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1.  In vivo nanoparticle-mediated radiopharmaceutical-excited fluorescence molecular imaging 
Nature Communications  2015;6:7560.
Cerenkov luminescence imaging utilizes visible photons emitted from radiopharmaceuticals to achieve in vivo optical molecular-derived signals. Since Cerenkov radiation is weak, non-optimum for tissue penetration and continuous regardless of biological interactions, it is challenging to detect this signal with a diagnostic dose. Therefore, it is challenging to achieve useful activated optical imaging for the acquisition of direct molecular information. Here we introduce a novel imaging strategy, which converts γ and Cerenkov radiation from radioisotopes into fluorescence through europium oxide nanoparticles. After a series of imaging studies, we demonstrate that this approach provides strong optical signals with high signal-to-background ratios, an ideal tissue penetration spectrum and activatable imaging ability. In comparison with present imaging techniques, it detects tumour lesions with low radioactive tracer uptake or small tumour lesions more effectively. We believe it will facilitate the development of nuclear and optical molecular imaging for new, highly sensitive imaging applications.
Insufficient imaging sensitivity can make it challenging to assess early stage tumour lesions in vivo. Here, the authors present the radiopharmaceutical-excited fluorescence imaging technique that can detect tumour lesions less than 2 mm in size in living mice.
PMCID: PMC4491820  PMID: 26123615
2.  Outcomes and Treatment of Lumbosacral Spinal Tuberculosis: A Retrospective Study of 53 Patients 
PLoS ONE  2015;10(6):e0130185.
Study Strategy
A retrospective clinic study.
To evaluate the efficacy of conservative and surgical treatment for lumbosacral tuberculosis.
This study retrospectively reviewed 53 patients with lumbosacral tuberculosis who were treated in our institution between January 2005 and January 2011. There were 29 males and 24 females with average ages of 37.53 ± 17.28 years (range 6–72 years). 11 patients were given only anti-TB drugs; the remainder underwent anterior debridement, interbody fusion with and without instrumentation, or one-stage anterior debridement combined with posterior instrumentation. Outcome data for these patients included neurologic status, lumbosacral angle, erythrocyte sedimentation rate value(ESR) and C-reactive protein value(CRP) were assessed before and after treatment.
The mean lumbosacral angles were 23.00°± 2.90°in the conservatively treated patients and 22.36°± 3.92o in the surgically treated patients. At the final follow-up, this had improved to 24.10o ± 2.96°in the conservatively treated patients and 28.13° ± 1.93°in the surgically treated patients (all P < 0.05). There were statistically significant differences before and after treatment in terms of ESR and CRP (all P < 0.05). All patients achieved bone fusion. The mean follow-up period was 32.34 ± 8.13 months (range 18 to 55 months). The neurological deficit did not worsen in any of the patients.
It has been proven that conservative and surgical treatments are safe and effective and produce good clinical outcomes for patients with lumbosacral tuberculosis. The advantages of operation include thoroughness of debridement, decompression of the spinal cord, and adequate spinal stabilization.
PMCID: PMC4485466  PMID: 26121685
3.  Molecular Features of Triple Negative Breast Cancer: Microarray Evidence and Further Integrated Analysis 
PLoS ONE  2015;10(6):e0129842.
Breast cancer is a heterogeneous disease usually including four molecular subtypes such as luminal A, luminal B, HER2-enriched, and triple-negative breast cancer (TNBC). TNBC is more aggressive than other breast cancer subtypes. Despite major advances in ER-positive or HER2-amplified breast cancer, there is no targeted agent currently available for TNBC, so it is urgent to identify new potential therapeutic targets for TNBC.
We first used microarray analysis to compare gene expression profiling between TNBC and non-TNBC. Furthermore an integrated analysis was conducted based on our own and published data, leading to more robust, reproducible and accurate predictions. Additionally, we performed qRT-PCR in breast cancer cell lines to verify the findings in integrated analysis.
After searching Gene Expression Omnibus database (GEO), two microarray studies were obtained according to the inclusion criteria. The integrated analysis was conducted, including 30 samples of TNBC and 77 samples of non-TNBC. 556 genes were found to be consistently differentially expressed (344 up-regulated genes and 212 down-regulated genes in TNBC). Functional annotation for these differentially expressed genes (DEGs) showed that the most significantly enriched Gene Ontology (GO) term for molecular functions was protein binding (GO: 0005515, P = 6.09E-21), while that for biological processes was signal transduction (GO: 0007165, P = 9.46E-08), and that for cellular component was cytoplasm (GO: 0005737, P = 2.09E-21). The most significant pathway was Pathways in cancer (P = 6.54E-05) based on Kyoto Encyclopedia of Genes and Genomes (KEGG). DUSP1 (Degree = 21), MYEOV2 (Degree = 15) and UQCRQ (Degree = 14) were identified as the significant hub proteins in the protein-protein interaction (PPI) network. Five genes were selected to perform qRT-PCR in seven breast cancer cell lines, and qRT-PCR results showed that the expression pattern of selected genes in TNBC lines and non-TNBC lines was nearly consistent with that in the integrated analysis.
