psychosis and posttreatment PSP score and a positive correlation with posttreatment PANSS total score. The most common treatment-emergent adverse events were extrapyramidal symptoms (12%), and agitation, somnolence, and xerostomia (4% each).
An 8-week, flexible-dose (3–12 mg/day) treatment with pali-ER resulted in significant improvements in psychotic symptoms and social functioning in Chinese patients with first-episode psychosis and was generally tolerable.
PMCID: PMC4295537  PMID: 25657581
paliperidone; first-episode psychosis; Personal and Social Performance score
6.  The Relationship Between Disability-Adjusted Life Years of Cataracts and Ambient Erythemal Ultraviolet Radiation in China 
Journal of Epidemiology  2015;25(1):57-65.
Cataracts are one of the major public health problems worldwide. Ultraviolet radiation (UVR) is one of the risk factors for cataract development. We analyzed the relationship between disability-adjusted life year (DALY) rates of cataracts and UVR exposure in China.
DALY rates of cataracts and UVR exposure in 31 regions of China were calculated based on data from the Second China National Sample Survey on Disability and the United States’ National Aeronautics and Space Administration database. The relationship between the DALY rates of cataracts and UVR was estimated by Spearman rank correlation analysis and linear regression analysis.
The elderly (≥65 years) had higher DALY rates of cataracts than the whole population. The DALY rate of cataracts in the agricultural population was higher than that observed in the non-agricultural population. The DALY rates of cataracts were positively associated with UVR The DALY rates of cataracts in regions with higher UVR were higher than those in regions with lower UVR. An increase in the daily ambient erythemal UVR of 1000 J/m2 was associated with an increase in the DALY rates of cataracts by 92 DALYs/100 000 (R2 = 0.676) among the whole population, 34 DALYs/100 000 among the population <65 years old (R2 = 0.423), 607 DALYs/100 000 among the population aged 65–74 years (R2 = 0.617), and by 1342 DALYs/100 000 among the population ≥75 years old (R2 = 0.758).
DALY rates of cataracts increased with increases in UVR exposure in 31 regions of China. Greater exposure to UVR increases the disease burden of cataracts in the whole population, especially in the elderly and among the agricultural population.
PMCID: PMC4275439
cataract; UVR exposure; disease burden; DALYs
7.  Human Connectome Module Pattern Detection Using A New Multi-Graph MinMax Cut Model 
Many recent scientific efforts have been devoted to constructing the human connectome using Diffusion Tensor Imaging (DTI) data for understanding the large-scale brain networks that underlie higher-level cognition in human. However, suitable computational network analysis tools are still lacking in human connectome research. To address this problem, we propose a novel multi-graph min-max cut model to detect the consistent network modules from the brain connectivity networks of all studied subjects. A new multi-graph MinMax cut model is introduced to solve this challenging computational neuroscience problem and the efficient optimization algorithm is derived. In the identified connectome module patterns, each network module shows similar connectivity patterns in all subjects, which potentially associate to specific brain functions shared by all subjects. We validate our method by analyzing the weighted fiber connectivity networks. The promising empirical results demonstrate the effectiveness of our method.
PMCID: PMC4203411  PMID: 25320814
8.  Overexpression of copper/zinc superoxide dismutase from mangrove Kandelia candel in tobacco enhances salinity tolerance by the reduction of reactive oxygen species in chloroplast 
Na+ uptake and transport in Kandelia candel and antioxidative defense were investigated under rising NaCl stress from 100 to 300 mM. Salinized K. candel roots had a net Na+ efflux with a declined flux rate during an extended NaCl exposure. Na+ buildup in leaves enhanced H2O2 levels, superoxide dismutase (SOD) activity, and increased transcription of CSD gene encoding a Cu/Zn SOD. Sequence and subcellular localization analyses have revealed that KcCSD is a typical Cu/Zn SOD in chloroplast. The transgenic tobacco experimental system was used as a functional genetics model to test the effect of KcCSD on salinity tolerance. KcCSD-transgenic lines were more Na+ tolerant than wild-type (WT) tobacco in terms of lipid peroxidation, root growth, and survival rate. In the latter, 100 mM NaCl led to a remarkable reduction in chlorophyll content and a/b ratio, decreased maximal chlorophyll a fluorescence, and photochemical efficiency of photosystem II. NaCl stress in WT resulted from H2O2 burst in chloroplast. Na+ injury to chloroplast was less pronounced in KcCSD-transgenic plants due to upregulated antioxidant defense. KcCSD-transgenic tobacco enhanced SOD activity by an increment in SOD isoenzymes under 100 mM NaCl stress from 24 h to 7 day. Catalase activity rose in KcCSD overexpressing tobacco plants. KcCSD-transgenic plants better scavenged NaCl-elicited reactive oxygen species (ROS) compared to WT ones. In conclusion, K. candel effectively excluded Na+ in roots during a short exposure; and increased CSD expression to reduce ROS in chloroplast in a long-term and high saline environment.
