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1.  Agent-based model with multi-level herding for complex financial systems 
Scientific Reports  2015;5:8399.
In complex financial systems, the sector structure and volatility clustering are respectively important features of the spatial and temporal correlations. However, the microscopic generation mechanism of the sector structure is not yet understood. Especially, how to produce these two features in one model remains challenging. We introduce a novel interaction mechanism, i.e., the multi-level herding, in constructing an agent-based model to investigate the sector structure combined with volatility clustering. According to the previous market performance, agents trade in groups, and their herding behavior comprises the herding at stock, sector and market levels. Further, we propose methods to determine the key model parameters from historical market data, rather than from statistical fitting of the results. From the simulation, we obtain the sector structure and volatility clustering, as well as the eigenvalue distribution of the cross-correlation matrix, for the New York and Hong Kong stock exchanges. These properties are in agreement with the empirical ones. Our results quantitatively reveal that the multi-level herding is the microscopic generation mechanism of the sector structure, and provide new insight into the spatio-temporal interactions in financial systems at the microscopic level.
doi:10.1038/srep08399
PMCID: PMC4323661  PMID: 25669427
2.  Lead accumulation and tolerance of Moso bamboo (Phyllostachys pubescens) seedlings: applications of phytoremediation*  
A hydroponics experiment was aimed at identifying the lead (Pb) tolerance and phytoremediation potential of Moso bamboo (Phyllostachys pubescens) seedlings grown under different Pb treatments. Experimental results indicated that at the highest Pb concentration (400 μmol/L), the growth of bamboo seedlings was inhibited and Pb concentrations in leaves, stems, and roots reached the maximum of 148.8, 482.2, and 4282.8 mg/kg, respectively. Scanning electron microscopy revealed that the excessive Pb caused decreased stomatal opening, formation of abundant inclusions in roots, and just a few inclusions in stems. The ultrastructural analysis using transmission electron microscopy revealed that the addition of excessive Pb caused abnormally shaped chloroplasts, disappearance of endoplasmic reticulum, shrinkage of nucleus and nucleolus, and loss of thylakoid membranes. Although ultrastructural analysis revealed some internal damage, even the plants exposed to 400 μmol/L Pb survived and no visual Pb toxicity symptoms such as necrosis and chlorosis were observed in these plants. Even at the highest Pb treatment, no significant difference was observed for the dry weight of stem compared with controls. It is suggested that use of Moso bamboo as an experimental material provides a new perspective for remediation of heavy metal contaminated soil owing to its high metal tolerance and greater biomass.
doi:10.1631/jzus.B1400107
PMCID: PMC4322423  PMID: 25644467
Moso bamboo; Pb; Phytoremediation; Scanning electron microscopy; Transmission electron microscopy
3.  Naringenin suppresses K562 human leukemia cell proliferation and ameliorates Adriamycin-induced oxidative damage in polymorphonuclear leukocytes 
Treatments for leukemia remain unsatisfactory. Conventional chemotherapy agents that aim to kill tumor cells may also damage normal cells and thus result in severe side-effects. Naringenin, a natural polyphenolic compound with antioxidant effects, has been revealed to have significant antitumor effects with low toxicity in preliminary studies. Thus, it is considered as one of the most promising flavonoids in the treatment of leukemia. In the present study, the effects of naringenin on the K562 human leukemia cell line and the underlying mechanisms were explored in vitro. In addition, human peripheral blood polymorphonuclear leukocytes (PMNs) were used as a normal control in order to evaluate the effects of naringenin on normal granulocytes and in the mediation of Adriamycin (ADM)-induced oxidative damage. The results revealed that K562 proliferation was significantly inhibited by naringenin in a time- and concentration-dependent manner; however, minimal cytotoxic effects were observed in PMNs when naringenin was used at concentrations <400 μmol/l. Morphological changes indicative of apoptosis were observed in naringenin-treated K562 cells. Flow cytometric analysis indicated that the K562 cells were arrested in the G0/G1 phase of the cell cycle with a significantly upregulated rate of apoptosis. Furthermore, in the naringenin-treated K562 cells, the labeling index of proliferating cell nuclear antigen was observed to be increased by immunochemical staining, the mRNA and protein expression levels of p21/WAF1 were strongly upregulated in reverse transcription-polymerase chain reaction and western blot analyses, whereas p53 gene expression was not significantly changed. In PMNs to which naringenin (50~80 μmol/l) was added 1 h subsequent to ADM, the cell damage induced by ADM was significantly reduced, coincident with reductions in the levels of reactive oxygen species (ROS) and malondialdehyde (MDA) and increases in the activity of superoxide dismutase and glutathione peroxidase. However, the cytotoxic effect of ADM in K562 cells was not significantly altered by naringenin, and the oxidative stress indices in K562 cells remained stable. In conclusion, the present study revealed the promising value of naringenin in leukemia treatment. Naringenin demonstrated a significant inhibitory effect on the growth of K562 cells but not on normal PMNs. Furthermore, naringenin protected PMNs from ADM-induced oxidative damage at low concentrations. Cell cycle arrest and apoptosis-inducing effects, achieved through p53-independent p21/WAF1 upregulation, are likely to be the mechanism of the antileukemic effects of naringenin, and the protective effect against ADM chemotherapy-induced damage in PMNs may be due to the antioxidant capability of this agent at low concentrations.