This study may help to understand the pathogenesis of different breast cancer subtypes, contributing to the successful identification of therapeutic targets for TNBC.
PMCID: PMC4478040  PMID: 26103053
4.  Apoptosis associated with Wnt/β-catenin pathway leads to steroid-induced avascular necrosis of femoral head 
The objective of the current study was to establish a rat model to investigate apoptosis in steroid-induced femoral head osteonecrosis occurring via the Wnt/β-catenin pathway.
Male Sprague–Dawley (SD) rats were randomly divided into a control group (group A), model group (group B) and sFRP1 group (group C), each consisting of 24 rats, and the rats were intravenously injected with LPS (10 μg/kg body weight). After 24 h, three injections of MPS (20 mg/kg body weight) were administered intramuscularly at 24-h intervals. The rats in group C were injected intramuscularly with 1 μg/kg sFRP1 protein per day for 30 days, beginning at the time of the first MPS administration. The group A rats were fed and housed under identical conditions but received saline injection. All animals were sacrificed at weeks 2, 4 and 8 from the first MPS injection. Histopathological staining was preformed to evaluated osteonecrosis. Apoptosis was detected via quantitative terminal deoxynucleotidyl transferase (TdT) deoxyuridine triphosphate nick-end labelling (TUNEL) staining, caspase-3 activity assay, and detection of Bcl-2 and Bax protein expression by immunohistochemistry and Western blotting. Wnt/β-catenin pathway signalling molecules, including activated β-catenin and c-Myc, were detected by immunohistochemistry and Western blotting.
Typical osteonecrosis was observed in groups B and C. Apoptosis gradually increased with increasing time in both groups B and C. More severe osteonecrosis and apoptosis were observed in group C compared with group B. The expression levels of caspase-3 and Bax were higher while that of Bcl-2 was lower in group C compared with group B. The expression levels of activated β-catenin and c-Myc gradually decreased with increasing time in both groups B and C, and they were lower in group C compared with group B.
The Wnt/β-catenin pathway is involved in the pathogenesis of early stage SANFH, as we have demonstrated in an SANFH rat model, and it may act through the regulation of c-Myc, which affects the cell cycle and cell apoptosis.
Electronic supplementary material
The online version of this article (doi:10.1186/s12891-015-0606-2) contains supplementary material, which is available to authorized users.
PMCID: PMC4453221  PMID: 26037065
Steroid-induced avascular necrosis of femoral head; Apoptosis; β-catenin; c-Myc; Rat
5.  Comparative transcriptomic analysis revealed adaptation mechanism of Phrynocephalus erythrurus, the highest altitude Lizard living in the Qinghai-Tibet Plateau 
Organisms living at high altitudes must overcome three major environmental challenges: hypoxia, cold, and intense UV radiation. The molecular mechanisms that enable these challenges to be overcome have mainly been studied in endothermic organisms; relatively little attention has been paid to poikilothermic species. Here, we present deep transcriptome sequencing in two closely related lizards, the high altitude-dwelling Phrynocephalus erythrurus and the lowland-dwelling P. putjatia, to identify candidate genes under positive selection and to explore the convergent evolutionary adaptation of poikilothermic animals to high altitude life.
More than 70 million sequence reads were generated for each species via Illumina sequencing. De novo assembly produced 56,845 and 63,140 transcripts for P. erythrurus and P. putjatia, respectively. P. erythrurus had higher Ka/Ks ratios than P. putjatia, implying an accelerated evolutionary rate in the high altitude lizard lineage. 206 gene ontology (GO) categories with accelerated evolutionary rates and 43 candidate positively selected genes were detected along the P. erythrurus lineage. Some of these GO categories have functions associated with responses to hypoxia, energy metabolism and responses to UV damage. We also found that the high-altitude ranid frog R. kukunoris had higher Ka/Ks ratios than the closely related low-altitude frog R. chensinensis, and that the functional categories with accelerated evolutionary rates in R. kukunoris overlapped extensively with those detected along the P. erythrurus lineage.
The mechanisms of high altitude adaptation in P. erythrurus were tentatively inferred. By comparing two pairs of low- and high-altitude poikilothermic species, we found that similar functional categories had undergone positive selection in high altitude-dwelling Phrynocephalus and Rana lineages, indicating that similar mechanisms of adaptation to high altitude might have evolved in both genera. Our findings provide important guidance for future functional studies on high altitude adaptation in poikilothermic animals.
Electronic supplementary material
The online version of this article (doi:10.1186/s12862-015-0371-8) contains supplementary material, which is available to authorized users.
PMCID: PMC4450828  PMID: 26031664
Lizard; High altitude adaptation; Positive selection; Accelerate evolutionary rate; Hypoxia; UV damage
6.  Exon Microarray Analysis of Human Dorsolateral Prefrontal Cortex in Alcoholism 
Alcohol abuse is associated with cellular and biochemical disturbances that impact upon protein and nucleic acid synthesis, brain development, function and behavioral responses. To further characterize the genetic influences in alcoholism and the effects of alcohol consumption on gene expression, we used a highly sensitive exon microarray to examine mRNA expression in human frontal cortex of alcoholics and control males.
