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1.  MBD-seq as a cost-effective approach for methylome-wide association studies: demonstration in 1500 case–control samples 
Epigenomics  2012;4(6):605-621.
Aim
We studied the use of methyl-CpG binding domain (MBD) protein-enriched genome sequencing (MBD-seq) as a cost-effective screening tool for methylome-wide association studies (MWAS).
Materials & methods
Because MBD-seq has not yet been applied on a large scale, we first developed and tested a pipeline for data processing using 1500 schizophrenia cases and controls plus 75 technical replicates with an average of 68 million reads per sample. This involved the use of technical replicates to optimize quality control for multi- and duplicate-reads, an in silico experiment to identify CpGs in loci with alignment problems, CpG coverage calculations based on multiparametric estimates of the fragment size distribution, a two-stage adaptive algorithm to combine data from correlated adjacent CpG sites, principal component analyses to control for confounders and new software tailored to handle the large data set.
Results
We replicated MWAS findings in independent samples using a different technology that provided single base resolution. In an MWAS of age-related methylation changes, one of our top findings was a previously reported robust association involving GRIA2. Our results also suggested that owing to the many confounding effects, a considerable challenge in MWAS is to identify those effects that are informative about disease processes.
Conclusion
This study showed the potential of MBD-seq as a cost-effective tool in large-scale disease studies.
doi:10.2217/epi.12.59
PMCID: PMC3923085  PMID: 23244307
MBD; methylome-wide association studies; next-generation sequencing; principal component analysis; pyrosequencing
2.  Visualization of Acute Liver Damage Induced by Cycloheximide in Rats Using PET with [18F]FEDAC, a Radiotracer for Translocator Protein (18 kDa) 
PLoS ONE  2014;9(1):e86625.
Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET) with N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-[18F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([18F]FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO) as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX) into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [18F]FEDAC. The uptake of [18F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [18F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells) and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [18F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage.
doi:10.1371/journal.pone.0086625
PMCID: PMC3900578  PMID: 24466178
3.  Real-world outcomes of initiating insulin glargine-based treatment versus premixed analog insulins among US patients with type 2 diabetes failing oral antidiabetic drugs 
Background
In patients with type 2 diabetes mellitus, basal-bolus strategies can improve treatment by offering dosing flexibility, and improved satisfaction, adherence, and clinical outcomes. The purpose of this study was to compare real-world outcomes between US patients initiating analog insulin therapy with insulin glargine and those initiating with a premixed analog insulin (PMX).
Methods
This was a retrospective study of data from patients (≥18 years) with type 2 diabetes mellitus in the IMPACT® database who initiated insulin treatment with insulin glargine (GLA) or a PMX. Clinical and economic outcomes were measured over one year, including persistence and adherence, consumption of insulin, glycemic outcomes, incident hypoglycemia, and health care resource utilization and cost.
Results
Data from 2,502 patients were included in the analyses (n = 834 for PMX, n = 1,668 for GLA). Compared with PMX, persistence was higher and consumption of insulin was lower for GLA (both P < 0.0001). Adherence, glycemic outcomes, and hypoglycemia-related events were similar between groups, as were health care utilization and total health care costs. Diabetes-related drug and supply costs were lower for GLA than for PMX (P < 0.0001 and P = 0.046, respectively).
Conclusion
In US patients with type 2 diabetes mellitus, initiating insulin with once-daily GLA, rather than a PMX, is associated with increased treatment persistence and similar clinical and hypoglycemic outcomes, but lower diabetes pharmacy and supply costs. GLA may be a more flexible option than PMX. However, these results also show suboptimal glycemic control in the real-world setting despite change in treatment regimens and call for optimization in management of patients with type 2 diabetes mellitus.
doi:10.2147/CEOR.S49279
PMCID: PMC3794873  PMID: 24124384
type 2 diabetes mellitus; insulin glargine; rapid acting insulin; premixed insulin; clinical outcomes; treatment persistence
4.  Real world outcomes of adding rapid-acting insulin versus switching to analog premix insulin among US patients with type 2 diabetes treated with insulin glargine 
Introduction
Patients with type 2 diabetes mellitus (T2DM) often require intensification of basal insulin therapy. This retrospective, observational study compared real-world outcomes in US patients with T2DM treated with insulin glargine who added a rapid-acting insulin (RAI) (basal–bolus approach) with those who switched to premixed insulin (PMX).
