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1.  Comprehensive molecular characterization of gastric adenocarcinoma 
Bass, Adam J. | Thorsson, Vesteinn | Shmulevich, Ilya | Reynolds, Sheila M. | Miller, Michael | Bernard, Brady | Hinoue, Toshinori | Laird, Peter W. | Curtis, Christina | Shen, Hui | Weisenberger, Daniel J. | Schultz, Nikolaus | Shen, Ronglai | Weinhold, Nils | Kelsen, David P. | Bowlby, Reanne | Chu, Andy | Kasaian, Katayoon | Mungall, Andrew J. | Robertson, A. Gordon | Sipahimalani, Payal | Cherniack, Andrew | Getz, Gad | Liu, Yingchun | Noble, Michael S. | Pedamallu, Chandra | Sougnez, Carrie | Taylor-Weiner, Amaro | Akbani, Rehan | Lee, Ju-Seog | Liu, Wenbin | Mills, Gordon B. | Yang, Da | Zhang, Wei | Pantazi, Angeliki | Parfenov, Michael | Gulley, Margaret | Piazuelo, M. Blanca | Schneider, Barbara G. | Kim, Jihun | Boussioutas, Alex | Sheth, Margi | Demchok, John A. | Rabkin, Charles S. | Willis, Joseph E. | Ng, Sam | Garman, Katherine | Beer, David G. | Pennathur, Arjun | Raphael, Benjamin J. | Wu, Hsin-Ta | Odze, Robert | Kim, Hark K. | Bowen, Jay | Leraas, Kristen M. | Lichtenberg, Tara M. | Weaver, Stephanie | McLellan, Michael | Wiznerowicz, Maciej | Sakai, Ryo | Getz, Gad | Sougnez, Carrie | Lawrence, Michael S. | Cibulskis, Kristian | Lichtenstein, Lee | Fisher, Sheila | Gabriel, Stacey B. | Lander, Eric S. | Ding, Li | Niu, Beifang | Ally, Adrian | Balasundaram, Miruna | Birol, Inanc | Bowlby, Reanne | Brooks, Denise | Butterfield, Yaron S. N. | Carlsen, Rebecca | Chu, Andy | Chu, Justin | Chuah, Eric | Chun, Hye-Jung E. | Clarke, Amanda | Dhalla, Noreen | Guin, Ranabir | Holt, Robert A. | Jones, Steven J.M. | Kasaian, Katayoon | Lee, Darlene | Li, Haiyan A. | Lim, Emilia | Ma, Yussanne | Marra, Marco A. | Mayo, Michael | Moore, Richard A. | Mungall, Andrew J. | Mungall, Karen L. | Nip, Ka Ming | Robertson, A. Gordon | Schein, Jacqueline E. | Sipahimalani, Payal | Tam, Angela | Thiessen, Nina | Beroukhim, Rameen | Carter, Scott L. | Cherniack, Andrew D. | Cho, Juok | Cibulskis, Kristian | DiCara, Daniel | Frazer, Scott | Fisher, Sheila | Gabriel, Stacey B. | Gehlenborg, Nils | Heiman, David I. | Jung, Joonil | Kim, Jaegil | Lander, Eric S. | Lawrence, Michael S. | Lichtenstein, Lee | Lin, Pei | Meyerson, Matthew | Ojesina, Akinyemi I. | Pedamallu, Chandra Sekhar | Saksena, Gordon | Schumacher, Steven E. | Sougnez, Carrie | Stojanov, Petar | Tabak, Barbara | Taylor-Weiner, Amaro | Voet, Doug | Rosenberg, Mara | Zack, Travis I. | Zhang, Hailei | Zou, Lihua | Protopopov, Alexei | Santoso, Netty | Parfenov, Michael | Lee, Semin | Zhang, Jianhua | Mahadeshwar, Harshad S. | Tang, Jiabin | Ren, Xiaojia | Seth, Sahil | Yang, Lixing | Xu, Andrew W. | Song, Xingzhi | Pantazi, Angeliki | Xi, Ruibin | Bristow, Christopher A. | Hadjipanayis, Angela | Seidman, Jonathan | Chin, Lynda | Park, Peter J. | Kucherlapati, Raju | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Kim, Sang-Bae | Lee, Ju-Seog | Lu, Yiling | Mills, Gordon | Laird, Peter W. | Hinoue, Toshinori | Weisenberger, Daniel J. | Bootwalla, Moiz S. | Lai, Phillip H. | Shen, Hui | Triche, Timothy | Van Den Berg, David J. | Baylin, Stephen B. | Herman, James G. | Getz, Gad | Chin, Lynda | Liu, Yingchun | Murray, Bradley A. | Noble, Michael S. | Askoy, B. Arman | Ciriello, Giovanni | Dresdner, Gideon | Gao, Jianjiong | Gross, Benjamin | Jacobsen, Anders | Lee, William | Ramirez, Ricardo | Sander, Chris | Schultz, Nikolaus | Senbabaoglu, Yasin | Sinha, Rileen | Sumer, S. Onur | Sun, Yichao | Weinhold, Nils | Thorsson, Vésteinn | Bernard, Brady | Iype, Lisa | Kramer, Roger W. | Kreisberg, Richard | Miller, Michael | Reynolds, Sheila M. | Rovira, Hector | Tasman, Natalie | Shmulevich, Ilya | Ng, Santa Cruz Sam | Haussler, David | Stuart, Josh M. | Akbani, Rehan | Ling, Shiyun | Liu, Wenbin | Rao, Arvind | Weinstein, John N. | Verhaak, Roeland G.W. | Mills, Gordon B. | Leiserson, Mark D. M. | Raphael, Benjamin J. | Wu, Hsin-Ta | Taylor, Barry S. | Black, Aaron D. | Bowen, Jay | Carney, Julie Ann | Gastier-Foster, Julie M. | Helsel, Carmen | Leraas, Kristen M. | Lichtenberg, Tara M. | McAllister, Cynthia | Ramirez, Nilsa C. | Tabler, Teresa R. | Wise, Lisa | Zmuda, Erik | Penny, Robert | Crain, Daniel | Gardner, Johanna | Lau, Kevin | Curely, Erin | Mallery, David | Morris, Scott | Paulauskis, Joseph | Shelton, Troy | Shelton, Candace | Sherman, Mark | Benz, Christopher | Lee, Jae-Hyuk | Fedosenko, Konstantin | Manikhas, Georgy | Potapova, Olga | Voronina, Olga | Belyaev, Smitry | Dolzhansky, Oleg | Rathmell, W. Kimryn | Brzezinski, Jakub | Ibbs, Matthew | Korski, Konstanty | Kycler, Witold | ŁaŸniak, Radoslaw | Leporowska, Ewa | Mackiewicz, Andrzej | Murawa, Dawid | Murawa, Pawel | Spychała, Arkadiusz | Suchorska, Wiktoria M. | Tatka, Honorata | Teresiak, Marek | Wiznerowicz, Maciej | Abdel-Misih, Raafat | Bennett, Joseph | Brown, Jennifer | Iacocca, Mary | Rabeno, Brenda | Kwon, Sun-Young | Penny, Robert | Gardner, Johanna | Kemkes, Ariane | Mallery, David | Morris, Scott | Shelton, Troy | Shelton, Candace | Curley, Erin | Alexopoulou, Iakovina | Engel, Jay | Bartlett, John | Albert, Monique | Park, Do-Youn | Dhir, Rajiv | Luketich, James | Landreneau, Rodney | Janjigian, Yelena Y. | Kelsen, David P. | Cho, Eunjung | Ladanyi, Marc | Tang, Laura | McCall, Shannon J. | Park, Young S. | Cheong, Jae-Ho | Ajani, Jaffer | Camargo, M. Constanza | Alonso, Shelley | Ayala, Brenda | Jensen, Mark A. | Pihl, Todd | Raman, Rohini | Walton, Jessica | Wan, Yunhu | Demchok, John A. | Eley, Greg | Mills Shaw, Kenna R. | Sheth, Margi | Tarnuzzer, Roy | Wang, Zhining | Yang, Liming | Zenklusen, Jean Claude | Davidsen, Tanja | Hutter, Carolyn M. | Sofia, Heidi J. | Burton, Robert | Chudamani, Sudha | Liu, Jia
Nature  2014;513(7517):202-209.
Gastric cancer is a leading cause of cancer deaths, but analysis of its molecular and clinical characteristics has been complicated by histological and aetiological heterogeneity. Here we describe a comprehensive molecular evaluation of 295 primary gastric adenocarcinomas as part of The Cancer Genome Atlas (TCGA) project. We propose a molecular classification dividing gastric cancer into four subtypes: tumours positive for Epstein–Barr virus, which display recurrent PIK3CA mutations, extreme DNA hypermethylation, and amplification of JAK2, CD274 (also known as PD-L1) and PDCD1LG2 (also knownasPD-L2); microsatellite unstable tumours, which show elevated mutation rates, including mutations of genes encoding targetable oncogenic signalling proteins; genomically stable tumours, which are enriched for the diffuse histological variant and mutations of RHOA or fusions involving RHO-family GTPase-activating proteins; and tumours with chromosomal instability, which show marked aneuploidy and focal amplification of receptor tyrosine kinases. Identification of these subtypes provides a roadmap for patient stratification and trials of targeted therapies.
doi:10.1038/nature13480
PMCID: PMC4170219  PMID: 25079317
2.  Genetic Analysis Identifies DDR2 as a Novel Gene Affecting Bone Mineral Density and Osteoporotic Fractures in Chinese Population 
PLoS ONE  2015;10(2):e0117102.
