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1.  The genetic map of goldfish (Carassius auratus) provided insights to the divergent genome evolutions in the Cyprinidae family 
Scientific Reports  2016;6:34849.
A high-density linkage map of goldfish (Carassius auratus) was constructed using RNA-sequencing. This map consists of 50 linkage groups with 8,521 SNP markers and an average resolution of 0.62 cM. Approximately 84% of markers are in protein-coding genes orthologous to zebrafish proteins. We performed comparative genome analysis between zebrafish and medaka, common carp, grass carp, and goldfish to study the genome evolution events in the Cyprinidae family. The comparison revealed large synteny blocks among Cyprinidae fish and we hypothesized that the Cyprinidae ancestor undergone many inter-chromosome rearrangements after speciation from teleost ancestor. The study also showed that goldfish genome had one more round of whole genome duplication (WGD) than zebrafish. Our results illustrated that most goldfish markers were orthologous to genes in common carp, which had four rounds of WGD. Growth-related regions and genes were identified by QTL analysis and association study. Function annotations of the associated genes suggested that they might regulate development and growth in goldfish. This first genetic map enables us to study the goldfish genome evolution and provides an important resource for selective breeding of goldfish.
doi:10.1038/srep34849
PMCID: PMC5052598  PMID: 27708388
2.  Maternal Antenatal Bereavement and Neural Tube Defect in Live-Born Offspring: A Cohort Study 
PLoS ONE  2016;11(9):e0163355.
Background
Maternal emotional stress during pregnancy has previously been associated with congenital neural malformations, but most studies are based on data collected retrospectively. The objective of our study was to investigate associations between antenatal maternal bereavement due to death of a close relative and neural tube defects (NTDs) in the offspring.
Methods
We performed a register-based cohort study including all live-born children (N = 1,734,190) from 1978–2008. Exposure was bereavement due to loss of a close relative from one year before conception to the end of the first trimester of pregnancy. The outcome was NTDs in the offspring according to the International Classification of Disease. We used multivariate logistic regression to estimate prevalence odds ratios (ORs).
Results
A total of 2% children were born to mothers who lost a close relative prenatally. During 30 years of follow-up, 1,115 children were diagnosed with any NTDs: spina bifida (n = 889), anencephaly (n = 85) and encephalocele (n = 164). And 23 children were diagnosed with two types of NTDs. Overall, when comparing bereaved mothers to non-bereaved mothers, no significant increased prevalence of NTDs in the offspring was seen (OR = 0.84; 95% confidence interval: 0.52–1.33).
Conclusion
Overall maternal bereavement in the antenatal period was not related to NTDs in liveborn offspring.
doi:10.1371/journal.pone.0163355
PMCID: PMC5042438  PMID: 27685943
3.  PEP_scaffolder: using (homologous) proteins to scaffold genomes 
Bioinformatics  2016;32(20):3193-3195.
Motivation: Recovering the gene structures is one of the important goals of genome assembly. In low-quality assemblies, and even some high-quality assemblies, certain gene regions are still incomplete; thus, novel scaffolding approaches are required to complete gene regions.
Results: We developed an efficient and fast genome scaffolding method called PEP_scaffolder, using proteins to scaffold genomes. The pipeline aims to recover protein-coding gene structures. We tested the method on human contigs; using human UniProt proteins as guides, the improvement on N50 size was 17% increase with an accuracy of ∼97%. PEP_scaffolder improved the proportion of fully covered proteins among all proteins, which was close to the proportion in the finished genome. The method provided a high accuracy of 91% using orthologs of distant species. Tested on simulated fly contigs, PEP_scaffolder outperformed other scaffolders, with the shortest running time and the highest accuracy.
Availability and Implementation: The software is freely available at http://www.fishbrowser.org/software/PEP_scaffolder/
Contact: lijt@cafs.ac.cn
Supplementary information: Supplementary data are available at Bioinformatics online.
doi:10.1093/bioinformatics/btw378
PMCID: PMC5048069  PMID: 27334475
4.  Hepatitis B virus X protein up-regulates C4b-binding protein α through activating transcription factor Sp1 in protection of hepatoma cells from complement attack 
Oncotarget  2016;7(19):28013-28026.