Methods
The national US IMPACT® database was used to identify data from adult patients (≥18 years of age) with T2DM who added bolus RAI to insulin glargine (GLA + RAI) or who switched from GLA to PMX between 2001 and 2009. A stringent 1:1 propensity score-matching method was used to address the selection bias by matching GLA + RAI patients and PMX patients. Clinical and economic outcomes were determined for 1 year after the initial pharmacy claim for RAI or for PMX. Outcomes included treatment persistence and adherence, average insulin doses, glycated hemoglobin (A1C) levels, the prevalence and incidence of hypoglycemia, and health care costs/utilization. Analysis was carried out using an intent-to-treat approach.
Results
The study included data from 746 propensity-matched patients (n = 373 in each cohort). Treatment persistence and adherence were higher in the GLA + RAI cohort. There was no significant difference in A1C reduction from baseline and the number of patients achieving target A1C levels of <7% in each cohort. The incidence of hypoglycemic events was also similar in both groups. However, during follow-up, many patients (48.8%) who initially switched from insulin glargine to PMX crossed back over to use GLA and/or RAI as part of their regimen. Health care costs and utilization levels were not significantly different.
Conclusion
Clinical and economic outcomes were similar in T2DM patients who added RAI to GLA and in those who switched to PMX, but a basal–bolus strategy appears to be associated with better treatment persistence and adherence.
doi:10.2147/PPA.S49287
PMCID: PMC3786817  PMID: 24086105
type 2 diabetes mellitus; insulin glargine; rapid-acting insulin; premixed insulin; clinical outcomes; treatment persistence
5.  In Vitro Mesenchymal Trilineage Differentiation and Extracellular Matrix Production by Adipose and Bone Marrow Derived Adult Equine Multipotent Stromal Cells on a Collagen Scaffold 
Stem Cell Reviews  2013;9:858-872.
Directed differentiation of adult multipotent stromal cells (MSC) is critical for effective treatment strategies. This study was designed to evaluate the capability of equine MSC from bone marrow (BMSC) and adipose tissue (ASC) on a type I collagen (COLI) scaffold to undergo chondrogenic, osteogenic and adipogenic differentiation and form extracellular matrix (ECM) in vitro. Following determination of surface antigen expression, MSC were loaded into scaffolds in a perfusion bioreactor and loading efficiency was quantified. Cell-scaffold constructs were assessed after loading and 7, 14 and 21 days of culture in stromal or induction medium. Cell number was determined with DNA content, cell viability and spatial uniformity with confocal laser microscopy and cell phenotype and matrix production with light and scanning electron microscopy and mRNA levels. The MSC were positive for CD29 (>90 %), CD44 (>99 %), and CD105 (>60 %). Loading efficiencies were >70 %. The ASC and BMSC cell numbers on scaffolds were affected by culture in induction medium differently. Viable cells remained uniformly distributed in scaffolds for up to 21 days and could be directed to differentiate or to maintain an MSC phenotype. Micro- and ultrastructure showed lineage-specific cell and ECM changes. Lineage-specific mRNA levels differed between ASC and BMSC with induction and changed with time. Based on these results, equine ASC and BMSC differentiate into chondrogenic, osteogenic and adipogenic lineages and form ECM similarly on COLI scaffolds. The collected data supports the potential for equine MSC-COLI constructs to support diverse equine tissue formation for controlled biological studies.
doi:10.1007/s12015-013-9456-1
PMCID: PMC3834181  PMID: 23892935
Adipose; Bone marrow; Multipotent stromal cell; Equine; Extra-cellular matrix; Bioreactor; Osteogenesis; Adipogenesis; Chondrogenesis
6.  Synthesis and evaluation of [11C]MMPIP as a potential radioligand for imaging of metabotropic glutamate 7 receptor in the brain 
EJNMMI Research  2013;3:54.
Background
Metabotropic glutamate 7 (mGlu7) receptor is a crucial target protein for the development of pharmaceuticals against central nervous system disorders. In the present study, we synthesized [11C]MMPIP, a putative radioligand for mGlu7 (binding constant KB = 30 nM), and evaluated its potential for imaging of mGlu7 via in vitro and in vivo techniques.