Messenger RNA was isolated from the dorsolateral prefrontal cortex (dlPFC, Brodmann area 9) of 7 adult Alcoholic (6 males, 1 female, mean age 48 years) and 7 matched controls. Affymetrix Human Exon 1.0 ST Array was performed according to standard procedures and the results analyzed at the gene level. Microarray findings were validated using qRT-PCR, and the ontology of disturbed genes characterized using Ingenuity Pathway Analysis (IPA).
Decreased mRNA expression was observed for genes involved in cellular adhesion (e.g., CTNNA3, ITGA2), transport (e.g., TF, ABCA8), nervous system development (e.g., LRP2, UGT8, GLDN) and signaling (e.g., RASGRP, LGR5) with influence over lipid and myelin synthesis (e.g., ASPA, ENPP2, KLK6). IPA identified disturbances in network functions associated with neurological disease, and development including cellular assembly and organization impacting on psychological disorders.
Our data in alcoholism support a reduction in expression of dlPFC mRNA for genes involved with neuronal growth, differentiation and signaling that targets white matter of the brain.
PMCID: PMC4047192  PMID: 24890784
Affymetrix; Exon Microarray; Alcoholism; Frontal Cortex; Myelin
7.  Cyclin C mediates stress-induced mitochondrial fission and apoptosis 
Molecular Biology of the Cell  2015;26(6):1030-1043.
Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission and apoptosis. This work describes the role of the transcription factor cyclin C in mediating both responses.
Mitochondria are dynamic organelles that undergo constant fission and fusion cycles. In response to cellular damage, this balance is shifted dramatically toward fission. Cyclin C–Cdk8 kinase regulates transcription of diverse gene sets. Using knockout mouse embryonic fibroblasts (MEFs), we demonstrate that cyclin C directs the extensive mitochondrial scission induced by the anticancer drug cisplatin or oxidative stress. This activity is independent of transcriptional regulation, as Cdk8 is not required for this activity. Furthermore, adding purified cyclin C to unstressed permeabilized MEF cultures induced complete mitochondrial fragmentation that was dependent on the fission factors Drp1 and Mff. To regulate fission, a portion of cyclin C translocates from the nucleus to the cytoplasm, where it associates with Drp1 and is required for its enhanced mitochondrial activity in oxidatively stressed cells. In addition, although HeLa cells regulate cyclin C in a manner similar to MEF cells, U2OS osteosarcoma cultures display constitutively cytoplasmic cyclin C and semifragmented mitochondria. Finally, cyclin C, but not Cdk8, is required for loss of mitochondrial outer membrane permeability and apoptosis in cells treated with cisplatin. In conclusion, this study suggests that cyclin C connects stress-induced mitochondrial hyperfission and programmed cell death in mammalian cells.
PMCID: PMC4357504  PMID: 25609094
8.  Pyrrolidine Dithiocarbamate Inhibits Nuclear Factor κB and Toll-Like Receptor 4 Expression in Rats with Acute Necrotizing Pancreatitis 
Gut and Liver  2014;9(3):411-416.
To investigate the expression of Toll-like receptor 4 (TLR4) in the pancreases of rats with acute necrotizing pancreatitis (ANP) and any changes upon treatment with pyrrolidine dithiocarbamate (PDTC), an inhibitor of nuclear factor κB (NF-κB), as well as to determine the relationship between TLR4 and NF-κB in ANP pathogenesis.
A total of 72 SD rats were randomly divided into three groups, namely, the control (sham-operation), ANP, and ANP with PDTC pretreatment groups. The PDTC-pretreated group was intraperitoneally injected with PDTC at a dose of 100 mg/kg 1 hour before the induction of ANP. The expressions of TLR4 and NF-κB in pancreatic tissue were evaluated by immunohistochemistry and Western blot analysis. The mRNA levels of cytokines tumor necrosis factor α, interleukin (IL)-1β, and IL-6 were measured by reverse transcription polymerase chain reaction.
The expressions of TLR4, NF-κB, and cytokine (NF-κB target) genes in the pancreatic tissue increased more significantly in the ANP groups than in the sham-operation group at 3, 6, and 12 hours. Pretreatment with PDTC alleviated the inflammatory activation in the pancreas with ANP, causing a significant decrease in the expressions of TLR4, NF-κB, and cytokine genes in the pancreatic tissue.
The expressions of TLR4 and NF-κB were increased in the pancreases of rats with ANP. PDTC not only inhibits NF-κB but also suppresses the expression of TLR4 and downregulates the expression of the related cytokine genes.
PMCID: PMC4413976  PMID: 25287011
Acute necrotizing pancreatitis; NF-kappa B; Toll-like receptor 4
9.  miR-761 regulates the mitochondrial network by targeting mitochondrial fission factor 
Mitochondria are dynamic organelles that constantly undergo fission and fusion. The balance between fission and fusion determines the fate of the cell. In this study, we show that mitochondrial fission factor (MFF) is upregulated upon hydrogen peroxide treatment or ischemia/reperfusion (I/R) injury. Knockdown of MFF attenuated hydrogen peroxide- and I/R injury-induced cardiomyocyte apoptosis and myocardial infarction. We found that MFF is a direct target of miR-761, and miR-761 inhibits mitochondrial fission and cardiomyocyte apoptosis by repressing MFF. This study reveals a novel model of mitochondrial fission regulation, which is composed of miR-761 and MFF. Modulation of their levels may provide a new approach for tackling apoptosis and myocardial infarction.