Hepatitis B virus X protein (HBx) plays crucial roles in the development of hepatocellular carcinoma (HCC). We previously showed that HBx protected hepatoma cells from complement attack by activation of CD59. Moreover, in this study we found that HBx protected hepatoma cells from complement attack by activation of C4b-binding protein α (C4BPα), a potent inhibitor of complement system. We observed that HBx were positively correlated with those of C4BPα in clinical HCC tissues. Mechanistically, HBx activated the promoter core region of C4BPα, located at −1199/−803nt, through binding to transcription factor Sp1. In addition, chromatin immunoprecipitation (ChIP) assays showed that HBx was able to bind to the promoter of C4BPα, which could be blocked by Sp1 silencing. Functionally, knockdown of C4BPα obviously increased the deposition of C5b-9, a complex of complement membrane attack, and remarkably abolished the HBx-induced resistance of hepatoma cells from complement attack in vitro and in vivo. Thus, we conclude that HBx up-regulates C4BPα through activating transcription factor Sp1 in protection of liver cancer cells from complement attack. Our finding provides new insights into the mechanism by which HBx enhances protection of hepatoma cells from complement attack.
doi:10.18632/oncotarget.8472
PMCID: PMC5053706  PMID: 27050367
HBx; C4BP; complement attack; HCC
5.  Prenatal and early life stress and risk of eating disorders in adolescent girls and young women 
European Child & Adolescent Psychiatry  2016;25(11):1245-1253.
Females are more likely than males to develop eating disorders (EDs) in the adolescence and youth, and the etiology remains unclear. We aimed to estimate the effect of severe early life stress following bereavement, the death of a close relative, on the risk of EDs among females aged 10–26 years. This population-based cohort study included girls born in Denmark (from 1973 to 2000) or Sweden (from 1970 to 1997). Girls were categorized as exposed if they were born to mothers who lost a close relative 1 year prior to or during pregnancy or if the girl herself lost a parent or a sibling within the first 10 years of life. All other girls were included in unexposed group. An ED case was defined by a diagnosis of EDs at ages of 10–26 years, including broadly defined bulimia nervosa, broadly defined anorexia nervosa and mixed EDs. Poisson regression models were used to estimate the incidence rate ratio (IRR) between exposed group and unexposed group.A total of 64453 (3.05 %) girls were included in the exposed group. We identified 9477 girls with a diagnosis of EDs, of whom 307 (3.24 %) were from the exposed group. Both prenatal and postnatal exposure following bereavement by unexpected death was associated with an increased overall risk of EDs (IRRprenatal: 1.49, 95 % CI: 1.01–2.19 and IRRpostnatal: 1.34, 95 % CI: 1.05–1.71). We observed similar results for subtypes of broadly defined bulimia nervosa (IRR: 2.47, 95 % CI: 1.67–3.65) and mixed EDs (IRR: 1.45, 95 % CI: 1.02–2.07).Our findings suggest that prenatal and early postnatal life stress due to unexpected death of a close relative is associated with an increased overall risk of eating disorders in adolescent girls and young women. The increased risk might be driven mainly by differences in broadly defined bulimia nervosa and mixed eating disorders, but not broadly defined anorexia nervosa.
doi:10.1007/s00787-016-0848-z
PMCID: PMC5083758  PMID: 27083434
Bereavement; Eating disorders; Cohort study; Prenatal stress; Postnatal stress
6.  Long-term risk of atrial fibrillation after the death of a partner 
Open Heart  2016;3(1):e000367.
Objectives
Severe psychological stress is generally associated with an increased risk of acute cardiovascular diseases, such as myocardial infarction, but it remains unknown whether it also applies to atrial fibrillation. We conducted a population-based case–control study using nationwide Danish health registers to examine the risk of atrial fibrillation after the death of a partner.
Methods
From 1995 through 2014, we identified 88 612 cases with a hospital diagnosis of atrial fibrillation and 886 120 age-matched and sex-matched controls based on risk-set sampling. The conditional logistic regression model was used to calculate adjusted ORs of atrial fibrillation with 95% CIs.