Methods
[11C]MMPIP was synthesized by the reaction of phenol precursor 3 with [11C]CH3I. In vitro autoradiography using [11C]MMPIP was performed on rat brain sections. To determine in vitro specific binding of [11C]MMPIP with mGlu7, a blocking study was conducted by co-incubation with excess AMN082, a selective antagonist for mGlu7, or unlabeled MMPIP. Positron emission tomography (PET) studies and ex vivo metabolite analysis were carried out on rat brains.
Results
[11C]MMPIP was obtained with two specific activity (SA) levels of average 58 (conventional) and 3,800 (high SA) GBq/μmol, respectively. High radioactive signals derived from conventional [11C]MMPIP in the in vitro autoradiography were seen in the thalamus, medulla oblongata, and striatum, corresponding with comprehensive brain distributions of mGlu7. Co-incubation with ANM082 or unlabeled MMPIP reduced the radioactive signals in the brain sections, respectively. In the PET studies with [11C]MMPIP, no specific uptake relative to mGlu7 was found in the examined brain regions.
Conclusion
Despite in vitro specific binding of [11C]MMPIP with mGlu7, visualization of mGlu7 in the living brain using PET was not successful. Development of new ligand candidates with higher affinity for mGlu7 is necessary.
doi:10.1186/2191-219X-3-54
PMCID: PMC3751550  PMID: 23870677
MMPIP; mGlu7; PET; 11C; Autoradiography; Specific activity
7.  Relationships of hip joint volume ratios with degrees of joint laxity and degenerative disease from youth to maturity in a canine population predisposed to hip joint osteoarthritis 
Objective
To assess relationships of acetabular volume (AV), femoral head volume (FV), and portion of the femoral head within in the acetabulum (FVIA) with each other and with degrees of hip joint laxity and degenerative joint disease from youth to maturity in dogs predisposed to developing hip joint osteoarthritis (OA).
Animals
46 mixed-breed half- or full-sibling hound-type dogs.
Procedures
The distraction index (DI), AV, FV, FVIA, and degree of osteoarthritis (OA score) were quantified in 1 hip joint at 16, 32, and 104 weeks of age. Relationships among variables were evaluated within and between ages. Ratios corresponding to OA scores were compared within ages. Differences among 16-week ratios corresponding to 32-week OA scores and among 16- and 32-week ratios corresponding to 104-week OA scores were evaluated.
Results
Significant positive relationships existed between FV and AV across ages as well as between FVIA/FV and FVIA/AV and between DI and OA score across and within most ages. Such relationships also existed within these variables across most ages. Negative relationships of DI and OA scores with FVIA/FV and FVIA/AV within and among all ages were significant. Sixteen-week AVs, FVs, and FVIAs were greater and FV/AVs and OA scores were less than 32- and 104-week values. The 32-week FVIA/FV was less than 16- and 104-week values, and the 32-week FVIA/AV was less than the 104-week value. The FVIA/FV and FVIA/AV were lower and the DI was higher with higher OA scores within and among most ages.
Conclusions and Clinical Relevance
Structural volumes in lax canine hip joints changed predictably relative to each other during growth, despite degenerative changes. Measures developed in this study may augment current diagnosis and treatment strategies for hip dysplasia in dogs.
doi:10.2460/ajvr.72.3.376
PMCID: PMC3711502  PMID: 21355741
9.  Interactions between Vascular Endothelial Growth Factor and Neuroglobin 
Neuroscience Letters  2012;519(1):47-50.
Vascular endothelial growth factor (VEGF) and neuroglobin (Ngb) participate in neuronal responses to hypoxia and ischemia, but the relationship between their effects, if any, is unknown. To address this issue, we measured Ngb levels in VEGF-treated mouse cerebrocortical cultures and VEGF levels in cerebrocortical cultures from Ngb-overexpressing transgenic mice. VEGF stimulated Ngb expression in a VEGFR2/Flk1 receptor-dependent manner, whereas Ngb overexpression suppressed expression of VEGF. These findings provide further insight into hypoxia-stimulated neuronal signaling pathways.
doi:10.1016/j.neulet.2012.05.018
PMCID: PMC3371093  PMID: 22583764
Vascular endothelial growth factor; neuroglobin; hypoxia
10.  Effect of a contralateral lesion on neurological recovery from stroke in rats 
Purpose
Clinical studies suggest a correlation between changes in activity of the contralesional cerebral cortex and spontaneous recovery from stroke, but whether this is a causal relationship is uncertain.