DDR2 gene, playing an essential role in regulating osteoblast differentiation and chondrocyte maturation, may influence bone mineral density (BMD) and osteoporosis, but the genetic variations actually leading to the association remain to be elucidated. Therefore, the aim of this study was to investigate whether the genetic variants in DDR2 are associated with BMD and fracture risk. This study was performed in three samples from two ethnicities, including 1,300 Chinese Han subjects, 700 Chinese Han subjects (350 with osteoporotic hip fractures and 350 healthy controls) and 2,286 US white subjects. Twenty-eight SNPs in DDR2 were genotyped and tested for associations with hip BMD and fractures. We identified 3 SNPs in DDR2 significantly associated with hip BMD in the Chinese population after multiple testing adjustments, which were rs7521233 (P = 1.06×10−4, β: −0.018 for allele C), rs7553831 (P = 1.30×10−4, β: −0.018 for allele T), and rs6697469 (P = 1.59×10−3, β: −0.015 for allele C), separately. These three SNPs were in high linkage disequilibrium. Haplotype analyses detected two significantly associated haplotypes, including one haplotype in block 2 (P = 9.54×10−4, β: −0.016) where these three SNPs located. SNP rs6697469 was also associated with hip fractures (P = 0.043, OR: 1.42) in the Chinese population. The effect on fracture risk was consistent with its association with lower BMD. However, in the white population, we didn’t observe significant associations with hip BMD. eQTL analyses revealed that SNPs associated with BMD also affected DDR2 mRNA expression levels in Chinese. Our findings, together with the prior biological evidence, suggest that DDR2 could be a new candidate for osteoporosis in Chinese population. Our results also reveal an ethnic difference, which highlights the need for further genetic studies in each ethnic group.
doi:10.1371/journal.pone.0117102
PMCID: PMC4319719  PMID: 25658585
3.  Confined-space synthesis of single crystal TiO2 nanowires in atmospheric vessel at low temperature: a generalized approach 
Scientific Reports  2015;5:8129.
Extensive efforts have been devoted to develop innovative synthesis strategies for nanomaterials in order to exploit the true potential of nanotechnology. However, most approaches require high temperature or high pressure to favor crystallization. Here we highlight an unconventional approach for the confined-space synthesis of the single crystal TiO2 nanowires in the atmospheric vessel at low temperature by cleverly manipulating the unique physical properties of straight-chain saturated fatty acids. Our method also applys to icosane due to its straight-chain saturated hydrocarbon structure and similar physical properties to the saturated fatty acids. Interestingly, we also found that the unsaturated fatty acids can facilitate the crystal growth, but their bent chains lead to the formation of TiO2 particle aggregates. In addition, we demonstrate the growth of TiO2 nanowires on arbitrary substrates, which are of great importance for their wider applications. We thus anticipate our presented method to be a possible starting point for non-classical crystallization strategies and be easily adapted for the fabrication of all other inorganic materials.
doi:10.1038/srep08129
PMCID: PMC4311246  PMID: 25634804
4.  Decoding the processing of lying using functional connectivity MRI 
Background
Previous functional MRI (fMRI) studies have demonstrated group differences in brain activity between deceptive and honest responses. The functional connectivity network related to lie-telling remains largely uncharacterized.
Methods
In this study, we designed a lie-telling experiment that emphasized strategy devising. Thirty-two subjects underwent fMRI while responding to questions in a truthful, inverse, or deceitful manner. For each subject, whole-brain functional connectivity networks were constructed from correlations among brain regions for the lie-telling and truth-telling conditions. Then, a multivariate pattern analysis approach was used to distinguish lie-telling from truth-telling based on the functional connectivity networks.
Results
The classification results demonstrated that lie-telling could be differentiated from truth-telling with an accuracy of 82.81% (85.94% for lie-telling, 79.69% for truth-telling). The connectivities related to the fronto-parietal networks, cerebellum and cingulo-opercular networks are most discriminating, implying crucial roles for these three networks in the processing of deception.
Conclusions
The current study may shed new light on the neural pattern of deception from a functional integration viewpoint.
Electronic supplementary material
The online version of this article (doi:10.1186/s12993-014-0046-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12993-014-0046-4
PMCID: PMC4316800  PMID: 25595193
fMRI; Deception; Multivariate pattern analysis; Functional connectivity
5.  Disruption of human papillomavirus 16 E6 gene by clustered regularly interspaced short palindromic repeat/Cas system in human cervical cancer cells 
OncoTargets and therapy  2014;8:37-44.
High-risk human papillomavirus (HPV), especially HPV16, is considered a main causative agent of cervical cancer. Upon HPV infection, the viral oncoprotein E6 disrupts the host tumor-suppressor protein p53, thus promoting malignant transformation of normal cervical cells. Here, we used the newly developed programmable ribonucleic acid-guided clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system to disrupt the HPV16 E6 gene. We showed that HPV16 E6 deoxyribonucleic acid was cleaved at specific sites, leading to apoptosis and growth inhibition of HPV16-positive SiHa and CaSki cells, but not HPV-negative C33A or human embryonic kidney 293 cells. We also observed downregulation of the E6 protein and restoration of the p53 protein. These data proved that the HPV16 E6 ribonucleic acid-guided CRISPR/Cas system might be an effective therapeutic agent in treating HPV infection-related cervical malignancy.
doi:10.2147/OTT.S64092
PMCID: PMC4278796  PMID: 25565864
CRISPR/Cas system; E6; p53; SiHa; CaSki; cervical cancer
6.  A stress steroid triggers anxiety via increased expression of α4βδ GABAA receptors in methamphetamine dependence 
Neuroscience  2013;254:10.1016/j.neuroscience.2013.08.033.
