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1.  Characterization of the DNA methylome and its interindividual variation in human peripheral blood monocytes 
Epigenomics  2013;5(3):10.2217/epi.13.18.
Aim
Peripheral blood monocytes (PBMs) play multiple and critical roles in the immune response, and abnormalities in PBMs have been linked to a variety of human disorders. However, the DNA methylation landscape in PBMs is largely unknown. In this study, we characterized epigenome-wide DNA methylation profiles in purified PBMs.
Materials & methods
PBMs were isolated from freshly collected peripheral blood from 18 unrelated healthy postmenopausal Caucasian females. Epigenome-wide DNA methylation profiles (the methylome) were characterized by using methylated DNA immunoprecipitation combined with high-throughput sequencing.
Results
Distinct patterns were revealed at different genomic features. For instance, promoters were commonly (~58%) found to be unmethylated; whereas protein coding regions were largely (~84%) methylated. Although CpG-rich and -poor promoters showed distinct methylation patterns, interestingly, a negative correlation between promoter methylation levels and gene transcription levels was consistently observed across promoters with high to low CpG densities. Importantly, we observed substantial interindividual variation in DNA methylation across the individual PBM methylomes and the pattern of this interindividual variation varied between different genomic features, with highly variable regions enriched for repetitive DNA elements. Furthermore, we observed a modest but significant excess (p < 2.2 × 10−16) of genes showing a negative correlation between interindividual promoter methylation and transcription levels. These significant genes were enriched in biological processes that are closely related to PBM functions, suggesting that alteration in DNA methylation is likely to be an important mechanism contributing to the interindividual variation in PBM function, and PBM-related phenotypic and disease-susceptibility variation in humans.
Conclusion
This study represents a comprehensive analysis of the human PBM methylome and its interindividual variation. Our data provide a valuable resource for future epigenomic and multiomic studies, exploring biological and disease-related regulatory mechanisms in PBMs.
doi:10.2217/epi.13.18
PMCID: PMC3874233  PMID: 23750642
DNA methylation; interindividual variation; peripheral blood monocyte
2.  Interplay Between the Cancer Genome and Epigenome 
Cell  2013;153(1):38-55.
Cancer arises as a consequence of cumulative disruptions to cellular growth control, with Darwinian selection for those heritable changes which provide the greatest clonal advantage. These traits can be acquired and stably maintained by either genetic or epigenetic means. Here we explore the ways in which alterations in the genome and epigenome influence each other and cooperate to promote oncogenic transformation. Disruption of epigenomic control is pervasive in malignancy, and can be classified as an enabling characteristic of cancer cells, akin to genome instability and mutation.
doi:10.1016/j.cell.2013.03.008
PMCID: PMC3648790  PMID: 23540689
3.  Constructing hierarchical submicrotubes from interconnected TiO2 nanocrystals for high reversible capacity and long-life lithium-ion batteries 
Scientific Reports  2014;4:4479.
Here, we report a facile hydrothermal approach for synthesizing anatase TiO2 hierarchical mesoporous submicrotubes (ATHMSs) with the aid of long-chain polymer as soft template. The TiO2 nanocrystals, with sizes of 6–8 nm, are well interconnected with each other to build tubular architectures with diameters of 0.3–1.5 μm and lengths of 10–25 μm. Such highly porous structures give rise to very large specific surface area of 201.9 m2 g−1 and 136.8 m2 g−1 for the as-prepared and annealed samples, respectively. By using structurally stable ATHMSs as anode materials for lithium-ion batteries, they exhibited high reversible capacity, long cycling life and excellent cycling stability. Even after 1000 cycles, such ATHMS electrodes retained a reversible discharge capacity as high as 150 mAh g−1 at the current density of 1700 mA g−1, maintaining 92% of the initial discharge capacity (163 mAh g−1).
doi:10.1038/srep04479
PMCID: PMC3966052  PMID: 24667431
4.  Modified total en bloc spondylectomy for thoracolumbar spinal tumors via a single posterior approach 
European Spine Journal  2012;22(3):556-564.
Purpose
The objectives of this study were to describe our surgical management with a modified total en bloc spondylectomy (TES) and to evaluate the clinical effects in patients with thoracolumbar tumors.
Methods
Sixteen consecutive patients with thoracolumbar neoplasms underwent a modified TES via single posterior approach followed by dorsoventral reconstruction from December 2008 to July 2011. Details of the modified technique were described and the patients’ clinical information was retrospectively reviewed and analyzed.
Results
Significant improvements in neurological function were achieved in most of the patients. Local pain or radicular leg pain was relieved postoperatively. The mean operation time was 7.2 h, with an average blood loss of 2,300 ml. No major complications, instrumentation failure or local recurrence was found at the final follow-up. Five patients died of the disease during mean 14-month (3.0–23) follow-up.
Conclusions
The modified TES with a single posterior approach is feasible, safe and effective for thoracolumbar spine tumors.
doi:10.1007/s00586-012-2460-3
PMCID: PMC3585635  PMID: 22864795
Total en bloc spondylectomy; Modified surgical techniques; Spinal tumors; Single posterior approach; Thoracolumbar spine
5.  Genome-Wide Association Study Identified UQCC Locus for Spine Bone Size in Humans 
Bone  2012;53(1):129-133.
Bone size (BS) contributes significantly to the risk of osteoporotic fracture. Osteoporotic spine fracture is one of the most disabling outcomes of osteoporosis. This study aims to identify genomic loci underlying spine BS variation in humans.
