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1.  The Incidence of Liver Injury in Uyghur Patients Treated for TB in Xinjiang Uyghur Autonomous Region, China, and Its Association with Hepatic Enzyme Polymorphisms NAT2, CYP2E1, GSTM1 and GSTT1 
PLoS ONE  2014;9(1):e85905.
Background and Objective
Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH-induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury.
Methods and Design
In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays.
2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes.
In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury.
PMCID: PMC3900431  PMID: 24465778
2.  Cadmium Accumulation and Metallothionein Biosynthesis in Cadmium-Treated Freshwater Mussel Anodonta woodiana 
PLoS ONE  2015;10(2):e0117037.
This study investigated the distribution of cadmium (Cd) and the protein level of metallothionein (MT) and examined the relationship of Cd accumulation and the MT concentration in different tissues of freshwater mussel Anodonta woodiana following Cd treatment. The mussels were exposed to Cd (4.21, 8.43, 16.86, 33.72 and 67.45 mg L-1) for 24, 48, 72 and 96 h, respectively. After Cd treatment, the gills, mantle, foot, visceral mass and digestive gland tissues were collected for analysis. We found that, in the controls, Cd distributed in all tissues in the concentration order of gills>mantle>foot>visceral mass>digestive gland. Upon Cd treatment, Cd concentration significantly increased in all tissues. The highest Cd accumulation was found in the digestive gland, which was 0.142 mg g-1 (P<0.05). MT levels in the gills and mantle of the mussels increased significantly (P<0.05), which were in positive correlation with Cd accumulation in the tissues (P<0.05). In conclusion, our results demonstrated a correlation between Cd accumulation and MT up-regulation in gills and mantle of the mussels after Cd treatment. It is suggested that the protein level of MT in gills and mantle of Anodonta woodiana is a good biomarker for Cd contamination.
PMCID: PMC4315577  PMID: 25647043
3.  Biocompatibility and osteogenic properties of porous tantalum 
Porous tantalum has been reported to be a promising material for use in bone tissue engineering. In the present study, the biocompatibility and osteogenic properties of porous tantalum were studied in vitro and in vivo. The morphology of porous tantalum was observed using scanning electron microscopy (SEM). Osteoblasts were cultured with porous tantalum, and cell morphology, adhesion and proliferation were investigated using optical microscopy and SEM. In addition, porous tantalum rods were implanted in rabbits, and osteogenesis was observed using laser scanning confocal microscopy and hard tissue slice examination. The osteoblasts were observed to proliferate over time and adhere to the tantalum surface and pore walls, exhibiting a variety of shapes and intercellular connections. The porous tantalum rod connected tightly with the host bone. At weeks 2 and 4 following implantation, new bone and small blood vessels were observed at the tantalum-host bone interface and pores. At week 10 after the porous tantalum implantation, new bone tissue was observed at the tantalum-host bone interface and pores. By week 12, the tantalum-host bone interface and pores were covered with new bone tissue and the bone trabeculae had matured and connected directly with the materials. Therefore, the results of the present study indicate that porous tantalum is non-toxic, biocompatible and a promising material for use in bone tissue engineering applications.
PMCID: PMC4316955  PMID: 25667628
porous tantalum; osteogenesis; biocompatibility; cell toxicity; bone tissue engineering
4.  A Differential Dielectric Affinity Glucose Sensor 
Lab on a chip  2013;14(2):294-301.
A continuous glucose monitor with a differential dielectric sensor implanted within the subcutaneous tissue that determines the glucose in the interstitial fluid is presented. The device, created using microelectromechanical systems (MEMS) technology, consists of sensing and reference modules that are identical in design and placed in close proximity. Each module contains a microchamber housing a pair of capacitive electrodes residing on the device substrate and embedded in a suspended, perforated polymer diaphragm. The microchambers, enclosed in semi-permeable membranes, are filled with either a polymer solution that has specific affinity to glucose or a glucose-insensitive reference solution. To accurately determine the glucose concentration, changes in the permittivity of the sensing and the reference solutions induced by changes in glucose concentration are measured differentially. In vitro characterization demonstrated the sensor capable of measuring glucose concentrations from 0 to 500 mg/dL with resolution and accuracy of ∼1.7 μg/dL and ∼1.74 mg/dL, respectively. In addition, device drift was reduced to 1.4% (uncontrolled environment) and 11% (5 °C of temperature variation) of that from non-differential measurements, indicating significant stability improvements. Preliminary animal testing demonstrated that the differential sensor accurately tracks glucose concentration in blood. This sensor can potentially be used clinically as a subcutaneously implanted continuous monitoring device in diabetic patients.
PMCID: PMC3893139  PMID: 24220675
5.  Receptor Binding Domain Based HIV Vaccines 
BioMed Research International  2015;2015:594109.