Methamphetamine (METH) is an addictive stimulant drug. In addition to drug craving and lethargy, METH withdrawal is associated with stress-triggered anxiety. However, the cellular basis for this stress-triggered anxiety is not understood. The present results suggest that during METH withdrawal (24 h) following chronic exposure (3 mg/kg, i.p. for 3-5 weeks) of adult, male mice, the effect of one neurosteroid released by stress, 3α,5α-THP (3α-OH-5α-pregnan-20-one), and its 3α,5β isomer reverse to trigger anxiety assessed by the acoustic startle response (ASR), in contrast to their usual anti-anxiety effects. This novel effect of 3α,5β-THP was due to increased (3-fold) hippocampal expression of α4βδ GABAA receptors (GABARs) during METH withdrawal (24 h – 4 wk) because anxiogenic effects of 3α,5β-THP were not seen in α4−/− mice. 3α,5β-THP reduces current at these receptors when it is hyperpolarizing, as observed during METH withdrawal. As a result, 3α,5β-THP (30 nM) increased neuronal excitability, assessed with current clamp and cell-attached recordings in CA1 hippocampus, one CNS site which regulates anxiety. α4βδ GABARs were first increased 1 h after METH exposure and recovered 6 wk after METH withdrawal. Similar increases in α4βδ GABARs and anxiogenic effects of 3α,5β-THP were noted in rats during METH withdrawal (24 h). In contrast, the ASR was increased by chronic METH treatment in the absence of 3α,5β-THP administration due to its stimulant effect. Although α4βδ GABARs were increased by chronic METH treatment, the GABAergic current recorded from hippocampal neurons at this time was a depolarizing, shunting inhibition, which was potentiated by 3α,5β-THP. This steroid reduced neuronal excitability and anxiety during chronic METH treatment, consistent with its typical effect. Flumazenil (10 mg/kg, i.p., 3x) reduced α4βδ expression and prevented the anxiogenic effect of 3α,5β-THP after METH withdrawal. Our findings suggest a novel mechanism underlying stress-triggered anxiety after METH withdrawal mediated by α4βδ GABARs.
doi:10.1016/j.neuroscience.2013.08.033
PMCID: PMC3857162  PMID: 23994152
CA1 hippocampus; pregnanolone; allopregnanolone; stress; withdrawal; flumazenil; methamphetamine
7.  An Epidemiologic and Genomic Investigation Into the Obesity Paradox in Renal Cell Carcinoma 
Background
Obesity increases risk for clear-cell renal cell carcinoma (ccRCC), yet obese patients appear to experience longer survival than nonobese patients. We examined body mass index (BMI) in relation to stage, grade, and cancer-specific mortality (CSM) while considering detection bias, nutritional status, and molecular tumor features.
Methods
Data were available from 2119 ccRCC patients who underwent renal mass surgery at Memorial Sloan-Kettering Cancer Center between 1995 and 2012. Logistic regression models produced associations between BMI and advanced disease. Multivariable competing risks regression models estimated associations between BMI and CSM. Somatic mutation, copy number, methylation, and expression data were examined by BMI among a subset of 126 patients who participated in the Cancer Genome Atlas Project for ccRCC using the Kruskal–Wallis or Fisher exact tests. All statistical tests were two-sided.
Results
Obese and overweight patients were less likely to present with advanced-stage disease compared with normal-weight patients (odds ratio [OR] = 0.61, 95% confidence interval [CI] = 0.48 to 0.79 vs OR = 0.65, 95% CI = 0.51 to 0.83, respectively). Higher BMI was associated with reduced CSM in univariable analyses (P < .005). It remained statistically significant after adjustment for comorbidities and albumin level, but it became non-statistically significant after adjusting for stage and grade (P > .10). Genome-wide interrogation by BMI suggested differences in gene expression of metabolic and fatty acid genes, including fatty acid synthase (FASN), consistent with the obesity paradox.
Conclusions
Our findings suggest that although BMI is not an independent prognostic factor for CSM after controlling for stage and grade, tumors developing in an obesogenic environment may be more indolent.
doi:10.1093/jnci/djt310
PMCID: PMC3866155  PMID: 24285872
8.  Serotonergic versus non-serotonergic dorsal raphe projection neurons: differential participation in reward circuitry 
Cell reports  2014;8(6):1857-1869.