PMCID: PMC4397917  PMID: 23867156
MicroRNAs; Mitochondrial fission; Apoptosis; MFF; Hydrogen peroxide; Ischemia/reperfusion; Free radicals
10.  Integrated Population Pharmacokinetic/Viral Dynamic Modeling of Lopinavir/Ritonavir in HIV-1 Treatment Naïve Patients 
Clinical pharmacokinetics  2014;53(4):361-371.
Lopinavir (LPV)/ritonavir (RTV) co-formulation (LPV/RTV) is a widely used protease inhibitor (PI) based regimen to treat HIV-infection. As with all PIs, the trough concentration (Ctrough) is a primary determinant of response, but the optimum exposure remains poorly defined. The primary objective was to develop an integrated LPV population pharmacokinetic model to investigate the influence of α-1-acid glycoprotein (AAG) and link total and free LPV exposure to pharmacodynamic changes in HIV-1 RNA and assess viral dynamic and drug efficacy parameters.
Data from 35 treatment-naïve HIV-infected patients initiating therapy with LPV/RTV 400/100 mg orally twice daily across two studies were used for model development and simulations using ADAPT. Total LPV (LPVt) and RTV concentrations were measured by high-performance liquid chromatography (HPLC) with ultraviolet (UV) detection. Free LPV (LPVf) concentrations were measured using equilibrium dialysis and mass spectrometry.
LPVt typical value of clearance (CLLPVt/F) was 4.73 L/h and distribution volume (VLPVt/F) was 55.7 L. Clearance (CLLPVf/F) and distibution volume (Vf/F) for LPVf were 596 L/h and 6370 L, respectively. Virion clearance rate was 0.0350 h-1. Simulated LPVLPVt Ctrough at 90% (EC90) and 95% (EC95) maximum response were 316 and 726 ng/mL, respectively.
The pharmacokinetic/pharmacodynamic model provides a useful tool to quantitatively describe the relationship between LPV/RTV exposure and viral response. This comprehensive modeling and simulation approach could be used as a surrogate assessment of ARV where adequate early phase dose-ranging studies are lacking in order to define target trough concentrations and possibly refine dosing recommendations.
PMCID: PMC3962720  PMID: 24311282
11.  Anti-Inflammatory Effects of Vitis thunbergii var. taiwaniana on Knee Damage Associated with Arthritis 
Journal of Medicinal Food  2014;17(4):479-486.
Vitis thunbergii Sieb. et Zucc. var. taiwaniana Lu (VT) is an indigenous plant in Taiwan that is traditionally used for promoting joint health. In this study, we used in vitro primary human chondrocytes (PHCs) and two in vivo animal models to evaluate the anti-inflammatory effects of VT on arthritis. Results showed that the water extract of the stems and roots from VT (VT-SR) was rich in flavones and phenols with 1.1 mg/g of resveratrol, 6.7 mg/g of hopeaphenol, and 5.1 mg/g of (+)-ɛ-viniferin. VT-SR significantly scavenged DPPH radicals and inhibited prostaglandin E2 (PGE2) production in lipopolysaccharide (LPS)-induced PHCs without exhibiting significant cytotoxicity. In in vivo models, the VT-SR (500 mg/kg) significantly decreased serum PGE2 and knee 2-18F-fluoro-2-deoxy-D-glucose (18F-FDG) levels in LPS-induced acute inflammatory arthritis in rabbits. In addition, dietary supplementation with VT-SR for 28 days significantly alleviated type II collagenase-induced rat osteoarthritis with improvements in weight bearing and range of motion tests. In conclusion, our results suggest that the VT-SR is a good candidate for developing dietary supplements to prevent joint deterioration and inhibit inflammation.
PMCID: PMC3993025  PMID: 24720858
dietary supplement; 18F-FDG uptake; inflammatory arthritis; type II collagenase; Vitis thunbergiivar.taiwaniana
12.  Expression profiles of miRNAs in Gossypium raimondii *  
miRNAs are a class of conserved, small, endogenous, and non-protein-coding RNA molecules with 20–24 nucleotides (nt) in length that function as post-transcriptional modulators of gene expression in eukaryotic cells. Functional studies have demonstrated that plant miRNAs are involved in the regulation of a wide range of plant developmental processes. To date, however, no research has been carried out to study the expression profiles of miRNAs in Gossypium raimondii, a model cotton species. We selected 16 miRNAs to profile their tissue-specific expression patterns in G. raimondii four different tissues, and these miRNAs are reported to play important roles in plant growth and development. Our results showed that the expression levels of these miRNAs varied significantly from one to another in a tissue-dependent manner. Eight miRNAs, including miR-159, miR-162, miR-164, miR-172, miR-390, miR-395, miR-397, and miR-398, exhibited exclusively high expression levels in flower buds, suggesting that these miRNAs may play significant roles in floral development. The expression level of miR-164 was relatively high in shoots beside flower buds, implying that the function of miR-164 is not only limited to floral development but it may also play an important role in shoot development. Certain miRNAs such as miR-166 and miR-160 were extremely highly expressed in all of the four tissues tested compared with other miRNAs investigated, suggesting that they may play regulatory roles at multiple development stages. This study will contribute to future studies on the functional characterization of miRNAs in cotton.