doi:10.3892/etm.2015.2185
PMCID: PMC4316947  PMID: 25667616
naringenin; cell line; K562; gene; p21; gene; p53; cell cycle; apoptosis
4.  Network-Constrained Group Lasso for High-Dimensional Multinomial Classification with Application to Cancer Subtype Prediction 
Cancer Informatics  2015;13(Suppl 6):25-33.
Classic multinomial logit model, commonly used in multiclass regression problem, is restricted to few predictors and does not take into account the relationship among variables. It has limited use for genomic data, where the number of genomic features far exceeds the sample size. Genomic features such as gene expressions are usually related by an underlying biological network. Efficient use of the network information is important to improve classification performance as well as the biological interpretability. We proposed a multinomial logit model that is capable of addressing both the high dimensionality of predictors and the underlying network information. Group lasso was used to induce model sparsity, and a network-constraint was imposed to induce the smoothness of the coefficients with respect to the underlying network structure. To deal with the non-smoothness of the objective function in optimization, we developed a proximal gradient algorithm for efficient computation. The proposed model was compared to models with no prior structure information in both simulations and a problem of cancer subtype prediction with real TCGA (the cancer genome atlas) gene expression data. The network-constrained mode outperformed the traditional ones in both cases.
doi:10.4137/CIN.S17686
PMCID: PMC4295837  PMID: 25635165
cancer subtype prediction; multinomial logit model; group lasso; network-constraint; proximal gradient algorithm
6.  The simulated microgravity enhances multipotential differentiation capacity of bone marrow mesenchymal stem cells 
Cytotechnology  2013;66(1):119-131.
Multi-differentiation capability is an essential characteristic of bone marrow mesenchymal stem cells (BMSCs). Method on obtaining higher-quality stem cells with an improved differentiation potential has gained significant attention for the treatment of clinical diseases and developmental biology. In our study, we investigated the multipotential differentiation capacity of BMSCs under simulated microgravity (SMG) condition. F-actin staining found that cytoskeleton took on a time-dependent change under SMG condition, which caused spindle to round morphological change of the cultured cells. Quantitative PCR and Western Blotting showed the pluripotency marker OCT4 was up-regulated in the SMG condition especially after SMG of 72 h, which we observed would be the most appropriate SMG duration for enhancing pluripotency of BMSCs. After dividing BMSCs into normal gravity (NG) group and SMG group, we induced them respectively in endothelium oriented, adipogenic and neuronal induction media. Immunostaining and Western Blotting found that endothelium oriented differentiated BMSCs expressed higher VWF and CD31 in the SMG group than in the NG group. The neuron-like cells derived from BMSCs in the SMG group also expressed higher level of MAP2 and NF-H. Furthermore, the quantity of induced adipocytes increased in the SMG group compared to the NG group shown by Oil Red O staining, The expression of PPARγ2 increased significantly under SMG condition. Therefore, we demonstrated that SMG could promote BMSCs to differentiate into many kinds of cells and predicted that enhanced multi-potential differentiation capacity response in BMSCs following SMG might be relevant to the changes of cytoskeleton and the stem cell marker OCT4.
Electronic supplementary material
The online version of this article (doi:10.1007/s10616-013-9544-8) contains supplementary material, which is available to authorized users.
doi:10.1007/s10616-013-9544-8
PMCID: PMC3886541  PMID: 23579245
Simulated microgravity; Bone marrow mesenchymal stem cells; Pluripotency; Differentiation; OCT4
7.  Widespread Increase of Functional Connectivity in Parkinson’s Disease with Tremor: A Resting-State fMRI Study 
Parkinson’s disease (PD) is a clinically heterogeneous disease in the symptomatology dominated by tremor, akinesia, or rigidity. Focusing on PD patients with tremor, this study investigated their discoordination patterns of spontaneous brain activity by combining voxel-wise centrality, seed-based functional connectivity, and network efficiency methods. Sixteen patients and 20 matched healthy controls (HCs) were recruited and underwent structural and resting-state functional MRI scan. Compared with the HCs, the patients exhibited increased centrality in the frontal, parietal, and occipital regions while decreased centrality in the cerebellum anterior lobe and thalamus. Seeded at these regions, a distributed network was further identified that encompassed cortical (default mode network, sensorimotor cortex, prefrontal and occipital areas) and subcortical (thalamus and basal ganglia) regions and the cerebellum and brainstem. Graph-based analyses of this network revealed increased information transformation efficiency in the patients. Moreover, the identified network correlated with clinical manifestations in the patients and could distinguish the patients from HCs. Morphometric analyses revealed decreased gray matter volume in multiple regions that largely accounted for the observed functional abnormalities. Together, these findings provide a comprehensive view of network disorganization in PD with tremor and have important implications for understanding neural substrates underlying this specific type of PD.