PMCID: PMC4302849  PMID: 25657655
Kandelia candel; Na+ flux; superoxide anion; hydrogen peroxide; salt; catalase; superoxide dismutase
9.  Exploring HIV Prevention Strategies among Street-Based Female Sex Workers in Chongqing, China 
Background: Commercial sex plays an increasingly important role in China’s growing HIV and sexually transmitted infection (STI) epidemics. In China, street-based sex workers (SSWs) are a subgroup of female sex workers with a particularly high risk of HIV/STI infections but are neglected in responses to HIV. This study assesses changes in HIV voluntary counseling and testing (VCT) utilization and high-risk sexual behaviors following a three-month HIV preventive intervention among SSWs in Chongqing, China. Methods: A three-month intervention was conducted by a team of peer educators, outreach workers from community-based organizations and health professionals. It mainly included distribution of free pamphlets and condoms and delivery of onsite and clinic-based VCT. Cross-sectional surveys were conducted prior to (n = 100) and immediately following (n = 112) the intervention to assess its impact. In-depth interviews were conducted among 12 SSWs after the intervention to further explore potential barriers to HIV prevention. Results: The intervention significantly increased SSWs’ participation in VCT (from 2.0%–15.2%, P < 0.001). Despite participants’ improved HIV-related knowledge level (from 24.0%–73.2%, P < 0.001), there were minimal changes in the levels of condom use with clients. Qualitative research revealed that fear of police arrest and stigma were the main barriers to VCT utilization. Low condom use was associated with family financial constraints, inadequate power in condom negotiation, low awareness and misconceptions of HIV infection risks. Conclusion: HIV intervention improved VCT utilization and knowledge but we did not observe an increase in condom use after this short intervention. SSWs faced substantial economic, social and environmental barriers to VCT utilization and condom use.
PMCID: PMC4306897  PMID: 25602971
street-based sex worker; Human Immunodeficiency Virus; condom use; commercial sex; peer-based intervention
10.  Asymmetric Synthesis and Evaluation of Danshensu-Cysteine Conjugates as Novel Potential Anti-Apoptotic Drug Candidates 
We have previously reported that the danshensu-cysteine conjugate N-((R)-3-benzylthio-1-methoxy-1-oxo-2-propanyl)-2-acetoxy-3-(3,4-diacetoxyphenyl) propanamide (DSC) is a potent anti-oxidative and anti-apoptotic agent. Herein, we further design and asymmetrically synthesize two diastereoisomers of DSC and explore their potential bioactivities. Our results show that DSC and its two diastereoisomers exert similar protective effects in hydrogen peroxide (H2O2)-induced cellular injury in SH-SY5Y cells, as evidenced by the increase of cell viability, superoxide dismutase (SOD), and reduced glutathione (GSH) activity, and glutathione peroxidase (GPx) expression, and the decrease of cellular morphological changes and nuclear condensation, lactate dehydrogenase (LDH) release, and malondialdehyde (MDA) production. In H2O2-stimulated human umbilical vein endothelial cells (HUVEC), DSC concentration-dependently attenuates H2O2-induced cell death, LDH release, mitochondrial membrane potential collapse, and modulates the expression of apoptosis-related proteins (Bcl-2, Bax, caspase-3, and caspase-9). Our results provide strong evidence that DSC and its two diastereoisomers have similar anti-oxidative activity and that DSC exerts significant vascular-protective effects, at least in part, through inhibition of apoptosis and modulation of endogenous antioxidant enzymes.
