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1.  Detection of selection utilizing molecular phylogenetics: a possible approach 
Genetica  2011;139(5):639-648.
The neutral theory of molecular evolution (Kimura 1985) is the basis for most current statistical tests for detecting selection, mainly using polymorphism data within species, divergence data between species, and/or genomic structures like linkage disequilibrium (Wang et al. 2006). In most cases informative tests can only be constructed with ample variations within these parameters and many common tests are difficult to formulate when identity-by-descent is not clear, for example in gene families or repetitive elements. With the current progress being made toward whole-genome sequencing and re-sequencing efforts, as well as protein sequencing via tandem mass spectrometry where genomic sequencing is lacking, we felt it was necessary to re-visit possible methods for rapid screening and detection of evolutionary outliers. These outliers might be of interest for other research, such as candidate gene association studies or genome annotations, drug- and disease-target searches, and functional studies. We focused on methods that would work on both protein and nucleotide data, could be used on large gene or protein domain families, and could be generated quickly in order for “first pass” annotation of large scale data. For these reasons, we chose properties of trees generated routinely in molecular phylogenetic studies; genetic distance, tree shape and balance, and internal node statistics (Heard 1992). Our current research looking at protein domain family data and phylogenetic trees from PFAM (Finn et al. 2008) suggests this approach towards detecting evolutionary outliers is feasible, but additional work will be necessary to determine the parameters that suggest either positive or negative selection is occurring in specific gene families. This is particularly true when other factors such as rapid duplication and deletion of genes containing these domains is taking place, and we suggest phylogenetic statistics may be useful in combination with existing methodologies for detailed studies of gene family data.
doi:10.1007/s10709-011-9560-6
PMCID: PMC3980844  PMID: 21400220
Phylogenetics; Selection; Evolution; Adaptation
2.  Expression Differences of Circulating MicroRNAs in Metastastic Castration Resistant Prostate Cancer and Low-risk, Localized Prostate Cancer 
The Prostate  2012;73(4):346-354.
Background
Recent studies show that microRNAs (miRNAs), small non-coding RNAs that negatively regulate gene expression, may have potential for monitoring cancer status. We investigated circulating miRNAs in prostate cancer that may be associated with the progression of hormone-sensitive primary tumors to metastatic castration resistant prostate cancer (CRPC) after androgen deprivation therapy.
Methods
Using genome-wide expression profiling by TaqMan Human MicroRNA Arrays (Applied Biosystems) and/or quantitative real-time polymerase chain reaction, we compared the expression levels of miRNAs in serum samples from 28 patients of low-risk localized disease, 30 of high-risk localized disease and 26 of metastatic CRPC.
Results
we demonstrated that serum samples from patients of low-risk, localized prostate cancer and metastatic CRPC patients exhibit distinct circulating miRNA signatures. MiR-375, miR-378*, and miR-141 were significantly over-expressed in serum from CRPC patients compared to serum from low-risk localized patients, while miR-409-3p was significantly under-expressed. In prostate primary tumor samples, miR-375 and miR-141 also had significantly higher expression levels compared to those in normal prostate tissue.
Conclusions
Circulating microRNAs, particularly miR-375, miR-141, miR-378* and miR-409-3p, are differentially expressed in serum samples from prostate cancer patients. In the search for improved minimally invasive methods to follow cancer pathogenesis, the correlation of disease status with the expression patterns of circulating miRNAs may indicate the potential importance of circulating miRNAs as prognostic markers for prostate cancer progression.
doi:10.1002/pros.22572
PMCID: PMC3980954  PMID: 22887127
circulating microRNAs; prostate cancer; castration resistant prostate cancer
3.  Complete Genome Sequence of a Porcine Circovirus 2 Strain Isolated in Central China 
Genome Announcements  2014;2(2):e00268-14.
We report here the complete genome sequence of the porcine circovirus type 2 (PCV2) XZBK strain, isolated from central China. This is the first report of a member of the 1B subgroup of PCV2b central China. This finding will help in understanding the epidemiology and molecular characteristics of PCV2.
doi:10.1128/genomeA.00268-14
PMCID: PMC3974943  PMID: 24699961
4.  Adenoviral-Mediated Glial Cell Line–Derived Neurotrophic Factor Gene Transfer Has a Protective Effect on Sciatic Nerve Following Constriction-Induced Spinal Cord Injury 
PLoS ONE  2014;9(3):e92264.