Results
Partner bereavement was experienced by 17 478 cases and 168 940 controls and was associated with a transiently higher risk of atrial fibrillation; the risk was highest 8–14 days after the loss (1.90; 95% CI 1.34 to 2.69), after which it gradually declined. One year after the loss, the risk was almost the same as in the non-bereaved population. Overall, the OR of atrial fibrillation within 30 days after bereavement was 1.41 (95% CI 1.17 to 1.70), but it tended to be higher in persons below the age of 60 years (2.34; 95% CI 1.02 to 5.40) and in persons whose partner had a low predicted mortality 1 month before the death, that is, ≤5 points on the age-adjusted Charlson Comorbidity Index (1.57; 95% CI 1.13 to 2.17).
Conclusions
The severely stressful life event of losing a partner was followed by a transiently increased risk of atrial fibrillation lasting for 1 year, especially for the least predicted losses.
doi:10.1136/openhrt-2015-000367
PMCID: PMC4823543  PMID: 27099762
7.  Early Life Bereavement and Schizophrenia 
Medicine  2016;95(3):e2434.
Supplemental Digital Content is available in the text
Abstract
We aimed to examine whether early life bereavement, as indicator of severe stress, was associated with an increased risk of schizophrenia later in life.
Based on population registers, we established a cohort of all children born in Denmark (N = 1 686 416) and Sweden (N = 2 563 659) from 1973 to 1997. Children were categorized as exposed if they lost a first-degree relative during the first 18 years of life. Outcome is the first diagnosis of schizophrenia as either inpatient or outpatient. Log-linear Poisson regression models were used to estimate incidence rate ratios (IRRs).
A total of 188,850 children (4.6%) experienced death of a first-degree relative from birth to 18 years of age. Compared with unexposed children, those exposed had overall a 39% higher risk of schizophrenia (= 1.39, 95% CI [confidence interval]: 1.32–1.47). The IRR was particularly high if the family member committed suicide (aIRR = 2.11, 95% CI: 1.90–2.34) or died due to an injury or accident (aIRR = 1.44, 95% CI: 1.27–1.63). The IRR of schizophrenia decreased with increasing child's age at bereavement (P < 0.0001). Children who experienced >1 death during the first 18 years of life (aIRR = 1.79, 95% CI: 1.46–2.19) had a higher risk than those with a single death (aIRR = 1.37, 95% CI: 1.30–1.45).
The study suggested that exposure to death of a first-degree relative before 18 years was associated with an increased risk of schizophrenia in later life. The complex mechanisms behind these associations remain to be elucidated.
doi:10.1097/MD.0000000000002434
PMCID: PMC4998249  PMID: 26817875
8.  Mortality in Children Aged 0-9 Years: A Nationwide Cohort Study from Three Nordic Countries 
PLoS ONE  2016;11(1):e0146669.
Background
Mortality in children under five years has been widely studied, whereas mortality at 5–9 years has received little attention. Using unique data from national registers in three Nordic countries, we aimed to characterize mortality directionality in children aged 0 to 9 years.
Methods and Findings
The cohort study included all children born in Denmark from 1973 to 2008 (n = 2,433,758), Sweden from 1973 to 2006 (n = 3,400,212), and a random sample of 89.3% of children born in Finland from 1987 to 2007 (n = 1,272,083). Children were followed from 0 to 9 years, and cumulative mortality and mortality rates were compared by age, gender, cause of death, and calendar periods. Among the 7,105,962 children, there were 48,299 deaths during study period. From 1981–1985 to 2001–2005, all-cause mortality rates were reduced by between 34% and 62% at different ages. Overall mortality rate ratio between boys and girls decreased from 1.25 to 1.21 with the most prominent reduction in children aged 5–9 years (from 1.59 to 1.19). Neoplasms, diseases of the nervous system and transport accidents were the most frequent cause of death after the first year of life. These three leading causes of death declined by 42% (from 6.2 to 3.6 per 100,000 person years), 43% (from 3.7 to 2.1) and 62% (from 3.9 to 1.5) in boys, and 25% (from 4.1 to 3.1 per 100000 person years), 42% (from 3.4 to 1.9) and 63% (from 3.0 to 1.1) in girls, respectively. Mortality from neoplasms was the highest in each age except infants when comparing cause-specific mortality, and half of deaths from diseases of the nervous system occurred in infancy. Mortality rate due to transport accidents increased with age and was highest in boys aged 5–9 years.