We performed a genome-wide association scan in 2,286 unrelated Caucasians using Affymetrix 6.0 SNP arrays. Areal BS (cm2) at lumbar spine was measured using dual energy X-ray absorptiometry scanners. SNPs of interest were subjected to replication analyses and meta-analyses with additional two independent Caucasian populations (N = 1,000 and 2,503) and one Chinese population (N = 1,627).
In the initial GWAS, 91 SNPs were associated with spine BS (P<1.0E-4). Eight contiguous SNPs were found clustering in a haplotype block within UQCC gene (ubiquinol-cytochrome creductase complex chaperone). Association of the above eight SNPs with spine BS were replicated in one Caucasian and one Chinese populations. Meta-analyses (N = 7,416) generated much stronger association signals for these SNPs (e.g., P = 1.86E-07 for SNP rs6060373), supporting association of UQCC with spine BS across ethnicities.
This study identified a novel locus, i.e., the UQCC gene, for spine BS variation in humans. Future functional studies will contribute to elucidating the mechanisms by which UQCC regulates bone growth and development.
doi:10.1016/j.bone.2012.11.028
PMCID: PMC3682469  PMID: 23207799
Spine bone size; GWAS; UQCC
6.  Psychological stress induced zinc accumulation and up-regulation of ZIP14 and metallothionein in rat liver 
BMC Gastroenterology  2014;14:32.
Background
Zinc is necessary for normal liver function; and vice versa, the liver plays a central role in zinc homeostasis. The aim of present study is to assess the effects of repeated psychological stress (PS) on the zinc metabolism and related mechanism involved in zinc homeostasis in rat liver.
Methods
In present study, we used communication box to create PS model and investigated the serum corticosterone (CORT), zinc level in serum and liver, liver metallothionein (MT) content and ZRT/IRT-like Protein 14 (ZIP14) mRNA expression.
Results
The results showed that the serum CORT level increased and serum zinc level decreased significantly after 7 d and 14 d PS treatment. Meanwhile, zinc and MT contents in liver were elevated after 14 d PS exposure, while those in 7 d PS exposure group did not change. ZIP14 mRNA was expressed markedly at 7 d after the onset of PS, while Zip14 mRNA expression in the liver after 14 d PS exposure reached normal level compared with control group.
Conclusions
The results suggest that PS exposure could induce hypozincemia, which might be related to liver zinc accumulation because of high level of MT through glucocorticoid-mediated MT synthesis and ZIP14 expression induced by interleukin-6.
doi:10.1186/1471-230X-14-32
PMCID: PMC3931483  PMID: 24548602
Psychological stress; Zinc; ZIP14; Metallothionein; Liver; Corticosterone
7.  Three Distinct Modes of Mec1/ATR and Tel1/ATM Activation Illustrate Differential Checkpoint Targeting during Budding Yeast Early Meiosis 
Molecular and Cellular Biology  2013;33(16):3365-3376.
Recombination and synapsis of homologous chromosomes are hallmarks of meiosis in many organisms. Meiotic recombination is initiated by Spo11-induced DNA double-strand breaks (DSBs), whereas chromosome synapsis is mediated by a tripartite structure named the synaptonemal complex (SC). Previously, we proposed that budding yeast SC is assembled via noncovalent interactions between the axial SC protein Red1, SUMO chains or conjugates, and the central SC protein Zip1. Incomplete synapsis and unrepaired DNA are monitored by Mec1/Tel1-dependent checkpoint responses that prevent exit from the pachytene stage. Here, our results distinguished three distinct modes of Mec1/Tec1 activation during early meiosis that led to phosphorylation of three targets, histone H2A at S129 (γH2A), Hop1, and Zip1, which are involved, respectively, in DNA replication, the interhomolog recombination and chromosome synapsis checkpoint, and destabilization of homology-independent centromere pairing. γH2A phosphorylation is Red1 independent and occurs prior to Spo11-induced DSBs. DSB- and Red1-dependent Hop1 phosphorylation is activated via interaction of the Red1-SUMO chain/conjugate ensemble with the Ddc1-Rad17-Mec3 (9-1-1) checkpoint complex and the Mre11-Rad50-Xrs2 complex. During SC assembly, Zip1 outcompetes 9-1-1 from the Red1-SUMO chain ensemble to attenuate Hop1 phosphorylation. In contrast, chromosome synapsis cannot attenuate DSB-dependent and Red1-independent Zip1 phosphorylation. These results reveal how DNA replication, DSB repair, and chromosome synapsis are differentially monitored by the meiotic checkpoint network.
doi:10.1128/MCB.00438-13
PMCID: PMC3753904  PMID: 23775120
8.  Impact of Rural Residence and Health System Structure on Quality of Liver Care 
PLoS ONE  2013;8(12):e84826.
Background
Specialist physician concentration in urban areas can affect access and quality of care for rural patients. As effective drug treatment for hepatitis C (HCV) becomes increasingly available, the extent to which rural patients needing HCV specialists face access or quality deficits is unknown. We sought to determine the influence of rural residency on access to HCV specialists and quality of liver care.
Methods
The study used a national cohort of 151,965 Veterans Health Administration (VHA) patients with HCV starting in 2005 and followed to 2009. The VHA’s constant national benefit structure reduces the impact of insurance as an explanation for observed disparities. Multivariate cox proportion regression models for each quality indicator were performed.