doi:10.3389/fnagi.2015.00006
PMCID: PMC4315047
Parkinson’s disease; tremor; connectome; centrality; resting functional connectivity
8.  Distinguishing Patients with Parkinson's Disease Subtypes from Normal Controls Based on Functional Network Regional Efficiencies 
PLoS ONE  2014;9(12):e115131.
Many studies have demonstrated that the pathophysiology and clinical symptoms of Parkinson's disease (PD) are inhomogeneous. However, the symptom-specific intrinsic neural activities underlying the PD subtypes are still not well understood. Here, 15 tremor-dominant PD patients, 10 non-tremor-dominant PD patients, and 20 matched normal controls (NCs) were recruited and underwent resting-state functional magnetic resonance imaging (fMRI). Functional brain networks were constructed based on randomly generated anatomical templates with and without the cerebellum. The regional network efficiencies (i.e., the local and global efficiencies) were further measured and used to distinguish subgroups of PD patients (i.e., with tremor-dominant PD and non-tremor-dominant PD) from the NCs using linear discriminant analysis. The results demonstrate that the subtype-specific functional networks were small-world-organized and that the network regional efficiency could discriminate among the individual PD subgroups and the NCs. Brain regions involved in distinguishing between the study groups included the basal ganglia (i.e., the caudate and putamen), limbic regions (i.e., the hippocampus and thalamus), the cerebellum, and other cerebral regions (e.g., the insula, cingulum, and calcarine sulcus). In particular, the performances of the regional local efficiency in the functional network were better than those of the global efficiency, and the performances of global efficiency were dependent on the inclusion of the cerebellum in the analysis. These findings provide new evidence for the neurological basis of differences between PD subtypes and suggest that the cerebellum may play different roles in the pathologies of different PD subtypes. The present study demonstrated the power of the combination of graph-based network analysis and discrimination analysis in elucidating the neural basis of different PD subtypes.
doi:10.1371/journal.pone.0115131
PMCID: PMC4274088  PMID: 25531436
9.  Primary malignant melanoma of lacrimal sac 
doi:10.3980/j.issn.2222-3959.2014.06.30
PMCID: PMC4270979  PMID: 25540768
10.  Direct bilirubin as a prognostic biomarker in enteric fistula patients complicated with sepsis: a case-control study 
Objective: The objective of this study was to evaluate the predictive value of serial bilirubin determinations for mortality in enteric fistula (EF) patients complicated with sepsis. Methods: From January 1st, 2012 to January 13rd, 2013, a prospective study enrolling 162 patients was performed. Patients were divided into the survivors group (n = 119) and non-survivors group (n = 43) according to 28-day outcomes. Laboratory variables on day 0, day 3 and day 7 after admission were recorded. DB0 was defined as serum direct bilirubin (DB) value in admission, while ΔDB3 as the changes from DB3 to DB0. The definition applied to other parameters. The results were validated in an independent cohort of 116 patients. Results: Compared with survivors, non-survivors had significantly higher DB7 (23.1 ± 10.6 vs. 11.2 ± 1.1, P < 0.001) and procalcitonin (PCT7) (5.2 ± 2.8 vs. 1.7 ± 0.3 P = 0.006). ROC analysis showed that DB7 > 12.8 μmol/L and ΔDB7 > 7.3 μmol/L were reliable predictors (DB7: 86.4% sensitivity, 88.6% specificity (area under the curve (AUC): 0.881, P < 0.001; ΔDB7: 84.4% sensitivity, 85.1% specificity, AUC: 0.865, P < 0.001) for mortality.The combination form (DB7 > 12.8 μmol/L + ΔPCT7 < 5.3 ng/ml) had greatest predictive value (AUC: 0.894, P < 0.001). Their predictive values were confirmed in the validation cohort. Conclusions: Serum direct bilirubin was a reliable predictor for mortality in enteric fistula patients, which should be paid close attention in the critical care.
PMCID: PMC4307463  PMID: 25664016
Bilirubin; direct bilirubin; predictor; enteric fistula; abdominal sepsis
11.  n-3 PUFA supplementation benefits microglial responses to myelin pathology 
Scientific Reports  2014;4:7458.