Conclusions
Mortality rate in children aged 0–9 years has been decreasing with diminished difference between genders over the past decades. Our results suggest the importance of further research on mortality by causes of neoplasms, and causes of transport accidents—especially in children aged 5–9 years.
doi:10.1371/journal.pone.0146669
PMCID: PMC4706349  PMID: 26744840
9.  Long non-coding RNA HULC promotes tumor angiogenesis in liver cancer by up-regulating sphingosine kinase 1 (SPHK1) 
Oncotarget  2015;7(1):241-254.
Highly up-regulated in liver cancer (HULC) is a long non-coding RNA (lncRNA). We found that HULC up-regulated sphingosine kinase 1 (SPHK1), which is involved in tumor angiogenesis. Levels of HULC were positively correlated with levels of SPHK1 and its product, sphingosine-1-phosphate (S1P), in patients HCC samples. HULC increased SPHK1 in hepatoma cells. Chicken chorioallantoic membrane (CAM) assays revealed that si-SPHK1 remarkably blocked the HULC-enhanced angiogenesis. Mechanistically, HULC activated the promoter of SPHK1 in hepatoma cells through the transcription factor E2F1. Chromatin immunoprecipitation (ChIP) and electrophoretic mobility shift assay (EMSA) further showed that E2F1 was capable of binding to the E2F1 element in the SPHK1 promoter. HULC increased the expression of E2F1 in hepatoma cells and levels of HULC were positively correlated with those of E2F1 in HCC tissues. Intriguingly, HULC sequestered miR-107, which targeted E2F1 mRNA 3′UTR, by complementary base pairing. Functionally, si-SPHK1 remarkably abolished the HULC-enhanced tumor angiogenesis in vitro and in vivo. Taken together, we conclude that HULC promotes tumor angiogenesis in liver cancer through miR-107/E2F1/SPHK1 signaling. Our finding provides new insights into the mechanism of tumor angiogenesis.
PMCID: PMC4807995  PMID: 26540633
HULC; HCC; SPHK1; angiogenesis; E2F1; miR-107
10.  Gene map of large yellow croaker (Larimichthys crocea) provides insights into teleost genome evolution and conserved regions associated with growth 
Scientific Reports  2015;5:18661.
The genetic map of a species is essential for its whole genome assembly and can be applied to the mapping of important traits. In this study, we performed RNA-seq for a family of large yellow croakers (Larimichthys crocea) and constructed a high-density genetic map. In this map, 24 linkage groups comprised 3,448 polymorphic SNP markers. Approximately 72.4% (2,495) of the markers were located in protein-coding regions. Comparison of the croaker genome with those of five model fish species revealed that the croaker genome structure was closer to that of the medaka than to the remaining four genomes. Because the medaka genome preserves the teleost ancestral karyotype, this result indicated that the croaker genome might also maintain the teleost ancestral genome structure. The analysis also revealed different genome rearrangements across teleosts. QTL mapping and association analysis consistently identified growth-related QTL regions and associated genes. Orthologs of the associated genes in other species were demonstrated to regulate development, indicating that these genes might regulate development and growth in croaker. This gene map will enable us to construct the croaker genome for comparative studies and to provide an important resource for selective breeding of croaker.
doi:10.1038/srep18661
PMCID: PMC4687042  PMID: 26689832
11.  Hepatitis B virus X protein promotes human hepatoma cell growth via upregulation of transcription factor AP2α and sphingosine kinase 1 
Acta Pharmacologica Sinica  2015;36(10):1228-1236.