PMCID: PMC4307265  PMID: 25551606
Danshensu derivative; apoptosis; asymmetric synthesis; endothelial cells
11.  Influence of morphology and hemodynamic factors on rupture of multiple intracranial aneurysms: matched-pairs of ruptured-unruptured aneurysms located unilaterally on the anterior circulation 
BMC Neurology  2014;14(1):253.
The authors evaluated the impact of morphological and hemodynamic factors on the rupture of matched-pairs of ruptured-unruptured intracranial aneurysms on one patient’s ipsilateral anterior circulation with 3D reconstruction model and computational fluid dynamic method simulation.
20 patients with intracranial aneurysms pairs on the same-side of anterior circulation but with different rupture status were retrospectively collected. Each pair was divided into ruptured-unruptured group. Patient-specific models based on their 3D-DSA images were constructed and analyzed. The relative locations, morphologic and hemodynamic factors of these two groups were compared.
There was no significant difference in the relative bleeding location. The morphological factors analysis found that the ruptured aneurysms more often had irregular shape and had significantly higher maximum height and aspect ratio. The hemodynamic factors analysis found lower minimum wall shear stress (WSSmin) and more low-wall shear stress-area (LSA) in the ruptured aneurysms than that of the unruptured ones. The ruptured aneurysms more often had WSSmin on the dome.
Intracranial aneurysms pairs with different rupture status on unilateral side of anterior circulation may be a good disease model to investigate possible characteristics linked to rupture independent of patient characteristics. Irregular shape, larger size, higher aspect ratio, lower WSSmin and more LSA may indicate a higher risk for their rupture.
PMCID: PMC4301794  PMID: 25551809
Intracranial aneurysms; Multiple aneurysm; Anterior circulation; Rupture; Computational fluid dynamics
12.  Dopamine Receptors Antagonistically Regulate Behavioral Choice between Conflicting Alternatives in C. elegans 
PLoS ONE  2014;9(12):e115985.
Caenorhabditis elegans is a useful model to study the neuronal or molecular basis for behavioral choice, a specific form of decision-making. Although it has been implied that both D1-like and D2-like dopamine receptors may contribute to the control of decision-making in mammals, the genetic interactions between D1-like and D2-like dopamine receptors in regulating decision-making are still largely unclear. In the present study, we investigated the molecular control of behavioral choice between conflicting alternatives (diacetyl and Cu2+) by D1-like and D2-like dopamine receptors and their possible genetic interactions with C. elegans as the assay system. In the behavioral choice assay system, mutation of dop-1 gene encoding D1-like dopamine receptor resulted in the enhanced tendency to cross the Cu2+ barrier compared with wild-type. In contrast, mutations of dop-2 or dop-3 gene encoding D2-like dopamine receptor caused the weak tendency to cross the Cu2+ barrier compared with wild-type. During the control of behavioral choice, DOP-3 antagonistically regulated the function of DOP-1. The behavioral choice phenotype of dop-2; dop-1dop-3 triple mutant further confirmed the possible antagonistic function of D2-like dopamine receptor on D1-like dopamine receptor in regulating behavioral choice. The genetic assays further demonstrate that DOP-3 might act through Gαo signaling pathway encoded by GOA-1 and EGL-10, and DOP-1 might act through Gαq signaling pathway encoded by EGL-30 and EAT-16 to regulate the behavioral choice. DOP-1 might function in cholinergic neurons to regulate the behavioral choice, whereas DOP-3 might function in GABAergic neurons, RIC, and SIA neurons to regulate the behavioral choice. In this study, we provide the genetic evidence to indicate the antagonistic relationship between D1-like dopamine receptor and D2-like dopamine receptor in regulating the decision-making of animals. Our data will be useful for understanding the complex functions of dopamine receptors in regulating decision-making in animals.
PMCID: PMC4275273  PMID: 25536037
13.  Structural Basis of Chronic Beryllium Disease: Linking Allergic Hypersensitivity and Autoimmunity 
Cell  2014;158(1):132-142.