Results
Thirty percent of VHA patients with HCV reside in rural and highly rural areas. Compared to urban residents, highly rural (HR 0.70, CI 0.65-0.75) and rural (HR 0.96, CI 0.94-0.97) residents were significantly less likely to access HCV specialty care. The quality indicators were more mixed. While rural residents were less likely to receive HIV screening, there were no significant differences in hepatitis vaccinations, endoscopic variceal and hepatocellular carcinoma screening between the geographic subgroups. Of note, highly rural (HR 1.31, CI 1.14-1.50) and rural residents (HR 1.06, CI 1.02-1.10) were more likely to receive HCV therapy. Of those treated for HCV, a third received therapy from a non-specialist provider.
Conclusion
Rural patients have less access to HCV specialists, but this does not necessarily translate to quality deficits. The VHA's efforts to improve specialty care access, rural patient behavior and decentralization of HCV therapy beyond specialty providers may explain this contradiction. Lessons learned within the VHA are critical for US healthcare systems restructuring into accountable care organizations that acquire features of integrated systems.
doi:10.1371/journal.pone.0084826
PMCID: PMC3873451  PMID: 24386420
9.  Inhibitory Effects of Caffeic Acid Phenethyl Ester Derivatives on Replication of Hepatitis C Virus 
PLoS ONE  2013;8(12):e82299.
Caffeic acid phenethyl ester (CAPE) has been reported as a multifunctional compound. In this report, we tested the effect of CAPE and its derivatives on hepatitis C virus (HCV) replication in order to develop an effective anti-HCV compound. CAPE and CAPE derivatives exhibited anti-HCV activity against an HCV replicon cell line of genotype 1b with EC50 values in a range from 1.0 to 109.6 µM. Analyses of chemical structure and antiviral activity suggested that the length of the n-alkyl side chain and catechol moiety are responsible for the anti-HCV activity of these compounds. Caffeic acid n-octyl ester exhibited the highest anti-HCV activity among the tested derivatives with an EC50 value of 1.0 µM and an SI value of 63.1 by using the replicon cell line derived from genotype 1b strain Con1. Treatment with caffeic acid n-octyl ester inhibited HCV replication of genotype 2a at a similar level to that of genotype 1b irrespectively of interferon signaling. Caffeic acid n-octyl ester could synergistically enhance the anti-HCV activities of interferon-alpha 2b, daclatasvir, and VX-222, but neither telaprevir nor danoprevir. These results suggest that caffeic acid n-octyl ester is a potential candidate for novel anti-HCV chemotherapy drugs.
doi:10.1371/journal.pone.0082299
PMCID: PMC3866116  PMID: 24358168
10.  Epigenetic analysis leads to identification of HNF1B as a subtype-specific susceptibility gene for ovarian cancer 
Shen, Hui | Fridley, Brooke L. | Song, Honglin | Lawrenson, Kate | Cunningham, Julie M. | Ramus, Susan J. | Cicek, Mine S. | Tyrer, Jonathan | Stram, Douglas | Larson, Melissa C. | Köbel, Martin | Ziogas, Argyrios | Zheng, Wei | Yang, Hannah P. | Wu, Anna H. | Wozniak, Eva L. | Woo, Yin Ling | Winterhoff, Boris | Wik, Elisabeth | Whittemore, Alice S. | Wentzensen, Nicolas | Weber, Rachel Palmieri | Vitonis, Allison F. | Vincent, Daniel | Vierkant, Robert A. | Vergote, Ignace | Van Den Berg, David | Van Altena, Anne M. | Tworoger, Shelley S. | Thompson, Pamela J. | Tessier, Daniel C. | Terry, Kathryn L. | Teo, Soo-Hwang | Templeman, Claire | Stram, Daniel O. | Southey, Melissa C. | Sieh, Weiva | Siddiqui, Nadeem | Shvetsov, Yurii B. | Shu, Xiao-Ou | Shridhar, Viji | Wang-Gohrke, Shan | Severi, Gianluca | Schwaab, Ira | Salvesen, Helga B. | Rzepecka, Iwona K. | Runnebaum, Ingo B. | Rossing, Mary Anne | Rodriguez-Rodriguez, Lorna | Risch, Harvey A. | Renner, Stefan P. | Poole, Elizabeth M. | Pike, Malcolm C. | Phelan, Catherine M. | Pelttari, Liisa M. | Pejovic, Tanja | Paul, James | Orlow, Irene | Omar, Siti Zawiah | Olson, Sara H. | Odunsi, Kunle | Nickels, Stefan | Nevanlinna, Heli | Ness, Roberta B. | Narod, Steven A. | Nakanishi, Toru | Moysich, Kirsten B. | Monteiro, Alvaro N.A. | Moes-Sosnowska, Joanna | Modugno, Francesmary | Menon, Usha | McLaughlin, John R. | McGuire, Valerie | Matsuo, Keitaro | Adenan, Noor Azmi Mat | Massuger, Leon F.A. G. | Lurie, Galina | Lundvall, Lene | Lubiński, Jan | Lissowska, Jolanta | Levine, Douglas A. | Leminen, Arto | Lee, Alice W. | Le, Nhu D. | Lambrechts, Sandrina | Lambrechts, Diether | Kupryjanczyk, Jolanta | Krakstad, Camilla | Konecny, Gottfried E. | Kjaer, Susanne Krüger | Kiemeney, Lambertus A. | Kelemen, Linda E. | Keeney, Gary L. | Karlan, Beth Y. | Karevan, Rod | Kalli, Kimberly R. | Kajiyama, Hiroaki | Ji, Bu-Tian | Jensen, Allan | Jakubowska, Anna | Iversen, Edwin | Hosono, Satoyo | Høgdall, Claus K. | Høgdall, Estrid | Hoatlin, Maureen | Hillemanns, Peter | Heitz, Florian | Hein, Rebecca | Harter, Philipp | Halle, Mari K. | Hall, Per | Gronwald, Jacek | Gore, Martin | Goodman, Marc T. | Giles, Graham G. | Gentry-Maharaj, Aleksandra | Garcia-Closas, Montserrat | Flanagan, James