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1.  Long-term effects of oral tea polyphenols and Lactobacillus brevis M8 on biochemical parameters, digestive enzymes, and cytokines expression in broilers 
This study investigates the long-term effects of oral tea polyphenols (TPs) and Lactobacillus brevis M8 (LB) on biochemical parameters, digestive enzymes, and cytokines expression in broilers. In experiment 1, 240 broiler chickens were selected to investigate the effects of 0.06 g/kg body weight (BW) TP and 1.0 ml/kg BW LB on broilers; in experiment 2, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of TP (0.03, 0.06, and 0.09 g/kg BW) combined with 1.0 ml/kg BW LB on broilers; in experiment 3, 180 broiler chickens were assigned randomly to three groups to investigate the effects of different dosages of LB (0.5, 1.0, and 1.5 ml/kg BW) combined with 0.06 g/kg BW TP on broilers. The results showed that TP and LB affected serum biochemical parameters, and TP reduced serum cholesterol (CHO) and low-density lipoprotein cholesterol (LDL-C) abundances in a dosage-dependent manner (P<0.05) on Day 84. Meanwhile, broilers fed a diet supplemented with TP or LB had a lower intestinal lipase activity on Day 84 compared with the control group (P<0.05). Middle and high dosages of TP increased pancreatic lipase and proventriculus pepsin activities (P<0.05). Also middle and high dosages of LB significantly enhanced pancreatic lipase activity (P<0.05), while high LB supplementation inhibited intestinal trypsase (P<0.05) on Day 84. Furthermore, both TP and LB reduced intestinal cytokine expression and nuclear factor-κ B (NF-κB) mRNA level on Days 56 and 84. In conclusion, long-term treatment of TP and LB improved lipid metabolism and digestive enzymes activities, and affected intestinal inflammatory status, which may be associated with the NF-κB signal.
doi:10.1631/jzus.B1500160
PMCID: PMC4678044  PMID: 26642185
Tea polyphenols; Lactobacillus brevis; Cytokines; Broilers
2.  Luoyutong Treatment Promotes Functional Recovery and Neuronal Plasticity after Cerebral Ischemia-Reperfusion Injury in Rats 
Luoyutong (LYT) capsule has been used to treat cerebrovascular diseases clinically in China and is now patented and approved by the State Food and Drug Administration. In this retrospective validation study we investigated the ability of LYT to protect against cerebral ischemia-reperfusion injury in rats. Cerebral ischemia-reperfusion injury was induced by middle cerebral artery occlusion followed by reperfusion. Capsule containing LYT (high dose and medium dose) as treatment group and Citicoline Sodium as positive control treatment group were administered daily to rats 30 min after reperfusion. Treatment was continued for either 3 days or 14 days. A saline solution was administered to control animals. Behavior tests were performed after 3 and 14 days of treatment. Our findings revealed that LYT treatment improved the neurological outcome, decreased cerebral infarction volume, and reduced apoptosis. Additionally, LYT improved neural plasticity, as the expression of synaptophysin, microtubule associated protein, and myelin basic protein was upregulated by LYT treatment, while neurofilament 200 expression was reduced. Moreover, levels of brain derived neurotrophic factor and basic fibroblast growth factor were increased. Our results suggest that LYT treatment may protect against ischemic injury and improve neural plasticity.
doi:10.1155/2015/369021
PMCID: PMC4678236  PMID: 26697095
3.  Haplotypes and Sequence Variation in the Ovine Adiponectin Gene (ADIPOQ) 
Genes  2015;6(4):1230-1241.
The adiponectin gene (ADIPOQ) plays an important role in energy homeostasis. In this study five separate regions (regions 1 to 5) of ovine ADIPOQ were analysed using PCR-SSCP. Four different PCR-SSCP patterns (A1-D1, A2-D2) were detected in region-1 and region-2, respectively, with seven and six SNPs being revealed. In region-3, three different patterns (A3-C3) and three SNPs were observed. Two patterns (A4-B4, A5-B5) and two and one SNPs were observed in region-4 and region-5, respectively. In total, nineteen SNPs were detected, with five of them in the coding region and two (c.46T/C and c.515G/A) putatively resulting in amino acid changes (p.Tyr16His and p.Lys172Arg). In region-1, -2 and -3 of 316 sheep from eight New Zealand breeds, variants A1, A2 and A3 were the most common, although variant frequencies differed in the eight breeds. Across region-1 and region-3, nine haplotypes were identified and haplotypes A1-A3, A1-C3, B1-A3 and B1-C3 were most common. These results indicate that the ADIPOQ gene is polymorphic and suggest that further analysis is required to see if the variation in the gene is associated with animal production traits.
doi:10.3390/genes6041230
PMCID: PMC4690037  PMID: 26610572
adiponectin; ADIPOQ; variation; haplotype; PCR-SSCP; sheep
4.  Haemophilia A Carriers Demonstrate Pathological and Radiological Evidence of Structural Joint Changes 
doi:10.1111/hae.12535
PMCID: PMC4214880  PMID: 25251752
Haemophilia carrier; Hemarthrosis; International Prophylaxis Study Group (IPSG) MRI score; Joint bleed; factor VIII deficiency
5.  F4+ ETEC infection and oral immunization with F4 fimbriae elicits an IL-17-dominated immune response 
Veterinary Research  2015;46:121.