Microglia represent rational but challenging targets for improving white matter integrity because of their dualistic protective and toxic roles. The present study examines the effect of Omega-3 polyunsaturated fatty acids (n-3 PUFAs) on microglial responses to myelin pathology in primary cultures and in the cuprizone mouse model of multiple sclerosis (MS), a devastating demyelination disease. Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA), the two main forms of n-3 PUFAs in the brain, inhibited the release of nitric oxide and tumor necrosis factor-α from primary microglia upon IFN-γ and myelin stimulation. DHA and EPA also enhanced myelin phagocytosis in vitro. Therefore, n-3 PUFAs can inhibit inflammation while at the same time enhancing beneficial immune responses such as microglial phagocytosis. In vivo studies demonstrated that n-3 PUFA supplementation reduced cuprizone-induced demyelination and improved motor and cognitive function. The positive effects of n-3 PUFAs were accompanied by a shift in microglial polarization toward the beneficial M2 phenotype both in vitro and in vivo. These results suggest that n-3 PUFAs may be clinically useful as immunomodulatory agents for demyelinating diseases through a novel mechanism involving microglial phenotype switching.
doi:10.1038/srep07458
PMCID: PMC4264015  PMID: 25500548
12.  Treatment with retinoic acid and lens epithelial cell-conditioned medium in vitro directed the differentiation of pluripotent stem cells towards corneal endothelial cell-like cells 
Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have extensive self-renewal capacity and the potential to differentiate into all tissue-specific cell lineages, including corneal endothelial cells (CECs). They are a promising prospect for the future of regenerative medicine. The method of derivation of CECs from ESCs and iPSCs, however, remains to be elucidated. In this study, mouse ESCs and iPSCs were induced to differentiate into CECs using CEC embryonic development events as a guide. All-trans retinoic acid (RA) treatment during the embryoid body (EB) differentiation step was used to promote neural crest (NC) cell differentiation as first step and was followed by a second induction in CEC- or lens epithelial cell (LEC)-conditioned medium (CM) to ultimately generate CEC-like cells. During the corresponding differentiation stages, NC developmental markers and CEC differentiation markers were detected at the protein level using immunocytochemistry (ICC) and at the mRNA level by reverse transcription-quantitative polymerase chain reaction (RT-qPCR). During the first stage, the data indicated that 4 days of treatment with 1 μM RA starting on day 4 of EB formation favored NC cell differentiation and that plating on gelatin-coated plates led to cell migration out of the EBs. The second-stage differentiation results showed that the CM, particularly the LEC-CM, enhanced the yield of polygonal cells with CEC-specific marker expression shown by ICC and RT-qPCR. This study demonstrates that mouse ESCs and iPSCs were induced and expressed CEC differentiation markers when subjected to a two-step inducement process, suggesting that they are a promising resource for corneal endothelium failure replacement therapy in the future.
doi:10.3892/etm.2014.2103
PMCID: PMC4280952  PMID: 25574197
embryonic stem cell; induced pluripotent stem cell; corneal endothelium cell; retinoic acid; conditioned medium; differentiation
13.  Magnetic resonance elastography of the human abdominal aorta: a preliminary study 
Journal of magnetic resonance imaging : JMRI  2013;38(6):10.1002/jmri.24056.
Purpose
To investigate the feasibility of using magnetic resonance elastography (MRE) for the evaluation of the stiffness of in vivo aortic wall.
Materials and Methods
To validate the experimental approach for imaging the aorta in vivo, a gel phantom with an embedded porcine aorta was imaged in the presence of fluid flow within the aorta. The potential changes in the elasticity of the vessel wall with changes in pressure were investigated. The feasibility of performing MRE of abdominal aorta was assessed in five volunteers (Age 22–40 years; BMI 21.5–25.2 kg/m2). The pulse-gated cine MRE technique was used to study the wave propagation along the aorta throughout the cardiac cycle and provide estimates of aortic stiffness in diastole.
Results
In the phantom study, the wave propagation was well visualized within the porcine aorta embedded in the gel phantom. An increase of the Young's modulus-wall thickness (E*t) product with the increase in static pressure was observed. In the in vivo study, the waves were well visualized within the lumen of abdominal aorta in the five volunteers in diastolic phase, but they were not well visualized during systole.