This paper analyzes the main trend of the development of acquired immunodeficiency syndrome (AIDS) vaccines in recent years. Designing an HIV-1 vaccine that provides robust protection from HIV-1 infection remains a challenge despite many years of effort. Therefore, we describe the receptor binding domain of gp120 as a target for developing AIDS vaccines. And we recommend some measures that could induce efficiently and produce cross-reactive neutralizing antibodies with high binding affinity. Those measures may offer a new way of the research and development of the potent and broad AIDS vaccines.
PMCID: PMC4312573  PMID: 25667925
6.  A Mechatronic System for Quantitative Application and Assessment of Massage-Like Actions in Small Animals 
Massage therapy has a long history and has been widely believed effective in restoring tissue function, relieving pain and stress, and promoting overall well-being. However, the application of massage-like actions and the efficacy of massage are largely based on anecdotal experiences that are difficult to define and measure. This leads to a somewhat limited evidence-based interface of massage therapy with modern medicine. In this study, we introduce a mechatronic device that delivers highly reproducible massage-like mechanical loads to the hind limbs of small animals (rats and rabbits), where various massage-like actions are quantified by the loading parameters (magnitude, frequency and duration) of the compressive and transverse forces on the subject tissues. The effect of massage is measured by the difference in passive viscoelastic properties of the subject tissues before and after mechanical loading, both obtained by the same device. Results show that this device is useful in identifying the loading parameters that are most conducive to a change in tissue mechanical properties, and can determine the range of loading parameters that result in sustained changes in tissue mechanical properties and function. This device presents the first step in our effort for quantifying the application of massage-like actions used clinically and measurement of their efficacy that can readily be combined with various quantitative measures (e.g., active mechanical properties and physiological assays) for determining the therapeutic and mechanistic effects of massage therapies.
PMCID: PMC3893773  PMID: 23943071
Medical devices; Massage therapy; Mechanics; Viscoelasticity
7.  Hierarchical Unbiased Graph Shrinkage (HUGS): A Novel Groupwise Registration for Large Data Set 
NeuroImage  2013;84:626-638.
Normalizing all images in a large data set into a common space is a key step in many clinical and research studies, e.g., for brain development, maturation, and aging. Recently, groupwise registration has been developed for simultaneous alignment of all images without selecting a particular image as template, thus potentially avoiding bias in the registration. However, most conventional groupwise registration methods do not explore the data distribution during the image registration. Thus, their performance could be affected by large inter-subject variations in the data set under registration. To solve this potential issue, we propose to use a graph to model the distribution of all image data sitting on the image manifold, with each node representing an image and each edge representing the geodesic pathway between two nodes (or images). Then, the procedure of warping all images to their population center turns to the dynamic shrinking of the graph nodes along their graph edges until all graph nodes become close to each other. Thus, the topology of image distribution on the image manifold is always preserved during the groupwise registration. More importantly, by modeling the distribution of all images via a graph, we can potentially reduce registration error since every time each image is warped only according to its nearby images with similar structures in the graph. We have evaluated our proposed groupwise registration method on both infant and adult data sets, by also comparing with the conventional group-mean based registration and the ABSORB methods. All experimental results show that our proposed method can achieve better performance in terms of registration accuracy and robustness.
PMCID: PMC4113479  PMID: 24055505
Unbiased groupwise registration; graph shrinking; image manifold; diffeomorphism
8.  Integrated prevention of mother-to-child transmission for human immunodeficiency virus, syphilis and hepatitis B virus in China 
China continues to face challenges in eliminating mother-to-child transmission of human immunodeficiency virus (HIV), syphilis and hepatitis B virus (HBV).
In 2010, a programme that integrated and standardized prevention of mother-to-child transmission (PMTCT) efforts for HIV, syphilis and HBV was implemented in 1156 counties. At participating antenatal care clinics, pregnant women were offered all three tests concurrently and free of charge. Further interventions such as free treatment, prophylaxis and testing for mothers and their children were provided for HIV and syphilis.
Local setting
China’s national PMTCT HIV programme started in 2003, at which time there were no national programmes for perinatal syphilis and HBV. In 2009, the rate of maternal-to-child transmission of HIV was 8.1% (57/702). Reported congenital syphilis was 60.8 per 100 000 live births. HBV infection was 7.2% of the overall population infected.
Relevant changes
Between 2010 and 2013 the number of pregnant women attending antenatal care clinics with integrated PMTCT services increased from 5.5 million to 13.1 million. In 2013, 12.7 million pregnant women were tested for HIV, 12.6 million for syphilis and 12.7 million for HBV. Mother-to-child transmission of HIV fell to 6.7% in 2013. Data on syphilis transmission are not yet available.
Lessons learnt
Integrated PMTCT services proved to be feasible and effective, and they are now part of the routine maternal and child health services provided to infected women. The services are provided through a collaboration between maternal and child health clinics, the national and local Centers for Disease Control and Prevention, and general hospitals.