Enterotoxigenic Escherichia coli (ETEC) are an important cause of post-weaning diarrhea (PWD) in piglets. Porcine-specific ETEC strains possess different fimbrial subtypes of which F4 fimbriae are the most frequently associated with ETEC-induced diarrhea in piglets. These F4 fimbriae are potent oral immunogens that induce protective F4-specific IgA antibody secreting cells at intestinal tissues. Recently, T-helper 17 (Th17) cells have been implicated in the protection of the host against extracellular pathogens. However, it remains unknown if Th17 effector responses are needed to clear ETEC infections. In the present study, we aimed to elucidate if ETEC elicits a Th17 response in piglets and if F4 fimbriae trigger a similar response. F4+ ETEC infection upregulated IL-17A, IL-17F, IL-21 and IL-23p19, but not IL-12 and IFN-γ mRNA expression in the systemic and mucosal immune system. Similarly, oral immunization with F4 fimbriae triggered a Th17 signature evidenced by an upregulated mRNA expression of IL-17F, RORγt, IL-23p19 and IL-21 in the peripheral blood mononuclear cells (PBMCs). Intriguingly, IL-17A mRNA levels were unaltered. To further evaluate this difference between systemic and mucosal immune responses, we assayed the cytokine mRNA profile of F4 fimbriae stimulated PBMCs. F4 fimbriae induced IL-17A, IL-17F, IL-22 and IL-23p19, but downregulated IL-17B mRNA expression. Altogether, these data indicate a Th17 dominated response upon oral immunization with F4 fimbriae and F4+ ETEC infection. Our work also highlights that IL-17B and IL-17F participate in the immune response to protect the host against F4+ ETEC infection and could aid in the design of future ETEC vaccines.
Electronic supplementary material
The online version of this article (doi:10.1186/s13567-015-0264-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s13567-015-0264-2
PMCID: PMC4618862  PMID: 26490738
6.  Increasing incidence of recent hepatitis C virus infection among persons seeking voluntary counselling and testing for HIV and sexually transmitted infections in Taiwan 
BMJ Open  2015;5(10):e008406.
Objectives
The incidence of hepatitis C virus (HCV) infection among HIV-negative men who have sex with men (MSM) is rarely investigated in the Asia-Pacific region. We aimed to estimate the incidence rate of and factors associated with recent HCV infection among the clients seeking voluntary counselling and testing (VCT) services for HIV in Taiwan.
Methods
During 2006–2013, 12 143 clients sought VCT services for HIV. Clients with subsequent follow-up tests at an interval of 6 months or longer were included to estimate the incidence rate of HCV seroconversion. Phylogenetic analysis of HCV sequences from VCT clients and HIV-positive patients was performed.
Results
The overall HCV seroprevalence at baseline was 0.3%. Of 2150 clients testing negative for anti-HCV antibody at baseline with a total of 5074.99 person-years of follow-up (PYFU), 17 (0.8%) developed HCV seroconversion, leading to an overall incidence rate of 3.35 per 1000 PYFU (95% CI 1.76 to 4.94), which increased from 2.28 (95% CI 0.05 to 4.51) in 2006–2009, to 3.33 (95% CI 0.86 to 5.80) in 2010 to 2011 and 4.94 per 1000 PYFU (95% CI 0.99 to 8.99) in 2012–2013; the incidence of early syphilis increased from 11.91 to 13.28 and 31.78 per 1000 PYFU in the three corresponding periods. In multivariate analysis, having HIV-positive partners (adjusted HR (AHR) =3.756; 95%CI 1.180 to 11.955) and developing a rapid plasma reagin titre of 4 or greater (AHR=9.978; 95% CI 1.550 to 64.233) were significantly associated with HCV seroconversion.