M. | Fasching, Peter A. | Ekici, Arif B. | Edwards, Robert | Eccles, Diana | Easton, Douglas F. | Dürst, Matthias | du Bois, Andreas | Dörk, Thilo | Doherty, Jennifer A. | Despierre, Evelyn | Dansonka-Mieszkowska, Agnieszka | Cybulski, Cezary | Cramer, Daniel W. | Cook, Linda S. | Chen, Xiaoqing | Charbonneau, Bridget | Chang-Claude, Jenny | Campbell, Ian | Butzow, Ralf | Bunker, Clareann H. | Brueggmann, Doerthe | Brown, Robert | Brooks-Wilson, Angela | Brinton, Louise A. | Bogdanova, Natalia | Block, Matthew S. | Benjamin, Elizabeth | Beesley, Jonathan | Beckmann, Matthias W. | Bandera, Elisa V. | Baglietto, Laura | Bacot, François | Armasu, Sebastian M. | Antonenkova, Natalia | Anton-Culver, Hoda | Aben, Katja K. | Liang, Dong | Wu, Xifeng | Lu, Karen | Hildebrandt, Michelle A.T. | Schildkraut, Joellen M. | Sellers, Thomas A. | Huntsman, David | Berchuck, Andrew | Chenevix-Trench, Georgia | Gayther, Simon A. | Pharoah, Paul D.P. | Laird, Peter W. | Goode, Ellen L. | Pearce, Celeste Leigh
Nature communications  2013;4:10.1038/ncomms2629.
HNF1B is overexpressed in clear cell epithelial ovarian cancer, and we observed epigenetic silencing in serous epithelial ovarian cancer, leading us to hypothesize that variation in this gene differentially associates with epithelial ovarian cancer risk according to histological subtype. Here we comprehensively map variation in HNF1B with respect to epithelial ovarian cancer risk and analyse DNA methylation and expression profiles across histological subtypes. Different single-nucleotide polymorphisms associate with invasive serous (rs7405776 odds ratio (OR) = 1.13, P = 3.1 × 10−10) and clear cell (rs11651755 OR = 0.77, P = 1.6 × 10−8) epithelial ovarian cancer. Risk alleles for the serous subtype associate with higher HNF1B-promoter methylation in these tumours. Unmethylated, expressed HNF1B, primarily present in clear cell tumours, coincides with a CpG island methylator phenotype affecting numerous other promoters throughout the genome. Different variants in HNF1B associate with risk of serous and clear cell epithelial ovarian cancer; DNA methylation and expression patterns are also notably distinct between these subtypes. These findings underscore distinct mechanisms driving different epithelial ovarian cancer histological subtypes.
doi:10.1038/ncomms2629
PMCID: PMC3848248  PMID: 23535649
11.  Local Administration of AAV-BDNF to Subventricular Zone Induces Functional Recovery in Stroke Rats 
PLoS ONE  2013;8(12):e81750.
Migration of new neuroprogenitor cells (NPCs) from the subventricular zone (SVZ) plays an important role in neurorepair after injury. Previous studies have shown that brain derived neurotrophic factor (BDNF) enhances the migration of NPCs from SVZ explants in neonatal mice in vitro. The purpose of this study was to identify the role of BDNF in SVZ cells using AAV-BDNF in an animal model of stroke. BDNF protein production after AAV‐BDNF infection was verified in primary neuronal culture. AAV-BDNF or AAV-RFP was injected into the left SVZ region of adult rats at 14 days prior to right middle cerebral artery occlusion (MCAo). SVZ tissues were collected from the brain and placed in Metrigel cultures 1 day after MCAo. Treatment with AAV-BDNF significantly increased the migration of SVZ cells in the stroke brain in vitro. In another set of animals, AAV-GFP was co-injected with AAV-BDNF or AAV-RFP to label cells in left SVZ prior to right MCAo. Local administration of AAV-BDNF significantly enhanced recovery of locomotor function and migration of GFP-positive cells from the SVZ toward the lesioned hemisphere in stroke rats. Our data suggest that focal administration of AAV-BDNF to the SVZ increases behavioral recovery post stroke, possibly through the enhancement of migration of cells from SVZ in stroke animals. Regional manipulation of BDNF expression through AAV may be a novel approach for neurorepair in stroke brains.
doi:10.1371/journal.pone.0081750
PMCID: PMC3847037  PMID: 24312581
12.  Inferring tumour purity and stromal and immune cell admixture from expression data 
Nature Communications  2013;4:2612.
Infiltrating stromal and immune cells form the major fraction of normal cells in tumour tissue and not only perturb the tumour signal in molecular studies but also have an important role in cancer biology. Here we describe ‘Estimation of STromal and Immune cells in MAlignant Tumours using Expression data’ (ESTIMATE)—a method that uses gene expression signatures to infer the fraction of stromal and immune cells in tumour samples. ESTIMATE scores correlate with DNA copy number-based tumour purity across samples from 11 different tumour types, profiled on Agilent, Affymetrix platforms or based on RNA sequencing and available through The Cancer Genome Atlas. The prediction accuracy is further corroborated using 3,809 transcriptional profiles available elsewhere in the public domain. The ESTIMATE method allows consideration of tumour-associated normal cells in genomic and transcriptomic studies. An R-library is available on https://sourceforge.net/projects/estimateproject/.