PMCID: PMC4271682  PMID: 25558108
9.  A Soluble Activin Receptor Type IIB Does Not Improve Blood Glucose in Streptozotocin-Treated Mice 
Type 1 diabetes mellitus (T1DM), or insulin dependent DM, is accompanied by decreased muscle mass. The growth factor myostatin (MSTN) is a negative regulator of muscle growth, and a loss of MSTN signaling has been shown to increase muscle mass and prevent the development of obesity, insulin resistance and lipodystrophic diabetes in mice. The effects of MSTN inhibition in a T1DM model on muscle mass and blood glucose are unknown. We asked whether MSTN inhibition would increase muscle mass and decrease hyperglycemia in mice treated with streptozotocin (STZ) to destroy pancreatic beta cells. After diabetes developed, mice were treated with a soluble MSTN/activin receptor fused to Fc (ACVR2B:Fc). ACVR2B:Fc increased body weight and muscle mass compared to vehicle treated mice. Unexpectedly, ACVR2B:Fc reproducibly exacerbated hyperglycemia within approximately one week of administration. ACVR2B:Fc treatment also elevated serum levels of the glucocorticoid corticosterone. These results suggest that although MSTN/activin inhibitors increased muscle mass, they may be counterproductive in improving health in patients with T1DM.
PMCID: PMC4279095  PMID: 25561902
activin receptor; glucocorticoid; myostatin; muscle hypertrophy; type 1 diabetes
10.  Recombinant Treponema pallidum Protein Tp0965 Activates Endothelial Cells and Increases the Permeability of Endothelial Cell Monolayer 
PLoS ONE  2014;9(12):e115134.
The recombinant Treponema pallidum protein Tp0965 (rTp0965), one of the many proteins derived from the genome of T. pallidum subsp. pallidum, shows strong immunogenicity and immunoreactivity. In this study, we investigated the effects of rTp0965 on the endothelial barrier. Treatment of human umbilical vein endothelial cells (HUVECs) with rTp0965 resulted in increased levels of ICAM-1, E-selectin, and MCP-1 mRNA and protein expression. These increases contributed to the adhesion and chemataxis of monocytes (THP-1 cells) to HUVECs preincubated with rTp0965. In addition, rTp0965 induced reorganization of F-actin and decreased expression of claudin-1 in HUVECs. Interestingly, inhibition of the RhoA/ROCK signal pathway protected against rTp0965-induced higher endothelial permeability as well as transendothelial migration of monocytes. These data indicate that Tp0965 protein may play an important role in the immunopathogenesis of syphilis.
PMCID: PMC4267829  PMID: 25514584
11.  Utilisation of adsorption and desorption for simultaneously improving protein crystallisation success rate and crystal quality 
Scientific Reports  2014;4:7308.
High-quality protein crystals of suitable size are an important prerequisite for applying X-ray crystallography to determine the 3-dimensional structure of proteins. However, it is often difficult to obtain protein crystals of appropriate size and quality because nucleation and growth processes can be unsuccessful. Here, we show that by adsorbing proteins onto porous polystyrene-divinylbenzene microspheres (SDB) floating on the surface of the crystallisation solution, a localised high supersaturation region at the surface of the microspheres and a low supersaturation region below the microspheres can coexist in a single solution. The crystals will easily nucleate in the region of high supersaturation, but when they grow to a certain size, they will sediment to the region of low supersaturation and continue to grow. In this way, the probability of crystallisation and crystal quality can be simultaneously increased in a single solution without changing other crystallisation parameters.
PMCID: PMC4255177  PMID: 25471817
12.  Microfluidic Array with Integrated Oxygenation Control for Real-Time Live-Cell Imaging: Effect of Hypoxia on Physiology of Microencapsulated Pancreatic Islets 
Analytical chemistry  2013;85(23):11240-11249.
In this report, we present a novel microfluidic islet array based on a hydrodynamic trapping principle. The lab-on-a-chip studies with live-cell multiparametric imaging allow understanding of physiological and pathophysiological changes of microencapsulated islets under hypoxic conditions. Using this microfluidic array and imaging analysis techniques, we demonstrate that hypoxia impairs the function of microencapsulated islets at single islet level, showing a heterogeneous pattern reflected in intracellular calcium signaling, mitochondrial energetic, and redox activity. Our approach demonstrates an improvement over conventional hypoxia chambers that is able to rapidly equilibrate to true hypoxia levels through the integration of dynamic oxygenation. This work demonstrates the feasibility of array-based cellular analysis and opens up new modality to conduct informative analysis and cell-based screening for microencapsulated pancreatic islets.