PMCID: PMC4399430  PMID: 25845363
Cotton; miRNA; Expression profiles; Quantitative real-time PCR (qRT-PCR); Gossypium raimondii
13.  LOTUS-DB: an integrative and interactive database for Nelumbo nucifera study 
Besides its important significance in plant taxonomy and phylogeny, sacred lotus (Nelumbo nucifera Gaertn.) might also hold the key to the secrets of aging, which attracts crescent attentions from researchers all over the world. The genetic or molecular studies on this species depend on its genome information. In 2013, two publications reported the sequencing of its full genome, based on which we constructed a database named as LOTUS-DB. It will provide comprehensive information on the annotation, gene function and expression for the sacred lotus. The information will facilitate users to efficiently query and browse genes, graphically visualize genome and download a variety of complex data information on genome DNA, coding sequence (CDS), transcripts or peptide sequences, promoters and markers. It will accelerate researches on gene cloning, functional identification of sacred lotus, and hence promote the studies on this species and plant genomics as well.
Database URL:
PMCID: PMC4383347  PMID: 25819075
14.  Discrete Imaging Models for Three-Dimensional Optoacoustic Tomography using Radially Symmetric Expansion Functions 
IEEE transactions on medical imaging  2014;33(5):1180-1193.
Optoacoustic tomography (OAT), also known as photoacoustic tomography, is an emerging computed biomedical imaging modality that exploits optical contrast and ultrasonic detection principles. Iterative image reconstruction algorithms that are based on discrete imaging models are actively being developed for OAT due to their ability to improve image quality by incorporating accurate models of the imaging physics, instrument response, and measurement noise. In this work, we investigate the use of discrete imaging models based on Kaiser-Bessel window functions for iterative image reconstruction in OAT. A closed-form expression for the pressure produced by a Kaiser-Bessel function is calculated, which facilitates accurate computation of the system matrix. Computer-simulation and experimental studies are employed to demonstrate the potential advantages of Kaiser-Bessel function-based iterative image reconstruction in OAT.
PMCID: PMC4374808  PMID: 24770921
Optoacoustic tomography; photoacoustic computed tomography; thermoacoustic tomography; iterative image reconstruction
15.  3-(3-Pyridylmethylidene)-2-indolinone Reduces the Severity of Colonic Injury in a Murine Model of Experimental Colitis 
Nrf2 is the key transcription factor regulating the antioxidant response which is crucial for cytoprotection against extracellular stresses. Numerous in vivo studies indicate that Nrf2 plays a protective role in anti-inflammatory response. 3-(3-Pyridylmethylidene)-2-indolinone (PMID) is a synthesized derivative of 2-indolinone compounds. Our previous study suggested that PMID induces the activation of Nrf2/ARE pathway, then protecting against oxidative stress-mediated cell death. However, little is known regarding the anti-inflammatory properties of PMID in severe inflammatory phenotypes. In the present study we determined if PMID treatment protects mice from dextran sodium sulphate- (DSS-) induced colitis. The result suggests that treatment with PMID prior to colitis induction significantly reduced body weight loss, shortened colon length, and decreased disease activity index compared to control mice. Histopathological analysis of the colon revealed attenuated inflammation in PMID pretreated animals. The levels of inflammatory markers in colon tissue and serum were reduced associated with inhibition of NF-κB activation. The expression levels of Nrf2-dependent genes such as HO-1, NQO1, and Nrf2 were increased in PMID pretreated mice. However, PMID pretreatment did not prevent DSS-induced colitis in Nrf2 knockout mice. These data indicate that PMID pretreatment in mice confers protection against DSS-induced colitis in Nrf2-dependent manner, suggesting a potential role of PMID in anti-inflammatory response.
PMCID: PMC4385690  PMID: 25874026
16.  Heme oxygenase-1 protects rat liver against warm ischemia/reperfusion injury via TLR2/TLR4-triggered signaling pathways 
AIM: To investigate the efficacy and molecular mechanisms of induced heme oxygenase (HO)-1 in protecting liver from warm ischemia/reperfusion (I/R) injury.
METHODS: Partial warm ischemia was produced in the left and middle hepatic lobes of SD rats for 75 min, followed by 6 h of reperfusion. Rats were treated with saline, cobalt protoporphyrin (CoPP) or zinc protoporphyrin (ZnPP) at 24 h prior to the ischemia insult. Blood and samples of ischemic lobes subjected to ischemia were collected at 6 h after reperfusion. Serum transaminases level, plasma lactate dehydrogenase and myeloperoxidase activity in liver were measured. Liver histological injury and inflammatory cell infiltration were evaluated by tissue section and liver immunohistochemical analysis. We used quantitative reverse transcription polymerase chain reaction to analyze liver expression of inflammatory cytokines and chemokines. The cell lysates were subjected to immunoprecipitation with anti-Toll-IL-1R-containing adaptor inducing interferon-β (TRIF) and anti-myeloid differentiation factor 88 (MyD88), and then the immunoprecipitates were analyzed by SDS-PAGE and immunoblotted with the indicated antibodies.
