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1.  GABAergic inhibition through synergistic astrocytic neuronal interaction transiently decreases vasopressin neuronal activity during hypoosmotic challenge 
The European journal of neuroscience  2013;37(8):1260-1269.
The neuropeptide vasopressin is crucial to mammalian osmotic regulation. Local hypoosmotic challenge transiently decreases and then increases vasopressin secretion. To investigate mechanisms underlying this transient response, we examined effects of hypoosmotic challenge on the electrical activity of rat hypothalamic supraoptic nucleus (SON) vasopressin neurones using patch-clamp recordings. We found that 5 min exposure of hypothalamic slices to hypoosmotic solution transiently increased IPSC frequency and reduced firing rate of vasopressin neurones. Recovery occurred by 10 min exposure, even though the osmolality remained low. The GABAA receptor blocker, gabazine, blocked the IPSCs and the hypoosmotic suppression of firing. The gliotoxin l-aminoadipic acid blocked the increase in IPSC frequency at 5 min and the recovery of firing at 10 min, indicating astrocytic involvement in hypoosmotic modulation of vasopressin neuronal activity. Moreover, β-alanine, an osmolyte of astrocytes and GABA transporter inhibitor, blocked the increase in IPSC frequency at 5 min of hypoosmotic challenge. Confocal microscopy of immunostained SON sections revealed that astrocytes and magnocellular neurones both showed positive staining of vesicular GABA transporters (VGAT). Hypoosmotic stimulation in vivo reduced the number of VGAT-expressing neurones and increased co-localisation and molecular association of VGAT with glial fibrillary acidic protein that increased significantly by 10 min. By 30 min, neuronal VGAT labelling was partially restored and astrocytic VGAT was relocated to ventral portion while decreased in the somatic zone of the SON. Thus, synergistic astrocytic and neuronal GABAergic inhibition could ensure that vasopressin neurone firing is only transiently suppressed under hypoosmotic conditions.
PMCID: PMC3627741  PMID: 23406012
glia; hypothalamo-neurohypophyseal system; in vitro brainstem slice; neuroendocrinology; transporters
2.  Shorter daily dwelling time in peritoneal dialysis attenuates the epithelial-to-mesenchymal transition of mesothelial cells 
BMC Nephrology  2014;15:35.
Peritoneal dialysis (PD) therapy is known to induce morphological and functional changes in the peritoneal membrane. Long-term exposure to conventional bio-incompatible dialysate and peritonitis is the main etiology of inflammation. Consequently, the peritoneal membrane undergoes structural changes, including angiogenesis, fibrosis, and hyalinizing vasculopathy, which ultimately results in technique failure. The epithelial-to-mesenchymal transition (EMT) of mesothelial cells (MCs) plays an important role during the above process; however, the clinical parameters associated with the EMT process of MCs remain to be explored.
To investigate the parameters impacting EMT during PD therapy, 53 clinical stable PD patients were enrolled. EMT assessments were conducted through human peritoneal MCs cultured from dialysate effluent with one consistent standard criterion (MC morphology and the expression of an epithelial marker, cytokeratin 18). The factors potentially associated with EMT were analyzed using logistic regression analysis. Primary MCs derived from the omentum were isolated for the in vitro study.
Forty-seven percent of the patients presented with EMT, 28% with non-EMT, and 15% with a mixed presentation. Logistic regression analysis showed that patients who received persistent PD therapy (dwelling time of 24 h/day) had significantly higher EMT tendency. These results were consistent in vitro.
Dwelling time had a significant effect on the occurrence of EMT on MCs.
PMCID: PMC4015532  PMID: 24555732
Dwelling time; Epithelial-to-mesenchymal transition; Mesothelial cells; Peritoneal dialysis
3.  Haemolytic uremic syndrome following fire ant bites 
BMC Nephrology  2014;15:5.
Haemolytic-uremic syndrome (HUS) is a severe, life-threatening disease with symptoms such as haemolytic anaemia, renal failure, and a low platelet count. Possible aetiology includes bacterial infections, medication, post-hematopoietic cell transplantation, pregnancy, autoimmune disease, and acquired immunodeficiency syndrome.
Case presentation
We report the case of a 21-year-old healthy man who developed acute renal failure caused by HUS. Typical symptoms of HUS combined with severe uraemia developed following a large local reaction after suspected Solenopsis invicta (fire ant) bites. He was successfully treated with plasma exchange and achieved complete recovery of renal function.
This is the first case illustrating a serious systemic reaction of HUS to fire ant bites, and highlights this severe complication in patients who sustain fire ant bites.
PMCID: PMC3890644  PMID: 24400942
Fire ant; Haemolytic-uremic syndrome; Plasma exchange; Renal failure; Venomous insects
4.  Risk factors for endotracheal re-intubation following coronary artery bypass grafting 
Endotracheal re-intubation following coronary artery bypass grafting (CABG) is often associated with significant morbidity and mortality. However, few reports have focused on the independent risk factors for re-intubation following CABG. This study aimed to evaluate the independent risk factors for re-intubation following CABG.