Conclusions
An increasing trend of recent HCV infection occurs among individuals seeking VCT services in Taiwan. Having HIV-positive partners and having syphilis are independently associated with recent HCV seroconversion.
doi:10.1136/bmjopen-2015-008406
PMCID: PMC4606383  PMID: 26463221
VIROLOGY
7.  Protective Effect of Tetrandrine on Sodium Taurocholate-Induced Severe Acute Pancreatitis 
Tet is a type of alkaloid extracted from Stephania tetrandra, and it has recently been demonstrated that Tet can protect against inflammation and free radical injury and inhibit the release of inflammatory mediators. The present study was designed to observe the protective effect of Tet on sodium taurocholate-induced severe acute pancreatitis (SAP). The rat model of SAP was induced by retrograde bile duct injection of sodium taurocholate and then treated with Verapamil and Tet. The results showed that Tet can reduce NF-κB activation in pancreas issue, inhibit the SAP cascade, and improve SAP through inducing pancreas acinar cell apoptosis and stabilizing intracellular calcium in the pancreas, thus mitigating the damage to the pancreas. Our study revealed that Tet may reduce systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndromes (MODS) to protect against damage, and these roles may be mediated through the NF-κB pathway to improve the proinflammatory/anti-inflammatory imbalance.
doi:10.1155/2015/129103
PMCID: PMC4618122  PMID: 26557854
8.  The Role of Subcellular Localization in Initiation of Apoptosis by Photodynamic Therapy 
Photochemistry and photobiology  1997;65(3):422-426.
Rapid initiation of apoptosis can be induced by photodynamic therapy, depending on the cell line and sensitizer employed. In this study, we evaluated the photodynamic responses to two structurally related photosensitizing agents, using the P388 murine leukemia cell line in culture. Photodamage mediated by tin etiopurpurin involved lysosomes and mitochondria and yielded a rapid apoptotic response; apoptotic nuclei were observed within 60 min after PDT. A drug analog, tin octaethylpurpurin amidine, targeted lysosomes, mitochondria and cell membranes; apoptotic nuclei were not observed until 24 h after PDT. These results, together with other recent reports, are consistent with the hypothesis that membrane photodamage can delay or prevent an apoptotic response to PDT.
PMCID: PMC4569128  PMID: 9077123
9.  Enhanced Apoptotic Response to Photodynamic Therapy after bcl-2 Transfection1 
Cancer research  1999;59(14):3429-3432.
Apoptosis is a cellular death process involving the sequential activation of a series of caspases, endonucleases, and other enzymes. The initiation of apoptosis can be inhibited by overexpression of bcl-2 and certain other members of a related family of proteins. We examined the effects of bcl-2 overexpression on the apoptotic response to photodynamic therapy (PDT), using aluminum phthalocyanine as the photosensitizing agent. In this study, we compared the immortalized human breast epithelial cell line MCF10A with a subline (MCF10A/bcl-2) transfected with the human bcl-2 gene. The latter was ~2-fold more sensitive to the phototoxic effects of PDT. At a 50 mJ/cm2 light dose, photodamage to MCF-10A/bcl-2 resulted in a greater loss of the mitochondrial membrane potential (ΔΨm), enhanced release of mitochondrial cytochrome c, a more rapid and greater activation of caspase-3, and a greater apoptotic response. Western blot analysis revealed that the transfected cell line showed overexpression of both bcl-2 and bax, and that PDT caused selective destruction of bcl-2, leaving bax unaffected. The greater apoptotic response by the transfected line is, therefore, attributed to the higher bax:bcl-2 ratio after photodamage.
PMCID: PMC4564253  PMID: 10416606
10.  Mitochondria: A Therapeutic Target for Parkinson’s Disease? 
Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The exact causes of neuronal damage are unknown, but mounting evidence indicates that mitochondrial-mediated pathways contribute to the underlying mechanisms of dopaminergic neuronal cell death both in PD patients and in PD animal models. Mitochondria are organized in a highly dynamic tubular network that is continuously reshaped by opposing processes of fusion and fission. Defects in either fusion or fission, leading to mitochondrial fragmentation, limit mitochondrial motility, decrease energy production and increase oxidative stress, thereby promoting cell dysfunction and death. Thus, the regulation of mitochondrial dynamics processes, such as fusion, fission and mitophagy, represents important mechanisms controlling neuronal cell fate. In this review, we summarize some of the recent evidence supporting that impairment of mitochondrial dynamics, mitophagy and mitochondrial import occurs in cellular and animal PD models and disruption of these processes is a contributing mechanism to cell death in dopaminergic neurons. We also summarize mitochondria-targeting therapeutics in models of PD, proposing that modulation of mitochondrial impairment might be beneficial for drug development toward treatment of PD.