RESULTS: HO-1 protected livers from I/R injury, as evidenced by diminished liver enzymes and well-preserved tissue architecture. In comparison with ZnPP livers 6 h after surgery, CoPP treatment livers showed a significant increase inflammatory cell infiltration of lymphocytes, plasma cells, neutrophils and macrophages. The Toll-like receptor (TLR)-4 and TANK binding kinase 1 protein levels of rats treated with CoPP significantly reduced in TRIF-immunoprecipitated complex, as compared with ZnPP treatment. In addition, pretreatment with CoPP reduced the expression levels of TLR2, TLR4, IL-1R-associated kinase (IRAK)-1 and tumor necrosis factor receptor-associated factor 6 in MyD88-immunoprecipitated complex. The inflammatory cytokines and chemokines mRNA expression rapidly decreased in CoPP-pretreated liver, compared with the ZnPP-treated group. However, the expression of negative regulators Toll-interacting protein, suppressor of cytokine signaling-1, IRAK-M and Src homology 2 domain-containing inositol-5-phosphatase-1 in CoPP treatment rats were markedly up-regulated as compared with ZnPP-treated rats.
CONCLUSION: HO-1 protects liver against I/R injury by inhibiting TLR2/TLR4-triggered MyD88- and TRIF-dependent signaling pathways and increasing expression of negative regulators of TLR signaling in rats.
PMCID: PMC4356913  PMID: 25780291
Heme oxygenase-1; Ischemia reperfusion injury; Toll-like receptor; Myeloid differentiation factor 88; Liver
17.  Investigation of the far-field approximation for modeling a transducer’s spatial impulse response in photoacoustic computed tomography 
Photoacoustics  2014;2(1):21-32.
When ultrasonic transducers with large detecting areas and/or compact measurement geometries are employed in photoacoustic computed tomography (PACT), the spatial resolution of reconstructed images can be significantly degraded. Our goal in this work is to clarify the domain of validity of an imaging model that mitigates such effects by use of a far-field approximation. Computer-simulation studies are described that demonstrate the far-field-based imaging model is highly accurate for a practical 3D PACT imaging geometry employed in an existing small animal imaging system. For use in special cases where the far-field approximation is violated, an extension of the far-field-based imaging model is proposed that divides the transducer face into a small number of rectangular patches that are each described accurately by use of the far-field approximation.
PMCID: PMC3932504  PMID: 24579061
Photoacoustic computed tomography; image reconstruction
18.  Coding and noncoding expression patterns associated with rare obesity-related disorders: Prader–Willi and Alström syndromes 
Advances in genomics and genetics  2015;2015(5):53-75.
Obesity is accompanied by hyperphagia in several classical genetic obesity-related syndromes that are rare, including Prader–Willi syndrome (PWS) and Alström syndrome (ALMS). We compared coding and noncoding gene expression in adult males with PWS, ALMS, and nonsyndromic obesity relative to nonobese males using readily available lymphoblastoid cells to identify disease-specific molecular patterns and disturbed mechanisms in obesity. We found 231 genes upregulated in ALMS compared with nonobese males, but no genes were found to be upregulated in obese or PWS males and 124 genes were downregulated in ALMS. The metallothionein gene (MT1X) was significantly downregulated in ALMS, in common with obese males. Only the complex SNRPN locus was disturbed (downregulated) in PWS along with several downregulated small nucleolar RNAs (snoRNAs) in the 15q11-q13 region (SNORD116, SNORD109B, SNORD109A, SNORD107). Eleven upregulated and ten downregulated snoRNAs targeting multiple genes impacting rRNA processing, developmental pathways, and associated diseases were found in ALMS. Fifty-two miRNAs associated with multiple, overlapping gene expression disturbances were upregulated in ALMS, and four were shared with obese males but not PWS males. For example, seven passenger strand microRNAs (miRNAs) (miR-93*, miR-373*, miR-29b-2*, miR-30c-1*, miR27a*, miR27b*, and miR-149*) were disturbed in association with six separate downregulated target genes (CD68, FAM102A, MXI1, MYO1D, TP53INP1, and ZRANB1). Cell cycle (eg, PPP3CA), transcription (eg, POLE2), and development may be impacted by upregulated genes in ALMS, while downregulated genes were found to be involved with metabolic processes (eg, FABP3), immune responses (eg, IL32), and cell signaling (eg, IL1B). The high number of gene and noncoding RNA disturbances in ALMS contrast with observations in PWS and males with nonsyndromic obesity and may reflect the progressing multiorgan pathology of the ALMS disease process.
PMCID: PMC4334166  PMID: 25705109
hyperphagia; microarray analysis; gene; obesity; exon expression; miRNA expression
19.  Musashi-2 promotes hepatitis Bvirus related hepatocellular carcinoma progression via the Wnt/β-catenin pathway 
American Journal of Cancer Research  2015;5(3):1089-1100.