Conclusion
MRE is feasible for noninvasively assessing the stiffness of the abdominal aorta and merits further investigation.
doi:10.1002/jmri.24056
PMCID: PMC3652910  PMID: 23371244
MRI; elastography; aorta; stiffness
14.  Tumor Necrosis Factor-alpha-mutant Mice Exhibit High Frequency Hearing Loss 
Exogenous tumor necrosis factor-alpha (TNF-α) plays a role in auditory hair cell death by altering the expression of apoptosis-related genes in response to noxious stimuli. Little is known, however, about the function of TNF-α in normal hair cell physiology. We, therefore, investigated the cochlear morphology and auditory function of TNF-α-deficient mice. Auditory evoked brainstem response showed significantly higher thresholds, especially at higher frequencies, in 1-month-old TNF-α−/− mice as compared to TNF-α+/− and wild type (WT); hearing loss did not progress further from 1 to 4 months of age. There was no difference in the gross morphology of the organ of Corti, lateral wall, and spiral ganglion cells in TNF-α−/− mice compared to WT mice at 4 months of age, nor were there differences in the anatomy of the auditory ossicles. Outer hair cells were completely intact in surface preparations of the organ of Corti of TNF-α−/− mice, and synaptic ribbon counts of TNF-α−/− and WT mice at 4 months of age were similar. Reduced amplitudes of distortion product otoacoustic emissions, however, indicated dysfunction of outer hair cells in TNF-α−/− mice. Scanning electron microscopy revealed that stereocilia were sporadically absent in the basal turn and distorted in the middle turn. In summary, our results demonstrate that TNF-α-mutant mice exhibit early hearing loss, especially at higher frequencies, and that loss or malformation of the stereocilia of outer hair cells appears to be a contributing factor.
doi:10.1007/s10162-013-0410-3
PMCID: PMC3825018  PMID: 23996384
TNF-alpha-deficient mice; higher frequency hearing loss; malformation of the stereocilia of outer hair cells
15.  Microglia/macrophage polarization dynamics in white matter after traumatic brain injury 
Mononuclear phagocytes are a population of multi-phenotypic cells and have dual roles in brain destruction/reconstruction. The phenotype-specific roles of microglia/macrophages in traumatic brain injury (TBI) are, however, poorly characterized. In the present study, TBI was induced in mice by a controlled cortical impact (CCI) and animals were killed at 1 to 14 days post injury. Real-time polymerase chain reaction (RT–PCR) and immunofluorescence staining for M1 and M2 markers were performed to characterize phenotypic changes of microglia/macrophages in both gray and white matter. We found that the number of M1-like phagocytes increased in cortex, striatum and corpus callosum (CC) during the first week and remained elevated until at least 14 days after TBI. In contrast, M2-like microglia/macrophages peaked at 5 days, but decreased rapidly thereafter. Notably, the severity of white matter injury (WMI), manifested by immunohistochemical staining for neurofilament SMI-32, was strongly correlated with the number of M1-like phagocytes. In vitro experiments using a conditioned medium transfer system confirmed that M1 microglia-conditioned media exacerbated oxygen glucose deprivation–induced oligodendrocyte death. Our results indicate that microglia/macrophages respond dynamically to TBI, experiencing a transient M2 phenotype followed by a shift to the M1 phenotype. The M1 phenotypic shift may propel WMI progression and represents a rational target for TBI treatment.
doi:10.1038/jcbfm.2013.146
PMCID: PMC3851898  PMID: 23942366
inflammation; macrophage; microglia; polarization; white matter injury
16.  Adoptive regulatory T cell therapy preserves systemic immune homeostasis following cerebral ischemia 
Background and Purpose
Cerebral ischemia has been shown to result in peripheral inflammatory responses followed by long-lasting immunosuppression. Our recent study demonstrated that intravenous delivery of Tregs markedly protected against transient cerebral ischemia by suppressing neutrophil-derived matrix metallopeptidase-9 production in the periphery. The impact of Tregs on systemic inflammatory responses and immune status, however, have not been fully characterized.
Methods
Cerebral ischemia was induced by middle cerebral artery occlusion (MCAO) for 60 minutes in mice or 120 minutes in rats. Tregs were isolated from donor animals by CD4 and CD25 double selection and transferred intravenously to ischemic recipients at 2 hours after MCAO. Animals were sacrificed on different days after reperfusion. The effects of Tregs on systemic inflammation and immune status were evaluated using flow cytometry, ELISAs, and immunohistochemistry.
Results
Systemic administration of purified Tregs raises functional Tregs in the blood and peripheral organs, including spleen and lymph nodes. These exogenous Tregs remain in the blood and peripheral organs for at least 12 days. Functionally, Treg adoptive transfer markedly inhibits MCAO-induced elevation of inflammatory cytokines (IL-6 and TNF-α) in the blood. Furthermore, Treg treatment corrects long-term lymphopenia and improves cellular immune functions after ischemic brain injury. As a result, Treg-treated animals exhibit decreased bacterial loads in the blood during the recovery from cerebral ischemic attack.
Conclusions
Treg treatment did not exacerbate post-stroke immunosuppression. On the contrary, Treg-treated animals displayed improved immune status after focal cerebral ischemia.
doi:10.1161/STROKEAHA.113.002637
PMCID: PMC3895539  PMID: 24092548
stroke; regulatory T cell; inflammation; immunosuppression
17.  Saccharomyces cerevisiae Vacuolar H+-ATPase Regulation by Disassembly and Reassembly: One Structure and Multiple Signals 
Eukaryotic Cell  2014;13(6):706-714.