Neuropathic pain due to peripheral nerve injury may be associated with abnormal central nerve activity. Glial cell-line-derived neurotrophic factor (GDNF) can help attenuate neuropathic pain in different animal models of nerve injury. However, whether GDNF can ameliorate neuropathic pain in the spinal cord dorsal horn (SCDH) in constriction-induced peripheral nerve injury remains unknown. We investigated the therapeutic effects of adenoviral-mediated GDNF on neuropathic pain behaviors, microglial activation, pro-inflammatory cytokine expression and programmed cell death in a chronic constriction injury (CCI) nerve injury animal model. In this study, neuropathic pain was produced by CCI on the ipsilateral SCDH. Mechanical allodynia was examined with von Frey filaments and thermal sensitivity was tested using a plantar test apparatus post-operatively. Target proteins GDNF-1, GDNFRa-1, MMP2, MMP9, p38, phospho-p38, ED1, IL6, IL1β, AIF, caspase-9, cleaved caspase-9, caspase-3, cleaved caspase-3, PARP, cleaved PARP, SPECTRIN, cleaved SPECTRIN, Beclin-1, PKCσ, PKCγ, iNOS, eNOS and nNOS were detected. Microglial activity was measured by observing changes in immunoreactivity with OX-42. NeuN and TUNEL staining were used to reveal whether apoptosis was attenuated by GDNF. Results showed that administrating GDNF began to attenuate both allodynia and thermal hyperalgesia at day 7. CCI-rats were found to have lower GDNF and GDNFRa-1 expression compared to controls, and GDNF re-activated their expression. Also, GDNF significantly down-regulated CCI-induced protein expression except for MMP2, eNOS and nNOS, indicating that the protective action of GDNF might be associated with anti-inflammation and prohibition of microglia activation. Immunocytochemistry staining showed that GDNF reduced CCI-induced neuronal apoptosis. In sum, GDNF enhanced the neurotrophic effect by inhibiting microglia activation and cytokine production via p38 and PKC signaling. GDNF could be a good therapeutic tool to attenuate programmed cell death, including apoptosis and autophagy, consequent to CCI-induced peripheral nerve injury.
doi:10.1371/journal.pone.0092264
PMCID: PMC3958488  PMID: 24642655
5.  Ginkgo biloba Extract Decreases Non-Small Cell Lung Cancer Cell Migration by Downregulating Metastasis-Associated Factor Heat-Shock Protein 27 
PLoS ONE  2014;9(3):e91331.
Heat-shock proteins (HSPs) are molecular chaperones that protect proteins from damage. HSP27 expression is associated with cancer transformation and invasion. Ginkgo biloba extract (EGb761), the most widely sold herbal supplement, has antiangiogenic effects and induces tumor apoptosis. Data regarding the effect of EGb761 on HSP expression is limited, particularly in cancer. HSP27 expression in paired tumors and normal lung tissues of 64 patients with non-small cell lung cancer (NSCLC) were detected by real-time PCR, western blotting, and immunohistochemistry. NSCLC cell lines (A549/H441) were used to examine the migratory abilities in vitro. NSCLC tissue showed higher HSP27 expression than normal lung tissue. Kaplan–Meier survival analysis showed that NSCLC patients with low HSP27 expression ratio (<1) had significantly longer survival time than those with a high expression ratio (>1) (p = 0.04). EGb761 inhibited HSP27 expression and migratory ability of A549/H441 cells, which is the same as HSP27-siRNA transfection effect. Moreover, EGb761 treatment activated the AKT and p38 pathways and did not affect the expression of PI3K, ERK, and JNK pathways. HSP27 is a poor prognostic indicator of NSCLC. EGb761 can decrease the migration ability of A549/H441 by inhibiting HSP27 expression most likely through AKT and p38 MAPK pathways activation.
doi:10.1371/journal.pone.0091331
PMCID: PMC3950153  PMID: 24618684
6.  Targeted Delivery of Erythropoietin by Transcranial Focused Ultrasound for Neuroprotection against Ischemia/Reperfusion-Induced Neuronal Injury: A Long-Term and Short-Term Study 
PLoS ONE  2014;9(2):e90107.
Erythropoietin (EPO) is a neuroprotective agent against cerebral ischemia/reperfusion (I/R)-induced brain injury. However, its crossing of blood-brain barrier is limited. Focused ultrasound (FUS) sonication with microbubbles (MBs) can effectively open blood-brain barrier to boost the vascular permeability. In this study, we investigated the effects of MBs/FUS on extending the therapeutic time window of EPO and its neuroprotective effects in both acute and chronic phases. Male Wistar rats were firstly subjected to two common carotid arteries and right middle cerebral artery occlusion (three vessels occlusion, 3VO) for 50 min, and then the rats were treated with hEPO (human recombinant EPO, 5000 IU/kg) with or without MBs/FUS at 5 h after occlusion/reperfusion. Acute phase investigation (I/R, I/R+MBs/FUS, I/R+hEPO, and I/R+hEPO+MBs/FUS) was performed 24 h after I/R; chronic tests including cylinder test and gait analysis were performed one month after I/R. The experimental results showed that MBs/FUS significantly increased the cerebral content of EPO by bettering vascular permeability. In acute phase, both significant improvement of neurological score and reduction of infarct volume were found in the I/R+hEPO+MBs/FUS group, as compared with I/R and I/R+hEPO groups. In chronic phase, long-term behavioral recovery and neuronal loss in brain cortex after I/R injury was significantly improved in the I/R+hEPO+MBs/FUS group. This study indicates that hEPO administration with MBs/FUS sonication even at 5 h after occlusion/reperfusion can produce a significant neuroprotection.
doi:10.1371/journal.pone.0090107
PMCID: PMC3938648  PMID: 24587228
7.  Hybrid Single-Packet IP Traceback with Low Storage and High Accuracy 
The Scientific World Journal  2014;2014:239280.