Methods
Young adult Sprague-Dawley male rats underwent unilateral or bilateral permanent distal middle cerebral artery occlusion (dMCAO). Infarct volume was determined by 2,3,5-triphenyltetrazolium chloride (TTC) staining 24 hr after dMCAO, and functional outcome was assessed 1–28 days after dMCAO using the ladder rung walking and limb placing tests.
Results
Infarct volume was unchanged, but functional neurological deficits were reduced 1 day after bilateral compared to unilateral dMCAO.
Conclusions
Activity in the contralesional cerebral cortex may inhibit functional motor recovery acutely after experimental stroke.
doi:10.3233/RNN-2012-120254
PMCID: PMC3652379  PMID: 22868223
Stroke; ischemia; recovery; rat
11.  Treatment of MM-associated spinal fracture with percutaneous vertebroplasty (PVP) and chemotherapy 
European Spine Journal  2011;21(5):912-919.
Purpose
To investigate the effect of treatment of multiple myeloma (MM)-associated spinal fracture with percutaneous vertebroplasty (PVP) and chemotherapy.
Methods
Patients with MM-associated spinal fracture were randomly divided into combined (PVP and chemotherapy) treatment group (n = 38) and single chemotherapy group (n = 38). For the combined treatment group, bone cement was injected into vertebral body via DSA guided-percutaneous puncture. M2 scheme was used for both groups. And a 5-year follow-up was conducted for the study.
Results
At the 1-year follow-up visits, PVP combined with chemotherapy achieved complete remission (CR) in six patients (15.8%); near complete remission (nCR) in ten patients (26.30%); partial remission (PR) in nine patients (23.7%); minimal response (MR) in three patients (7.9%); no change (NC) in four patients (10.5%), and disease progression (DP) in five patients (13.2%). Only chemotherapy alone resulted in 3 CR (7.9%); 8 nCR (26.30%); 19 PR (77.5%); 4 MR (17.5%); 4 NC (17.5%), and 2 DP (5.0%). While the overall response rate (ORR) in the combined treatment group (65.8%) and the single chemotherapy group (50.0%) were significantly different, their visual analog pain scales (3.01 ± 0.62 and 5.97 ± 0.40, respectively) and Karnofsky performance scores (89.4 ± 6.3 and 80.3 ± 7.2, respectively) were significantly improved after treatment (P = 0.032 and P = 0.002, respectively). And the ORR between the two groups were significantly different (P = 0.001).
Conclusion
Percutaneous vertebroplasty is a minimally invasive surgery for MM-associated pathologic fracture. PVP had the characteristics of minimal trauma, easy operation and less complication. PVP can achieve long-term analgesic effect, and enhance the spinal stability.
doi:10.1007/s00586-011-2105-y
PMCID: PMC3337900  PMID: 22173608
Percutaneous puncture; Spine; Multiple myeloma; Fracture; Bone cement
12.  Vascular endothelial growth factor-B expression in postischemic rat brain 
Vascular Cell  2013;5:8.
Background
Vascular endothelial growth factor-B (VEGF-B) protects against experimental stroke, but the effect of stroke on VEGF-B expression is uncertain.
Methods
We examined VEGF-B expression by immunohistochemistry in the ischemic border zone 1–7 days after middle cerebral artery occlusion in rats.
Results
VEGF-B immunoreactivity in the border zone was increased after middle cerebral artery occlusion and was associated with neurons and macrophages/microglia, but not astrocytes or endothelial cells.
Conclusions
These findings provide additional evidence for a role of VEGF-B in the endogenous response to cerebral ischemia.
doi:10.1186/2045-824X-5-8
PMCID: PMC3671984  PMID: 23601533
Vascular endothelial growth factor-B (VEGF-B); Stroke; Ischemia
13.  High quality methylome-wide investigations through next-generation sequencing of DNA from a single archived dry blood spot 
Epigenetics  2013;8(5):542-547.