Summary
The dorsal raphe nucleus (DRN) contains the largest group of serotonin-producing neurons in the brain and projects to regions controlling reward. Although pharmacological studies suggest that serotonin inhibits reward-seeking, electrical stimulation of the DRN strongly reinforces instrumental behavior. Here, we provide a targeted assessment of the behavioral, anatomical, and electrophysiological contributions of serotonergic and non-serotonergic DRN neurons to reward processes. To explore DRN heterogeneity, we used a simultaneous two-vector knockout/optogenetic stimulation strategy, as well as cre-induced and cre-silenced vectors in several cre-expressing transgenic mouse lines. We found that the DRN is capable of reinforcing behavior primarily via non-serotonergic neurons, whose main projection target is the ventral tegmental area (VTA). Furthermore, these non-serotonergic projections provide glutamatergic excitation of VTA dopamine neurons and account for a large majority of the DRN-VTA pathway. These findings help to resolve apparent discrepancies between the roles of serotonin versus the DRN in behavioral reinforcement.
doi:10.1016/j.celrep.2014.08.037
PMCID: PMC4181379  PMID: 25242321
9.  Methamphetamine alters reference gene expression in nigra and striatum of adult rat brain 
Neurotoxicology  2013;39:138-145.
The nigrostriatal dopaminergic system is a major lesion target for methamphetamine (MA), one of the most addictive and neurotoxic drugs of abuse. High doses of MA alter the expression of a large number of genes. Reference genes (RGs) are considered relatively stable and are often used as standards for quantitative real-time PCR (qRT-PCR) reactions. The purpose of this study was to determine whether MA altered the expression of RGs and to identify the appropriate RGs for gene expression studies in animals receiving MA. Adult male Sprague-Dawley rats were treated with high doses of MA or saline. Striatum and substantia nigra were harvested at 2 hours or 24 hours after MA administration. The expression and stability of 10 commonly used RGs were examined using qRT-PCR and then evaluated by geNorm and Normfinder. We found that MA altered the expression of selected RGs. These candidate RGs presented differential stability in the striatum and in substantia nigra at both 2 hours and 24 hours after MA injection. Selection of an unstable RG as a standard altered the significance of tyrosine hydroxylase (TH) mRNA expression after MA administration. In conclusion, our data show that MA site- and time- dependently altered the expression of RGs in nigrostriatal dopaminergic system. These temporal and spatial factors should be considered when selecting appropriate RGs for interpreting the expression of target genes in animals receiving MA.
doi:10.1016/j.neuro.2013.08.009
PMCID: PMC3918345  PMID: 24042092
Methamphetamine; Housekeeping genes; Nigra; Real-time PCR; Reference genes; Striatum
10.  SNP rs6265 Regulates Protein Phosphorylation and Osteoblast Differentiation and Influences BMD in Humans 
Bone Mineral Density (BMD) is major index for diagnosing osteoporosis. PhosSNPs are non-synonymous SNPs that affect protein phosphorylation. The relevance and significance of phosSNPs to BMD and osteoporosis is unknown. This study aims to identify and characterize phosSNPs significant for BMD in humans. We conducted a pilot genome-wide phosSNP association study for BMD in three independent population samples, involving ~5,000 unrelated individuals. We identified and replicated three phosSNPs associated with both spine BMD and hip BMD in Caucasians. Association with hip BMD for one of these phosSNPs, i.e., rs6265 (major/minor allele: G/A) in BDNF gene, was also suggested in Chinese. Consistently in both ethnicities, individuals carrying AA genotype have significant lower hip BMD than carriers of GA and GG genotypes. Through in vitro molecular and cellular studies, we found that compared to osteoblastic cells transfected with wild-type BDNF-Val66 (encoded with allele G at rs6265), transfection of variant BDNF-Met66 (encoded with allele A at rs6265) significantly decreased BDNF protein phosphorylation (at amino acid residue T62), expression of osteoblastic genes (OPN, BMP2, and ALP), and osteoblastic activity. The findings are consistent with and explain our prior observations in general human populations. We conclude that phosSNP rs6265, via regulating BDNF protein phosphorylation and osteoblast differentiation, influence hip BMD in humans. This study represents our first endeavor to dissect the functions of phosSNPs in bone, which might stimulate extended large-scale studies on bone or similar studies on other human complex traits and diseases.
doi:10.1002/jbmr.1997
PMCID: PMC4127979  PMID: 23712400
BMD; SNP; protein phosphorylation; BDNF; osteoblast
11.  Bicycling crash circumstances vary by route type: a cross-sectional analysis 
BMC Public Health  2014;14(1):1205.
Background
Widely varying crash circumstances have been reported for bicycling injuries, likely because of differing bicycling populations and environments. We used data from the Bicyclists’ Injuries and the Cycling Environment Study in Vancouver and Toronto, Canada, to describe the crash circumstances of people injured while cycling for utilitarian and leisure purposes. We examined the association of crash circumstances with route type.
Methods
Adult cyclists injured and treated in a hospital emergency department described their crash circumstances. These were classified into major categories (collision vs. fall, motor vehicle involved vs. not) and subcategories. The distribution of circumstances was tallied for each of 14 route types defined in an earlier analysis. Ratios of observed vs. expected were tallied for each circumstance and route type combination.