Tumour biopsies contain contaminating normal cells and these can influence the analysis of tumour samples. In this study, Yoshihara et al. develop an algorithm based on gene expression profiles from The Cancer Genome Atlas to estimate the number of contaminating normal cells in tumour samples.
doi:10.1038/ncomms3612
PMCID: PMC3826632  PMID: 24113773
13.  RPS8—a New Informative DNA Marker for Phylogeny of Babesia and Theileria Parasites in China 
PLoS ONE  2013;8(11):e79860.
Piroplasmosis is a serious debilitating and sometimes fatal disease. Phylogenetic relationships within piroplasmida are complex and remain unclear. We compared the intron–exon structure and DNA sequences of the RPS8 gene from Babesia and Theileria spp. isolates in China. Similar to 18S rDNA, the 40S ribosomal protein S8 gene, RPS8, including both coding and non-coding regions is a useful and novel genetic marker for defining species boundaries and for inferring phylogenies because it tends to have little intra-specific variation but considerable inter-specific difference. However, more samples are needed to verify the usefulness of the RPS8 (coding and non-coding regions) gene as a marker for the phylogenetic position and detection of most Babesia and Theileria species, particularly for some closely related species.
doi:10.1371/journal.pone.0079860
PMCID: PMC3820542  PMID: 24244571
14.  Impaired Lymphocyte Reactivity Measured by Immune Function Testing in Untransplanted Patients with Cirrhosis 
The immune function test is an integrated measure of total mitogen-inducible CD4+ T cell metabolic activity in the peripheral blood, and it is used to guide the dosing of immunosuppressive medications after solid organ transplantation. Recently, low CD4+ T cell metabolic activity due to pharmacologic immunosuppression has been linked to rapidly progressive cirrhosis in hepatitis C virus (HCV)-infected liver transplant recipients. We speculate that either cirrhosis or HCV might adversely affect the CD4+ T cell reactivity even in the absence of immunosuppressive medications. We thus performed this assay on a cohort of untransplanted hepatology patients who were not taking immunomodulatory drugs. Low mitogen-stimulated CD4+ T cell metabolic reactivity was more commonly seen in untransplanted patients with HCV cirrhosis or with cirrhosis due to other causes but not in control patients or in those with chronic HCV in the absence of cirrhosis. The lowest mean CD4+ T cell reactivities were seen in patients with both cirrhosis and HCV. Caution should be exercised when immune function test results are used to guide immunomodulatory therapy in transplant recipients with suspected cirrhosis, as low immune function test results may be a consequence of hepatic cirrhosis or of pharmacologic immunosuppression.
doi:10.1128/CVI.00595-12
PMCID: PMC3623409  PMID: 23389930
15.  Risk Assessment of Heavy Metals Pollution in Agricultural Soils of Siling Reservoir Watershed in Zhejiang Province, China 
BioMed Research International  2013;2013:590306.
Presence of heavy metals in agriculture soils above the permissible limit poses threats to public health. In this study, concentrations of seven metals were determined in agricultural soils from Yuhang county, Zhejiang, China. Multivariate statistical approaches were used to study the variation of metals in soils during summer and winter seasons. Contamination of soils was evaluated on the basis of enrichment factor (EF), geoaccumulation index (Igeo), contamination factor (Cf), and degree of contamination (Cdeg). Heavy metal concentrations were observed higher in winter as compared to summer season. Cr and Cd revealed random distribution with diverse correlations in both seasons. Principal component analysis and cluster analysis showed significant anthropogenic intrusions of Zn, Cd, Pb, Cr, and Cu in the soils. Enrichment factor revealed significant enrichment (EF > 5) of Zn, Cd, and Pb, whereas geoaccumulation index and contamination factor exhibited moderate to high contamination for Zn, Cr, Cd, and Pb. In light of the studied parameters, permissible limit to very high degree of contamination (Cdeg > 16) was observed in both seasons.
doi:10.1155/2013/590306
PMCID: PMC3787591  PMID: 24151611
16.  A retrospective study of posterior malleolus fractures 
International Orthopaedics  2012;36(9):1929-1936.
Purpose
In this retrospective study, we evaluated the treatment effect of ankle joint fracture surgery involving the posterior malleolus, and discuss relevant factors influencing the occurrence of traumatic arthritis of the ankle joint.
Methods
A total of 102 cases of ankle joint fractures involving the posterior malleolus in five large-scale skeletal trauma centres in China, from January 2000 to July 2009, were retrospectively analysed in terms of surgical treatment and complete follow-up. Ankle joint mobility, posterior malleolus fragment size, articular surface evenness, Ankle-Hindfoot Scale of the American Orthopedic Foot and Ankle Society (AOFAS) score, and imaging scale score for arthritis were recorded. The degree of fracture pain during rest, active movement, and weight-bearing walking, and satisfaction with treatment were evaluated using a visual analogue scale (VAS).
Results
The average AOFAS score was 95.9, excellence rate was 92.2 %, and average VAS scores for degree of fracture pain during rest, active movement, and weight-bearing walking were 0.15, 0.31, and 0.68, respectively. Thirty-six cases showed arthritic manifestations. Ankle joint mobility along all directions on the injured side was lower than that on the unaffected side. There was no obvious difference in treatment effect between the fixed and unfixed posterior malleolus fragment groups for all and for fragment size of <25 %; between fixing the posterior malleolus fragment from front to back or from back to front; or between elderly patients (≥60 years old) and young patients (<60 years old). There was a distinct difference in the treatment effect between articular surface evenness and unevenness for all and for fragment size of ≥25 %.