T cell-mediated hypersensitivity to metal cations is common in humans. How the T cell antigen receptor (TCR) recognizes these cations bound to a major histocompatibility complex (MHC) protein and self-peptide is unknown. Individuals carrying the MHCII allele, HLA-DP2, are at risk for chronic beryllium disease (CBD), a debilitating inflammatory lung condition caused by the reaction of CD4 T cells to inhaled beryllium. We show here that the T cell ligand is created when a Be2+ cation becomes buried in an HLA-DP2/peptide complex, where it is coordinated by both MHC and peptide acidic amino acids. Surprisingly, the TCR does not interact with the Be2+ itself, but rather with surface changes induced by the firmly bound Be2+ and an accompanying Na+ cation. Thus, CBD, by creating a new antigen by indirectly modifying the structure of pre-existing self MHC-peptide complex, lies on the border between allergic hypersensitivity and autoimmunity.
PMCID: PMC4269484  PMID: 24995984
14.  Acupuncture promotes white adipose tissue browning by inducing UCP1 expression on DIO mice 
To study the influence of acupuncture and its possible mechanism on white adipose tissue of high fat diet-induced obese.
Four-week-old C57BL/6 J mice were randomly divided into a normal diet group and a high-fat diet (HFD) group. After 8 weeks, the HFD mice were randomly divided into Electro-acupuncture (EA) group and control group. Mice in the EA group were electro-acupunctured, under physical restraint, on Zusanli (ST36) and Neiting (ST44) acupoints, while the mice in the control group were under physical restraint only. Body weight and food intake were monitored, and serum leptin, cholesterol and triglyceride levels were measured by using biochemistrical methods. The effect of EA on white adipose tissues (WAT) was assessed by qPCR, immunobloting, immunohistochemistry (IHC), immunoprecipitation and cold endurance experiment.
The WAT/body weight ratio decreased (P < 0.05) in the EA group, albeit no significant difference on food consumption between EA and control groups. The difference in the darkness of Epi-WAT between EA and control groups could be distinguished visually. HE staining indicated that the EA mice had an increased number of UCP1-immunoreactive paucilocular adipocytes in their WAT. The expressions of brown adipose tissue (BAT) markers, including UCP1, COX4il and Nrtf1 were increased in the WAT of EA mice, acetylation of Pparγ was decreased by electro-acupuncture.
EA can remodel WAT to BAT through inducing UCP1 expression, and this may be one of the mechanisms by which acupuncture affects weight loss.
PMCID: PMC4301852  PMID: 25514854
Acupuncture; Browning; Obesity; UCP1; White adipose tissue
15.  Genes associated with thermosensitive genic male sterility in rice identified by comparative expression profiling 
BMC Genomics  2014;15(1):1114.
Thermosensitive genic male sterile (TGMS) lines and photoperiod-sensitive genic male sterile (PGMS) lines have been successfully used in hybridization to improve rice yields. However, the molecular mechanisms underlying male sterility transitions in most PGMS/TGMS rice lines are unclear. In the recently developed TGMS-Co27 line, the male sterility is based on co-suppression of a UDP-glucose pyrophosphorylase gene (Ugp1), but further study is needed to fully elucidate the molecular mechanisms involved.
Microarray-based transcriptome profiling of TGMS-Co27 and wild-type Hejiang 19 (H1493) plants grown at high and low temperatures revealed that 15462 probe sets representing 8303 genes were differentially expressed in the two lines, under the two conditions, or both. Environmental factors strongly affected global gene expression. Some genes important for pollen development were strongly repressed in TGMS-Co27 at high temperature. More significantly, series-cluster analysis of differentially expressed genes (DEGs) between TGMS-Co27 plants grown under the two conditions showed that low temperature induced the expression of a gene cluster. This cluster was found to be essential for sterility transition. It includes many meiosis stage-related genes that are probably important for thermosensitive male sterility in TGMS-Co27, inter alia: Arg/Ser-rich domain (RS)-containing zinc finger proteins, polypyrimidine tract-binding proteins (PTBs), DEAD/DEAH box RNA helicases, ZOS (C2H2 zinc finger proteins of Oryza sativa), at least one polyadenylate-binding protein and some other RNA recognition motif (RRM) domain-containing proteins involved in post-transcriptional processes, eukaryotic initiation factor 5B (eIF5B), ribosomal proteins (L37, L1p/L10e, L27 and L24), aminoacyl-tRNA synthetases (ARSs), eukaryotic elongation factor Tu (eEF-Tu) and a peptide chain release factor protein involved in translation. The differential expression of 12 DEGs that are important for pollen development, low temperature responses or TGMS was validated by quantitative RT-PCR (qRT-PCR).