PMCID: PMC3921903  PMID: 24083835
Microfluidic; Hydrodynamic trap; Islet trapping array; Microencapsulation; Pancreatic islets of Langerhans; Hypoxia; Calcium; Mitochondrial potential; Insulin secretion
13.  Population genetic evidence for speciation pattern and gene flow between Picea wilsonii, P. morrisonicola and P. neoveitchii 
Annals of Botany  2013;112(9):1829-1844.
Background and Aims
Genetic drift due to geographical isolation, gene flow and mutation rates together make it difficult to determine the evolutionary relationships of present-day species. In this study, population genetic data were used to model and decipher interspecific relationships, speciation patterns and gene flow between three species of spruce with similar morphology, Picea wilsonii, P. neoveitchii and P. morrisonicola. Picea wilsonii and P. neoveitchii occur from central to north-west China, where they have overlapping distributions. Picea morrisonicola, however, is restricted solely to the island of Taiwan and is isolated from the other two species by a long distance.
Sequence variations were examined in 18 DNA fragments for 22 populations, including three fragments from the chloroplast (cp) genome, two from the mitochondrial (mt) genome and 13 from the nuclear genome.
Key Results
In both the cpDNA and the mtDNA, P. morrisonicola accumulated more species-specific mutations than the other two species. However, most nuclear haplotypes of P. morrisonicola were shared by P. wilsonii, or derived from the dominant haplotypes found in that species. Modelling of population genetic data supported the hypothesis that P. morrisonicola derived from P. wilsonii within the more recent past, most probably indicating progenitor–derivative speciation with a distinct bottleneck, although further gene flow from the progenitor to the derivative continued. In addition, the occurrence was detected of an obvious mtDNA introgression from P. neoveitchii to P. wilsonii despite their early divergence.
The extent of mutation, introgression and lineage sorting taking place during interspecific divergence and demographic changes in the three species had varied greatly between the three genomes. The findings highlight the complex evolutionary histories of these three Asian spruce species.
PMCID: PMC3838563  PMID: 24220103
Gene flow; island speciation; mtDNA introgression; nuclear loci; Picea wilsonii; P. neoveitchii; P. morrisonicola; spruce
14.  Acceptance of Male Circumcision Among Male Rural-to-Urban Migrants in Western China 
AIDS Research and Human Retroviruses  2013;29(12):1582-1588.
To describe the acceptability of male circumcision (MC) and explore potential factors associated with MC acceptability among male rural-to-urban migrants in western China, a cross-sectional survey of MC acceptability was conducted with 1,904 subjects in three western provinces with high HIV prevalence (Guangxi, Chongqing, and Xinjiang) in China between June 2009 and November 2009. Through face-to-face interviews, the participants completed a self-administered questionnaire about demographics, MC knowledge, willingness and reasons to accept or refuse MC, sexual behaviors, and other psychosocial variables. Factors associated with acceptability of MC were identified by multiple logistic regression analysis. Of the participants (n=1,904), 710 men were willing to accept MC (37.3%); the reasons included promotion of the partners' genital hygiene (54.9%), redundant prepuce or phimosis (43.1%), enhancement of sexual pleasure (40.6%), prevention of penile inflammation or cancer (35.5%), and protection against HIV and sexual transmitted diseases (STDs)(31.1%). A multivariable logistic regression showed that four factors were associated with acceptability of MC, including education level (OR=1.286, 95% CI=1.025∼1.614), redundant prepuce or phimosis (OR=13.751, 95% CI=10.087∼18.745), having one or more circumcised friends (OR=2.468, 95% CI=1.953∼3.119), and having sexual intercourse with a temporary partner in the past year (OR=1.543, 95% CI=1.101∼2.162). Compared with previously published data among the general population in China or worldwide, the acceptability of MC (37.3%) was low among the male rural-to-urban migrants in western China. Nevertheless, appropriate education could greatly improve the acceptability of MC. More public campaigns and health education on MC are needed to increase the rate of MC in China.
PMCID: PMC3848437  PMID: 23931654
15.  Chronic progressive external ophthalmoplegia with inflammatory myopathy 
Chronic progressive external ophthalmoplegia is one of mitochondrial disorders, characterized by ptosis, limitation of eye movement, variably severe bulbar muscle weakness and proximal limb weakness. Chronic progressive external ophthalmoplegia complicated with acquired disease is extremely rare. We report a 44 years old male patient with more than 20 years of chronic progressive bilateral ptosis and limitation of eye movements manifested dysarthria, dysphagia and neck muscle weakness for 3 years. The first muscle biopsy showed red-ragged fibers and cytochrome c oxidase negative fibers as well as inflammatory cells infiltration. Electron microscopy revealed paracrystalline inclusions. Mitochondrial genetic analysis demonstrated a large-scale mtDNA deletion of m.8470_13446del4977. The patient was treated with prednisone. In a three-year follow-up study, the second biopsy was performed. Before the treatment, except bilateral ptosis and external ophthalmopelgia, this patient presented bulbar muscle weakness and neck muscle weakness. After treated with prednisone, the symptoms of dysphagia, dysarthria and neck muscle weakness were significantly improved, and the second biopsy showed only mitochondrial myopathy pathology but the inflammations disappeared. Here, we report a patient with chronic progressive external ophthalmoplegia complicated with inflammatory myopathy and after treated with prednisone as myositis, he had a significant therapeutic effect.