Conclusions
For all 102 cases of ankle joint fracture involving the posterior malleolus, the treatment effect was satisfactory. Restoration of an even articular surface, especially when fragment size ≥25 %, should be attempted during treatment.
doi:10.1007/s00264-012-1591-9
PMCID: PMC3427438  PMID: 22777382
17.  CDNF protects the nigrostriatal dopamine system and promotes recovery after MPTP treatment in mice 
Cell transplantation  2011;21(6):1213-1223.
Cerebral dopamine neurotrophic factor (CDNF) is a recently discovered protein, which belongs to the evolutionarily conserved CDNF/MANF family of neurotrophic factors. CDNF has been shown to promote the survival of midbrain dopamine neurons in vivo. The degeneration of dopamine neurons following 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) -treatment is well characterized and efficacy in this model is considered a standard criterion for development of parkinsonian therapies. MPTP is a neurotoxin, which produces parkinsonian symptoms in humans, and in C57/Bl6 mice. To date, there are no reports about the effects of CDNF on dopamine neuron survival or function in the MPTP rodent model, a critical gap. Therefore, we studied whether CDNF has neuroprotective and neurorestorative properties for the nigrostriatal dopamine system after MPTP injections in C57/Bl6 mice. We found that bilateral striatal CDNF injections, given 20-h before MPTP, improved horizontal and vertical motor behavior. CDNF pre-treatment increased tyrosine hydroxylase (TH)-immunoreactivity in the striatum and in the substantia nigra pars reticulata (SNpr), as well as the number of TH-positive cells in substantia nigra pars compacta (SNpc). Post-treatment with CDNF, given 1 week after MPTP injections, increased horizontal and vertical behavior of mice, as well as dopamine fiber densities in the striatum and the number of TH-positive cells in SNpc. CDNF did not alter any of the analyzed dopaminergic biomarkers or locomotor behavior in MPTP-untreated animals. We conclude that striatal CDNF administration is both neuroprotective and neurorestorative for the TH-positive cells in the nigrostriatal dopamine system in the MPTP model, which supports the development of CDNF-based treatment for Parkinson’s disease.
doi:10.3727/096368911X600948
PMCID: PMC3753365  PMID: 21943517
CDNF; MANF; MPTP; Parkinson’s disease
18.  Convergent and Divergent Functional Connectivity Patterns in Schizophrenia and Depression 
PLoS ONE  2013;8(7):e68250.
Major depression and schizophrenia are two of the most serious psychiatric disorders and share similar behavioral symptoms. Whether these similar behavioral symptoms underlie any convergent psychiatric pathological mechanisms is not yet clear. To address this issue, this study sought to investigate the whole-brain resting-state functional magnetic resonance imaging (MRI) of major depression and schizophrenia by using multivariate pattern analysis. Thirty-two schizophrenic patients, 19 major depressive disorder patients and 38 healthy controls underwent resting-state functional MRI scanning. A support vector machine in conjunction with intrinsic discriminant analysis was used to solve the multi-classification problem, resulting in a correct classification rate of 80.9% via leave-one-out cross-validation. The depression and schizophrenia groups both showed altered functional connections associated with the medial prefrontal cortex, anterior cingulate cortex, thalamus, hippocampus, and cerebellum. However, the prefrontal cortex, amygdala, and temporal poles were found to be affected differently by major depression and schizophrenia. Our preliminary study suggests that altered connections within or across the default mode network and the cerebellum may account for the common behavioral symptoms between major depression and schizophrenia. In addition, connections associated with the prefrontal cortex and the affective network showed promise as biomarkers for discriminating between the two disorders.
doi:10.1371/journal.pone.0068250
PMCID: PMC3699547  PMID: 23844175
19.  Regulation of the surface expression of α4β2δ GABAA receptors by high efficacy states 
Brain Research  2012;1463:1-20.
α4βδ GABAA receptors (GABARs) have low CNS expression, but their expression is increased by 48 h exposure to the neurosteroid THP (3α-OH-5α[β]-pregnan-20-one). THP also increases the efficacy of δ-containing GABARs acutely, where GABA is a partial agonist. Thus, we examined effects of THP (100 nM) and full GABA agonists at α4β2δ (gaboxadol, 10 μM, and β-alanine, 10 μM – 1 mM), on surface expression of α4β2δ. To this end, we used an α4 construct tagged with a 3XFLAG (F) epitope or measured expression of native α4 and δ. HEK-293 cells or cultured hippocampal neurons were transfected with α4Fβ2δ and treated 24 h later with GABA agonists, THP, GABA plus THP or vehicle (0.01% DMSO) for 0.5 h – 48 h. Immunocytochemistry was performed under both non-permeabilized and permeabilized conditions to detect surface and intracellular labeling, respectively, using confocal microscopy. The high efficacy agonists and GABA (1 or 10μM) plus THP increased α4β2δ surface expression up to 3-fold after 48 h, an effect first seen by 0.5 h. This effect was not dependent upon the polarity of GABAergic current, although expression was increased by KCC2. Intracellular labeling was decreased while functional expression was confirmed by whole cell patch clamp recordings of responses to GABA agonists. GABA plus THP treatment did not alter the rate of receptor removal from the surface membrane, suggesting that THP-induced α4β2δ expression is likely via receptor insertion. Surface expression of α4β2δ was decreased by rottlerin (10 μM), suggesting a role for PKC- δ. These results suggest that trafficking of α4β2δ GABARs is regulated by high efficacy states.
doi:10.1016/j.brainres.2012.04.047
PMCID: PMC3371167  PMID: 22609410
α4; δ; GABAA receptor; trafficking; pregnanolone; β-alanine; KCC2
20.  Atrial natriuretic peptide modulates the proliferation of human gastric cancer cells via KCNQ1 expression 
Oncology Letters  2013;6(2):407-414.