Temperature strongly affects global gene expression and may be the common regulator of fertility in PGMS/TGMS rice lines. The identified expression changes reflect perturbations in the transcriptomic regulation of pollen development networks in TGMS-Co27. Findings from this and previous studies indicate that sets of genes involved in post-transcriptional and translation processes are involved in thermosensitive male sterility transitions in TGMS-Co27.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2164-15-1114) contains supplementary material, which is available to authorized users.
PMCID: PMC4320516  PMID: 25512054
Transcriptome profiling; TGMS; Male sterility transition; Meiosis stage
16.  Hyperbaric oxygen therapy improves local microenvironment after spinal cord injury 
Neural Regeneration Research  2014;9(24):2182-2188.
Clinical studies have shown that hyperbaric oxygen therapy improves motor function in patients with spinal cord injury. In the present study, we explored the mechanisms associated with the recovery of neurological function after hyperbaric oxygen therapy in a rat model of spinal cord injury. We established an acute spinal cord injury model using a modification of the free-falling object method, and treated the animals with oxygen at 0.2 MPa for 45 minutes, 4 hours after injury. The treatment was administered four times per day, for 3 days. Compared with model rats that did not receive the treatment, rats exposed to hyperbaric oxygen had fewer apoptotic cells in spinal cord tissue, lower expression levels of aquaporin 4/9 mRNA and protein, and more NF-200 positive nerve fibers. Furthermore, they had smaller spinal cord cavities, rapid recovery of somatosensory and motor evoked potentials, and notably better recovery of hindlimb motor function than model rats. Our findings indicate that hyperbaric oxygen therapy reduces apoptosis, downregulates aquaporin 4/9 mRNA and protein expression in injured spinal cord tissue, improves the local microenvironment for nerve regeneration, and protects and repairs the spinal cord after injury.
PMCID: PMC4316452  PMID: 25657740
nerve regeneration; spinal cord injury; hyperbaric oxygen; motor function; rats; microenvironment; aquaporin 4; aquaporin 9; neural regeneration
17.  Automation Practices in Large Molecule Bioanalysis: Recommendations from Group L5 of the Global Bioanalytical Consortium 
The AAPS Journal  2013;16(1):164-171.
In recent years, the use of automated sample handling instrumentation has come to the forefront of bioanalytical analysis in order to ensure greater assay consistency and throughput. Since robotic systems are becoming part of everyday analytical procedures, the need for consistent guidance across the pharmaceutical industry has become increasingly important. Pre-existing regulations do not go into sufficient detail in regard to how to handle the use of robotic systems for use with analytical methods, especially large molecule bioanalysis. As a result, Global Bioanalytical Consortium (GBC) Group L5 has put forth specific recommendations for the validation, qualification, and use of robotic systems as part of large molecule bioanalytical analyses in the present white paper. The guidelines presented can be followed to ensure that there is a consistent, transparent methodology that will ensure that robotic systems can be effectively used and documented in a regulated bioanalytical laboratory setting. This will allow for consistent use of robotic sample handling instrumentation as part of large molecule bioanalysis across the globe.
PMCID: PMC3889521  PMID: 24311307
automation; documentation; large molecule bioanalysis; robotic system
18.  Robust estimation of fractal measures for characterizing the structural complexity of the human brain: optimization and reproducibility 
NeuroImage  2013;83:646-657.