Results
Of 690 crashes, 683 could be characterized for this analysis. Most (74%) were collisions. Collisions included those with motor vehicles (34%), streetcar (tram) or train tracks (14%), other surface features (10%), infrastructure (10%), and pedestrians, cyclists, or animals (6%). The remainder of the crashes were falls (26%), many as a result of collision avoidance manoeuvres. Motor vehicles were involved directly or indirectly with 48% of crashes. Crash circumstances were distributed differently by route type, for example, collisions with motor vehicles, including “doorings”, were overrepresented on major streets with parked cars. Collisions involving streetcar tracks were overrepresented on major streets. Collisions involving infrastructure (curbs, posts, bollards, street furniture) were overrepresented on multiuse paths and bike paths.
Conclusions
These data supplement our previous analyses of relative risks by route type by indicating the types of crashes that occur on each route type. This information can guide municipal engineers and planners towards improvements that would make cycling safer.
doi:10.1186/1471-2458-14-1205
PMCID: PMC4253622  PMID: 25416928
Bicycling injuries; Bike lanes; Traffic accidents
12.  Genome-wide association study of copy number variation identified gremlin1 as a candidate gene for lean body mass 
Journal of human genetics  2011;57(1):33-37.
Lean body mass (LBM) is a heritable trait predicting a series of health problems, such as osteoporotic fracture and sarcopenia. We aim to identify sequence variants associated with LBM by a genome-wide association study (GWAS) of copy number variants (CNVs). We genotyped genome-wide CNVs of 1627 individuals of the Chinese population with Affymetrix SNP6.0 genotyping platform, which comprised of 9 40 000 copy number probes. We then performed a GWAS of CNVs with lean mass at seven sites: left and right arms, left and right legs, total of limb, trunk and whole body. We identified a CNV that is associated with LBM variation at the genome-wide significance level (CNV2073, Bonferroni corrected P-value 0.002 at right arm). CNV2073 locates at chromosome 15q13.3, which has been implicated as a candidate region for LBM by our previous linkage studies. The nearest gene, gremlin1, has a key role in the regulation of skeletal muscle formation and repair. Our results suggest that the gremlin1 gene is a potentially important gene for LBM variation. Our findings also show the utility and efficacy of CNV as genetic markers in association studies.
doi:10.1038/jhg.2011.125
PMCID: PMC4169267  PMID: 22048656
association; copy number variation; gremlin1 gene; lean body mass; 15q13.3
13.  Gene-gene interaction between RBMS3 and ZNF516 influences bone mineral density 
Osteoporosis is characterized by low bone mineral density (BMD), a highly heritable trait that is determined, in part, by the actions and interactions of multiple genes. While an increasing number of genes have been identified to have independent effects on BMD, few studies have been performed to identify genes that interact with one another to affect BMD. In this study, we performed gene-gene interaction analyses in selected candidate genes in individuals with extremely high vs. low hip BMD (20% tails of the distributions), in two independent US Caucasian samples. The first sample contained 916 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 2,286 subjects. The second sample consisted of 400 unrelated subjects with extreme hip BMD Z-scores selected from a population composed of 1,000 subjects. Combining results from these two samples, we found one interacting gene pair (RBMS3 vs. ZNF516) which, even after Bonferroni correction for multiple testing, showed consistently significant effects on hip BMD. RMBS3 harbored two SNPs, rs6549904 and rs7640046, both of which had significant interactions with a SNP, rs4891159, located on ZNF516 (P values: 7.04×10−11 and 1.03×10−10). We further validated these results in two additional samples of Caucasian and African descent. The gene pair, RBMS3 vs. ZNF516, was successfully replicated in the Caucasian sample (P values: 8.07×10−3 and 2.91×10−3). For the African sample, a significant interaction was also detected (P values: 0.031 and 0.043), but the direction of the effect was opposite to that observed in the three Caucasian samples. By providing evidence for genetic interactions underlying BMD, this study further delineated the genetic architecture of osteoporosis.
doi:10.1002/jbmr.1788
PMCID: PMC4127986  PMID: 23045156
interaction; association; BMD; osteoporosis
14.  Synergistic Antifungal Effect of Glabridin and Fluconazole 
PLoS ONE  2014;9(7):e103442.
The incidence of invasive fungal infections is increasing in recent years. The present study mainly investigated glabridin (Gla) alone and especially in combination with fluconazole (FLC) against Cryptococcus neoformans and Candida species (Candida albicans, Candida tropicalis, Candida krusei, Candida parapsilosis and Candida Glabratas) by different methods. The minimal inhibitory concentration (MIC) and the minimal fungicidal concentration (MFC) indicated that Gla possessed a broad-spectrum antifungal activity at relatively high concentrations. After combining with FLC, Gla exerted a potent synergistic effect against drug-resistant C. albicans and C. tropicalis at lower concentrations when interpreted by fractional inhibitory concentration index (FICI). Disk diffusion test and time-killing test confirming the synergistic fungicidal effect. Cell growth tests suggested that the synergistic effect of the two drugs depended more on the concentration of Gla. The cell envelop damage including a significant decrease of cell size and membrane permeability increasing were found after Gla treatment. Together, our results suggested that Gla possessed a synergistic effect with FLC and the cell envelope damage maybe contributed to the synergistic effect, which providing new information for developing novel antifungal agents.
doi:10.1371/journal.pone.0103442
PMCID: PMC4110026  PMID: 25058485
15.  Disruption of HPV16-E7 by CRISPR/Cas System Induces Apoptosis and Growth Inhibition in HPV16 Positive Human Cervical Cancer Cells 
BioMed Research International  2014;2014:612823.