The pre-, intra-, and post-operative materials in patients who had selective and isolated CABG performed on them from January 2004 to July 2012 in our hospital were analyzed retrospectively. Unvariate analysis and logistic regression were used to analyze the risk factor of postoperative re-intubation following CABG.
Among the 1,244 patients investigated, 97 cases suffered from postoperative re-intubation, and the incidence rate of postoperative re-intubation was 7.8%. The in-hospital mortality in the re-intubation group was significantly higher than that in the non-re-intubation group (9.3% versus 1.4%, P = 0.004). Re-intubation also correlated with many negative outcomes such as pneumonia, tracheotomy, acute renal failure, infection of incision, prolonged mechanical ventilation time, prolonged intensive care unit (ICU) stay and prolonged hospital stay. The most commonly cause of re-intubation after CABG was hypoxemia due to cardiogenic and noncardiogenic disease, which accounted for 72.2%. The relative factors of postoperative re-intubation were tested through unvariate analysis and logistic regression, and the associated factors were obtained. The associated factors for re-intubation following CABG included preoperative chronic obstructive pulmonary disease (COPD) (OR = 2.134, 95% CI = 1.472-2.967), preoperative congestive heart failure (CHF) (OR = 2.325, 95% CI = 1.512-3.121), postoperative relative hypoxemia (OR = 2.743, 95% CI = 1.657-3.326), postoperative acute kidney injury (AKI) (OR = 2.976, 95% CI = 2.127-4.023), postoperative total mechanical ventilation time (OR = 1.976, 95% CI = 1.347-2.645).
Preoperative COPD, preoperative CHF, postoperative relative hypoxemia, postoperative AKI and postoperative total mechanical ventilation time were five independent risk factors for re-intubation following CABG.
PMCID: PMC3842842  PMID: 24209453
Coronary artery bypass grafting; Risk factors; Complication
5.  A Bayesian Approach to Dose-Response Assessment and Synergy and Its Application to In Vitro Dose-Response Studies 
Biometrics  2010;66(4):1275-1283.
In this article, we propose a Bayesian approach to dose-response assessment and the assessment of synergy between two combined agents. We consider the case of an in vitro ovarian cancer research study aimed at investigating the antiproliferative activities of four agents, alone and paired, in two human ovarian cancer cell lines. In this study, independent dose-response experiments were repeated three times. Each experiment included replicates at investigated dose levels including control (no drug). We have developed a Bayesian hierarchical nonlinear regression model that accounts for variability between-experiments, variability within experiments (i.e., replicates), and variability in the observed responses of the controls. We use Markov chain Monte Carlo (MCMC) to fit the model to the data and carry out posterior inference on quantites of interest (e.g., median inhibitory concentration IC50). In addition, we have developed a method, based on Loewe additivity, that allows one to assess the presence of synergy with honest accounting of uncertainty. Extensive simulation studies show that our proposed approach is more reliable in declaring synergy compared to current standard analyses such as the Median-Effect Principle/Combination Index method (Chou and Talalay, 1984), that ignore important sources of variability and uncertainty.
PMCID: PMC3773943  PMID: 20337630
Combination Index method; Drug interaction; Emax model; Interaction index; Median-effect principle; Loewe additivity model
6.  Green tea extract protects against nonalcoholic steatohepatitis in ob/ob mice by decreasing oxidative and nitrative stress responses induced by proinflammatory enzymes☆ 
Oxidative and nitrative stress responses resulting from inflammation exacerbate liver injury associated with nonalcoholic steatohepatitis (NASH) by inducing lipid peroxidation and protein nitration. The objective of this study was to investigate whether the anti-inflammatory properties of green tea extract (GTE) would protect against NASH by suppressing oxidative and nitrative damage mediated by proinflammatory enzymes. Obese mice (ob/ob) and their 5-week-old C57BL6 lean littermates were fed 0%, 0.5% or 1% GTE for 6 weeks (n=12–13 mice/group). In obese mice, hepatic lipid accumulation, inflammatory infiltrates and serum alanine aminotransferase activity were markedly increased, whereas these markers of hepatic steatosis, inflammation and injury were significantly reduced among obese mice fed GTE. GTE also normalized hepatic 4-hydroxynonenal and 3-nitro-tyrosine (N-Tyr) concentrations to those observed in lean controls. These oxidative and nitrative damage markers were correlated with alanine aminotransferase (P<.05; r=0.410–0.471). Improvements in oxidative and nitrative damage by GTE were also associated with lower hepatic nicotinamide adenine dinucleotide phosphate oxidase activity. Likewise, GTE reduced protein expression levels of hepatic myeloperoxidase and inducible nitric oxide synthase and decreased the concentrations of nitric oxide metabolites. Correlative relationships between nicotinamide adenine dinucleotide phosphate oxidase and hepatic 4-hydroxynonenal (r=0.364) as well as nitric oxide metabolites and N-Tyr (r=0.598) suggest that GTE mitigates lipid peroxidation and protein nitration by suppressing the generation of reactive oxygen and nitrogen species. Further study is warranted to determine whether GTE can be recommended as an effective dietary strategy to reduce the risk of obesity-triggered NASH.