Traceback schemes have been proposed to trace the sources of attacks that usually hide by spoofing their IP addresses. Among these methods, schemes using packet logging can achieve single-packet traceback. But packet logging demands high storage on routers and therefore makes IP traceback impractical. For lower storage requirement, packet logging and packet marking are fused to make hybrid single-packet IP traceback. Despite such attempts, their storage still increases with packet numbers. That is why RIHT bounds its storage with path numbers to guarantee low storage. RIHT uses IP header's ID and offset fields to mark packets, so it inevitably suffers from fragment and drop issues for its packet reassembly. Although the 16-bit hybrid IP traceback schemes, for example, MORE, can mitigate the fragment problem, their storage requirement grows up with packet numbers. To solve the storage and fragment problems in one shot, we propose a single-packet IP traceback scheme that only uses packets' ID field for marking. Our major contributions are as follows: (1) our fragmented packets with tracing marks can be reassembled; (2) our storage is not affected by packet numbers; (3) it is the first hybrid single-packet IP traceback scheme to achieve zero false positive and zero false negative rates.
doi:10.1155/2014/239280
PMCID: PMC3953451
8.  An Efficient Fitness Function in Genetic Algorithm Classifier for Landuse Recognition on Satellite Images 
The Scientific World Journal  2014;2014:264512.
Genetic algorithm (GA) is designed to search the optimal solution via weeding out the worse gene strings based on a fitness function. GA had demonstrated effectiveness in solving the problems of unsupervised image classification, one of the optimization problems in a large domain. Many indices or hybrid algorithms as a fitness function in a GA classifier are built to improve the classification accuracy. This paper proposes a new index, DBFCMI, by integrating two common indices, DBI and FCMI, in a GA classifier to improve the accuracy and robustness of classification. For the purpose of testing and verifying DBFCMI, well-known indices such as DBI, FCMI, and PASI are employed as well for comparison. A SPOT-5 satellite image in a partial watershed of Shihmen reservoir is adopted as the examined material for landuse classification. As a result, DBFCMI acquires higher overall accuracy and robustness than the rest indices in unsupervised classification.
doi:10.1155/2014/264512
PMCID: PMC3948504
9.  Studies Based on Preparation, Physical Characteristics, and Cellular Pharmacological Activities of Thin PLGA Film Loaded with Geniposide 
In this primary study, thin polylactic-co-glycolic acid (PLGA) film loaded with geniposide was first prepared and demonstrated on both physical and pharmacological aspects for its potential application on drug-eluting vascular stents. Physical parameters of geniposide-loaded thin film, such as crystal structure, molecular spectral characteristics, and release behavior in the whole process were detected. From X-Ray diffraction, the characteristic peak of crystal geniposide disappeared on geniposide-loaded PLGA film (GLPF) after it formed, which meant there was no agglomeration phenomenon, as geniposide was distributed in the form of single molecule. According to scanning electron microscopy (SEM) figure, the GLPF was more flat and uniform with better compactness. It inferred that release behavior of geniposide at the early stage (0~15 d) was in the form of free diffusion. Carrier PLGA began to degrade 15 days later, so the residual geniposide was also dissolved. Cellular pharmacological effects of geniposide on endothelial cells (ECs) and smooth muscle cells (SMCs) were also demonstrated on GLPF. 5% and 10% (w/w) geniposide-loaded PLGA (60 : 40) membrane indicated its significant effect on ECs promotion and SMCs inhibition. All provided feasible evidences for the development of new geniposide-coating vascular stent using PLGA as carrier.
doi:10.1155/2014/352423
PMCID: PMC3944942
10.  Validating and Improving Interrill Erosion Equations 
PLoS ONE  2014;9(2):e88275.