Vacuolar H+-ATPases (V-ATPases) are highly conserved ATP-driven proton pumps responsible for acidification of intracellular compartments. V-ATPase proton transport energizes secondary transport systems and is essential for lysosomal/vacuolar and endosomal functions. These dynamic molecular motors are composed of multiple subunits regulated in part by reversible disassembly, which reversibly inactivates them. Reversible disassembly is intertwined with glycolysis, the RAS/cyclic AMP (cAMP)/protein kinase A (PKA) pathway, and phosphoinositides, but the mechanisms involved are elusive. The atomic- and pseudo-atomic-resolution structures of the V-ATPases are shedding light on the molecular dynamics that regulate V-ATPase assembly. Although all eukaryotic V-ATPases may be built with an inherent capacity to reversibly disassemble, not all do so. V-ATPase subunit isoforms and their interactions with membrane lipids and a V-ATPase-exclusive chaperone influence V-ATPase assembly. This minireview reports on the mechanisms governing reversible disassembly in the yeast Saccharomyces cerevisiae, keeping in perspective our present understanding of the V-ATPase architecture and its alignment with the cellular processes and signals involved.
doi:10.1128/EC.00050-14
PMCID: PMC4054264  PMID: 24706019
18.  Enhanced in Vivo Delivery of 5-Fluorouracil by Ethosomal Gels in Rabbit Ear Hypertrophic Scar Model 
Applying Ethosomal Gels (EGs) in transdermal drug delivery systems has evoked considerable interest because of their good water-solubility and biocompatibility. However, there has not been an explicit description of applying EGs as a vehicle for hypertrophic scars treatment. Here, a novel transdermal EGs loaded with 5-fluorouracil (5-FU EGs) was successfully prepared and characterized. The stability assay in vitro revealed that 5-FU EGs stored for a period of 30 days at 4 ± 1 °C had a better size stability than that at 25 ± 1 °C. Furthermore, using confocal laser scanning microscopy, EGs labeled with Rhodamine 6 G penetrated into the deep dermis of the hypertrophic scar within 24 h in the rabbit ear hypertrophic model suggested that the EGs were an optional delivery carrier through scar tissues. In addition, the value of the Scar Elevation Index (SEI) of 5-FU EGs group in the rabbit ear scar model was lower than that of 5-FU Phosphate Buffered Saline gel and Control groups. To conclude, these results suggest that EGs delivery system loaded 5-fluorouracil is a perfect candidate drug for hypertrophic scars therapy in future.
doi:10.3390/ijms151222786
PMCID: PMC4284737  PMID: 25501333
drug delivery; ethosome; 5-fluorouracil; gel; hypertrophic scars penetration
19.  Diffusion tensor smoothing through weighted Karcher means 
Diffusion tensor magnetic resonance imaging (MRI) quantifies the spatial distribution of water Diffusion at each voxel on a regular grid of locations in a biological specimen by Diffusion tensors– 3 × 3 positive definite matrices. Removal of noise from DTI is an important problem due to the high scientific relevance of DTI and relatively low signal to noise ratio it provides. Leading approaches to this problem amount to estimation of weighted Karcher means of Diffusion tensors within spatial neighborhoods, under various metrics imposed on the space of tensors. However, it is unclear how the behavior of these estimators varies with the magnitude of DTI sensor noise (the noise resulting from the thermal e!ects of MRI scanning) as well as the geometric structure of the underlying Diffusion tensor neighborhoods. In this paper, we combine theoretical analysis, empirical analysis of simulated DTI data, and empirical analysis of real DTI scans to compare the noise removal performance of three kernel-based DTI smoothers that are based on Euclidean, log-Euclidean, and affine-invariant metrics. The results suggest, contrary to conventional wisdom, that imposing a simplistic Euclidean metric may in fact provide comparable or superior noise removal, especially in relatively unstructured regions and/or in the presence of moderate to high levels of sensor noise. On the contrary, log-Euclidean and affine-invariant metrics may lead to better noise removal in highly structured anatomical regions, especially when the sensor noise is of low magnitude. These findings emphasize the importance of considering the interplay of sensor noise magnitude and tensor field geometric structure when assessing Diffusion tensor smoothing options. They also point to the necessity for continued development of smoothing methods that perform well across a large range of scenarios.
PMCID: PMC4239671  PMID: 25419264
Tensor space; Diffusion MRI; Karcher mean; kernel smoothing; perturbation analysis.
20.  E6-associated transcription patterns in human papilloma virus 16-positive cervical tissues 
Oncology Letters  2014;9(1):478-482.