PMCID: PMC3704146  PMID: 21543212
Green tea; NADPH oxidase; Myeloperoxidase; Lipid peroxidation; Protein nitration; Nonalcoholic steatohepatitis
7.  Coupling visualization and data analysis for knowledge discovery from multi-dimensional scientific data 
Procedia computer science  2010;1(1):1757-1764.
Knowledge discovery from large and complex scientific data is a challenging task. With the ability to measure and simulate more processes at increasingly finer spatial and temporal scales, the growing number of data dimensions and data objects presents tremendous challenges for effective data analysis and data exploration methods and tools. The combination and close integration of methods from scientific visualization, information visualization, automated data analysis, and other enabling technologies —such as efficient data management— supports knowledge discovery from multi-dimensional scientific data. This paper surveys two distinct applications in developmental biology and accelerator physics, illustrating the effectiveness of the described approach.
PMCID: PMC3677775  PMID: 23762211
scientific visualization; information visualization; data analysis; multi-dimensional data; laser wakefield particle acceleration; 3D gene expression
8.  Molecular mechanisms of chemopreventive phytochemicals against gastroenterological cancer development 
Cancer is one of the leading causes of death worldwide. Commonly used cancer treatments, including chemotherapy and radiation therapy, often have side effects and a complete cure is sometimes impossible. Therefore, prevention, suppression, and/or delaying the onset of the disease are important. The onset of gastroenterological cancers is closely associated with an individual’s lifestyle. Thus, changing lifestyle, specifically the consumption of fruits and vegetables, can help to protect against the development of gastroenterological cancers. In particular, naturally occurring bioactive compounds, including curcumin, resveratrol, isothiocyanates, (-)-epigallocatechin gallate and sulforaphane, are regarded as promising chemopreventive agents. Hence, regular consumption of these natural bioactive compounds found in foods can contribute to prevention, suppression, and/or delay of gastroenterological cancer development. In this review, we will summarize natural phytochemicals possessing potential antioxidant and/or anti-inflammatory and anti-carcinogenic activities, which are exerted by regulating or targeting specific molecules against gastroenterological cancers, including esophageal, gastric and colon cancers.
PMCID: PMC3582010  PMID: 23467658
Curcumin; Resveratrol; (-)-Epigallocatechin gallate; Isothiocyanates; Sulforaphane; Gastroenterological cancers; Molecular target
9.  Identification of Chromosomal HP0892-HP0893 Toxin-Antitoxin Proteins in Helicobacter pylori and Structural Elucidation of Their Protein-Protein Interaction* 
The Journal of Biological Chemistry  2013;288(8):6004-6013.
Background: HP0892 of H. pylori shares high structural similarity with other toxin-antitoxin (TA) system toxins.
Results: RNase activity and cell toxicity of HP0892 is inhibited by HP0893 via strong protein-protein interaction.
Conclusion: HP0892-HP0893 pair is a TA system with a protein-protein interaction mode similar to other TA pairs.
Significance: It is highly probable that HP0892-HP0893 TA pair is involved in H. pylori virulence.
Bacterial chromosomal toxin-antitoxin (TA) systems have been proposed not only to play an important role in the stress response, but also to be associated with antibiotic resistance. Here, we identified the chromosomal HP0892-HP0893 TA proteins in the gastric pathogen, Helicobacter pylori, and structurally characterized their protein-protein interaction. Previously, HP0892 protein was suggested to be a putative TA toxin based on its structural similarity to other RelE family TA toxins. In this study, we demonstrated that HP0892 binds to HP0893 strongly with a stoichiometry of 1:1, and HP0892-HP0893 interaction occurs mainly between the N-terminal secondary structure elements of HP0892 and the C-terminal region of HP0893. HP0892 cleaved mRNA in vitro, preferentially at the 5′ end of A or G, and the RNase activity of HP0892 was inhibited by HP0893. In addition, heterologous expression of HP0892 in Escherichia coli cells led to cell growth arrest, and the cell toxicity of HP0892 was neutralized by co-expression with HP0893. From these results and a structural comparison with other TA toxins, it is concluded that HP0892 is a toxin with intrinsic RNase activity and HP0893 is an antitoxin against HP0892 from a TA system of H. pylori. It has been known that hp0893 gene and another TA antitoxin gene, hp0895, of H. pylori, are both genomic open reading frames that correspond to genes that are potentially expressed in response to interactions with the human gastric mucosa. Therefore, it is highly probable that TA systems of H. pylori are involved in virulence of H. pylori.
PMCID: PMC3581365  PMID: 23297406
Helicobacter pylori; Nuclear Magnetic Resonance; Protein Structure; Protein-Protein Interactions; Ribonuclease; HP0892; HP0893; YafQ; Toxin-Antitoxin System; Virulence
10.  Risk factor analysis of coexisting endometrial carcinoma in patients with endometrial hyperplasia: a retrospective observational study of Taiwanese Gynecologic Oncology Group 
To evaluate the clinical outcome and parameters related to coexisting endometrial carcinoma in women with tissue-diagnosed endometrial hyperplasia.