Existing interrill erosion equations based on mini-plot experiments have largely ignored the effects of slope length and plot size on interrill erosion rate. This paper describes a series of simulated rainfall experiments which were conducted according to a randomized factorial design for five slope lengths (0.4, 0.8, 1.2, 1.6, and 2 m) at a width of 0.4 m, five slope gradients (17%, 27%, 36%, 47%, and 58%), and five rainfall intensities (48, 62.4, 102, 149, and 170 mm h−1) to perform a systematic validation of existing interrill erosion equations based on mini-plots. The results indicated that the existing interrill erosion equations do not adequately describe the relationships between interrill erosion rate and its influencing factors with increasing slope length and rainfall intensity. Univariate analysis of variance showed that runoff rate, rainfall intensity, slope gradient, and slope length had significant effects on interrill erosion rate and that their interactions were significant at p = 0.01. An improved interrill erosion equation was constructed by analyzing the relationships of sediment concentration with rainfall intensity, slope length, and slope gradient. In the improved interrill erosion equation, the runoff rate and slope factor are the same as in the interrill erosion equation in the Water Erosion Prediction Project (WEPP), with the weight of rainfall intensity adjusted by an exponent of 0.22 and a slope length term added with an exponent of −0.25. Using experimental data from WEPP cropland soil field interrill erodibility experiments, it has been shown that the improved interrill erosion equation describes the relationship between interrill erosion rate and runoff rate, rainfall intensity, slope gradient, and slope length reasonably well and better than existing interrill erosion equations.
doi:10.1371/journal.pone.0088275
PMCID: PMC3916424  PMID: 24516624
11.  Slow Diffusion Underlies Alternation of Fast and Slow Growth Periods of Microtubule Assembly 
The Scientific World Journal  2014;2014:601898.
In vitro microtubule assembly exhibits a rhythmic phenomenon, that is, fast growth periods alternating with slow growth periods. Mechanism underlying this phenomenon is unknown. Here a simple diffusion mechanism coupled with small diffusion coefficients is proposed to underlie this phenomenon. Calculations based on previously published results demonstrate that such a mechanism can explain the differences in the average duration of the interval encompassing a fast growth period and a slow growth period in in vitro microtubule assembly experiments in different conditions. Because no parameter unique to the microtubule assembly process is involved in the analysis, the proposed mechanism is expected to be generally applicable to heterogeneous chemical reactions. Also because biological systems are characterized by heterogeneous chemical reactions, the diffusion-based rhythmic characteristic of heterogeneous reactions is postulated to be a fundamental element in generating rhythmic behaviors in biological systems.
doi:10.1155/2014/601898
PMCID: PMC3925585  PMID: 24605057
12.  Fully Automated Detection of Corticospinal Tract Damage in Chronic Stroke Patients 
Structural integrity of the corticospinal tract (CST) after stroke is closely linked to the degree of motor impairment. However, current methods for measurement of fractional atrophy (FA) of CST based on region of interest (ROI) are time-consuming and open to bias. Here, we used tract-based spatial statistics (TBSS) together with a CST template with healthy volunteers to quantify structural integrity of CST automatically. Two groups of patients after ischemic stroke were enrolled, group 1 (10 patients, 7 men, and Fugl-Meyer assessment (FMA) scores ⩽ 50) and group 2 (12 patients, 12 men, and FMA scores = 100). CST of FAipsi, FAcontra, and FAratio was compared between the two groups. Relative to group 2, FA was decreased in group 1 in the ipsilesional CST (P < 0.01), as well as the FAratio (P < 0.01). There was no significant difference between the two subgroups in the contralesional CST (P = 0.23). Compared with contralesional CST, FA of ipsilesional CST decreased in group 1 (P < 0.01). These results suggest that the automated method used in our study could detect a surrogate biomarker to quantify the CST after stroke, which would facilitate implementation of clinical practice.
doi:10.1155/2014/370849
PMCID: PMC3914349  PMID: 24527059
13.  Oncometabolites: linking altered metabolism with cancer 
The Journal of Clinical Investigation  2013;123(9):3652-3658.
The discovery of cancer-associated mutations in genes encoding key metabolic enzymes has provided a direct link between altered metabolism and cancer. Advances in mass spectrometry and nuclear magnetic resonance technologies have facilitated high-resolution metabolite profiling of cells and tumors and identified the accumulation of metabolites associated with specific gene defects. Here we review the potential roles of such “oncometabolites” in tumor evolution and as clinical biomarkers for the detection of cancers characterized by metabolic dysregulation.
doi:10.1172/JCI67228
PMCID: PMC3754247  PMID: 23999438
14.  Effectiveness of a hydroxynaphthoquinone fraction from Arnebia euchroma in rats with experimental colitis 
AIM: To evaluate the potential effectiveness of hydroxynaphthoquinone mixture (HM) in rats with 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced colitis.
METHODS: Colitis was induced by intracolonic administration of TNBS (80 mg/kg, dissolved in 50% ethanol). Rats were treated daily for 7 d with HM (2.5, 5, 10 mg/kg) and mesalazine 100 mg/kg 24 h after TNBS instillation. Disease progression was monitored daily by observation of clinical signs and body weight change. At the end of the experiment, macroscopic and histopathologic lesions of rats were scored, and myeloperoxidase (MPO) activity was determined. We also determined inflammatory cytokine tumor necrosis factor (TNF)-α level by ELISA, Western blotting and immunochemistry to explore the potential mechanisms of HM.