Atrial natriuretic peptide (ANP) and brain NP (BNP) belong to the NP family that regulates mammalian blood volume and blood pressure. ANP signaling through NP receptor A (NPR-A)/cyclic guanosine 3′5′-monophosphate (cGMP)/ cGMP-dependent protein kinase (PKG) activates various downstream effectors involved in cell growth, apoptosis, proliferation and inflammation. Evidence has shown the critical role of plasma K+ channels in the regulation of tumor cell proliferation. However, the role of ANP in the proliferation of gastric cancer cells is not clear. In the present study, the expression of NPR-A in the human gastric cancer cell line, AGS, and the effect of ANP on the proliferation of AGS cells were investigated using western blotting, immunofluorescence, qPCR and patch clamp assays. The K+ current was also analyzed in the effect of ANP on the proliferation of AGS cells. NPR-A was expressed in the human gastric cancer AGS cell line. Lower concentrations of ANP promoted the proliferation of the AGS cells, although higher concentrations decreased their proliferation. Significant increases in the levels of cGMP activity were observed in the AGS cells treated with 10−10, 10−9 and 10−8 M ANP compared with the controls, but no significant differences were observed in the 10−7 and 10−6 M ANP groups. The patch clamp results showed that 10−9 M ANP significantly increased the tetraethylammonium (TEA)- and 293B-sensitive K+ current, while 10−6 M ANP significantly decreased the TEA- and 293B-sensitive K+ current. The results showed that 10−10 and 10−9 M ANP significantly upregulated the expression of potassium voltage-gated channel, KQT-like subfamily, member 1 (KCNQ1) at the protein and mRNA levels, although 10−7 and 10−6 M ANP significantly downregulated the expression of KCNQ1. The data indicated that lower and higher concentrations of ANP have opposite effects on the proliferation of AGS cells through cGMP-dependent or -independent pathways. KCNQ1 upregulation and downregulation by lower and higher concentrations of ANP, respectively, have separate effects on the promotion and inhibition of proliferation.
doi:10.3892/ol.2013.1425
PMCID: PMC3789098  PMID: 24137337
atrial natriuretic peptide; KCNQ1; proliferation; gastric cancer
21.  Genome Sequence of the Banana Pathogen Dickeya zeae Strain MS1, Which Causes Bacterial Soft Rot 
Genome Announcements  2013;1(3):e00317-13.
We report a draft genome sequence of Dickeya zeae strain MS1, which is the causative agent of banana soft rot in China, and we show several of its specific properties compared with those of other D. zeae strains. Genome sequencing provides a tool for understanding the genomic determination of the pathogenicity and phylogeny placement of this pathogen.
doi:10.1128/genomeA.00317-13
PMCID: PMC3707573  PMID: 23766402
22.  Suppression of endogenous PPARγ increases vulnerability to methamphetamine –induced injury in mouse nigrostriatal dopaminergic pathway 
Psychopharmacology  2011;221(3):479-492.
Rationale
Methamphetamine is a commonly abused drug and dopaminergic neurotoxin. Repeated administration of high doses of methamphetamine induces programmed cell death, suppression of dopamine release, and reduction in locomotor activity. Previous studies have shown that pretreatment with Peroxisome Proliferator-Activated Receptor gamma (PPARγ) agonist reduced Methamphetamine -induced neurodegeneration.
Objectives
The purpose of this study was to examine the role of endogenous PPARγ in protecting against methamphetamine toxicity.
Methods
Adeno-associated virus (AAV) encoding the Cre recombinase gene was unilaterally injected into the left substantia nigra of loxP-PPARγ or control wild type mice. Animals were treated with high doses of methamphetamine 1-month after viral injection. Behavioral tests were examined using Rotarod and rotometer. In vivo voltammetry was used to examine dopamine release/clearance and at 2 months after methamphetamine injection.
Results
Administration of AAV-Cre selectively removed PPARγ in left nigra in loxP-PPARγ mice but not in the wild type mice. The loxP-PPARγ/AAV-Cre mice that received methamphetamine showed a significant reduction in time on the rotarod and exhibited increased ipislateral rotation using a rotometer. The peak of dopamine release induced by local application of KCl and the rate of dopamine clearance were significantly attenuated in the left striatum of loxP-PPARγ/AAV-Cre animals. Tyrosine hydroxylase immunoreactivity was reduced in the left, compared to right, nigra and dorsal striatum in loxP-PPARγ/AAV-Cre mice receiving high doses of methamphetamine.
Conclusion
A deficiency in PPARγ increases vulnerability to high doses of methamphetamine. Endogenous PPARγ may play an important role in reducing methamphetamine toxicity in vivo.
doi:10.1007/s00213-011-2595-7
PMCID: PMC3351577  PMID: 22160138
23.  Enhanced characteristics of genetically modified switchgrass (Panicum virgatum L.) for high biofuel production 
Background
Lignocellulosic biomass is one of the most promising renewable and clean energy resources to reduce greenhouse gas emissions and dependence on fossil fuels. However, the resistance to accessibility of sugars embedded in plant cell walls (so-called recalcitrance) is a major barrier to economically viable cellulosic ethanol production. A recent report from the US National Academy of Sciences indicated that, “absent technological breakthroughs”, it was unlikely that the US would meet the congressionally mandated renewable fuel standard of 35 billion gallons of ethanol-equivalent biofuels plus 1 billion gallons of biodiesel by 2022. We here describe the properties of switchgrass (Panicum virgatum) biomass that has been genetically engineered to increase the cellulosic ethanol yield by more than 2-fold.