The potential importance of DNA methylation in the etiology of complex diseases has led to interest in the development of methylome-wide association studies (MWAS) aimed at interrogating all methylation sites in the human genome. When using blood as biomaterial for a MWAS the DNA is typically extracted directly from fresh or frozen whole blood that was collected via venous puncture. However, DNA extracted from dry blood spots may also be an alternative starting material. In the present study, we apply a methyl-CpG binding domain (MBD) protein enrichment-based technique in combination with next generation sequencing (MBD-seq) to assess the methylation status of the ~27 million CpGs in the human autosomal reference genome. We investigate eight methylomes using DNA from blood spots. This data are compared with 1,500 methylomes previously assayed with the same MBD-seq approach using DNA from whole blood. When investigating the sequence quality and the enrichment profile across biological features, we find that DNA extracted from blood spots gives comparable results with DNA extracted from whole blood. Only if the amount of starting material is ≤ 0.5µg DNA we observe a slight decrease in the assay performance. In conclusion, we show that high quality methylome-wide investigations using MBD-seq can be conducted in DNA extracted from archived dry blood spots without sacrificing quality and without bias in enrichment profile as long as the amount of starting material is sufficient. In general, the amount of DNA extracted from a single blood spot is sufficient for methylome-wide investigations with the MBD-seq approach.
doi:10.4161/epi.24508
PMCID: PMC3741224  PMID: 23644822
archived blood spots; methylation; next-generation sequencing; DNA extraction; MBD-seq
14.  Genome-Wide Identification of Bone Metastasis-Related MicroRNAs in Lung Adenocarcinoma by High-Throughput Sequencing 
PLoS ONE  2013;8(4):e61212.
Background
MicroRNAs (miRNAs) are a class of small noncoding RNAs that regulate gene expression at the post-transcriptional level. They participate in a wide variety of biological processes, including apoptosis, proliferation and metastasis. The aberrant expression of miRNAs has been found to play an important role in many cancers.
Results
To understand the roles of miRNAs in the bone metastasis of lung adenocarcinoma, we constructed two small RNA libraries from blood of lung adenocarcinoma patients with and without bone metastasis. High-throughput sequencing combined with differential expression analysis identified that 7 microRNAs were down-regulated and 21 microRNAs were up-regulated in lung adenocarcinoma with bone metastasis. A total of 797 target genes of the differentially expressed microRNAs were identified using a bioinformatics approach. Functional annotation analysis indicated that a number of pathways might be involved in bone metastasis, survival of the primary origin and metastatic angiogenesis of lung adenocarcinoma. These include the MAPK, Wnt, and NF-kappaB signaling pathways, as well as pathways involving the matrix metalloproteinase, cytoskeletal protein and angiogenesis factors.
Conclusions
This study provides some insights into the molecular mechanisms that underlie lung adenocarcinoma development, thereby aiding the diagnosis and treatment of the disease.
doi:10.1371/journal.pone.0061212
PMCID: PMC3620207  PMID: 23593434
15.  Analysis of the relationship between psoriasis symptom severity and quality of life, work productivity, and activity impairment among patients with moderate-to-severe psoriasis using structural equation modeling 
Background
Plaque psoriasis is a chronic disease characterized by scaly plaques on the skin that can itch and bleed. Psoriasis covering over 10% of the body is classified as moderate to severe, and can impact patient quality of life.
Objectives
To assess the relationship between plaque psoriasis self-reported severity symptoms and health-related quality of life, work productivity, and activity impairment among patients with moderate-to-severe psoriasis.
Methods
The study sample included 199 patients recruited from internet panels, of which 179 respondents had plaque psoriasis and 20 had plaque and inverse psoriasis. Itching, pain, and scaling symptoms were studied. A structural equation modeling framework was used to estimate the effect of these symptoms on patient outcomes. First, each severity variable was regressed on a set of covariates to generate a predicted severity score. These predicted values were placed in a second-stage model with patient mental and physical scores (Short-Form 12 questionnaire), work productivity, and activity impairment indicators as dependent variables.
Results
Itching severity had a marginal negative effect (P < 0.06) on patients’ Short-Form 12 physical and mental component scores. Pain severity also negatively affected physical and mental health scores (P < 0.02). Patients were more likely to miss work because of itching (odds ratio [OR]: 2.31, 95% confidence interval [CI]: 1.30, 4.10), pain (OR: 1.78, 95% CI: 1.25, 2.52), and scaling (OR: 2.15, 95% CI: 1.31, 3.52) symptoms. These symptoms also lowered self-reported productivity. As itching (OR: 1.74, 95% CI: 1.03, 2.95), scaling (OR: 1.84, 95% CI: 1.16, 2.90), and pain symptoms (OR: 1.53, 95% CI: 1.12, 2.09) increased, so did the odds that a patient would be less productive at work.