PMCID: PMC4314000
Chronic progressive external ophthalmoplegia; mitochondrial DNA deletions; inflammatory myopathy
16.  Col10a1-Runx2 transgenic mice with delayed chondrocyte maturation are less susceptible to developing osteoarthritis 
Osteoarthritis (OA) is the most common joint disease affecting close to 27 million Americans. The pathological change of OA joint is characterized by cartilage degradation and osteophyte formation that have been associated with OA initiation and progression respectively. Upon OA progression, articular chondrocytes undergo hypertrophic differentiation, a process usually occurs only in growth plate chondrocytes during endochondral ossification, suggesting a role of chondrocyte hypertrophy in OA pathogenesis. However, how altered chondrocyte hypertrophy, i.e. accelerated or delayed chondrocyte hypertrophy, influences OA development has not been fully elucidated. We have previously generated transgenic (TG) mice over-expressing Runx2, an essential transcription factor for chondrocyte hypertrophy, using hypertrophic chondrocyte-specific mouse type X collagen gene (Col10a1) control elements. These Col10a1-Runx2 TG mice show delayed chondrocyte hypertrophy and apoptosis in long bone sections of embryonic and new-born mice compared to their wild-type (WT) littermates. Here, we report further analysis of the skeletal phenotypes of these mice at postnatal stages. We have performed histological analysis of 1-month old TG and WT mice. Delayed chondrocyte hypertrophy was also observed in growth plate of TG mice. In addition, μCT analysis showed that the femur length was significantly shorter in TG mice (p = 0.033). Thinner cortical bone and markedly decreased BV/TV were also detected in TG mice compared to their WT littermates (p = 0.027), suggesting that delayed chondrocyte hypertrophy affects postnatal long bone development. Interestingly, histological analysis detected less articular cartilage absorption, while immunohistochemistry assay detected upregulated Sox9 expression in TG mouse joints compared to WT controls, implying that delayed chondrocyte hypertrophy may be OA protective. Indeed, we have performed Tgf-β1 injection and enforced uphill treadmill running (TTR model) to induce OA in TG and WT littermates. The results showed that WT littermates displayed characteristic pathology of fibrotic remodeling at the joint margins and focal cartilage erosion, while the joints in TG mice were essentially protected from remodeling responses, demonstrating that mice with delayed chondrocyte hypertrophy are not susceptible to developing OA. Further translational studies characterizing the role of chondrocyte hypertrophy during OA progression will facilitate identification of therapeutic targets to stop or slow down this degenerative and progressive human joint disease.
PMCID: PMC4297341  PMID: 25628784
Col10a1; Runx2; transgenic mice; Tgf-β1 injection; treadmill running; chondrocyte hypertrophy or maturation; osteoarthritis
17.  Preliminary study of the association between corneal histocytological changes and surgically induced astigmatism after phacoemulsification 
BMC Ophthalmology  2014;14(1):134.
Surgically induced astigmatism (SIA) was one of the factors that influences the desirable refractive outcome, and it was related to the length, type, location, structure of the incision and to the suture closure technique, etc. The aim was to evaluate the association of corneal histocytological changes with SIA after phacoemulsification.
The study enrolled 68 cases of cataract patient (68 eyes). Corneal histocytological parameters at corneal incision, central cornea and contralateral incision obtained by confocal microscope through focusing (CMTF) were compared preoperatively and 1 week, 2 weeks, 1 month, 3 months and 6 months postoperatively. These biometric parameters included the endothelial cell density, keratocyte density of posterior stromal layer, and the morphological changes. SIA was calculated by Jaffe’s vector analysis.
1 From preoperatively to 1 week, 2 weeks, 1 month, 3 months and 6 months postoperatively, the endothelail cell density was decreased significantly (p < 0.05). Keratocyte density of posterior stroma layer was increased significantly only at 1 week, 2 weeks, 1 month, 3 months postoperatively (p <0.05), but not statistically significant (p = 0.173) at 6 months postoperatively compared to preoperative values. 2 The histocytological observations indicated that the morphology changed significantly postoperatively at the corneal incision, including the cell absent area, wave-like area, dot-like and mass-like hyperreflection, stripe-like absent area, in the endothelial layer, and the keratocyte activation, microfolds, irregular hyporeflective or hyperreflective belt, and a little dot-like hyperreflection in the posterior stroma layer. 3 The reduction of the endothelial cell density at the corneal incision at 1 week, 2 weeks, 1 month postoperatively, were positively correlated with SIA (P1 week = 0.003, P2 weeks = 0.003, P1 month = 0.032), while others were not associated with SIA statistically.