High-resolution isotropic three-dimensional reconstructions of human brain gray and white matter structures can be characterized to quantify aspects of their shape, volume and topological complexity. In particular, methods based on fractal analysis have been applied in neuroimaging studies to quantify the structural complexity of the brain in both healthy and impaired conditions. The usefulness of such measures for characterizing individual differences in brain structure critically depends on their within-subject reproducibility in order to allow the robust detection of between-subject differences. This study analyzes key analytic parameters of three fractal-based methods that rely on the box-counting algorithm with the aim to maximize within-subject reproducibility of the fractal characterizations of different brain objects, including the pial surface, the cortical ribbon volume, the white matter volume and the grey matter/white matter boundary. Two separate datasets originating from different imaging centers were analyzed, comprising, 50 subjects with three and 24 subjects with four successive scanning sessions per subject, respectively. The reproducibility of fractal measures was statistically assessed by computing their intra-class correlations. Results reveal differences between different fractal estimators and allow the identification of several parameters that are critical for high reproducibility. Highest reproducibility with intra-class correlations in the range of 0.9–0.95 is achieved with the correlation dimension. Further analyses of the fractal dimensions of parcellated cortical and subcortical gray matter regions suggest robustly estimated and region-specific patterns of individual variability. These results are valuable for defining appropriate parameter configurations when studying changes in fractal descriptors of human brain structure, for instance in studies of neurological diseases that do not allow repeated measurements or for disease-course longitudinal studies.
PMCID: PMC3897251  PMID: 23831414
19.  Rural–urban differences in acute myocardial infarction mortality: Evidence from Nebraska 
Acute myocardial infarction (AMI) remains a major cause of death and disability in the United States and worldwide. Despite the importance of surveillance and secondary prevention, the incidence of and mortality from AMI are not continuously monitored, and little is known about survival outcomes after 30 days of AMI hospitalization or associated risk factors, especially in the rural areas. The current study examines rural–urban differences in both in- and out-hospital survival outcomes for AMI patients.
We performed a retrospective analysis using hospital discharge data in Nebraska for January 2005 to December 2009 and Nebraska death certificate records through October 2011. Multivariate logistic regression was used to estimate the rural–urban difference in 30-day mortality. A Cox proportional hazard model was used to predict out-of-hospital and overall survival rate.
In the 30-day mortality model, after controlling for age, comorbidities, and rehabilitation, patients in urban areas were less likely to die than patients in rural areas (odds ratio: 0.709, 95% confidence interval: 0.626–0.802). In the overall survival model, patients in urban areas had a lower hazard of AMI death (hazard ratio: 0.86, 95% confidence interval: 0.806–0.931) than patients in rural areas. Patients with a previous history of heart failure had a significantly higher likelihood of 30-day mortality, while atrial fibrillation, heart failure, and chronic kidney disease were associated with lower overall survival. Patients who attended at least 1 cardiac rehabilitation session had significantly lower 30-day and overall mortality (p < 0.0001).
This study confirms previous findings on rural–urban disparities in 30-day mortality following AMI hospitalization, and reports new findings on overall rural–urban mortality disparity. The study also found an association between cardiac rehabilitation and reduced mortality, a finding never before reported at the population level. Further efforts are needed to develop systems in rural hospitals and communities to ensure that AMI patients receive recommended care.
PMCID: PMC3953688  PMID: 24653583
Acute myocardial infarction; Rural health; Acute myocardial infarction survival difference
20.  Moderate Dynamic Compression Inhibits Pro-Catabolic Response of Cartilage to Mechanical Injury, TNF-α and IL-6, but Accentuates Degradation Above a Strain Threshold 
Traumatic joint injury can initiate early cartilage degeneration in the presence of elevated inflammatory cytokines (e.g., TNF-α and IL-6). The positive/negative effects of post-injury dynamic loading on cartilage degradation and repair in vivo is not well-understood. This study examined the effects of dynamic strain on immature bovine cartilage in vitro challenged with TNF-α + IL-6 and its soluble receptor (sIL-6R) with/without initial mechanical injury.
Groups of mechanically injured or non-injured explants were cultured in TNF-α + IL-6/sIL-6R for 8 days. Intermittent dynamic compression was applied concurrently at 10%, 20%, or 30% strain amplitude. Outcome measures included sGAG loss (DMMB), aggrecan biosynthesis (35S-incorporation), aggrecanase activity (Western blot), chondrocyte viability (fluorescence staining) and apoptosis (nuclear blebbing via light microscopy), and gene expression (qPCR).