RESULTS: After intracolonic instillation of TNBS, animals developed colitis associated with soft stool, diarrhea and marked colonic destruction. Administration of HM significantly attenuated clinical and histopathologic severity of TNBS-induced colitis in a dose-dependent manner. It abrogated body weight loss, diarrhea and inflammation, decreased macroscopic damage score, and improved histological signs, with a significant reduction of inflammatory infiltration, ulcer size and the severity of goblet cell depletion (all P < 0.05 vs TNBS alone group). HM could reduce MPO activity. In addition, it also decreased serum TNF-α level and down-regulated TNF-α expression in colonic tissue. This reduction was statistically significant when the dose of HM was 10 mg/kg (P < 0.05 vs TNBS alone group), and the effect was comparable to that of mesalazine and showed no apparent adverse effect. The underlying mechanism may be associated with TNF-α inhibition.
CONCLUSION: These findings suggest that HM possesses favourable therapeutic action in TNBS-induced colitis, which provides direct pharmacological evidence for its clinical application.
doi:10.3748/wjg.v19.i48.9318
PMCID: PMC3882404  PMID: 24409058
Arnebia euchroma (Royle) Johnst; Hydroxynaphthoquinones; Inflammatory bowel disease; 2,4,6-trinitrobenzene sulfonic acid-induced colitis; Tumor necrosis factor
15.  Characterization, pharmacokinetics, and hypoglycemic effect of berberine loaded solid lipid nanoparticles 
The high aqueous solubility, poor permeability, and absorption of berberine (BBR) result in its low plasma level after oral administration, which greatly limits its clinical application. BBR solid lipid nanoparticles (SLNs) were prepared to achieve improved bioavailability and prolonged effect. Developed SLNs showed homogeneous spherical shapes, small size (76.8 nm), zeta potential (7.87 mV), encapsulation efficiency (58%), and drug loading (4.2%). The power of X-ray diffraction combined with 1H nuclear magnetic resonance spectroscopy was employed to analyze chemical functional groups and the microstructure of BBR-SLNs, and indicated that the drug was wrapped in a lipid carrier. Single dose (50 mg/kg) oral pharmacokinetic studies in rats showed significant improvement (P<0.05) in the peak plasma concentration, area under the curve, and variance of mean residence time of BBR-SLNs when compared to BBR alone (P<0.05), suggesting improved bioavailability. Furthermore, oral administration of both BBR and BBR-SLNs significantly suppressed body weight gain, fasting blood glucose levels, and homeostasis assessment of insulin resistance, and ameliorated impaired glucose tolerance and insulin tolerance in db/db diabetic mice. BBR-SLNs at high dose (100 mg/kg) showed more potent effects when compared to an equivalent dose of BBR. Morphologic analysis demonstrated that BBR-SLNs potentially promoted islet function and protected the islet from regeneration. In conclusion, our study demonstrates that by entrapping BBR into SLNs the absorption of BBR and its anti-diabetic action were effectively enhanced.
doi:10.2147/IJN.S51262
PMCID: PMC3862509  PMID: 24353417
berberine; solid lipid nanoparticles; pharmacokinetic; hypoglycemic effect
16.  Activation of Extracellular Signal-Regulated Kinase but Not of p38 Mitogen-Activated Protein Kinase Pathways in Lymphocytes Requires Allosteric Activation of SOS 
Molecular and Cellular Biology  2013;33(12):2470-2484.
Thymocytes convert graded T cell receptor (TCR) signals into positive selection or deletion, and activation of extracellular signal-related kinase (ERK), p38, and Jun N-terminal protein kinase (JNK) mitogen-activated protein kinases (MAPKs) has been postulated to play a discriminatory role. Two families of Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP, activate Ras and the downstream RAF-MEK-ERK pathway. The pathways leading to lymphocyte p38 and JNK activation are less well defined. We previously described how RasGRP alone induces analog Ras-ERK activation while SOS and RasGRP cooperate to establish bimodal ERK activation. Here we employed computational modeling and biochemical experiments with model cell lines and thymocytes to show that TCR-induced ERK activation grows exponentially in thymocytes and that a W729E allosteric pocket mutant, SOS1, can only reconstitute analog ERK signaling. In agreement with RasGRP allosterically priming SOS, exponential ERK activation is severely decreased by pharmacological or genetic perturbation of the phospholipase Cγ (PLCγ)-diacylglycerol-RasGRP1 pathway. In contrast, p38 activation is not sharply thresholded and requires high-level TCR signal input. Rac and p38 activation depends on SOS1 expression but not allosteric activation. Based on computational predictions and experiments exploring whether SOS functions as a RacGEF or adaptor in Rac-p38 activation, we established that the presence of SOS1, but not its enzymatic activity, is critical for p38 activation.
doi:10.1128/MCB.01593-12
PMCID: PMC3700092  PMID: 23589333
17.  Altered MAPK Signaling in Progressive Deterioration of Endothelial Function in Diabetic Mice 
Diabetes  2012;61(12):3181-3188.