The reduction of endothelail cell density and the histocytological changes at the corneal incision were associated with SIA. The underlining mechanism needs further study.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2415-14-134) contains supplementary material, which is available to authorized users.
PMCID: PMC4256752  PMID: 25409954
Cataract; Phacoemulsification; Corneal endothelium; Corneal keratocytes; Confocal microscopy; SIA
18.  Correlation analysis of peripheral blood T cell subgroups, immunoglobulin and prognosis of early hepatocellular carcinoma after hepatectomy 
To investigate the prediction value of preoperative changes in the immunological function for the prognosis of hepatocellular carcinoma (HCC) after hepatectomy, 158 cases of HCC patients who received liver resection in our hospital from 2009 to 2010 were enrolled in this study. Immune indices [CD3+, CD4+, CD8+, CD19+ and natural killer (NK), IgA, IgM, IgG], AFP level were calculated. The differences between preoperation and postoperation group, exclude were not both statistically significant (both P > 0.05), whereas IgA group was not (P < 0.05),The follow-up data showed that the 3-year recurrence rates of high level group on HBsAg, CD3, CD4, CD8, CD19 and IgGwerelarger than that of low level group,while the 3-year recurrence rates of high level group on AFP, NK, IgA and IgM smaller than that of low level group, and we found that CD3+, CD4+, CD8+ and NK+, CD19+, HBsAg, IgA and IgG above were statistically different (P < 0.05), AFP and IgM were no difference with prognosis of HCC (P > 0.05).The markers level were not both statistically significant with age, gender, grade, tumor size (P > 0.05). Multiple logistic regression analysis indicated that CD4+, CD8+ and NK+ were closely correlated with HCC postoperative survival rate (P < 0.05) (Y = 1.262×CD4++1.448×CD8+-0.646×NK+). Construction of Cox’s proportional hazards regression model showed IgA and IgG were correlated with HCC postoperative survival rate at a trend (P = 0.079) (Y = 127.9×IgG-28.7×IgM). Preoperative Immune indices (CD4+, CD8+, NK+, IgA, IgG) were closely correlated with HCC survival rate and these were considerable predictive value for the malignantfeature and prognosis of HCC.
PMCID: PMC4276201  PMID: 25550943
Subgroups; immunoglobulin; hepatocellular carcinoma; hepatectomy; Prognosis
19.  Ectromelia Virus Encodes a BTB/kelch Protein, EVM150, That Inhibits NF-κB Signaling 
Journal of Virology  2014;88(9):4853-4865.
The NF-κB signaling pathway plays a critical role in inflammation and innate immunity. Consequently, many viruses have evolved strategies to inhibit NF-κB in order to facilitate replication and evasion of the host immune response. Recently, we determined that ectromelia virus, the causative agent of mousepox, contains a family of four BTB/kelch proteins that interact with cullin-3-based ubiquitin ligases. We demonstrate here that expression of EVM150, one of the four BTB/kelch proteins, inhibited NF-κB activation induced by tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). Although EVM150 inhibited NF-κB p65 nuclear translocation, IκBα degradation was observed, indicating that EVM150 functioned downstream of IκBα degradation. Significantly, expression of the BTB-only domain of EVM150 blocked NF-κB activation, demonstrating that EVM150 functioned independently of the kelch domain and its role as an adapter for cullin-3-based ubiquitin ligases. Furthermore, cullin-3 knockdown by small interfering RNA demonstrated that cullin-3-based ubiquitin ligases are dispensable for TNF-α-induced NF-κB activation. Interestingly, nuclear translocation of IRF3 and STAT1 still occurred in the presence of EVM150, indicating that EVM150 prevented NF-κB nuclear translocation specifically. In addition to identifying EVM150 as an inhibitor of the NF-κB pathway, this study provides new insights into the role of BTB/kelch proteins during virus infection.
IMPORTANCE With the exception of virulence studies, little work has been done to determine the role of poxviral BTB/kelch proteins during infection. This study, for the first time, has identified a mechanism for the ectromelia virus BTB/kelch protein EVM150. Here, we show that EVM150 is a novel inhibitor of the cellular NF-κB pathway, an important component of the antiviral response. This study adds EVM150 to the growing list of NF-κB inhibitors in poxviruses and provides new insights into the role of BTB/kelch proteins during virus infection.
PMCID: PMC3993801  PMID: 24522926
20.  Homer1 Alternative Splicing Is Regulated by Gonadotropin-Releasing Hormone and Modulates Gonadotropin Gene Expression 
Molecular and Cellular Biology  2014;34(10):1747-1756.