Conclusion
Plaque psoriasis significantly affects patient quality of life. In addition to greater mental and physical pain, patients are more likely to miss work and have diminished productivity as symptom severity increases.
doi:10.2147/PPA.S39887
PMCID: PMC3597339  PMID: 23508007
psoriasis; severity; activity impairment; work productivity loss; structural equation modeling
16.  Estimation of CpG coverage in whole methylome next-generation sequencing studies 
BMC Bioinformatics  2013;14:50.
Background
Methylation studies are a promising complement to genetic studies of DNA sequence. However, detailed prior biological knowledge is typically lacking, so methylome-wide association studies (MWAS) will be critical to detect disease relevant sites. A cost-effective approach involves the next-generation sequencing (NGS) of single-end libraries created from samples that are enriched for methylated DNA fragments. A limitation of single-end libraries is that the fragment size distribution is not observed. This hampers several aspects of the data analysis such as the calculation of enrichment measures that are based on the number of fragments covering the CpGs.
Results
We developed a non-parametric method that uses isolated CpGs to estimate sample-specific fragment size distributions from the empirical sequencing data. Through simulations we show that our method is highly accurate. While the traditional (extended) read count methods resulted in severely biased coverage estimates and introduces artificial inter-individual differences, through the use of the estimated fragment size distributions we could remove these biases almost entirely. Furthermore, we found correlations of 0.999 between coverage estimates obtained using fragment size distributions that were estimated with our method versus those that were “observed” in paired-end sequencing data.
Conclusions
We propose a non-parametric method for estimating fragment size distributions that is highly precise and can improve the analysis of cost-effective MWAS studies that sequence single-end libraries created from samples that are enriched for methylated DNA fragments.
doi:10.1186/1471-2105-14-50
PMCID: PMC3599116  PMID: 23398781
Methylation; Next-generation sequencing; MBD/MeDIP; Association studies
17.  Complete Genome Sequence of a Rabies Virus Isolate from Cattle in Guangxi, Southern China 
Genome Announcements  2013;1(1):e00137-12.
A street rabies virus (RV) isolate, GXHXN, was obtained from brain tissue of rabid cattle in the Guangxi Zhuang Autonomous Region of China in 2009. GXHXN is the first isolate from cattle in China with its entire genome sequenced and is closely related to BJ2011E from horse in Beijing, WH11 from donkey in the Hubei Province, and isolates from dogs in the Guangxi and Fujian Provinces, with homologies of 97.6% to 99.6%. It is more distantly related to isolates from domestic cat, pig, Chinese ferret badger, and vaccine strains, with homologies of 83.1% to 88.0%.
doi:10.1128/genomeA.00137-12
PMCID: PMC3569373  PMID: 23405368
18.  The Pharmacokinetic-Pharmacodynamic Model of Azithromycin for Lipopolysaccharide-Induced Depressive-Like Behavior in Mice 
PLoS ONE  2013;8(1):e54981.
A mechanism-based model was developed to describe the time course of lipopolysaccharide-induced depressive-like behavior and azithromycin pharmacodynamics in mice. The lipopolysaccharide-induced disease progression was monitored by lipopolysaccharide, proinflammatory cytokines, and kynrenine concentration in plasma. The depressive-like behavior was investigated by forced swimming test and tail suspension test. Azithromycin was selected to inhibit the surge of proinflammatory cytokines induced by lipopolysaccharide. Disease progression model and azithromycin pharmacodynamics were constructed from transduction and indirect response models. A delay in the onset of increased proinflammatory cytokines, kynrenine, and behavior test compared to lipopolysaccharide was successfully characterized by series transduction models. The inhibition of azithromycin on proinflammatory cytokines was described by an indirect response model. After lipopolysaccharide challenging, the proinflammatory cytokines, kynrenine and behavior tests would peak approximately at 3, 12, and 24 h respectively, and then the time courses slowly declined toward a baseline state after peak response. During azithromycin administration, the peak levels of proinflammatory cytokines, kynrenine and behavior indexes decreased. Model parameters indicated that azithromycin significantly inhibited the proinflammatory cytokines level in plasma and improved the depressive-like behavior induced by inflammation. The integrated model for disease progression and drug intervention captures turnovers of proinflammatory cytokines, kynrenine and the behavior results in the different time phases and conditions.
doi:10.1371/journal.pone.0054981
PMCID: PMC3554664  PMID: 23358536
19.  Hypoxia-inducible Factor-1 and Neuroglobin Expression 
Neuroscience letters  2012;514(2):137-140.