In bovine explants, cytokine-alone and injury-plus-cytokine treatments markedly increased sGAG loss and aggrecanase activity, and induced chondrocyte apoptosis. These effects were abolished by moderate 10% and 20% strains. However, 30% strain-amplitude greatly increased apoptosis and had no inhibitory effect on aggrecanase activity. TNF+IL-6/sIL-6R downregulated matrix gene expression and upregulated expression of inflammatory genes, effects that were rescued by moderate dynamic strains but not by 30% strain.
Moderate dynamic compression inhibits the pro-catabolic response of cartilage to mechanical injury and cytokine challenge, but there is a threshold strain-amplitude above which loading becomes detrimental to cartilage. Our findings support the concept of appropriate loading for post-injury rehabilitation.
PMCID: PMC3855909  PMID: 24007885
Dynamic Compression; Cartilage; Injury; Cytokines; Apoptosis; Rehabilitation post-injury
21.  Vertically stacked multi-heterostructures of layered materials for logic transistors and complementary inverters 
Nature materials  2012;12(3):246-252.
The layered materials such as graphene have attracted considerable interest for future electronics. Here we report the vertical integration of multi-heterostructures of layered materials to enable high current density vertical field-effect transistors (VFETs). An n-channel VFET is created by sandwiching few-layer molybdenum disulfide (MoS2) as the semiconducting channel between a monolayer graphene and a metal thin film. The VFETs exhibit a room temperature on-off ratio >103, while at same time deliver a high current density up to 5,000 A/cm2, sufficient for high performance logic applications. This study offers a general strategy for the vertical integration of various layered materials to obtain both p- and n-channel transistors for complementary logic functions. A complementary inverter with larger than unit voltage gain is demonstrated by vertically stacking the layered materials of graphene, Bi2Sr2Co2O8 (p-channel), graphene, MoS2 (n-channel), and metal thin film in sequence. The ability to simultaneously achieve high on-off ratio, high current density, and logic integration in the vertically stacked multi-heterostructures can open up a new dimension for future electronics to enable three-dimensional integration.
PMCID: PMC4249642  PMID: 23241535
22.  Diagnostic implications of Ki-67 expression in adipocytes and lipoblasts: an immunohistochemical study 
Ki-67 expression is an important tool for distinguishing between malignant and benign tumors. It usually shows the nuclear staining. However, the cell membrane staining of MIB-1, which is one of the clones of Ki-67, in the hyalinizing trabecular adenoma of the thyroid gland and other tumors had also been reported. In our practice, we found that the 7B11 antibody could be immunoreactived with the adipose tissues inside or around tumors in the membrane. Thus, in this study, we determined if Ki-67 expression would be useful in recognizing the lipoblasts and adipocytes. The five clones of the Ki-67 antibody, namely, 7B11, K-2, SP5, MIB-1, and SP6 were selected. The adipocytes showed strong 7B11 staining in the cell membrane. The brown fat cells were strongly immunoreactive with 7B11 in the arachnoid layer of the cytoplasm. The adipocytes and brown fat cells showed positive, albeit weaker K-2 staining in the cell membrane and cytoplasm, respectively, compared to 7B11. The adipose tissues and brown fat cells were non-reactive to clones SP5, MIB-1, and SP6. All adipocytes in the lipomas, angiolipomas, uterine lipoleiomyomas, and angioleiomyolipomas showed diffusedly positive 7B11 and K-2 staining in the cell membrane, with stronger immunoreactivity to 7B11 compared with K-2. All hibernomas showed diffusedly cytoplasmic arachnoid staining of 7B11, but only focal to K-2. The lipoblasts in adipocytic tumors also showed positive 7B11 and K-2 staining; however, nearly all of the vacuolated lipoblasts showed strong 7B11 staining, only focal vacuolated lipoblasts in the adipocytic tumors were immunoreactive to K-2 positivity. All other components of the adipocytic tumors were non-reactive to 7B11, K-2, SP5, MIB-1, and SP6 in the cell membrane and cytoplasm. Our results showed that the 7B11 could well help to identify the lipoblasts, which would be useful to diagnose the malignant adipocytic tumors.