Hypothalamic gonadotropin-releasing hormone (GnRH) plays a critical role in reproductive physiology by regulating follicle-stimulating hormone (FSH) and luteinizing hormone (LH) gene expression in the pituitary. Analysis of gonadotrope deep-sequencing data identified a global regulation of pre-mRNA splicing by GnRH. Homer1, a gene encoding a postsynaptic density scaffolding protein, was selected for further study. Homer1 expresses a short splice form, Homer1a, and more-abundant long transcripts Homer1b/c. GnRH induced a modest increase in Homer1b/c expression and a dramatic increase in the Homer1a splice form. G protein knockdown studies suggested that the Homer1 induction, but not the regulated splicing, was Gαq/11 dependent. Phosphorylation of the splicing regulator SRp20 was found to be induced by GnRH. SRp20 depletion attenuated the GnRH-induced increase in the Homer1a-to-Homer1b/c ratio and modulated the effects of GnRH on FSHβ and LHβ expression. Homer1 gene knockdown resulted in increased GnRH-induced FSHβ and LHβ transcript levels. Furthermore, splice-form-specific reduction of Homer1b/c increased both FSHβ and LHβ mRNA induction, whereas reduction of Homer1a had the opposite effect on FSHβ induction. These results indicate that the regulation of Homer1 splicing by GnRH contributes to gonadotropin gene control.
PMCID: PMC4019030  PMID: 24591653
21.  Next generation sequencing unravels the biosynthetic ability of Spearmint (Mentha spicata) peltate glandular trichomes through comparative transcriptomics 
BMC Plant Biology  2014;14(1):292.
Plant glandular trichomes are chemical factories with specialized metabolic capabilities to produce diverse compounds. Aromatic mint plants produce valuable essential oil in specialised glandular trichomes known as peltate glandular trichomes (PGT). Here, we performed next generation transcriptome sequencing of different tissues of Mentha spicata (spearmint) to identify differentially expressed transcripts specific to PGT. Our results provide a comprehensive overview of PGT’s dynamic metabolic activities which will help towards pathway engineering.
Spearmint RNAs from 3 different tissues: PGT, leaf and leaf stripped of PGTs (leaf-PGT) were sequenced by Illumina paired end sequencing. The sequences were assembled de novo into 40,587 non-redundant unigenes; spanning a total of 101 Mb. Functions could be assigned to 27,025 (67%) unigenes and among these 3,919 unigenes were differentially expressed in PGT relative to leaf - PGT. Lack of photosynthetic transcripts in PGT transcriptome indicated the high levels of purity of isolated PGT, as mint PGT are non-photosynthetic. A significant number of these unigenes remained unannotated or encoded hypothetical proteins. We found 16 terpene synthases (TPS), 18 cytochrome P450s, 5 lipid transfer proteins and several transcription factors that were preferentially expressed in PGT. Among the 16 TPSs, two were characterized biochemically and found to be sesquiterpene synthases.
The extensive transcriptome data set renders a complete description of genes differentially expressed in spearmint PGT. This will facilitate the metabolic engineering of mint terpene pathway to increase yield and also enable the development of strategies for sustainable production of novel or altered valuable compounds in mint.
Electronic supplementary material
The online version of this article (doi:10.1186/s12870-014-0292-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4232691  PMID: 25367433
Spearmint; Next generation sequencing; Transcriptome; Glandular trichomes; Terpenes; Carvone; Terpene synthases
22.  Predictive Value of Decoy Receptor 3 in Postoperative Nosocomial Bacterial Meningitis 
Nosocomial bacterial meningitis requires timely treatment, but what is difficult is the prompt and accurate diagnosis of this disease. The aim of this study was to assess the potential role of decoy receptor 3 (DcR3) levels in the differentiation of bacterial meningitis from non-bacterial meningitis. A total of 123 patients were recruited in this study, among them 80 patients being with bacterial meningitis and 43 patients with non-bacterial meningitis. Bacterial meningitis was confirmed by bacterial culture of cerebrospinal fluid (CSF) culture and enzyme-linked immunosorbent assay (ELISA) was used to detect the level of DcR3 in CSF. CSF levels of DcR3 were statistically significant between patients with bacterial meningitis and those with non-bacterial meningitis (p < 0.001). A total of 48.75% of patients with bacterial meningitis received antibiotic >24 h before CSF sampling, which was much higher than that of non-bacterial meningitis. CSF leucocyte count yielded the highest diagnostic value, with an area under the receiver operating characteristic curve (ROC) of 0.928, followed by DcR3. At a critical value of 0.201 ng/mL for DcR3, the sensitivity and specificity were 78.75% and 81.40% respectively. DcR3 in CSF may be a valuable predictor for differentiating patients with bacterial meningitis from those with non-bacterial meningitis. Further studies are needed for the validation of this study.