Neuroglobin (Ngb) is a hypoxia-inducible protein with cytoprotective effects in animal models of stroke, Alzheimer's disease, and related disorders, but the molecular mechanisms involved in its induction are unknown. We tested the hypothesis that hypoxia-inducible factor-1 (HIF-1) regulates Ngb levels, using shRNA-mediated knockdown and lentiviral vector-mediated overexpression of the HIF-1α subunit, in cultured neural (HN33) cells. HIF-1α knockdown decreased and HIF-1α overexpression increased Ngb levels, consistent with a connection between HIF-1 and Ngb induction. These findings may have implications for understanding the hypoxia-response repertoire of neural cells and devising therapeutic strategies for neurologic disorders.
doi:10.1016/j.neulet.2012.01.080
PMCID: PMC3526664  PMID: 22342914
neuroglobin; hypoxia; hypoxia-inducible factor-1; stroke
20.  Ablation of Neurogenesis Attenuates Recovery of Motor Function after Focal Cerebral Ischemia in Middle-Aged Mice 
PLoS ONE  2012;7(10):e46326.
Depletion of neurogenesis worsens functional outcome in young-adult mice after focal cerebral ischemia, but whether a similar effect occurs in older mice is unknown. Using middle-aged (12-month-old) transgenic (DCX-TK(+)) mice that express herpes simplex virus thymidine kinase (HSV-TK) under control of the doublecortin (DCX) promoter, we conditionally depleted DCX-positive cells in the subventricular zone (SVZ) and hippocampus by treatment with ganciclovir (GCV) for 14 days. Focal cerebral ischemia was induced by permanent occlusion of the middle cerebral artery (MCAO) or occlusion of the distal segment of middle cerebral artery (dMCAO) on day 14 of vehicle or GCV treatment and mice were killed 24 hr or 12 weeks later. Increased infarct volume or brain atrophy was found in GCV- compared to vehicle-treated middle-aged DCX-TK(+) mice, both 24 hr after MCAO and 12 weeks after dMCAO. More severe motor deficits were also observed in GCV-treated, middle-aged DCX-TK(+) transgenic mice at both time points. Our results indicate that ischemia-induced newborn neurons contribute to anatomical and functional outcome after experimental stroke in middle-aged mice.
doi:10.1371/journal.pone.0046326
PMCID: PMC3482223  PMID: 23110048
21.  PET Imaging of Lung Inflammation with [18F]FEDAC, a Radioligand for Translocator Protein (18 kDa) 
PLoS ONE  2012;7(9):e45065.
Purpose
The translocator protein (18 kDa) (TSPO) is highly expressed on the bronchial and bronchiole epithelium, submucosal glands in intrapulmonary bronchi, pneumocytes and alveolar macrophages in human lung. This study aimed to perform positron emission tomography (PET) imaging of lung inflammation with [18F]FEDAC, a specific TSPO radioligand, and to determine cellular sources enriching TSPO expression in the lung.
Methods
An acute lung injury model was prepared by intratracheal administration of lipopolysaccharide (LPS) to rat. Uptake of radioactivity in the rat lungs was measured with small-animal PET after injection of [18F]FEDAC. Presence of TSPO was examined in the lung tissue using Western blot and immunohistochemical assays.
Results
The uptake of [18F]FEDAC increased in the lung with the progress of inflammation by treatment with LPS. Pretreatment with a TSPO-selective ligand PK11195 showed a significant decrease in the lung uptake of [18F]FEDAC due to competitive binding to TSPO. TSPO expression was elevated in the inflamed lung section and its level responded to the [18F]FEDAC uptake and severity of inflammation. Increase of TSPO expression was mainly found in the neutrophils and macrophages of inflamed lungs.
Conclusion
From this study we conclude that PET with [18F]FEDAC may be a useful tool for imaging TSPO expression and evaluating progress of lung inflammation. Study on human lung using [18F]FEDAC-PET is promising.
doi:10.1371/journal.pone.0045065
PMCID: PMC3440397  PMID: 22984611
22.  CORPUS CALLOSUM AND EXPERIMENTAL STROKE: STUDIES IN CALLOSOTOMIZED RATS AND ACALLOSAL MICE 
Background and Purpose
Interhemispheric inhibition via the corpus callosum has been proposed as an exacerbating factor in outcome from stroke.