Aim:
Sphingosine kinase 1 (SPHK1) is involved in various cellular functions, including cell growth, migration, apoptosis, cytoskeleton architecture and calcium homoeostasis, etc. As an oncogenic kinase, SPHK1 is associated with the development and progression of cancers. The aim of this study was to investigate whether SPHK1 was involved in hepatocarcinogenesis induced by the hepatitis B virus X protein (HBx).
Methods:
The expression of SPHK1 in hepatocellular carcinoma (HCC) tissue and hepatoma cells were measured using qRT-PCR and Western blot analysis. HBx expression levels in hepatoma cells were modulated by transiently transfected with HBx or psi-HBx plasmids. The SPHK1 promoter activity was measured using luciferase reporter gene assay, and the interaction of the transcription factor AP2α with the SPHK1 promoter was studied with chromatin immunoprecipitation assay. The growth of hepatoma cells was evaluated in vitro using MTT and colony formation assays, and in a tumor xenograft model.
Results:
A positive correlation was found between the mRNA levels of SPHK1 and HBx in 38 clinical HCC samples (r=+0.727, P<0.01). Moreover, the expression of SPHK1 was markedly increased in the liver cancer tissue of HBx-transgenic mice. Overexpressing HBx in normal liver cells LO2 and hepatoma cells HepG2 dose-dependently increased the expression of SPHK1, whereas silencing HBx in HBx-expressing hepatoma cells HepG2-X and HepG2.2.15 suppressed SPHK1 expression. Furthermore, overexpressing HBx in HepG2 cells dose-dependently increased the SPHK1 promoter activity, whereas silencing HBx in HepG2-X cells suppressed this activity. In HepG2-X cells, AP2α was found to directly interact with the SPHK1 promoter, and silencing AP2α suppressed the SPHK1 promoter activity and SPHK1 expression. Silencing HBx in HepG2-X cells abolished the HBx-enhanced proliferation and colony formation in vitro, and tumor growth in vivo.
Conclusion:
HBx upregulates SPHK1 through the transcription factor AP2α, which promotes the growth of human hepatoma cells
doi:10.1038/aps.2015.38
PMCID: PMC4814204  PMID: 26073327
hepatitis B virus X protein; hepatocellular carcinoma; HepG2 cells; tumor xenograft model; sphingosine kinase 1; transcription factor AP2α; cell proliferation
12.  Prenatal maternal bereavement and risk of eating disorders in infants and toddlers: a population-based cohort study 
BMC Psychiatry  2015;15:229.
Background
Prenatal stress has been associated to a number of neuropsychiatric diseases but its role on the development of eating disorders (ED) remains unknown. Infants and toddlers with feeding or eating disorders are also at an increased risk of such diseases in later childhood and adolescence. We aimed to examine whether prenatal stress following maternal bereavement is associated with ED in infants and toddlers.
Methods
This population-based cohort study included children born from 1977 to 2008 in Denmark (N = 2,127,126) and from 1977 to 2006 in Sweden (N = 2,974,908). Children were categorized as exposed if they were born to mothers who lost a close relative one year prior to or during pregnancy and were categorized as unexposed otherwise. They were followed until the age of 3 for a first diagnosis of ED. Poisson regression models were used to examine incidence rate ratio (IRR) between the exposed and the unexposed cohort.
Results
A total of 9,403 ED cases were identified and 179 of whom were in the exposed cohort. Offspring born to mothers bereaved by loss of a core family member (older child or spouse) within the six months before pregnancy had a higher risk of ED than the unexposed offspring (IRR: 1.63, 95 % confidence intervals (CI): 1.07–2.47). In stratified analyses, bereavement during the six months before pregnancy was associated with an increased risk of ED in boys (IRR: 2.21, 95 % CI: 1.28–3.82), but not in girls (IRR: 1.18, 95 % CI: 0.61–2.27).
Discussion
This is the first population-based study to explore the association between prenatal stress and the risk of ED in infants and toddlers within two Nordic countries. This study added new evidence of early life stress for etiology of ED while the potential mechanism still needs further studies.