High-risk human papillomavirus (HR-HPV) has been recognized as a major causative agent for cervical cancer. Upon HPV infection, early genes E6 and E7 play important roles in maintaining malignant phenotype of cervical cancer cells. By using clustered regularly interspaced short palindromic repeats- (CRISPR-) associated protein system (CRISPR/Cas system), a widely used genome editing tool in many organisms, to target HPV16-E7 DNA in HPV positive cell lines, we showed for the first time that the HPV16-E7 single-guide RNA (sgRNA) guided CRISPR/Cas system could disrupt HPV16-E7 DNA at specific sites, inducing apoptosis and growth inhibition in HPV positive SiHa and Caski cells, but not in HPV negative C33A and HEK293 cells. Moreover, disruption of E7 DNA directly leads to downregulation of E7 protein and upregulation of tumor suppressor protein pRb. Therefore, our results suggest that HPV16-E7 gRNA guided CRISPR/Cas system might be used as a therapeutic strategy for the treatment of cervical cancer.
doi:10.1155/2014/612823
PMCID: PMC4127252  PMID: 25136604
16.  The Potential of Using Brain Images for Authentication 
The Scientific World Journal  2014;2014:749096.
Biometric recognition (also known as biometrics) refers to the automated recognition of individuals based on their biological or behavioral traits. Examples of biometric traits include fingerprint, palmprint, iris, and face. The brain is the most important and complex organ in the human body. Can it be used as a biometric trait? In this study, we analyze the uniqueness of the brain and try to use the brain for identity authentication. The proposed brain-based verification system operates in two stages: gray matter extraction and gray matter matching. A modified brain segmentation algorithm is implemented for extracting gray matter from an input brain image. Then, an alignment-based matching algorithm is developed for brain matching. Experimental results on two data sets show that the proposed brain recognition system meets the high accuracy requirement of identity authentication. Though currently the acquisition of the brain is still time consuming and expensive, brain images are highly unique and have the potential possibility for authentication in view of pattern recognition.
doi:10.1155/2014/749096
PMCID: PMC4121282  PMID: 25126604
17.  Elevated Serum and Synovial Fluid Levels of Interleukin-34 in Rheumatoid Arthritis: Possible Association with Disease Progression via Interleukin-17 Production 
To measure the levels of interleukin-34 (IL-34) in serum and synovial fluid (SF) of patients with rheumatoid arthritis (RA) and to evaluate the effect of recombination human (rh) IL-34 on IL-17 production by peripheral blood mononuclear cells (PBMC) in RA patients, the serum and SF levels of IL-34, and the production of IL-17 by rhIL-34-treated PBMC of RA patients were measured by enzyme-linked immunosorbent assay. We also tested the change of IL-34 level after tumor necrosis factor (TNF)-α blockade therapy in 30 RA patients. In contrast to almost no detectable IL-34 in osteoarthritis (OA) and healthy serum, IL-34 could be detected in 93 out of the 125 RA cases (74.4%). Sera IL-34 levels were significantly higher in RA patients compared with the controls and correlated with disease activity. IL-34 levels were higher in SF samples than in sera in 11 RA patients. The level of serum IL-34 decreased after anti-TNF treatment. In the presence of rhIL-34, stimulation of PBMC from RA patients resulted in increased production of IL-17. These findings suggest that IL-34 may play a role in the pathogenesis of RA.
doi:10.1089/jir.2012.0122
PMCID: PMC3708624  PMID: 23421370
18.  Replication of 6 Obesity Genes in a Meta-Analysis of Genome-Wide Association Studies from Diverse Ancestries 
PLoS ONE  2014;9(5):e96149.
Obesity is a major public health problem with a significant genetic component. Multiple DNA polymorphisms/genes have been shown to be strongly associated with obesity, typically in populations of European descent. The aim of this study was to verify the extent to which 6 confirmed obesity genes (FTO, CTNNBL1, ADRB2, LEPR, PPARG and UCP2 genes) could be replicated in 8 different samples (n = 11,161) and to explore whether the same genes contribute to obesity-susceptibility in populations of different ancestries (five Caucasian, one Chinese, one African-American and one Hispanic population). GWAS-based data sets with 1000 G imputed variants were tested for association with obesity phenotypes individually in each population, and subsequently combined in a meta-analysis. Multiple variants at the FTO locus showed significant associations with BMI, fat mass (FM) and percentage of body fat (PBF) in meta-analysis. The strongest association was detected at rs7185735 (P-value = 1.01×10−7 for BMI, 1.80×10−6 for FM, and 5.29×10−4 for PBF). Variants at the CTNNBL1, LEPR and PPARG loci demonstrated nominal association with obesity phenotypes (meta-analysis P-values ranging from 1.15×10−3 to 4.94×10−2). There was no evidence of association with variants at ADRB2 and UCP2 genes. When stratified by sex and ethnicity, FTO variants showed sex-specific and ethnic-specific effects on obesity traits. Thus, it is likely that FTO has an important role in the sex- and ethnic-specific risk of obesity. Our data confirmed the role of FTO, CTNNBL1, LEPR and PPARG in obesity predisposition. These findings enhanced our knowledge of genetic associations between these genes and obesity-related phenotypes, and provided further justification for pursuing functional studies of these genes in the pathophysiology of obesity. Sex and ethnic differences in genetic susceptibility across populations of diverse ancestries may contribute to a more targeted prevention and customized treatment of obesity.