We aimed to investigate specific roles of mitogen-activated protein kinases (MAPK) in the deterioration of endothelial function during the progression of diabetes and the potential therapeutic effects of MAPK inhibitors and agonists in the amelioration of endothelial function. Protein expression and phosphorylation of p38, c-Jun NH2-terminal kinase (JNK), and extracellular signal–regulated kinase (Erk) were assessed in mesenteric arteries of 3- (3M) and 9-month-old (9M) male diabetic and control mice. The expression of p38, JNK, and Erk was comparable in all groups of mice, but the phosphorylation of p38 and JNK was increased in 3M and further increased in 9M diabetic mice, whereas the phosphorylation of Erk was substantially reduced in 9M diabetic mice. NADPH oxidase–dependent superoxide production was significantly increased in vessels of two ages of diabetic mice. Inhibition of either p38 with SB203580 or JNK with SP600125 reduced superoxide production and improved shear stress–induced dilation (SSID) in 3M, but not in 9M, diabetic mice. Treating the vessels of 9M diabetic mice with resveratrol increased Erk phosphorylation and shear stress–induced endothelial nitric oxide synthase (eNOS) phosphorylation and activity, but resveratrol alone did not improve SSID. Administration of resveratrol and SB203580 or resveratrol and SP600125 together significantly improved SSID in vessels of 9M diabetic mice. The improved response was prevented by U0126, an Erk inhibitor. Thus, p38/JNK-dependent increase in oxidative stress diminished nitric oxide–mediated dilation in vessels of 3M diabetic mice. Oxidative stress and impaired Erk-dependent activation of eNOS exacerbates endothelial dysfunction in the advanced stage of diabetes.
doi:10.2337/db12-0559
PMCID: PMC3501862  PMID: 22933112
18.  Activation of Olfactory Receptors on Mouse Pulmonary Macrophages Promotes Monocyte Chemotactic Protein-1 Production 
PLoS ONE  2013;8(11):e80148.
Background
Emerging evidence suggests that non-olfactory tissues and cells can express olfactory receptors (ORs), however, the exact function of ectopic OR expression remains unknown. We have previously shown in mouse models that a unique cooperation between interferon-γ (IFN-γ) and lipopolysaccharide (LPS) drives the activation of pulmonary macrophages and leads to the induction of pathogenic responses in the respiratory tract. Further, through gene array studies, we have shown that activation of macrophages by these molecules results in the selective expression of a number of ORs. In this study, we validated the expression of these ORs in mouse airway and pulmonary macrophages in response to IFN-γ and LPS (γ/LPS) stimulation, and further explored the effect of odorant stimulation on macrophage function.
Methodology/Principal Findings
OR expression in airway and pulmonary macrophages in response to IFN-γ, LPS or γ/LPS treatments was assessed by microarray and validated by q-PCR. OR expression (e.g. OR622) on macrophages was confirmed by visualization in immunofluoresence assays. Functional responses to odorants were assessed by quantifying inflammatory cytokine and chemokine expression using q-PCR and cell migration was assessed by a modified Boyden chamber migration assay. Our results demonstrate that eight ORs are expressed at basal levels in both airway and pulmonary macrophages, and that γ/LPS stimulation cooperatively increased this expression. Pulmonary macrophages exposed to the combined treatment of γ/LPS+octanal (an odorant) exhibited a 3-fold increase in MCP-1 protein production, compared to cells treated with γ/LPS alone. Supernatants from γ/LPS+octanal exposed macrophages also increased macrophage migration in vitro.
Conclusions/Significance
Eight different ORs are expressed at basal levels in pulmonary macrophages and expression is upregulated by the synergistic action of γ/LPS. Octanal stimulation further increased MCP-1 production and the motility of macrophages. Our results suggest that ORs may mediate macrophage function by regulating MCP-1 production and cell migration.
doi:10.1371/journal.pone.0080148
PMCID: PMC3836993  PMID: 24278251
19.  Biodegradable mucus-penetrating nanoparticles composed of diblock copolymers of polyethylene glycol and poly(lactic-co-glycolic acid) 
Drug delivery and translational research  2012;2(2):10.1007/s13346-011-0048-9.