The change in transcription pattern induced by post-transcriptional RNA splicing is an important mechanism in the regulation of the early gene expression of human papilloma virus (HPV). The present study was conducted to establish a method to specifically amplify HPV-16 E6-associated transcripts. The E6-related transcripts from 63 HPV-16-positive cervical tumor tissue samples were amplified, consisting of eight cases of low-risk intraepithelial lesions, 38 cases of high-risk intraepithelial lesions and 17 cases of cervical cancer (CxCa). The appropriate amplified segments were recovered following agarose gel electrophoresis, and subjected to further sequencing and sequence alignment analysis. Six groups of E6 transcription patterns were identified from HPV-16-positive cervical tumor tissue, including five newly-discovered transcripts. Different HPV-16 E6-associated transcription patterns were detected during the development of CxCa. Over the course of the progression of the low-grade squamous intraepithelial lesions to CxCa, the specific HPV-16 E6-associated transcription patterns and the dominant transcripts were all different. As indicated by this study, the transcription pattern of the E6 early gene of HPV-16 was closely associated with the stages of cervical carcinogenesis, and may also be involved in the development of CxCa.
doi:10.3892/ol.2014.2698
PMCID: PMC4246687  PMID: 25436012
HPV-16; cervical cancer; amplification of papillomavirus oncogene transcripts; papillomavirus
21.  Transcatheter Arterial Chemoembolization and Chemotherapy plus Sorafenib in a Large Hepatocellular Carcinoma with Arterioportal Shunt 
Introduction. Arterioportal shunts (APS) are sometimes encountered in patients with hepatocellular carcinoma (HCC) and associated with poor prognosis. The management of HCC with APS is a challenge so far. Case Presentations. We report here in detail a 37-year-old man who was diagnosed as an advanced HCC accompanied with severe APS and treated by two sessions of transcatheter arterial chemoembolization (TACE) and three sessions of transcatheter arterial chemotherapy (TAC) plus sorafenib therapy. The tumor shrinks were revealed continuously during 152 days after the diagnosis. Although tumor progress emerged at 209 days after the diagnosis, the patient remarkably achieved 366-day survival. Discussion. TACE plus sorafenib may be a promising treatment for advanced HCC accompanied with APS. Prospective case-control studies should be advocated to evaluate the combination of TACE, TAC, and sorafenib in the management of HCC with APS.
doi:10.1155/2014/392403
PMCID: PMC4241331  PMID: 25431715
22.  Opposing Influence of Intracellular and Membrane Thiols on the Toxicity of Reducible Polycations 
Biomaterials  2013;34(34):8843-8850.
Toxicity of polycations has been recognized since their first use in gene delivery. Bioreducible polycations attract attention because of their improved safety due to selective intracellular degradation by glutathione (GSH). Here we present a systematic study of the toxicity of bioreducible poly(amido amine)s (PAA). PAA with increasing content of disulfide bonds were synthesized by Michael addition. Toxicity of PAA was evaluated in two cell lines with different innate levels of intracellular GSH. Increasing the content of disulfide bonds decreased the toxicity of PAA, with more significant decrease observed in cells with high GSH. Depleting intracellular GSH by diethyl maleate resulted in increased toxicity of bioreducible PAA. In contrast, increasing the GSH concentrations by growing cells in hypoxic conditions resulted in further decreased toxicity compared with cells grown in normoxic conditions. The presence of exofacial plasma membrane thiols selectively increased toxicity of bioreducible PAA while having no effect on non-degradable controls. These results improve our understanding of the cellular mechanisms of polycation toxicity. They also shed light on the opposing effects of different cellular thiol pools on the toxicity of bioreducible polycations.
doi:10.1016/j.biomaterials.2013.07.095
PMCID: PMC3776455  PMID: 23948163
non-viral gene delivery; polycations; bioreducible polycations; glutathione; toxicity
23.  Transgenic Overproduction of Omega-3 Polyunsaturated Fatty Acids Provides Neuroprotection and Enhances Endogenous Neurogenesis after Stroke 
Current molecular medicine  2013;13(9):1465-1473.
Strokes are devastating as there are no current therapies to prevent the long term neurological deficits that they cause. Soon after ischemic stroke, there is proliferation and differentiation of neural stem/progenitor cells as an important mechanism for neuronal restoration. However, endogenous neurogenesis by itself is insufficient for effective brain repair after stroke as most newborn neurons do not survive. One fascinating strategy for stroke treatment would thus be maintaining the survival and/or promoting the differentiation of endogenous neural stem/progenitor cells. Using transgenic (Tg) mice over-expressing the C. elegans fat-1 gene encoding an enzyme that converts endogenous omega-6 to omega-3 polyunsaturated fatty acids (n-3 PUFAs), we showed that fat-1 Tg mice with chronically elevated brain levels of n-3 PUFAs exhibited less brain damage and significantly improved long-term neurological performance compared to wild type littermates. Importantly, post-stroke neurogenesis occurred more robustly in fat-1 Tg mice after focal ischemia. This was manifested by enhanced neural stem cell proliferation/differentiation and increased migration of neuroblasts to the ischemic sites where neuroblasts matured into resident neurons. Moreover, these neurogenic effects were accompanied by significantly increased oligodendrogenesis. Our results suggest that n-3 PUFA supplementation is a potential neurogenic and oligodendrogenic treatment to naturally improve post-stroke brain repair and long-term functional recovery.