doi:10.1371/journal.pone.0096149
PMCID: PMC4039436  PMID: 24879436
19.  Meta-Analysis of Genome-Wide Scans Provides Evidence for Sex- and Site-Specific Regulation of Bone Mass 
Several genome-wide scans have been performed to detect loci that regulate BMD, but these have yielded inconsistent results, with limited replication of linkage peaks in different studies. In an effort to improve statistical power for detection of these loci, we performed a meta-analysis of genome-wide scans in which spine or hip BMD were studied. Evidence was gained to suggest that several chromosomal loci regulate BMD in a site-specific and sex-specific manner.
Introduction
BMD is a heritable trait and an important predictor of osteoporotic fracture risk. Several genome-wide scans have been performed in an attempt to detect loci that regulate BMD, but there has been limited replication of linkage peaks between studies. In an attempt to resolve these inconsistencies, we conducted a collaborative meta-analysis of genome-wide linkage scans in which femoral neck BMD (FN-BMD) or lumbar spine BMD (LS-BMD) had been studied.
Materials and Methods
Data were accumulated from nine genome-wide scans involving 11,842 subjects. Data were analyzed separately for LS-BMD and FN-BMD and by sex. For each study, genomic bins of 30 cM were defined and ranked according to the maximum LOD score they contained. While various densitometers were used in different studies, the ranking approach that we used means that the results are not confounded by the fact that different measurement devices were used. Significance for high average rank and heterogeneity was obtained through Monte Carlo testing.
Results
For LS-BMD, the quantitative trait locus (QTL) with greatest significance was on chromosome 1p13.3-q23.3 (p = 0.004), but this exhibited high heterogeneity and the effect was specific for women. Other significant LS-BMD QTLs were on chromosomes 12q24.31-qter, 3p25.3-p22.1, 11p12-q13.3, and 1q32-q42.3, including one on 18p11-q12.3 that had not been detected by individual studies. For FN-BMD, the strongest QTL was on chromosome 9q31.1-q33.3 (p = 0.002). Other significant QTLs were identified on chromosomes 17p12-q21.33, 14q13.1-q24.1, 9q21.32-q31.1, and 5q14.3-q23.2. There was no correlation in average ranks of bins between men and women and the loci that regulated BMD in men and women and at different sites were largely distinct.
Conclusions
This large-scale meta-analysis provided evidence for replication of several QTLs identified in previous studies and also identified a QTL on chromosome 18p11-q12.3, which had not been detected by individual studies. However, despite the large sample size, none of the individual loci identified reached genome-wide significance.
doi:10.1359/jbmr.060806
PMCID: PMC4016811  PMID: 17228994
osteoporosis; BMD; linkage; meta-analysis; genome search; genome scan
20.  Relationship between P53 Status and Response to Chemotherapy in Patients with Gastric Cancer: A Meta-Analysis 
PLoS ONE  2014;9(4):e95371.
Background
Previous studies have yielded conflicting results regarding the relationship between p53 status and response to chemotherapy in patients with gastric cancer. We therefore performed a meta-analysis to expound the relationship between p53 status and response to chemotherapy.
Methods/Findings
Thirteen previously published eligible studies, including 564 cases, were identified and included in this meta-analysis. p53 positive status (high expression of p53 protein and/or a mutant p53 gene) was associated with improved response in gastric cancer patients who received chemotherapy (good response: risk ratio [RR]  = 0.704; 95% confidence intervals [CI]  = 0.550–0.903; P = 0.006). In further stratified analyses, association with a good response remained in the East Asian population (RR = 0.657; 95% CI = 0.488–0.884; P = 0.005), while in the European subgroup, patients with p53 positive status tended to have a good response to chemotherapy, although this did not reach statistical significance (RR = 0.828, 95% CI = 0.525–1.305; P = 0.417). As five studies used neoadjuvant chemotherapy (NCT) and one used neoadjuvant chemoradiotherapy (NCRT), we also analyzed these data, and found that p53 positive status was associated with a good response in gastric cancer patients who received chemotherapy-based neoadjuvant treatment (RR = 0.675, 95% CI = 0.463–0.985; P = 0.042).
Conclusion
This meta-analysis indicated that p53 status may be a useful predictive biomarker for response to chemotherapy in gastric cancer. Further prospective studies with larger sample sizes and better study designs are required to confirm our findings.
doi:10.1371/journal.pone.0095371
PMCID: PMC3989310  PMID: 24740294
21.  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
22.  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
23.  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
24.  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
25.  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

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