Mucus secretions coating entry points to the human body that are not covered by skin efficiently trap and clear conventional drug carriers, limiting controlled drug delivery at mucosal surfaces. To overcome this challenge, we recently engineered nanoparticles that readily penetrate a variety of human mucus secretions, which we termed mucus-penetrating particles (MPP). Here, we report a new biodegradable MPP formulation based on diblock copolymers of poly(lactic-co-glycolic acid) and poly(ethylene glycol) (PLGA-PEG). PLGA-PEG nanoparticles prepared by a solvent diffusion method rapidly diffused through fresh, undiluted human cervicovaginal mucus (CVM) with an average speed only eightfold lower than their theoretical speed in water. In contrast, PLGA nanoparticles were slowed more than 12,000-fold in the same CVM secretions. Based on the measured diffusivities, as much as 75% of the PLGA-PEG nanoparticles are expected to penetrate a 10-μm-thick mucus layer within 30 min, whereas virtually no PLGA nanoparticles are expected to do so over the same duration. These results encourage further development of PLGA-PEG nanoparticles as mucus-penetrating drug carriers for improved drug and gene delivery to mucosal surfaces.
doi:10.1007/s13346-011-0048-9
PMCID: PMC3818113  PMID: 24205449
Drug delivery; Human mucus; Mucus-penetrating particles
20.  The Changes in mGluR2 and mGluR7 Expression in Rat Medial Vestibular Nucleus and Flocculus Following Unilateral Labyrinthectomy 
It is known that the medial vestibular nucleus (MVN) and the cerebellar flocculus are the key areas, which contribute to the behavioral recovery (“vestibular compensation”) after unilateral labyrinthectomy (UL). In these areas, how the genetic activities of the metabotropic glutamate receptors mGluR2 and mGluR7 performance after UL is unknown. With the means of quantitative real-time PCR, Western blotting, and immunohistochemistry, we analyzed the expression of mGluR2 and mGluR7 in the bilateral MVN and the flocculus of rats in different stages after UL (the 1st, 3rd, and 7th day). Our results show that in the MVN, the mRNA, and protein expressions of mGluR7 were ipsilaterally decreased at the 1st day following UL. However, in the MVN, no change was observed in the mRNA and protein expressions of mGluR2. On the other hand, the mRNA and protein expression of mGluR2 were enhanced in the ipsilateral flocculus at the 1st day following UL, while in the flocculus no change was shown in mGluR7 mRNA and protein expressions. Our results suggest that mGluR2 and mGluR7 may contribute to the early rebalancing of spontaneous resting activity in the MVN.
doi:10.3390/ijms141122857
PMCID: PMC3856095  PMID: 24264036
flocculus; medial vestibular nucleus; mGluR2; mGluR7; vestibular compensation
21.  Fabrication and Characterization of CMOS-MEMS Magnetic Microsensors 
Sensors (Basel, Switzerland)  2013;13(11):14728-14739.
This study investigates the design and fabrication of magnetic microsensors using the commercial 0.35 μm complementary metal oxide semiconductor (CMOS) process. The magnetic sensor is composed of springs and interdigitated electrodes, and it is actuated by the Lorentz force. The finite element method (FEM) software CoventorWare is adopted to simulate the displacement and capacitance of the magnetic sensor. A post-CMOS process is utilized to release the suspended structure. The post-process uses an anisotropic dry etching to etch the silicon dioxide layer and an isotropic dry etching to remove the silicon substrate. When a magnetic field is applied to the magnetic sensor, it generates a change in capacitance. A sensing circuit is employed to convert the capacitance variation of the sensor into the output voltage. The experimental results show that the output voltage of the magnetic microsensor varies from 0.05 to 1.94 V in the magnetic field range of 5–200 mT.
doi:10.3390/s131114728
PMCID: PMC3871104  PMID: 24172287
magnetic sensor; Lorentz force; CMOS; post-process
22.  Application of Genetic Algorithm for Discovery of Core Effective Formulae in TCM Clinical Data 
Research on core and effective formulae (CEF) does not only summarize traditional Chinese medicine (TCM) treatment experience, it also helps to reveal the underlying knowledge in the formulation of a TCM prescription. In this paper, CEF discovery from tumor clinical data is discussed. The concepts of confidence, support, and effectiveness of the CEF are defined. Genetic algorithm (GA) is applied to find the CEF from a lung cancer dataset with 595 records from 161 patients. The results had 9 CEF with positive fitness values with 15 distinct herbs. The CEF have all had relative high average confidence and support. A herb-herb network was constructed and it shows that all the herbs in CEF are core herbs. The dataset was divided into CEF group and non-CEF group. The effective proportions of former group are significantly greater than those of latter group. A Synergy index (SI) was defined to evaluate the interaction between two herbs. There were 4 pairs of herbs with high SI values to indicate the synergy between the herbs. All the results agreed with the TCM theory, which demonstrates the feasibility of our approach.
doi:10.1155/2013/971272
PMCID: PMC3830796  PMID: 24288577
23.  The Altered Expression of MiR-221/-222 and MiR-23b/-27b Is Associated With the Development of Human Castration Resistant Prostate Cancer 
The Prostate  2011;72(10):10.1002/pros.22456.