doi:10.3390/ijms160920704
PMCID: PMC4613227  PMID: 26340618
Parkinson’s disease; mitochondrial dysfunction; mitochondrial dynamics
11.  Narcissism predicts impulsive buying: phenotypic and genetic evidence 
Impulsive buying makes billions of dollars for retail businesses every year, particularly in an era of thriving e-commerce. Narcissism, characterized by impulsivity and materialism, may serve as a potential antecedent to impulsive buying. To test this hypothesis, two studies examined the relationship between narcissism and impulsive buying. In Study 1, we surveyed an online sample and found that while adaptive narcissism was not correlated with impulsive buying, maladaptive narcissism was significantly predictive of the impulsive buying tendency. By investigating 304 twin pairs, Study 2 showed that global narcissism and its two components, adaptive and maladaptive narcissism, as well as the impulsive buying tendency were heritable. The study found, moreover, that the connections between global narcissism and impulsive buying, and between maladaptive narcissism and impulsive buying were genetically based. These findings not only establish a link between narcissism and impulsive buying but also help to identify the origins of the link. The present studies deepen our understanding of narcissism, impulsive buying, and their interrelationship.
doi:10.3389/fpsyg.2015.00881
PMCID: PMC4493767  PMID: 26217251
impulsive buying; narcissism; maladaptive narcissism; adaptive narcissism; behavior genetics; twin study
12.  Responses in gut microbiota and fat metabolism to a halogenated methane analogue in Sprague Dawley rats 
Microbial Biotechnology  2015;8(3):519-526.
Recent studies on germ-free mice show that intestinal methanogens may be closely associated with host's adipose metabolism. The present study aimed to investigate effects of inhibition of intestinal methanogen populations on host fat metabolism by establishing a healthy Sprague Dawley (SD) rat model through the intragastric administration of bromochlordomethane (BCM). Forty-five 8-week old healthy male SD rats were randomly divided into five groups including one control and four BCM treatments. The experiment lasted 60 days with two separate 30-day experimental periods. At the end of first period, three BCM treatment groups were further used: one group continued with BCM treatment, one group stopped with BCM treatment, and the other one inoculated with faecal mixture of methanogens from rats. Results showed that the methanogen population in feces was reduced sixfold with no effect on the bacterial community by daily dosing with BCM. Daily gain, epididymal fat pad weight, levels of plasma low-density lipoprotein and cholesterol were significantly higher in the BCM-treated animals, while the high-density lipoprotein was lower than that of the control. The expression of PPARγ, LPL, PP2A, SREBP-1c, ChREBP, FASN and adiponectin genes in BCM treatment group was universally upregulated, while the expression of Fiaf gene was downregulated. After termination of BCM treatment and followed either with or without re-inocubation with faecal methanogen mixture, the rats had their faecal methanogen populations, blood parameters and gene expression returned to the original level. Results suggest that regulation of gut methanogens might be a possible approach to control host body weight.
doi:10.1111/1751-7915.12256
PMCID: PMC4408184  PMID: 25752448
13.  The Shh Signaling Pathway Is Upregulated in Multiple Cell Types in Cortical Ischemia and Influences the Outcome of Stroke in an Animal Model 
PLoS ONE  2015;10(4):e0124657.
Recently the sonic hedgehog (shh) signaling pathway has been shown to play an important role in regulating repair and regenerative responses after brain injury, including ischemia. However, the precise cellular components that express and upregulate the shh gene and the cellular components that respond to shh signaling remain to be identified. In this study, using a distal MCA occlusion model, our data show that the shh signal is upregulated both at the cortical area near the injury site and in the adjacent striatum. Multiple cell types upregulate shh signaling in ischemic brain, including neurons, reactive astrocytes and nestin-expressing cells. The shh signaling pathway genes are also expressed in the neural stem cells (NSCs) niche in the subventricular zone (SVZ). Conditional deletion of the shh gene in nestin-expressing cells both at the SVZ niche and at the ischemic site lead to significantly more severe behavioral deficits in these shh iKO mice after cortical stroke, measured using an automated open field locomotion apparatus (Student’s t-test, p<0.05). In contrast, animals given post-stroke treatment with the shh signaling agonist (SAG) demonstrated less deficits in behavioral function, compared to vehicle-treated mice. At 7 days after stroke, SAG-treated mice showed higher values in multiple horizontal movement parameters compared to vehicle treated mice (Student’s t-test, p<0.05) whereas there were no differences in pre-stroke measurements, (Student’s t-test, p>0.05). In summary, our data demonstrate that shh signaling plays critical and ongoing roles in response to ischemic injury and modulation of shh signaling in vivo alters the functional outcome after cortical ischemic injury.
doi:10.1371/journal.pone.0124657
PMCID: PMC4415811  PMID: 25927436
14.  High-order localized spoof surface plasmon resonances and experimental verifications 
Scientific Reports  2015;5:9590.
We theoretically demonstrated and experimentally verified high-order radial spoof localized surface plasmon resonances supported by textured metal particles. Through an effective medium theory and exact numerical simulations, we show the emergence of these geometrically-originated electromagnetic modes at microwave frequencies. The occurrence of high-order radial spoof plasmon resonances is experimentally verified in ultrathin disks. Their spectral and near-field properties are characterized experimentally, showing an excellent agreement with theoretical predictions. Our findings shed light into the nature of spoof localized surface plasmons, and open the way to the design of broadband plasmonic devices able to operate at very different frequency regimes.
doi:10.1038/srep09590
PMCID: PMC4397533  PMID: 25873523
15.  Addition to inhaled corticosteroids of leukotriene receptor antagonists versus theophylline for symptomatic asthma: a meta-analysis 
Journal of Thoracic Disease  2015;7(4):644-652.