Methods
We measured infarct volume and behavioral outcome following middle cerebral artery occlusion in callosotomized rats and acallosal mice.
Results
Neither callosotomy in rats nor callosal agenesis in mice improved infarct volume or behavioral outcome after middle cerebral artery occlusion.
Conclusions
These findings argue against a role for transcallosal projections in exacerbating focal cerebral ischemia.
doi:10.1161/STROKEAHA.111.613349
PMCID: PMC3164743  PMID: 21737800
corpus callosum; stroke; ischemia; callosotomy; callosal agenesis
23.  Nutrigenetics and Nutrigenomics: Viewpoints on the Current Status and Applications in Nutrition Research and Practice 
Nutrigenetics and nutrigenomics hold much promise for providing better nutritional advice to the public generally, genetic subgroups and individuals. Because nutrigenetics and nutrigenomics require a deep understanding of nutrition, genetics and biochemistry and ever new ‘omic’ technologies, it is often difficult, even for educated professionals, to appreciate their relevance to the practice of preventive approaches for optimising health, delaying onset of disease and diminishing its severity. This review discusses (i) the basic concepts, technical terms and technology involved in nutrigenetics and nutrigenomics; (ii) how this emerging knowledge can be applied to optimise health, prevent and treat diseases; (iii) how to read, understand and interpret nutrigenetic and nutrigenomic research results, and (iv) how this knowledge may potentially transform nutrition and dietetic practice, and the implications of such a transformation. This is in effect an up-to-date overview of the various aspects of nutrigenetics and nutrigenomics relevant to health practitioners who are seeking a better understanding of this new frontier in nutrition research and its potential application to dietetic practice.
doi:10.1159/000327772
PMCID: PMC3121546  PMID: 21625170
Dietetics; Nutrigenetics; Nutrigenomics; Nutrition Research; Personalised nutrition
24.  Conditional Depletion of Neurogenesis Inhibits Long-Term Recovery after Experimental Stroke in Mice 
PLoS ONE  2012;7(6):e38932.
We reported previously that ablation of doublecortin (DCX)-immunopositive newborn neurons in mice worsens anatomical and functional outcome measured 1 day after experimental stroke, but whether this effect persists is unknown. We generated transgenic mice that express herpes simplex virus thymidine kinase under control of the DCX promoter (DCX-TK transgenic mice). DCX-expressing and recently divided cells in the rostral subventricular zone (SVZ) and hippocampus of DCX-TK transgenic mice, but not wild-type mice, were specifically depleted after ganciclovir (GCV) treatment for 14 days. Focal cerebral ischemia was induced by permanent distal middle cerebral artery occlusion (MCAO) on day 14 of vehicle or GCV treatment, and mice were killed 12 weeks after MCAO. Infarct volume was significantly increased and neurologic deficits were more severe in GCV- compared to vehicle-treated DCX-TK transgenic mice at first 8 weeks, after depletion of DCX- and bromodeoxyuridine-immunoreactive cells in the SVZ and dentate gyrus following focal ischemia. Our results indicate that endogenous neurogenesis in a critical period following experimental stroke influences the course of long-term recovery.
doi:10.1371/journal.pone.0038932
PMCID: PMC3378583  PMID: 22723908
25.  Effect of Human Neural Precursor Cell Transplantation on Endogenous Neurogenesis after Focal Cerebral Ischemia in the Rat 
Brain research  2010;1374:56-62.
Little is known about the relationship between neuronal cell transplantation and endogenous neurogenesis after experimental stroke. We found previously that transplantation of neuronal precursors derived from BG01 human embryonic stem cells reduced infarct volume and improved behavioral outcome after distal middle cerebral artery occlusion (MCAO) in rats. In this study, transplantation was performed 14 d after distal MCAO and doublecortin (Dcx)-expressing cells in the subventricular zone (SVZ) and subgranular zone of dentate gyrus (SGZ) were counted 60 d post-transplant. Transplantation increased neurogenesis (Dcx expression) in ipsilateral SVZ, but not in contralateral SVZ or either SGZ, in both young adult (3 mo-old) and aged (24-mo-old) rats. These findings suggest that cell-based therapy for stroke may be associated with changes in endogenous adaptive processes, including neurogenesis.
doi:10.1016/j.brainres.2010.12.037
PMCID: PMC3057169  PMID: 21167824
Ischemia; stroke; transplantation; neurogenesis; subventricular zone

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