Between January 1991 and December 2009, three hundred and eighty-six patients with the presumptive diagnosis of endometrial hyperplasia were retrieved. Among these, one hundred and twenty-five patients were identified as having coexisting endometrial carcinoma in hysterectomy specimens. The three hundred and eighty-six patients were divided into two groups: the hyperplasia-benign group (261 cases) and the hyperplasia-malignant group (125 cases). Several clinical parameters including age, menopausal status, history of abnormal uterine bleeding, obstetrical history, medical history of diabetes and hypertension, BMI, and preoperative pathologic results were investigated.
Age ≥53 (odds ratio [OR], 2.40; 95% confidence interval [CI], 1.26 to 4.57), menopausal status (OR, 2.07; 95% CI, 1.14 to 3.76), diabetes history (OR, 7.33; 95% CI, 2.79 to 19.26), abnormal uterine bleeding (OR, 3.99; 95% CI, 1.22 to 13.02), atypical endometrial hyperplasia (OR, 7.38; 95% CI, 4.03 to 13.49), and body mass index ≥27 (OR, 3.24; 95% CI, 1.76 to 5.97) were independent risk factors for prediction of endometrial hyperplasia coexisting with endometrial carcinoma. The diagnostic efficacy of atypical endometrial hyperplasia to predict the endometrial hyperplasia coexisting with endometrial carcinoma was better than or similar to those of other independent factors and combinations of these factors.
Coexisting malignancy should be considered when examining endometrial hyperplasia patients with the related risk factors, especially atypical endometrial hyperplasia.
PMCID: PMC3549502  PMID: 23346309
Coexisting endometrial carcinoma; Endometrial hyperplasia; Hysterectomy; Risk factors
11.  Health-Related Quality of Life in Breast Cancer Patients with Lymphedema Who Survived More than One Year after Surgery 
Journal of Breast Cancer  2012;15(4):449-453.
To identify the influence of lymphedema on health-related quality of life (HRQOL) more than 1 year after breast cancer surgery.
Ninety-six breast cancer patients who survived more than 1 year after surgery and 104 members of the general population were recruited. Patients were divided into 2 groups according to the presence of lymphedema. HRQOL was evaluated with the Short-Form 36-Item Health Survey.
There were no statistically significant differences in any scales between groups: groups of breast cancer survivors with and without lymphedema. Compared with the general population, breast cancer survivors had lower quality of life scores in all scales, although the vitality and mental health scales did not differ from chance variation at the 5% level.
In this study, the presence of lymphedema in breast cancer patients who survived over 1 year after surgery might not affect the quality of life. However quality of life of breast cancer survivors is lower than in general population except for some mental health components.
PMCID: PMC3542854  PMID: 23346175
Breast neoplasms; Lymphedema; Quality of life
12.  Bidirectional Scaling of Astrocytic Metabotropic Glutamate Receptor Signaling following Long-Term Changes in Neuronal Firing Rates 
PLoS ONE  2012;7(11):e49637.
Very little is known about the ability of astrocytic receptors to exhibit plasticity as a result of changes in neuronal activity. Here we provide evidence for bidirectional scaling of astrocytic group I metabotropic glutamate receptor signaling in acute mouse hippocampal slices following long-term changes in neuronal firing rates. Plasticity of astrocytic mGluRs was measured by recording spontaneous and evoked Ca2+ elevations in both astrocytic somata and processes. An exogenous astrocytic Gq G protein-coupled receptor was resistant to scaling, suggesting that the alterations in astrocyte Ca2+ signaling result from changes in activity of the surface mGluRs rather than a change in intracellular G protein signaling molecules. These findings suggest that astrocytes actively detect shifts in neuronal firing rates and adjust their receptor signaling accordingly. This type of long-term plasticity in astrocytes resembles neuronal homeostatic plasticity and might be important to ensure an optimal or expected level of input from neurons.
PMCID: PMC3499417  PMID: 23166735
13.  Effects of Synchronization of Carbohydrate and Protein Supply in Total Mixed Ration with Korean Rice Wine Residue on Ruminal Fermentation, Nitrogen Metabolism and Microbial Protein Synthesis in Holstein Steers 
Three Holstein steers in the growing phase, each with a ruminal cannula, were used to test the hypothesis that the synchronization of the hourly rate of carbohydrate and nitrogen (N) released in the rumen would increase the amount of retained nitrogen for growth and thus improve the efficiency of microbial protein synthesis (EMPS). In Experiment 1, in situ degradability coefficients of carbohydrate and N in feeds including Korean rice wine residue (RWR) were determined. In Experiment 2, three total mixed ration (TMR) diets having different rates of carbohydrate and N release in the rumen were formulated using the in situ degradability of the feeds. All diets were made to contain similar contents of crude protein (CP) and neutral detergent fiber (NDF) but varied in their hourly pattern of nutrient release. The synchrony index of the three TMRs was 0.51 (LS), 0.77 (MS) and 0.95 (HS), respectively. The diets were fed at a restricted level (2% of the animal’s body weight) in a 3×3 Latin-square design. Synchronizing the hourly supply of energy and N in the rumen did not significantly alter the digestibility of dry matter, organic matter, crude protein, NDF or acid detergent fiber (ADF) (p>0.05). The ruminal NH3-N content of the LS group at three hours after feeding was significantly higher (p<0.05) than that of the other groups; however, the mean values of ruminal NH3-N, pH and VFA concentration among the three groups were not significantly different (p>0.05). In addition, the purine derivative (PD) excretion in urine and microbial-N production (MN) among the three groups were not significantly different (p>0.05). In conclusion, synchronizing dietary energy and N supply to the rumen did not have a major effect on nutrient digestion or microbial protein synthesis (MPS) in Holstein steers.