Background
Inhaled corticosteroids (ICSs) are widely used in combination with second controller medications in the management of asthma in adults and children. There lacks a systematic comparison between addition of leukotriene receptor antagonists (LTRAs) and theophylline to ICS. The purpose of this meta-analysis was to evaluate the difference of the efficacy and safety profile of adding either LTRAs or theophylline to ICS in adults and children with symptomatic asthma.
Methods
Randomised controlled trials (RCTs) published prior to November 2014 were acquired through systematically searching and selected based on the established inclusion criteria for publications. The data extracted from the included studies were further analyzed by a meta-analysis.
Results
We included eight RCTs, of which six recruited adults and two recruited children aged 5 to 14 years. The primary outcomes were changes in lung function from baseline, including forced expiratory volume in the first second (FEV1) and peak expiratory flow (PEF). Overall, addition of LTRAs led to significantly better morning PEF {mean difference (MD) 16.94 [95% confidence interval (CI): 11.49-22.39] L/min, P<0.01} and FEV1 [MD 0.09 (95% CI: 0.03-0.15) L, P=0.005] as compared to addition of theophylline. There were no differences between the two treatments in terms of evening PEF, adverse events, rescue medication use and asthma exacerbation.
Conclusions
The combination of LTRA and ICS leads to modestly greater improvement in lung function than the combination of theophylline and ICS in the treatment of symptomatic asthma. Long-term trials are required to assess the efficacy and safety of these two therapies.
doi:10.3978/j.issn.2072-1439.2015.04.12
PMCID: PMC4419319  PMID: 25973230
Inhaled corticosteroids (ICSs); leukotriene receptor antagonists (LTRAs); theophylline; meta-analysis
16.  Structure of a filament of stacked octamers of human DMC1 recombinase 
Acta Crystallographica Section F  2013;69(Pt 4):382-386.
Octameric rings of DMC1 stacked into filaments in the crystal. Similar DMC1–DNA filaments have been observed previously using electron microscopy.
Eukaryal DMC1 proteins play a central role in homologous recombination in meiosis by assembling at the sites of programmed DNA double-strand breaks and carrying out a search for allelic DNA sequences located on homologous chromatids. They are close homologs of eukaryal Rad51 and archaeal RadA proteins and are remote homologs of bacterial RecA proteins. These recombinases (also called DNA strand-exchange proteins) promote a pivotal strand-exchange reaction between homologous single-stranded and double-stranded DNA substrates. An octameric form of a truncated human DMC1 devoid of its small N-terminal domain (residues 1–83) has been crystallized. The structure of the truncated DMC1 octamer is similar to that of the previously reported full-length DMC1 octamer, which has disordered N-terminal domains. In each protomer, only the ATP cap regions (Asp317–Glu323) show a noticeable conformational difference. The truncated DMC1 octamers further stack with alternate polarity into a filament. Similar filamentous assemblies of DMC1 have been observed to form on DNA by electron microscopy.
doi:10.1107/S1744309113005678
PMCID: PMC3614161  PMID: 23545642
DMC1 proteins; DNA strand-exchange proteins; recombinases
17.  Effects of dexamethasone on aquaporin-4 expression in brain tissue of rat with bacterial meningitis 
Aquaporin-4 (AQP4) is the most popular water channel protein expressed in brain tissue and plays a very important role in regulating the water balance in and outside of brain parenchyma. To investigate the expression of aquaporin-4 in the rat brain tissue after dexamethasone therapy of meningitis induced by Streptococcus pneumonia, total 40 of 3-week old Sprague-Dawley rats were divided into infection group (n=30) and normal control group (n=10). The meningitis groups were infected with 1×107 cfu/ml of Streptococcus pneumoniae and then randomized into no treatment (untreated group, n=10), treatment with ceftriaxone (CTRX group, n=10) and treatment with dexamethasone combined ceftriaxone (CTRX + DEXA group, n=10). The normal control group was established by using saline. The rats were euthanized when they reached terminal illness or five days after infection, followed by detection of AQP4 through using immunohistochemistry and Western blot methods. Data has showed that expression of AQP4 in model group remained higher than the control and treatment group (P<0.05). AQP4 expression in CTRX + DEXA group was lower than that in CTRX group (P<0.05). There was no statistical difference between CTRX + DEXA group and the control group (P>0.05). These data suggested that Dexamethasone could down-regulate the expression of AQP4 in the brain tissue of rats with meningitis and provides evidence for the mechanism of protective effect of Dexamethasone on central neurosystem.