PMCID: PMC4083810  PMID: 23971733
omega-3 polyunsaturated fatty acids; stroke; neuroprotection; neurogenesis; oligodendrogenesis
24.  Exploring the Chemodiversity and Biological Activities of the Secondary Metabolites from the Marine Fungus Neosartorya pseudofischeri 
Marine Drugs  2014;12(11):5657-5676.
The production of fungal metabolites can be remarkably influenced by various cultivation parameters. To explore the biosynthetic potentials of the marine fungus, Neosartorya pseudofischeri, which was isolated from the inner tissue of starfish Acanthaster planci, glycerol-peptone-yeast extract (GlyPY) and glucose-peptone-yeast extract (GluPY) media were used to culture this fungus. When cultured in GlyPY medium, this fungus produced two novel diketopiperazines, neosartins A and B (1 and 2), together with six biogenetically-related known diketopiperazines,1,2,3,4-tetrahydro-2,3-dimethyl-1,4-dioxopyrazino[1,2-a]indole (3), 1,2,3,4-tetrahydro-2-methyl-3-methylene-1,4-dioxopyrazino[1,2-a]indole (4), 1,2,3,4-tetrahydro-2-methyl-1,3,4-trioxopyrazino[1,2-a] indole (5), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio)gliotoxin (11), didehydrobisdethiobis(methylthio)gliotoxin (12) and N-methyl-1H-indole-2-carboxamide (6). However, a novel tetracyclic-fused alkaloid, neosartin C (14), a meroterpenoid, pyripyropene A (15), gliotoxin (7) and five known gliotoxin analogues, acetylgliotoxin (8), reduced gliotoxin (9), 6-acetylbis(methylthio)gliotoxin (10), bisdethiobis(methylthio) gliotoxin (11) and bis-N-norgliovictin (13), were obtained when grown in glucose-containing medium (GluPY medium). This is the first report of compounds 3, 4, 6, 9, 10 and 12 as naturally occurring. Their structures were determined mainly by MS, 1D and 2D NMR data. The possible biosynthetic pathways of gliotoxin-related analogues and neosartin C were proposed. The antibacterial activity of compounds 2–14 and the cytotoxic activity of compounds 4, 5 and 7–13 were evaluated. Their structure-activity relationships are also preliminarily discussed.
doi:10.3390/md12115657
PMCID: PMC4245550  PMID: 25421322
marine fungus; Neosartorya pseudofischeri; neosartin; diketopiperazine; antibacterial activity; cytotoxic activity
25.  Development and validation of a convenient formula evaluating the value and applicability of medical literature in clinical practice 
Pakistan Journal of Medical Sciences  2014;30(6):1377-1382.
Objective: Evidence-based medicine offers explicit methods to evaluate the evidence grades of literature. However, evidence grades do not meet all the practical needs of physicians. This study is aimed to develop a convenient method for evaluating the clinical value of medical literature from the perspective of the clinician.
Methods: A literature applicability equation was formulated through the Delphi method and the analytic hierarchy process. A consistency check was used to ascertain the efficacy of the formula. Three senior clinicians assessed 30 articles based on their clinical experiences and subjective opinions, while one independent researcher performed independent assessments of the applicability of 30 articles using the evaluation formula.
Results: The literature applicability equation was Y = 3.93X1 + 11.78X2 + 14.83X3 + 44.53X4 + 24.93X5, where Y = literature applicability, X1 = years since publication, X2 = target question covered or not, X3 = sample size, X4 = study type, and X5 = journal quality. Consistency index (CI) values for the first-level indicator (“literature applicability”) and the second-level indicators (“pertinence and timeliness” and “quality of results”) were 0.0325, 0.0012, and 0.0001, respectively. The weights used to calculate the matrix indicators had satisfactory accordance (random coincidence coefficient = 0.056). A consistency check for the efficacy of the formula revealed kappa = 0.749 and P < .001.
Conclusion : The developed and validated literature applicability evaluation formula may be a useful and convenient tool for identifying clinically valuable medical literature.
doi:10.12669/pjms.306.5450
PMCID: PMC4320734
Evidence-based medicine; Analytic hierarchy process; Delphi method; Literature applicability; Medical literature; Evaluation method

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