Conclusions
Prenatal stress following maternal bereavement by loss of a core family member is associated with an increased risk of ED among infants and toddlers. The six months before conception may be a susceptible time window, especially for boys.
doi:10.1186/s12888-015-0612-9
PMCID: PMC4582887  PMID: 26403981
Bereavement; Eating disorders; Hypothalamus-pituitary-adrenal axis; Prenatal stress
13.  Discovery and validation of potential bacterial biomarkers for lung cancer 
American Journal of Cancer Research  2015;5(10):3111-3122.
Microbes are residents in a number of body sites, including the oral and nasal cavities, which are connected to the lung via the pharynx. The associations between oral diseases and increased risk of lung cancer have been reported in previous prospective studies. In this study, we measured variations of salivary microbiota and evaluated their potential association with lung cancer, including squamous cell carcinoma (SCC) and adenocarcinoma (AC). A three-phase study was performed: First, we investigated the salivary microbiota from 20 lung cancer patients (10 SCC and 10 AC) and control subjects (n=10) using a deep sequencing analysis. Salivary Capnocytophaga, Selenomonas, Veillonella and Neisseria were found to be significantly altered in patients with SCC and AC when compared to that in control subjects. Second, we confirmed the significant changes of Capnocytophaga, Veillonella and Neisseria in the same lung cancer patients using quantitative PCR (qPCR). Finally, these bacterial species were further validated on new patient/control cohorts (n=56) with qPCR. The combination of two bacterial biomarkers, Capnocytophaga and Veillonella, yielded a receiver operating characteristic (ROC) value of 0.86 with an 84.6% sensitivity and 86.7% specificity in distinguishing patients with SCC from control subjects and a ROC value of 0.80 with a 78.6% sensitivity and 80.0% specificity in distinguishing patients with AC from control subjects. In conclusion, we have for the first time demonstrated the association of saliva microbiota with lung cancer. Particularly, the combination of the 16S sequencing discovery with qPCR validation studies revealed that the levels of Capnocytophaga and Veillonella were significantly higher in the saliva from lung cancer patients, which may serve as potential biomarkers for the disease detection/classification.
PMCID: PMC4656734  PMID: 26693063
Lung cancer; 16S rDNA sequencing; Capnocytophaga; Veillonella; saliva microbiota
14.  Gene Expression Variations of Red—White Skin Coloration in Common Carp (Cyprinus carpio) 
Teleosts have more types of chromatophores than other vertebrates and the genetic basis for pigmentation is highly conserved among vertebrates. Therefore, teleosts are important models to study the mechanism of pigmentation. Although functional genes and genetic variations of pigmentation have been studied, the mechanisms of different skin coloration remains poorly understood. The koi strain of common carp has various colors and patterns, making it a good model for studying the genetic basis of pigmentation. We performed RNA-sequencing for red skin and white skin and identified 62 differentially expressed genes (DEGs). Most of them were validated with RT-qPCR. The up-regulated DEGs in red skin were enriched in Kupffer’s vesicle development while the up-regulated DEGs in white skin were involved in cytoskeletal protein binding, sarcomere organization and glycogen phosphorylase activity. The distinct enriched activity might be associated with different structures and functions in erythrophores and iridophores. The DNA methylation levels of two selected DEGs inversely correlated with gene expression, indicating the participation of DNA methylation in the coloration. This expression characterization of red—white skin along with the accompanying transcriptome-wide expression data will be a useful resource for further studies of pigment cell biology.
doi:10.3390/ijms160921310
PMCID: PMC4613254  PMID: 26370964
pigmentation; transcriptome sequencing; DNA methylation; teleost
15.  Social Conditions for People With Down Syndrome: A Register-Based Cohort Study in Denmark 
Today, most persons with Down syndrome (DS) survive into middle age, but information on their social conditions as adults is limited. We addressed this knowledge gap using data from national registers in Denmark. We identified a national cohort of 1,998 persons with DS who were born between 1968 and 2007 (1,852 with standard trisomy 21, 80 with Robertsonian translocations and 66 with mosaicism) using the Danish Cytogenetic Register. We followed this cohort from 1980 to 2007. Information on social conditions (education, employment, source of income, marital status, etc.) was obtained by linkages to national registers, including the Integrated Database for Longitudinal Labor Market Research. For those aged 18 and older, more than 80%of persons with DS attended 10 years of primary school, with about 2% completing secondary or post-secondary education. About 4% obtained a full-time job, whereas the remaining mainly received public support from the government. Only a few (1–2%) of persons with DS were married or had a child. No significant differences in these social conditions were seen between males and females. More persons with mosaic DS attended secondary or post-secondary education, had a full-time job, were married, or had a child (18%, 28%, 15%, and 7%, respectively), compared with persons with standard DS (1%, 2%, 1%, and 1%, respectively). These data may provide families with better insight into social conditions and society with a better understanding of the social support needed for persons with DS.