PMCID: PMC4440131  PMID: 26045822
Dexamethasone; bacterial meningitis; aquaporin-4
18.  Epigenetic modulation of insulin-like growth factor-II overexpression by hepatitis B virus X protein in hepatocellular carcinoma 
Hepatitis B virus X protein (HBx) is involved in the pathogenesis of hepatocellular carcinoma (HCC). Overexpression of the transcripts from the P3 and P4 promoters of the insulin-like growth factor-II (IGF-II) gene is observed in HCC. The present study investigated the involvement of HBx in IGF-II overexpression and its epigenetic regulation. Firstly, the effects of HBx on P3 and P4 mRNA expression, the methylation status of the P3 and P4 promoters, and MBD2 expression were analyzed in human HCC cells and HCC samples. Next, interaction between HBx and MBD2 or CBP/p300 was assessed by co-immunoprecipitation, and HBx-mediated binding of MBD2 and CBP/p300 to the P3 and P4 promoters and the acetylation of the corresponding histones H3 and H4 were evaluated by quantitative chromatin immunoprecipitation. Finally, using siRNA knockdown, we investigated the roles of MBD2 and CBP/p300 in IGF-II overexpression and its epigenetic regulation. Our results showed that HBx promotes IGF-II expression via inducing the hypomethylation of the P3 and P4 promoters, and that HBx increases MBD2 expression, directly interacts with MBD2 and CBP/p300, and elevates their recruitment to the hypomethylated P3 and P4 promoters with increased acetylation levels of the corresponding histones H3 and H4. Further results showed that endogenous MBD2 and CBP/p300 are necessary for HBx-induced IGF-II overexpression and that CBP/p300 presence and CBP/p300-mediated acetylation of histones H3 and H4 are partially required for MBD2 binding and its demethylase activity. These data suggest that HBx induces MBD2-HBx-CBP/p300 complex formation via interaction with MBD2 and CBP/p300, which contributes to the hypomethylation and transcriptional activation of the IGF-II-P3 and P4 promoters and that CBP/p300-mediated acetylation of histones H3 and H4 may be a rate-limiting step for the hypomethylation and activation of these two promoters. This study provides an alternative mechanism for understanding the pathogenesis of HBx-mediated HCC.
PMCID: PMC4449429  PMID: 26045980
Hepatitis B virus X protein; hepatocellular carcinoma; insulin-like growth factor II; hypomethylation; MBD2-HBx-CBP/p300 complex
19.  Crystal Structures of PI3Kα Complexed with PI103 and Its Derivatives: New Directions for Inhibitors Design 
ACS Medicinal Chemistry Letters  2013;5(2):138-142.
The phosphatidylinositol 3-kinase (PI3K) signaling pathway plays important roles in cell proliferation, growth, and survival. Hyperactivated PI3K is frequently found in a wide variety of human cancers, validating it as a promising target for cancer therapy. We determined the crystal structure of the human PI3Kα–PI103 complex to unravel molecular interactions. Based on the structure, substitution at the R1 position of the phenol portion of PI103 was demonstrated to improve binding affinity via forming a new H-bond with Lys802 at the bottom of the ATP catalytic site. Interestingly, the crystal structure of the PI3Kα–9d complex revealed that the flexibility of Lys802 can also induce additional space at the catalytic site for further modification. Thus, these crystal structures provide a molecular basis for the strong and specific interactions and demonstrate the important role of Lys802 in the design of novel PI3Kα inhibitors.
doi:10.1021/ml400378e
PMCID: PMC4027628  PMID: 24900786
PI3K; PI103; crystal structure; drug design; cancer therapy
20.  A tracer liquid image velocimetry for multi-layer radial flow in bioreactors 
Background
This paper presents a Tracer Liquid Image Velocimetry (TLIV) for multi-layer radial flow in bioreactors used for cells cultivation of tissue engineering. The goal of this approach is to use simple devices to get good measuring precision, specialized for the case in which the uniform level of fluid shear stress was required while fluid velocity varied smoothly.
Methods
Compared to the widely used Particles Image Velocimetry (PIV), this method adopted a bit of liquid as tracer, without the need of laser source. Sub-pixel positioning algorithm was used to overcome the adverse effects of the tracer liquid deformation. In addition, a neighborhood smoothing algorithm was used to restrict the measurement perturbation caused by diffusion. Experiments were carried out in a parallel plates flow chamber. And mathematical models of the flow chamber and Computational Fluid Dynamics (CFD) simulation were separately employed to validate the measurement precision of TLIV.
Results
The mean relative error between the simulated and measured data can be less than 2%, while in similar validations using PIV, the error was around 8.8%.