PMCID: PMC4093039
By-product; Dairy Steer; Microbial Protein Synthesis; Purine Derivative; Rice Wine Residue; Synchronization)
14.  Effectiveness of sensory processing strategies on activity level in inclusive preschool classrooms 
The purpose of this study was to investigate the effectiveness of sensory processing strategies in improving the activity level of children with sensory integration dysfunction.
The study used a matching-only pretest–posttest control group design, which requires random matching of sensory integration dysfunction to the corresponding intervention group (n = 18) and control group (n = 18). The intervention group comprised 3–6-year-old children who received an 8-week school-day intervention during implementation of the theme curriculum.
The 8-week treatment significantly reduced the activity level and foot-swinging episodes in children with sensory integration dysfunction, and obtained a medium-effect size. However, the level of improvement in the control group did not show any statistically significant change.
Sensory processing strategies could improve activity levels in children with sensory integration dysfunction. However, this study was unable to exclude a developmental effect. The social validity results show that sensory processing strategies can be integrated into the theme curriculum and improve activity levels in children.
PMCID: PMC3484897  PMID: 23118541
activity level; preschool inclusive classroom; sensory integration dysfunction; sensory processing strategy
15.  Cyclin B1 Vaccine Delays Spontaneous Tumors 
We previously identified cyclin B1-specific T cells and antibodies in cancer patients with cyclin B1+ tumors and also in some healthy individuals. We also demonstrated that these responses may be important in cancer immunosurveillance by showing that vaccination against cyclin B1 prevents growth of transplantable cyclin B1+ tumors in mice. Constitutive overexpression of cyclin B1 was determined to correlate with the lack of p53 function. This allowed us to use p53−/− mice as a model that better approximates human disease. p53−/− mice spontaneously develop cyclin B1+ tumors. At 5–6 weeks of age, when the mice were still healthy with no evidence of tumor, they received the cyclin B1 vaccine and were then observed for tumor growth. We demonstrate that cyclin B1 vaccination can delay spontaneous cyclin B1+ tumor growth and increases median survival of tumor bearing p53−/− mice.
PMCID: PMC3472441  PMID: 19769738
cancer vaccines; immunosurveillance; mouse model
16.  Decitabine and suberoylanilide hydroxamic acid (SAHA) inhibit growth of ovarian cancer cell lines and xenografts while inducing expression of imprinted tumor suppressor genes, apoptosis, G2/M arrest and autophagy 
Cancer  2011;117(19):4424-4438.
Epigenetic therapy has had a significant impact on the management of hematologic malignancies, but its role in the treatment of ovarian cancer remains to be defined. We have shown earlier that treatment of ovarian and breast cancer cells with DNA methyltransferase and HDAC inhibitors can upregulate expression of imprinted tumor suppressors. In this study, demethylating agents and HDAC inhibitors were tested for their ability to induce re-expression of tumor suppressor genes, inhibiting growth of ovarian cancer cells in culture and in xenografts.
Ovarian cancer cells (Hey and SKOv3) were treated with demethylating agents [decitabine (DAC), azacytidine (AZA)] or HDAC inhibitors [(suberoylanilide hydroxamic acid (SAHA), trichosporin A (TSA)] to determine their impact on cellular proliferation, cell cycle regulation, apoptosis, autophagy and re-expression of ARHI and PEG3, two growth inhibitory imprinted tumor suppressor genes. The in vivo activity of DAC and SAHA was assessed in a Hey xenograft model.
A combination of DAC and SAHA produced synergistic inhibition of Hey and SKOv3 growth, by apoptosis and cell cycle arrest. DAC induced autophagy in Hey cells that could be enhanced by SAHA. Treatment with both agents induced re-expression of ARHI and PEG3 in cultured cells and in xenografts, correlating with growth inhibition. Knockdown of ARHI decreased DAC-induced autophagy. DAC and SAHA inhibited growth of Hey xenografts and induced autophagy in vivo.
A combination of DAC and SAHA inhibited ovarian cancer growth while inducing apoptosis, G2/M arrest, autophagy and re-expression of imprinted tumor suppressor genes.