doi:10.1002/ajmg.a.36272
PMCID: PMC4490827  PMID: 24273114
Down syndrome; mosaic trisomy 21; social conditions; offspring
17.  CAN Canopy Addition of Nitrogen Better Illustrate the Effect of Atmospheric Nitrogen Deposition on Forest Ecosystem? 
Scientific Reports  2015;5:11245.
Increasing atmospheric nitrogen (N) deposition could profoundly impact community structure and ecosystem functions in forests. However, conventional experiments with understory addition of N (UAN) largely neglect canopy-associated biota and processes and therefore may not realistically simulate atmospheric N deposition to generate reliable impacts on forest ecosystems. Here we, for the first time, designed a novel experiment with canopy addition of N (CAN) vs. UAN and reviewed the merits and pitfalls of the two approaches. The following hypotheses will be tested: i) UAN overestimates the N addition effects on understory and soil processes but underestimates those on canopy-associated biota and processes, ii) with low-level N addition, CAN favors canopy tree species and canopy-dwelling biota and promotes the detritus food web, and iii) with high-level N addition, CAN suppresses canopy tree species and other biota and favors rhizosphere food web. As a long-term comprehensive program, this experiment will provide opportunities for multidisciplinary collaborations, including biogeochemistry, microbiology, zoology, and plant science to examine forest ecosystem responses to atmospheric N deposition.
doi:10.1038/srep11245
PMCID: PMC4462050  PMID: 26059183
18.  Retinoic Acid Promotes Interleukin-4 Plasmid-Dimethylsulfoxide Topical Transdermal Delivery for Treatment of Psoriasis 
Annals of Dermatology  2015;27(2):121-127.
Background
Psoriasis is an autoimmune disease that is caused by a shift in the Th1/Th2 balance toward Th1-dominant immunity. It has been established as an effective treatment to counteract psoriasis by subcutaneous injection of recombinant interleukin (IL)-4, and IL-4 gene therapy by topical transdermal penetration has shown its antipsoriatic effect in mice. Retinoic acid (RA) and dimethylsulfoxide can increase the efficiency of gene transfection in the topical transdermal delivery system.
Objective
We investigated whether RA could improve anti-psoriasis efficiency using IL-4 expression plasmid pORF-mIL-4 (pIL-4) via transdermal delivery system in K14-vascular endothelial growth (K14-VEGF) factor transgenic mice.
Methods
After pretreatment with RA, plasmid pIL-4 in 10% dimethylsulfoxide was applied to the ear skin by topical transdermal penetration. Hematoxylin- eosin staining and immunohistochemistry were performed with ear samples to evaluate anti-psoriasis efficiency in mice.
Results
The psoriasis pathological features were relieved and psoriasis-associated factors were significantly reduced.
Conclusion
Our results reveal that topical application of pIL-4 in dimethylsulfoxide by transdermal delivery with RA pretreatment can improve psoriasis significantly.
doi:10.5021/ad.2015.27.2.121
PMCID: PMC4377399  PMID: 25834349
Dimethyl sulfoxide; Gene therapy; Interleukin-4; Psoriasis; Retinoic acid; Transdermal
19.  Paternal Age and Offspring Congenital Heart Defects: A National Cohort Study 
PLoS ONE  2015;10(3):e0121030.