Conclusions
TLIV avoided the contradiction between the particles’ visibility and following performance with tested fluid, which is difficult to overcome in PIV. And TLIV is easier to popularize for its simple experimental condition and low cost.
doi:10.1186/s12938-015-0002-z
PMCID: PMC4339657  PMID: 25888748
Bioreactor; Fluid shear stress; Image velocimetry; Computational Fluid Dynamics; Parallel plates flow chamber
21.  Immune Function Abnormalities in Peripheral Blood Mononuclear Cell Cytokine Expression Differentiates Stages of Cutaneous T-Cell Lymphoma/Mycosis Fungoides 
Purpose
Mycosis fungoides (MF) is a cutaneous T-cell lymphoma (CTCL) characterized by neoplastic skin-homing T cells. To better understand the immunopathogenesis of MF, we analyzed the functional ability of peripheral blood mononuclear cells (PBMC) from early and late MF/CTCL patients to express cytokine genes. In late stage MF/CTCL, patients were separated into those with blood involvement (+B) and without blood involvement (−B).
Experimental Design
We analyzed TH1 (interleukin 2 (IL-2), IFN-γ), TH2 (IL-4, IL-5, IL-10, IL-13), and TH17 (IL-17) cytokine gene expression from activated PBMCs from normal (n = 12), psoriasis (n = 6), early MF/CTCL (n = 11), and late MF/CTCL+B (n = 4) and MF/CTCL-B (n = 3) by quantitative real-time PCR.
Results
PBMCs from early MF/CTCL and psoriasis showed higher induction of IL-2, IL-4, and IFN-γ genes than those from normal and late MF/CTCL-B and MF/CTCL+B (P < 0.05) in descending order. PBMCs from late MF/CTCL-B exhibited generally the highest level of IL-5, IL-10, IL-13, and IL-17 expression compared with the other groups. PBMCs from early MF/CTCL and late MF/CTCL−B had similarly elevated IL-13 and IL-17. Of all groups, PBMCs from late MF/CTCL+B had the lowest levels of IL-2 (P < 0.05), IL-4, IFN-γ, IL-13, and IL-17.
Conclusions
The different pattern of cytokine gene expression suggests a change in immune function in MF/CTCL from early MF/CTCL to late MF/CTCL−B to late MF/CTCL+B. These stages are consistent with localized disease associated with an anti-tumor immune response and late MF/CTCL associated with a loss of immune function mediated by malignant T cells that share regulatory T cell – like properties.
doi:10.1158/1078-0432.CCR-07-0610
PMCID: PMC4309376  PMID: 18245523
22.  Suppression of Mic60 compromises mitochondrial transcription and oxidative phosphorylation 
Scientific Reports  2015;5:7990.
Precise regulation of mtDNA transcription and oxidative phosphorylation (OXPHOS) is crucial for human health. As a component of mitochondrial contact site and cristae organizing system (MICOS), Mic60 plays a central role in mitochondrial morphology. However, it remains unclear whether Mic60 affects mitochondrial transcription. Here, we report that Mic60 interacts with mitochondrial transcription factors TFAM and TFB2M. Furthermore, we found that Mic60 knockdown compromises mitochondrial transcription and OXPHOS activities. Importantly, Mic60 deficiency decreased TFAM binding and mitochondrial RNA polymerase (POLRMT) recruitment to the mtDNA promoters. In addition, through mtDNA immunoprecipitation (mIP)-chromatin conformation capture (3C) assays, we found that Mic60 interacted with mtDNA and was involved in the architecture of mtDNA D-loop region. Taken together, our findings reveal a previously unrecognized important role of Mic60 in mtDNA transcription.
doi:10.1038/srep07990
PMCID: PMC4303897  PMID: 25612828
23.  Circulating MicroRNAs as a Novel Class of Diagnostic Biomarkers in Gastrointestinal Tumors Detection: A Meta-Analysis Based on 42 Articles 
PLoS ONE  2014;9(11):e113401.
Objective
MicroRNAs (miRNAs) have become the focus of most recent efforts in cancer research. However, there have been inconsistencies in the literature regarding the suitability of circulating miRNAs for early detection of gastrointestinal cancers. This study aims to assess the diagnostic performance of circulating miRNAs in detection of gastrointestinal cancer through a meta-analysis.
Methods
Eligible studies were selected by conducting a systematic literature search of public databases. The sensitivity and specificity were used to plot the summary receiver operator characteristic (SROC) curve and calculate the area under the SROC curve (AUC). The between-study heterogeneity was evaluated by Q test and I2 statistics. Subgroup analyses and meta-regression were further performed to explore the potential sources of heterogeneity. All analyses were performed using the STATA 12.0 software.