PMCID: PMC3137708  PMID: 21491416
ovarian cancer; autophagy; decitabine (DAC); suberoylanilide hydroxamic acid (SAHA); imprinted tumor suppressor genes; ARHI; PEG3
17.  Calcium Signaling and Gliotransmission in Normal vs. Reactive Astrocytes 
A prominent area of neuroscience research over the past 20 years has been the acute modulation of neuronal synaptic activity by Ca2+-dependent release of the transmitters ATP, D-serine, and glutamate (called gliotransmitters) by astrocytes. Although the physiological relevance of this mechanism is under debate, emerging evidence suggests that there are critical factors in addition to Ca2+ that are required for gliotransmitters to be released from astrocytes. Interestingly, these factors include activated microglia and the proinflammatory cytokine Tumor Necrosis Factor α (TNFα), chemotactic cytokine Stromal cell-Derived Factor-1α (SDF-1α), and inflammatory mediator prostaglandin E2 (PGE2). Of note, microglial activation and release of inflammatory molecules from activated microglia and reactive astrocytes can occur within minutes of a triggering stimulus. Therefore, activation of astrocytes by inflammatory molecules combined with Ca2+ elevations may lead to gliotransmitter release, and be an important step in the early sequence of events contributing to hyperexcitability, excitotoxicity, and neurodegeneration in the damaged or diseased brain. In this review, we will first examine evidence questioning Ca2+-dependent gliotransmitter release from astrocytes in healthy brain tissue, followed by a close examination of recent work suggesting that Ca2+-dependent gliotransmitter release occurs as an early event in the development of neurological disorders and neuroinflammatory and neurodegenerative diseases.
PMCID: PMC3395812  PMID: 22811669
glia; IP3R; microglia; neurological disorder; neurodegenerative disease; TNFα; Gq GPCR; inflammation
18.  Structural and biochemical characterization of HP0315 from Helicobacter pylori as a VapD protein with an endoribonuclease activity 
Nucleic Acids Research  2012;40(9):4216-4228.
VapD-like virulence-associated proteins have been found in many organisms, but little is known about this protein family including the 3D structure of these proteins. Recently, a relationship between the Cas2 family of ribonucleases associated with the CRISPR system of microbial immunity and VapD was suggested. Here, we show for the first time the structure of a member of the VapD family and present a relationship of VapD with Cas2 family and toxin–antitoxin (TA) systems. The crystal structure of HP0315 from Helicobacter pylori was solved at a resolution of 2.8 Å. The structure of HP0315, which has a modified ferredoxin-like fold, is very similar to that of the Cas2 family. Like Cas2 proteins, HP0315 shows endoribonuclease activity. HP0315-cleaved mRNA, mainly before A and G nucleotides preferentially, which means that HP0315 has purine-specific endoribonuclease activity. Mutagenesis studies of HP0315 revealed that D7, L13, S43 and D76 residues are important for RNase activity, in contrast, to the Cas2 family. HP0315 is arranged as an operon with HP0316, which was found to be an antitoxin-related protein. However, HP0315 is not a component of the TA system. Thus, HP0315 may be an evolutionary intermediate which does not belong to either the Cas2 family or TA system.
PMCID: PMC3351183  PMID: 22241770
19.  Perception of environmental sounds by experienced cochlear implant patients 
Ear and hearing  2011;32(4):511-523.
Environmental sound perception serves an important ecological function by providing listeners with information about objects and events in their immediate environment. Environmental sounds such as car horns, baby cries or chirping birds can alert listeners to imminent dangers as well as contribute to one's sense of awareness and well being. Perception of environmental sounds as acoustically and semantically complex stimuli, may also involve some factors common to the processing of speech. However, very limited research has investigated the abilities of cochlear implant (CI) patients to identify common environmental sounds, despite patients' general enthusiasm about them. This project (1) investigated the ability of patients with modern-day CIs to perceive environmental sounds, (2) explored associations among speech, environmental sounds and basic auditory abilities, and (3) examined acoustic factors that might be involved in environmental sound perception.
Seventeen experienced postlingually-deafened CI patients participated in the study. Environmental sound perception was assessed with a large-item test composed of 40 sound sources, each represented by four different tokens. The relationship between speech and environmental sound perception, and the role of working memory and some basic auditory abilities were examined based on patient performance on a battery of speech tests (HINT, CNC, and individual consonant and vowel tests), tests of basic auditory abilities (audiometric thresholds, gap detection, temporal pattern and temporal order for tones tests) and a backward digit recall test.
The results indicated substantially reduced ability to identify common environmental sounds in CI patients (45.3%). Except for vowels, all speech test scores significantly correlated with the environmental sound test scores: r = 0.73 for HINT in quiet, r = 0.69 for HINT in noise, r = 0.70 for CNC, r = 0.64 for consonants and r = 0.48 for vowels. HINT and CNC scores in quiet moderately correlated with the temporal order for tones. However, the correlation between speech and environmental sounds changed little after partialing out the variance due to other variables.