PMCID: PMC4313985
Ki-67; adipocyte; lipoblast
23.  The association between occupational stress and depressive symptoms and the mediating role of psychological capital among Chinese university teachers: a cross-sectional study 
BMC Psychiatry  2014;14(1):329.
Depression is a major public health problem that affects both individuals and society. Previous studies report that university teachers are particularly susceptible to high levels of occupational stress and depressive symptoms. The aims of this study were to explore the association between occupational stress and depressive symptoms in a group of university teachers, and assess the mediating role of psychological capital between these variables.
A cross-sectional study was performed between November 2013 and January 2014. Teachers from six universities were randomly sampled in Shenyang. The Center for Epidemiologic Studies Depression Scale, effort-reward imbalance scale, and psychological capital questionnaire (PCQ-24), as well as questions about demographic and working factors, were administered in questionnaires distributed to 1,500 university teachers. Completed questionnaires were received from 1,210 participants. Hierarchical linear regression analysis was used to examine the mediating role of psychological capital.
In the present study, 58.9% (95% CI (Confidence Intervals): 56.1% to 61.7%) of university teachers had a CES-D score equal to or above the cut-off of 16. Both effort–reward ratio (ERR) and scores of over-commitment were positively associated with depressive symptoms, whereas psychological capital was negatively associated with depressive symptoms among university teachers. Psychological capital partially mediated the relationship between occupational stress and depressive symptoms.
Among Chinese university teachers, occupational stress may be a risk factor for depressive symptoms, whereas psychological capital might be protective against depressive symptoms. Our results suggest that college administrators could support the development of psychological capital in their staff to alleviate depressive symptoms.
PMCID: PMC4261521  PMID: 25433676
Depressive symptoms; Psychological capital; Occupational stress; University teachers
24.  Searching the Cytochrome P450 Enzymes for the Metabolism of Meranzin Hydrate: A Prospective Antidepressant Originating from Chaihu-Shugan-San 
PLoS ONE  2014;9(11):e113819.
Meranzin hydrate (MH), an absorbed bioactive compound from the Traditional Chinese Medicine (TCM) Chaihu-Shugan-San (CSS), was first isolated in our laboratory and was found to possess anti-depression activity. However, the role of cytochrome P450s (CYPs) in the metabolism of MH was unclear. In this study, we screened the CYPs for the metabolism of MH in vitro by human liver microsomes (HLMs) or human recombinant CYPs. MH inhibited the enzyme activities of CYP1A2 and CYP2C19 in a concentration-dependent manner in the HLMs. The Km and Vmax values of MH were 10.3±1.3 µM and 99.1±3.3 nmol/mg protein/min, respectively, for the HLMs; 8.0±1.6 µM and 112.4±5.7 nmol/nmol P450/min, respectively, for CYP1A2; and 25.9±6.6 µM and 134.3±12.4 nmol/nmol P450/min, respectively, for CYP2C19. Other human CYP isoforms including CYP2A6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4 showed minimal or no effect on MH metabolism. The results suggested that MH was simultaneously a substrate and an inhibitor of CYP1A2 and CYP2C9, and MH had the potential to perpetrate drug-drug interactions with other CYP1A2 and CYP2C19 substrates.
PMCID: PMC4245237  PMID: 25427198
25.  General and Practical Carboxyl-Group-Directed Remote C–H Oxygenation Reactions of Arenes 
Chemistry (Weinheim an der Bergstrasse, Germany)  2013;19(47):10.1002/chem.201303511.
Two methods for remote aromatic C–H oxygenation reaction have been developed. Method 1, the Cu-catalyzed oxygenation reaction is highly efficient for cyclization of electron-neutral and electron-rich biaryl carboxylic acids into 3,4-benzocoumarins. Method 2, the K2S2O8-mediated oxygenation reaction, is more general and practical for cyclization of substrates with electron- donating and -withdrawing groups (see scheme).
PMCID: PMC3855880  PMID: 24150970
benzocoumarins; carboxylic acids; C–H activation; oxygenation; radical reactions

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