Results
We have increased the cellulosic ethanol yield from switchgrass by 2.6-fold through overexpression of the transcription factor PvMYB4. This strategy reduces carbon deposition into lignin and phenolic fermentation inhibitors while maintaining the availability of potentially fermentable soluble sugars and pectic polysaccharides. Detailed biomass characterization analyses revealed that the levels and nature of phenolic acids embedded in the cell-wall, the lignin content and polymer size, lignin internal linkage levels, linkages between lignin and xylans/pectins, and levels of wall-bound fucose are all altered in PvMYB4-OX lines. Genetically engineered PvMYB4-OX switchgrass therefore provides a novel system for further understanding cell wall recalcitrance.
Conclusions
Our results have demonstrated that overexpression of PvMYB4, a general transcriptional repressor of the phenylpropanoid/lignin biosynthesis pathway, can lead to very high yield ethanol production through dramatic reduction of recalcitrance. MYB4-OX switchgrass is an excellent model system for understanding recalcitrance, and provides new germplasm for developing switchgrass cultivars as biomass feedstocks for biofuel production.
doi:10.1186/1754-6834-6-71
PMCID: PMC3652750  PMID: 23651942
Switchgrass; Bioenergy; Biofuel; Feedstock; Cellulosic ethanol; PvMYB4; Transcription factor; Cell wall; Recalcitrance; Lignin; Hemicellulose; Pectin
24.  Knockout of the γ-aminobutyric acid receptor subunit α4 reduces functional δ-containing extrasynaptic receptors in hippocampal pyramidal cells at the onset of puberty 
Brain Research  2012;1450:11-23.
Increased plasmalemmal localization of α4βδ GABAA receptors (GABARs) occurs in the hippocampal pyramidal cells of female mice at pubertal onset (Shen et al., 2010). This increase occurs on both dendritic spines and shafts of CA1 pyramidal cells and is in response to hormone fluctuations that occur at pubertal onset. However, little is known about how the α4 and δ subunits individually mediate the formation of functional, plasmalemmal α4βδ GABARs. To determine whether expression of the α4 subunit is necessary for plasmalemmal δ subunit localization at pubertal onset, electron microscopic-immunocytochemistry (EM-ICC) was employed. CA1 pyramidal cells of female α4 knockout (KO) mice were tested for plasmalemmal levels of the δ subunit within dendritic spine and shaft profiles at the onset of puberty. EM-ICC revealed that the α4 and δ subunits localize on dendritic spines and shafts at sites extrasynaptic to GABAergic input at pubertal onset in tissue of wild-type (WT) mice. At pubertal onset, plasmalemmal localization of the δ subunit is reduced 45.9% on dendritic spines, and 56.7% on dendritic shafts with KO of the α4 subunit, as compared to WT tissue, yet levels of intracellular δ immunoreactivity remain unchanged. The decline in plasmalemmal localization is manifested as decreased responsiveness to the GABA agonist gaboxadol at concentrations that are selective for δ-containing GABARs. Additionally, α4 KO mice have larger dendritic spine and shaft profiles. Our findings demonstrate that α4 subunit expression strongly influences the pubertal increase of δ subunits at the plasma membrane, and that genetic deletion of α4 serves as a functional knock-down of δ-containing GABARs.
doi:10.1016/j.brainres.2012.02.035
PMCID: PMC3319511  PMID: 22418059
Puberty; GABA type A receptor; THP; tonic inhibition; alpha 4; delta; allopregnanolone
25.  Comprehensive Characterization of Human Genome Variation by High Coverage Whole-Genome Sequencing of Forty Four Caucasians 
PLoS ONE  2013;8(4):e59494.
Whole genome sequencing studies are essential to obtain a comprehensive understanding of the vast pattern of human genomic variations. Here we report the results of a high-coverage whole genome sequencing study for 44 unrelated healthy Caucasian adults, each sequenced to over 50-fold coverage (averaging 65.8×). We identified approximately 11 million single nucleotide polymorphisms (SNPs), 2.8 million short insertions and deletions, and over 500,000 block substitutions. We showed that, although previous studies, including the 1000 Genomes Project Phase 1 study, have catalogued the vast majority of common SNPs, many of the low-frequency and rare variants remain undiscovered. For instance, approximately 1.4 million SNPs and 1.3 million short indels that we found were novel to both the dbSNP and the 1000 Genomes Project Phase 1 data sets, and the majority of which (∼96%) have a minor allele frequency less than 5%. On average, each individual genome carried ∼3.3 million SNPs and ∼492,000 indels/block substitutions, including approximately 179 variants that were predicted to cause loss of function of the gene products. Moreover, each individual genome carried an average of 44 such loss-of-function variants in a homozygous state, which would completely “knock out” the corresponding genes. Across all the 44 genomes, a total of 182 genes were “knocked-out” in at least one individual genome, among which 46 genes were “knocked out” in over 30% of our samples, suggesting that a number of genes are commonly “knocked-out” in general populations. Gene ontology analysis suggested that these commonly “knocked-out” genes are enriched in biological process related to antigen processing and immune response. Our results contribute towards a comprehensive characterization of human genomic variation, especially for less-common and rare variants, and provide an invaluable resource for future genetic studies of human variation and diseases.
doi:10.1371/journal.pone.0059494
PMCID: PMC3618277  PMID: 23577066

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