Our recent study observed that the expression of Musashi-2 (MSI2), a member of the Musashi family, was up-regulated in hepatitis B virus (HBV) related hepatocellular carcinoma parenchymal cells. Using quantitative PCR, tissue microarray (TMA) and immunohistochemical staining, we evaluated MSI2 mRNA and protein levels in tumor tissues from patients with different stages of hepatocellular carcinoma with paired adjacent noncancerous sample sets. The following techniques were used to further investigate MSI2 function and its potential molecular mechanism: RNAi, wound healing assay, Transwell assay, quantitative PCR and western blot analysis. Immunohistochemical detection of MSI2 on a TMA containing 106 paired specimens showed that increased cytoplasmic and nuclear MSI2 staining was significantly associated with tumor size, tumor differentiation, recurrence, TNM stage, vessel invasion and Ki-67 proliferative index. Patients with MSI2-positive tumors had a significantly higher disease recurrence rate and poorer survival than patients with MSI2-negative tumors after radical surgery. Based on univariate analysis, MSI2 expression showed an unfavorable influence on both disease-free survival and overall survival. Multivariate analysis revealed that higher MSI2 expression, together with tumor size, tumor differentiation, tumor thrombus, and Ki-67 expression were independent predictors of overall survival. With MSI2 knockdown, hepatoma cell migration and invasion were inhibited and the expression of β-catenin, T cell factor (TCF) and lymphoid enhancer factor (LEF) were dysregulated. Thus, we propose that MSI2 may predict unfavorable outcomes in hepatitis B virus related hepatocellular carcinoma and promote cancer progression via the Wnt/β-catenin signaling pathway.
PMCID: PMC4449437  PMID: 26045988
Musashi-2; hepatocellular carcinoma; progression; tissue microarray; Wnt/β-catenin pathway
20.  Tripling the detection view of high-frequency linear-array-based photoacoustic computed tomography by using two planar acoustic reflectors 
Linear-array-based photoacoustic computed tomography (PACT) suffers from a limited view. Circular scanning does increase the detection view angle but is time-consuming. Therefore, it is desirable to increase the detection view angle of linear-array-based PACT without sacrificing imaging speed.
Two planar acoustic reflectors placed at 120 degrees to each other were added to a linear-array-based PACT system. Each reflector redirects originally undetectable photoacoustic waves back to the transducer array elements, and together they triple the original detection view angle of the PACT system.
Adding two reflectors increased the detection view angle from 80 to 240 degrees. As a comparison, a single-reflector PACT has a detection view angle of only 160 degrees. A leaf skeleton phantom with a rich vascular network was imaged with the double-reflector PACT, and most of its features were recovered.
The two acoustic reflectors triple the detection view angle of a linear-array-based PACT without compromising the original imaging speed. This nearly full-view detection capability produces higher-quality images than single-reflector PACT or conventional PACT without reflectors.
PMCID: PMC4312304  PMID: 25694954
Photoacoustic computed tomography (PACT); linear transducer array; limited view; view angle; acoustic reflector
21.  Complete Genome Sequence of Human Enterovirus Strain 71 (EV71/Taipei/3118/2011), Isolated from a Patient in Taiwan 
Genome Announcements  2015;3(1):e01375-14.
This full-length genome sequence of human enterovirus strain 71 (EV71/Taipei/3118/2011) was isolated from a clinical patient in Taiwan in 2011. According to the phylogenetic analysis, the complete genome sequence in this study is part of the subgenotype C4.
PMCID: PMC4290987  PMID: 25573934
22.  Association between ADIPOQ +45T>G Polymorphism and Type 2 Diabetes: A Systematic Review and Meta-Analysis 
Recently, a number of studies have reported the association between the single nucleotide polymorphisms (SNPs) +45T>G polymorphism in the adiponectin (ADIPOQ) gene and type 2 diabetes mellitus (T2DM) risk, though the results are inconsistent. In order to obtain a more precise estimation of the relationship, a meta-analysis was performed. In this current study, the Medline, Embase, Pubmed, ISI Web of Knowledge, Ovid, Science Citation Index Expanded Database, Wanfang Database, and China National Knowledge Infrastructure were searched for eligible studies. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to estimate the strength of association. Forty-five publications were included in the final meta-analysis with 9986 T2DM patients and 16,222 controls for ADIPOQ +45T>G polymorphism according to our inclusion and exclusion criteria. The +45T>G polymorphism was associated with an overall significantly increased risk of T2DM (G vs. T: OR = 1.18, 95% CI = 1.06–1.32; The dominant model: OR = 1.18, 95% CI = 1.03–1.33; The recessive model: OR = 1.47, 95% CI = 1.20–1.78; The homozygous model: OR = 1.62, 95% CI = 1.25–2.09; Except the heterozygous model: OR = 1.11, 95% CI = 0.98–1.24). Subgroup analysis revealed a significant association between the +45T>G polymorphism and T2D in an Asian population. Thus, this meta-analysis indicates that the G allele of the ADIPOQ +45T>G polymorphisms associated with a significantly increased risk of T2DM in the Asian population.