Present findings indicate that environmental sound identification is difficult for CI patients. They further suggest that speech and environmental sounds may overlap considerably in their perceptual processing. Certain spectro-temproral processing abilities are separately associated with speech and environmental sound performance. However, they do not appear to mediate the relationship between speech and environmental sounds in CI patients. Environmental sound rehabilitation may be beneficial to some patients. Environmental sound testing may have potential diagnostic applications, especially with difficult-to-test populations, and could be predictive of speech performance for prelingually deafened patients with cochlear implants.
PMCID: PMC3115425  PMID: 21248643
20.  Visual Exploration of Three-dimensional Gene Expression Using Physical Views and Linked Abstract Views 
During animal development, complex patterns of gene expression provide positional information within the embryo. To better understand the underlying gene regulatory networks, the Berkeley Drosophila Transcription Network Project (BDTNP) has developed methods that support quantitative computational analysis of three-dimensional (3D) gene expression in early Drosophila embryos at cellular resolution. We introduce PointCloudXplore, an interactive visualization tool that supports visual exploration of relationships between different genes’ expression using a combination of established visualization techniques.
Two aspects of gene expression are of particular interest: (i) gene expression patterns defined by the spatial locations of cells expressing a gene, and (ii) relationships between the expression levels of multiple genes. PointCloudXplore provides users with two corresponding classes of data views: (i) Physical Views based on the spatial relationships of cells in the embryo, and (ii) Abstract Views that discard spatial information and plot expression levels of multiple genes with respect to each other. Cell Selectors highlight data associated with subsets of embryo cells within a View. Using linking, these selected cells can be viewed in multiple representations. We describe PCX as a 3D gene expression visualization tool and provide examples of how it has been used by BDTNP biologists to generate new hypotheses.
PMCID: PMC3045837  PMID: 19407353
interactive data exploration; three-dimensional
21.  Effect of erythropoietin on level of circulating endothelial progenitor cells and outcome in patients after acute ischemic stroke 
Critical Care  2011;15(1):R40.
Erythropoietin (EPO) enhances the circulating level of endothelial progenitor cells (EPCs), which has been reported to be associated with prognostic outcome in ischemic stroke (IS) patients. The aim of this study was to evaluate the time course of circulating EPC level and the impact of EPO therapy on EPC level and clinical outcome in patients after acute IS.
In total, 167 patients were prospectively randomized to receive either EPO therapy (group 1) (5,000 IU each time, subcutaneously) at 48 h and 72 h after acute IS, or serve as placebo (group 2). The circulating level of EPCs (double-stained markers: CD31/CD34 (E1), CD62E/CD34 (E2) and KDR/CD34 (E3)) was determined using flow cytometry at 48 h and on days 7 and 21 after IS. EPC level was also evaluated once in 60 healthy volunteers.
Circulating EPC (E1 to E3) level at 48 h after IS was remarkably higher in patients than in control subjects (P < 0.02). At 48 h and on Day 7 after IS, EPC (E1 to E3) level did not differ between groups 1 and 2 (all P > 0.1). However, by Day 21, EPC (E1 to E3) level was significantly higher in group 1 than in group 2 (all P < 0.03). Additionally, 90-day recurrent stroke rate was notably lower in group 1 compared with group 2 (P = 0.022). Multivariate analysis demonstrated that EPO therapy (95% confidence interval (CI), 0.153 to 0.730; P = 0.006) and EPC (E3) (95% CI, 0.341 to 0.997; P = 0.049) levels were significantly and independently predictive of a reduced 90-day major adverse neurological event (MANE) (defined as recurrent stroke, National Institutes of Health Stroke scale ≥8, or death).
EPO therapy significantly improved circulating EPC level and 90-day MANE.
Trial registration number
PMCID: PMC3221969  PMID: 21269484
22.  Clinical and molecular characterization of Wilson's disease in China: identification of 14 novel mutations 
BMC Medical Genetics  2011;12:6.
Wilson's disease (WND) is a rare autosomal recessive disorder. Here we have evaluated 62 WND cases (58 probands) from the Chinese Han population to expand our knowledge of ATP7B mutations and to more completely characterize WND in China.
The coding and promoter regions of the ATP7B gene were analyzed by direct sequencing in 62 Chinese patients (58 probands) with WND (male, n = 37; female, n = 25; age range, 2 ~ 61 years old).
Neurologic manifestations were associated with older age at diagnosis (p < 0.0001) and longer diagnostic delay (p < 0.0001). Age at diagnosis was also correlated with urinary copper concentration (r = 0.58, p < 0.001). Forty different mutations, including 14 novel mutations, were identified in these patients. Common mutations included p.Arg778Leu (31.9%) and p.Pro992Leu (11.2%). Homozygous p.Arg778Leu and nonsense mutation/frameshift mutations were more often associated with primary hepatic manifestations (p = 0.0286 and p = 0.0383, respectively) and higher alanine transaminase levels at diagnosis (p = 0.0361 and p = 0.0047, respectively). Nonsense mutation/frameshift mutations were also associated with lower serum ceruloplasmin (p = 0.0065).