BACKGROUND
We have previously identified seven miRs-miR-221, -222, -23b, -27b, -15a, -16-1, and -203, that are differentially expressed in the hormone sensitive LNCaP cell line and the hormone resistant LNCaP-abl cell line and hypothesized that these miRs may characterize certain subtypes of human castration resistant prostate cancer (CRPC).
METHODS
Functional studies in cell culture systems have been performed to determine the effect of alternated expression level on cellular response to androgen treatment. To determine the clinical relevance of the expression patterns of these miRs, we compared the expression levels of these seven miRs in normal prostate tissues from 86 individuals, prostate tumor tissues from 34 individuals with localized hormone naïve disease, and bone-derived metastatic CRPC tissues from 17 individuals.
RESULTS
The altered expression of miR-221/-222 (as previously described) or miR-203 affected the cellular response to androgen treatment, suggesting their potential involvement in the transition to CRPC. However, the expression of miR-23b, -27b, -15a, and -16-1 did not have a significant influence in the cellular response to androgen treatment, suggesting that these miRs may not play a causative role in the CRPC phenotype. Comparison of the expression levels of these miRs in tissue samples revealed that strikingly, ~90% of the analyzed metastatic CRPC tumors could be characterized by the increased miR-221/-222 expression and the down-regulated miR-23b/-27b expression.
CONCLUSIONS
This finding suggests that altered miR-221/-222 and miR-23b/-27b expression may be associated with the CRPC process.
doi:10.1002/pros.22456
PMCID: PMC3810996  PMID: 22127852
microRNA; miR-221/-222; prostate cancer
24.  Acupuncture Deqi Intensity and Propagated Sensation along Channels May, Respectively, Differ due to Different Body Positions of Subjects 
Acupuncture as an essential component of complementary and alternative medicine is gradually recognized and accepted by the mainstream of contemporary medicine. For obtaining preferable clinical effectiveness, Deqi is commonly regarded as efficacy predictor and parameter which is necessary to be achieved. Influential factors for acupuncture efficacy, like Deqi sensation as well as propagated sensation along channels (PSCs), enjoyed a long history in acupuncture basic research. Concerning this study, taking into account different positions on acupuncture Deqi sensation and PSCs, we would like to attest whether different body positions for subjects during needling procedure yield differed acupuncture Deqi sensation, particularly in terms of intensity, and PSCs. Methods. We used self-controlled method and selected 30 healthy subjects to perform needle insertion at Futu point (ST32) bilaterally. Then they were instructed to record the value of intensity of acupuncture sensation and the length and width of PSCs after removing the needle. Results. In regard to intensity of Deqi, kneeling seat position is stronger than supine position, accounting for 90% of the total number of subjects. In length of PSCs, kneeling seat position is greater than supine position, accounting for 56.7%. In width of PSCs, kneeling seat position is greater than supine position, accounting for 66.7%. Conclusion. Our findings show that needle inserting at Futu point (ST32) in kneeling seat position achieve better needle sensation and provide reference for clinical.
doi:10.1155/2013/897048
PMCID: PMC3819913  PMID: 24250720
25.  Colonic diverticulitis with comorbid diseases may require elective colectomy 
AIM: To investigate the comorbid disease could be the predictors for the elective colectomy in colonic diverticulitis.
METHODS: A retrospective chart review of 246 patients with colonic diverticulitis admitted between 2000 and 2008 was conducted, and 19 patients received emergent operation were identified and analyzed. Data were collected with regard to age, sex, albumin level on admission, left or right inflammation site, the history of recurrent diverticulitis, preoperative comorbidity, smoking habits, medication, treatment policy, morbidity, and mortality. Preoperative comorbid diseases included cardiovascular disease, diabetes, pulmonary disease, peptic ulcer disease, gouty arthritis, and uremia. Medications in use included non-steroidal anti-inflammatory drugs, acetylsalicylic acid (Aspirin), and corticosteroids. Univariate and multivariate logistic regression analyses were performed to identify the relevant risk factors correlating to colectomy.
RESULTS: The mean age of the 246 patients was 69.5 years (range, 24-94 years). Most diverticulitis could be managed with conservative treatment (n = 227, 92.3%), and urgent colectomy was performed in 19 patients (7.7%). There were three deaths in the surgical group and four deaths in the nonsurgical group. The overall mortality rate in the study was 1.7% among patients with conservative treatment and 15.7% among patients undergoing urgent colectomy. Multiple logistic regression analysis indicated that comorbidities were risk factors for urgent colectomy for diverticulitis.
CONCLUSION: To avoid high mortality and morbidity related to urgent colectomy, we suggest that patients with colonic diverticulitis and comorbid diseases may require elective colectomy.
doi:10.3748/wjg.v19.i39.6613
PMCID: PMC3801376  PMID: 24151389
Colonic diverticulitis; Colectomy; Comorbid disease

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