PMCID: PMC4264149  PMID: 25372942
decoy receptor 3; DcR3; bacterial meningitis; diagnosis
23.  Carboxypeptidase B serves as a protective mediator in osteoarthritis 
We previously demonstrated that carboxypeptidase B (CPB) protects against joint erosion in rheumatoid arthritis by inactivating complement component C5a. We also found that levels of CPB are abnormally high in the synovial fluid of individuals with another joint disease, osteoarthritis (OA). In this study, we investigated whether CPB has a role in the pathogenesis of OA.
We compared the development of OA in CPB-deficient (Cpb2−/−) mice and wild-type mice by subjecting them to medial meniscectomy and four months later histologically assessing cartilage damage, osteophyte formation, and synovitis in the mouse stifle joints. We measured levels of proCPB, proinflammatory cytokines, and complement components in synovial fluid samples from patients with symptomatic and radiographic knee OA. Finally, we used ELISA, flow cytometry, and hemolytic assays to assess the effect of CPB on formation of membrane attack complex (MAC)—a complement effector critical to OA pathogenesis.
Cpb2−/− mice developed dramatically greater cartilage damage than wild-type mice (P<0.01) and had a greater number of osteophytes (P<0.05) and degree of synovitis (P<0.05). In synovial fluids from OA patients, high levels of proCPB were associated with high levels of proinflammatory cytokines and complement components, and levels of proCPB correlated positively with those of MAC. In in vitro complement activation assays, activated CPB suppressed the formation of MAC as well as MAC-induced hemolysis.
Our data suggest that CPB protects against inflammatory destruction of the joints in OA, at least in part by inhibiting complement activation.
PMCID: PMC4215006  PMID: 24449579
24.  Unique Epitopes Recognized by Monoclonal Antibodies against HP-PRRSV: Deep Understanding of Antigenic Structure and Virus-Antibody Interaction 
PLoS ONE  2014;9(10):e111633.
Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) is a member of the genus Arterivirus within the family Arteriviridae. N and GP3 proteins are the immunodominance regions of the PRRSV viral proteins. To identify the B-cell linear antigenic epitopes within HP-PRRSV N and GP3 proteins, two monoclonal antibodies (mAbs) against N and GP3 proteins were generated and characterized, designated as 3D7 and 1F10 respectively. The mAb 3D7 recognized only HuN4-F112 not the corresponding virulent strain (HuN4-F5). It also recognized two other commercial vaccines (JXA1-R and TJM-F92), but not two other HP-PRRSV strains (HNZJJ-F1 and HLJMZ-F2). The B-cell epitope recognized by the mAb 3D7 was localized to N protein amino acids 7–33. Western blot showed that the only difference amino acid between HuN4-F112-N and HuN4-F5-N did not change the mAb 3D7 recognization to N protein. The epitope targeted by the mAb 1F10 was mapped by truncated proteins. We found a new epitope (68-76aa) can be recognized by the mAb. However, the epitope could not be recognized by the positive sera, suggesting the epitope could not induce antibody in pigs. These results should extend our understanding of the antigenic structure of the N protein and antigen-antibody reactions of the GP3 protein in different species.
PMCID: PMC4216098  PMID: 25360600
25.  Suppression of Alzheimer-Associated Inflammation by Microglial Prostaglandin-E2 EP4 Receptor Signaling 
The Journal of Neuroscience  2014;34(17):5882-5894.
A persistent and nonresolving inflammatory response to accumulating Aβ peptide species is a cardinal feature in the development of Alzheimer's disease (AD). In response to accumulating Aβ peptide species, microglia, the innate immune cells of the brain, generate a toxic inflammatory response that accelerates synaptic and neuronal injury. Many proinflammatory signaling pathways are linked to progression of neurodegeneration. However, endogenous anti-inflammatory pathways capable of suppressing Aβ-induced inflammation represent a relatively unexplored area. Here we report that signaling through the prostaglandin-E2 (PGE2) EP4 receptor potently suppresses microglial inflammatory responses to Aβ42 peptides. In cultured microglial cells, EP4 stimulation attenuated levels of Aβ42-induced inflammatory factors and potentiated phagocytosis of Aβ42. Microarray analysis demonstrated that EP4 stimulation broadly opposed Aβ42-driven gene expression changes in microglia, with enrichment for targets of IRF1, IRF7, and NF-κB transcription factors. In vivo, conditional deletion of microglial EP4 in APPSwe-PS1ΔE9 (APP-PS1) mice conversely increased inflammatory gene expression, oxidative protein modification, and Aβ deposition in brain at early stages of pathology, but not at later stages, suggesting an early anti-inflammatory function of microglial EP4 signaling in the APP-PS1 model. Finally, EP4 receptor levels decreased significantly in human cortex with progression from normal to AD states, suggesting that early loss of this beneficial signaling system in preclinical AD development may contribute to subsequent progression of pathology.
PMCID: PMC3996215  PMID: 24760848
Aβ peptide; Alzheimer's disease; microglia; neuroinflammation; PGE2; receptor

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