PMCID: PMC4307270  PMID: 25561226
ADIPOQ; single nucleotide polymorphisms (SNPs); type 2 diabetes mellitus; meta-analysis
23.  Time-Frequency Feature Representation Using Multi-Resolution Texture Analysis and Acoustic Activity Detector for Real-Life Speech Emotion Recognition 
Sensors (Basel, Switzerland)  2015;15(1):1458-1478.
The classification of emotional speech is mostly considered in speech-related research on human-computer interaction (HCI). In this paper, the purpose is to present a novel feature extraction based on multi-resolutions texture image information (MRTII). The MRTII feature set is derived from multi-resolution texture analysis for characterization and classification of different emotions in a speech signal. The motivation is that we have to consider emotions have different intensity values in different frequency bands. In terms of human visual perceptual, the texture property on multi-resolution of emotional speech spectrogram should be a good feature set for emotion classification in speech. Furthermore, the multi-resolution analysis on texture can give a clearer discrimination between each emotion than uniform-resolution analysis on texture. In order to provide high accuracy of emotional discrimination especially in real-life, an acoustic activity detection (AAD) algorithm must be applied into the MRTII-based feature extraction. Considering the presence of many blended emotions in real life, in this paper make use of two corpora of naturally-occurring dialogs recorded in real-life call centers. Compared with the traditional Mel-scale Frequency Cepstral Coefficients (MFCC) and the state-of-the-art features, the MRTII features also can improve the correct classification rates of proposed systems among different language databases. Experimental results show that the proposed MRTII-based feature information inspired by human visual perception of the spectrogram image can provide significant classification for real-life emotional recognition in speech.
PMCID: PMC4327087  PMID: 25594590
multi-resolution; discrete wavelet transform; time-frequency texture; acoustic activity detection; spectrogram; Laws masks
24.  A new modified Tsuge suture for flexor tendon repairs: the biomechanical analysis and clinical application 
This study is to develop a new suturing technique for flexor tendon repair by modifying the extant Tsuge repair techniques and to use biomechanical analysis to compare the new method with four established repair techniques and evaluate its clinical efficacy in the repair of 47 flexor tendons in 22 patients.
The biomechanical analysis relied on 50 flexor digitorum profundus tendons harvested from fresh cadavers. The tendons were randomly divided into five groups, transected, and repaired by use of a 1. double-loop suture, 2. double modified locking Kessler, 3. four-strand Savage, 4. modified six-strand Savage, and 5. the new technique. The tensile force and breaking force of all repaired tendons were measured by static loading trials. For clinical application, 22 patients with acute flexor tendon injuries were treated with the new modified Tsuge suture and follow-up for more than 12 months.
While differences in the tensile force and breaking force in the modified Tsuge sutures and modified six-strand Savage sutures were not statistically significant, static loading trials showed the tensile force, in the form of a 2-mm gap formation, and the breaking force of the new modified Tsuge sutures were, statistically, both higher than the ones characteristic of double-loop sutures, double modified locking Kessler, and four-strand Savage sutures. After 12 months, restored functions were observed in all the patients during the postoperative 12 months. Total active motion (TAM) score demonstrated that more than 90% fingers were estimated as excellent or good.
The new modified Tsuge sutures described here have evident higher tensile and breaking forces compared to other four-strand core suture techniques, suggesting, in turn, that this new technique is a good alternative for flexor tendon repairs in clinical applications.
PMCID: PMC4305253  PMID: 25551285
Flexor tendon; Repair; Modified Tsuge; Biomechanics; Clinical practice
25.  Effectiveness of tranexamic acid in reducing blood loss in spinal surgery: a meta-analysis 
The aim of present meta-analysis was to evaluate the effectiveness of tranexamic acid (TXA) use in reducing blood loss and the related thrombotic complications in spinal surgery.
Three databases (MEDLINE, EMBASE, and the Cochrane Library) were searched through October 2012 to identify the relevant randomized controlled trials (RCTs) regarding the TXA effective in spinal surgery. Mean differences (MDs) of blood loss, blood transfusions, and postoperative partial thromboplastic time (PTT), odds ratios (ORs) of blood transfusion and thrombotic complication in TXA-treated group compared to placebo group were extracted and combined using random-effect meta-analysis.
A total of 6 RCTs comprising 411 patients were included in the meta-analysis according to the pre-defined selection criteria. TXA-treated group had significantly less amount of blood loss and blood transfusions per patient, and had smaller proportion of patients who required a blood transfusion compared with the placebo group. The use of TXA can significantly reduce the postoperative PTT with weighted MD of -1.59 [(95% confidence interval (CI):-3.07, -0.10] There is a null association between thrombosis complications and the use of TXA.
We conclude that the use of TXA in patients undergoing spinal surgery appears to be effective in reducing the amount of blood loss, the volume of blood transfusion, the transfusion rate, and the postoperative PTT. However, data were too limited for any conclusions regarding safety. More high-quality RCTs are required before recommending the administered of TXA in spinal surgery.
PMCID: PMC4326491  PMID: 25532706
Tranexamic acid; Spine; Surgery; Meta-analysis

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