We identified 14 novel mutations and found that the spectrum of mutations of ATP7B in China is quite distinct from that of Western countries. The mutation type plays a role in predicting clinical manifestations. Genetic testing is a valuable tool to detect WND in young children, especially in patients younger than 8 years old. Four exons (8, 12, 13, and 16) and two mutations (p.Arg778Leu, p.Pro992Leu) should be considered high priority for cost-effective testing in China.
PMCID: PMC3025937  PMID: 21219664
23.  Two-Year Body Composition Analyses of Long-Lived GHR Null Mice 
Growth hormone receptor gene–disrupted (GHR−/−) mice exhibit increased life span and adipose tissue mass. Although this obese phenotype has been reported extensively for young adult male GHR−/− mice, data for females and for other ages in either gender are lacking. Thus, the purpose of this study was to evaluate body composition longitudinally in both male and female GHR−/− mice. Results show that GHR−/− mice have a greater percent fat mass with no significant difference in absolute fat mass throughout life. Lean mass shows an opposite trend with percent lean mass not significantly different between genotypes but absolute mass reduced in GHR−/− mice. Differences in body composition are more pronounced in male than in female mice, and both genders of GHR−/− mice show specific enlargement of the subcutaneous adipose depot. Along with previously published data, these results suggest a consistent and intriguing protective effect of excess fat mass in the subcutaneous region.
PMCID: PMC2796884  PMID: 19901018
Body composition; Growth hormone; Obesity; Adipose depots; Gender differences
24.  Acute ingestion of a novel whey-derived peptide improves vascular endothelial responses in healthy individuals: a randomized, placebo controlled trial 
Nutrition Journal  2009;8:34.
Whey protein is a potential source of bioactive peptides. Based on findings from in vitro experiments indicating a novel whey derived peptide (NOP-47) increased endothelial nitric oxide synthesis, we tested its effects on vascular function in humans.
A randomized, placebo-controlled, crossover study design was used. Healthy men (n = 10) and women (n = 10) (25 ± 5 y, BMI = 24.3 ± 2.3 kg/m2) participated in two vascular testing days each preceded by 2 wk of supplementation with a single dose of 5 g/day of a novel whey-derived peptide (NOP-47) or placebo. There was a 2 wk washout period between trials. After 2 wk of supplementation, vascular function in the forearm and circulating oxidative stress and inflammatory related biomarkers were measured serially for 2 h after ingestion of 5 g of NOP-47 or placebo. Macrovascular and microvascular function were assessed using brachial artery flow mediated dilation (FMD) and venous occlusion strain gauge plethysmography.
Baseline peak FMD was not different for Placebo (7.7%) and NOP-47 (7.8%). Placebo had no effect on FMD at 30, 60, and 90 min post-ingestion (7.5%, 7.2%, and 7.6%, respectively) whereas NOP-47 significantly improved FMD responses at these respective postprandial time points compared to baseline (8.9%, 9.9%, and 9.0%; P < 0.0001 for time × trial interaction). Baseline reactive hyperemia forearm blood flow was not different for placebo (27.2 ± 7.2%/min) and NOP-47 (27.3 ± 7.6%/min). Hyperemia blood flow measured 120 min post-ingestion (27.2 ± 7.8%/min) was unaffected by placebo whereas NOP-47 significantly increased hyperemia compared to baseline (29.9 ± 7.8%/min; P = 0.008 for time × trial interaction). Plasma myeloperoxidase was increased transiently by both NOP-47 and placebo, but there were no changes in markers inflammation. Plasma total nitrites/nitrates significantly decreased over the 2 hr post-ingestion period and were lower at 120 min after placebo (-25%) compared to NOP-47 (-18%).
These findings indicate that supplementation with a novel whey-derived peptide in healthy individuals improves vascular function.
PMCID: PMC2723133  PMID: 19624856
25.  Translational Attenuation and mRNA Stabilization as Mechanisms of erm(B) Induction by Erythromycin▿  
Translational attenuation has been proposed to be the mechanism by which the erm(B) gene is induced. Here, we report genetic and biochemical evidence, obtained by using erythromycin as the inducing antibiotic, that supports this hypothesis. We also show that erythromycin increases the level of the erm(B) transcript by stalling the ribosome on the leader mRNA and thereby facilitating the stabilization and processing of the mRNA. Erythromycin-induced mRNA stabilization and processing were observed with an ochre stop at codons 11 to 13 of the leader but not with an ochre stop at codon 10. This suggests that erythromycin does not stall the ribosome before codon 11 of the leader reaches the aminoacyl site. Secondary structure analyses of the erm(B) transcripts by in vitro and in vivo chemical probing techniques identified conformational changes in the transcripts that result from induction by erythromycin. These findings demonstrate that stalling of erythromycin-bound ribosomes at leader codon 11 causes the refolding of mRNA into a conformation in which the translational initiation site for the structural gene is unmasked and renders erm(B) translationally active.
PMCID: PMC2346635  PMID: 18299414

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