Results
A total of 107 studies from 42 articles were included for the meta-analysis according to the inclusion criteria. The overall analysis of all gastrointestinal cancers showed that circulating miRNAs have a relatively good diagnostic performance in gastrointestinal cancers, with a sensitivity of 0.75, a specificity of 0.81 and an AUC of 0.85. In addition, subgroup analyses based on different type of miRNA assay suggested that single-miRNA assay displayed a relatively low diagnostic performance with the AUC values of 0.84 for gastric cancer (GC) and 0.79 for colorectal cancer (CRC), while multiple-miRNAs assay significantly improved the diagnosing accuracy with AUC rising to 0.92 for GC and 0.89 for CRC. Another interesting finding was that plasma-based miRNA assay reach a higher accuracy compared with serum-based one for GC, while opposite conclusion was drawn for CRC.
Conclusions
In conclusion, circulating miRNAs, particularly the combination of multiple miRNAs, may present as promising biomarkers for the diagnosis of gastrointestinal cancers. Further large-scale prospective studies are necessary to validate their potential applicability in human cancer diagnosis.
doi:10.1371/journal.pone.0113401
PMCID: PMC4236157  PMID: 25406082
24.  The Neural Response to Maternal Stimuli: An ERP Study 
PLoS ONE  2014;9(11):e111391.
Mothers are important to all humans. Research has established that maternal information affects individuals' cognition, emotion, and behavior. We measured event-related potentials (ERPs) to examine attentional and evaluative processing of maternal stimuli while participants completed a Go/No-go Association Task that paired mother or others words with good or bad evaluative words. Behavioral data showed that participants responded faster to mother words paired with good than the mother words paired with bad but showed no difference in response to these others across conditions, reflecting a positive evaluation of mother. ERPs showed larger P200 and N200 in response to mother than in response to others, suggesting that mother attracted more attention than others. In the subsequent time window, mother in the mother + bad condition elicited a later and larger late positive potential (LPP) than it did in the mother + good condition, but this was not true for others, also suggesting a positive evaluation of mother. These results suggest that people differentiate mother from others during initial attentional stage, and evaluative mother positively during later stage.
doi:10.1371/journal.pone.0111391
PMCID: PMC4222870  PMID: 25375157
25.  Safety of rilpivirine plus nucleoside reverse-transcriptase inhibitors in HIV-infected Taiwanese with a higher prevalence of hepatitis virus infection 
Journal of the International AIDS Society  2014;17(4Suppl 3):19580.
Introduction
Combination antiretroviral therapy (cART) containing rilpivirine plus 2 NRTIs are effective antiretroviral (ARV) regimens for ARV-naive HIV-infected patients who had baseline plasma HIV RNA load (PVL) <5 log10 copies/mL and as switch therapy for those with viral suppression. In this study, we aimed to assess the short-term safety of rilpivirine-containing regimens among HIV-infected patients who initiated or switched to rilpivirine plus two NRTIs in Taiwan.
Materials and Methods
Between January and June 2014, medical records of all HIV-infected patients who initiated or switched to rilpivirine plus two NRTIs, during the follow-up were reviewed to assess the tolerance and adverse effects. Using a standardized data collection form, we recorded data of PVL and CD4 count, serologies for hepatitis B and C virus (HBV and HCV, respectively), haemogram, aminotransferases, bilirubin and serum creatinine before starting rilpivirine-containing regimens at four weeks and every 12 weeks thereafter.
Results
During the study period, medical records of 246 patients initiated their first ARV therapy with rilpivirine-containing regimens (n=90) or switched to rilpivirine-containing regimen from other regimens (156). Of the 246 patients, 73.4% were men who have sex with men and 9.1% and 25.6% tested positive for HBsAg and anti-HCV antibody, respectively. Baseline CD4 was 395 cells/mm3 (range, 2-1581) and PVL, 2.76 log10 copies/mL (range, <1.3>7.0 log10 copies/mL). As of 10 July, 23 patients (9.3%) stopped rilpivirine-containing regimens due to gastrointestinal upset (n=4), skin rash (2), depression (2), poor sleep (3), anaemia (4, all being with zidovudine/lamivudine), nail hyperpigmentation (1), presence of transmitted drug resistance (4), and elevated aminotransferase levels (1). The proportion of the patients with aminotransferases of fivefold or higher than the upper limit of normal (ULN) was 1.7% and 1.5% for AST and ALT, respectively, before starting rilpivirine-containing regimens; the respective value was 1.4% and 2.4% after 12 weeks of cART.
Conclusions
Rilpivirine-containing regimens were generally well tolerated and less than 10% of the patients had to stop rilpivirine due to various reasons. Despite a higher prevalence of chronic HBV or HCV infection, rilpivirine-containing regimens did not cause significant changes of aminotransferases from baseline.
doi:10.7448/IAS.17.4.19580
PMCID: PMC4224849  PMID: 25394087

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