Paternal age has been associated with offspring congenital heart defects (CHDs), which might be caused by increased mutations in the germ cell line because of cumulated cell replications. Empirical evidences, however, remain inconclusive. Furthermore, it is unknown whether all subtypes of CHDs are affected by paternal age. We aimed to explore the relationship between paternal age and the risk of offspring CHDs and its five common subtypes using national register data in Denmark. A total of 1 893 899 singletons born in Denmark from 1977 to 2008 were included in this national-based cohort study. Cox’s proportion hazards model with robust sandwich estimate option was used to estimate the hazards ratio (95% confidence interval) for the associations between paternal age and all CHDs, as well as subtypes of CHDs (patent ductus arteriosus (PDA), ventricular septal defect (VSD), atrial septal defect (ASD), tetralogy of fallot (TOF) and coarctation of the aorta (CoA)). We did not observe an overall association between paternal age and offspring CHDs. However, compared to the paternal age of 25–29 years, paternal age of older than 45 years was associated with a 69% increased risk of PDA (HR45+ = 1.69, 95%CI:1.17–2.43). We observed similar results when subanalyses were restricted to children born to mothers of 27–30 years old. After taking into consideration of maternal age, our data suggested that advanced paternal age was associated with an increased prevalence of one subtype of offspring congenital heart defects (CHDs), namely patent ductus arteriosus (PDA).
doi:10.1371/journal.pone.0121030
PMCID: PMC4373953  PMID: 25806788
20.  Prenatal Parental Separation and Body Weight, Including Development of Overweight and Obesity Later in Childhood 
PLoS ONE  2015;10(3):e0119138.
Background
Early parental separation may be a stress factor causing a long-term alteration in the hypothalamic-pituitary-adrenal-axis activity possibly impacting on the susceptibility to develop overweight and obesity in offspring. We aimed to examine the body mass index (BMI) and the risk of overweight and obesity in children whose parents lived separately before the child was born.
Methods
A follow-up study was conducted using data from the Aarhus Birth Cohort in Denmark and included 2876 children with measurements of height and weight at 9-11-years-of-age, and self-reported information on parental cohabitation status at child birth and at 9-11-years-of-age. Quantile regression was used to estimate the difference in median BMI between children whose parents lived separately (n = 124) or together (n = 2752) before the birth. We used multiple logistic regression to calculate odds ratio (OR) for overweight and obesity, adjusted for gender, parity, breast feeding status, and maternal pre-pregnancy BMI, weight gain during pregnancy, age and educational level at child birth; with and without possible intermediate factors birth weight and maternal smoking during pregnancy. Due to a limited number of obese children, OR for obesity was adjusted for the a priori confounder maternal pre-pregnancy BMI only.
Results
The difference in median BMI was 0.54 kg/m2 (95% confidence intervals (CI): 0.10; 0.98) between children whose parents lived separately before birth and children whose parents lived together. The risk of overweight and obesity was statistically significantly increased in children whose parents lived separately before the birth of the child; OR 2.29 (95% CI: 1.18; 4.45) and OR 2.81 (95% CI: 1.05; 7.51), respectively. Additional, adjustment for possible intermediate factors did not substantially change the estimates.
Conclusion
Parental separation before child birth was associated with higher BMI, and increased risk of overweight and obesity in 9-11-year-old children; this may suggest a fetal programming effect or unmeasured difference in psychosocial factors between separated and non-separated parents.
doi:10.1371/journal.pone.0119138
PMCID: PMC4361592  PMID: 25775129
21.  Non-canonical Wnt4 prevents skeletal aging and inflammation by inhibiting NF-κB 
Nature medicine  2014;20(9):1009-1017.
Aging-related bone loss and osteoporosis affect millions of patients worldwide. Chronic inflammation associated with aging and arthritis promotes bone resorption and impairs bone formation. Here we show that Wnt4 attenuated bone loss in osteoporosis and skeletal aging by inhibiting nuclear factor-kappa B (NF-κB) via non-canonical Wnt signaling. Transgenic mice expressing Wnt4 from osteoblasts were significantly protected from bone loss and chronic inflammation induced by ovariectomy, tumor necrosis factor or natural aging. In addition to promoting bone formation, Wnt4 could inhibit osteoclast formation and bone resorption. Mechanistically, Wnt4 inhibited transforming growth factor beta-activated kinase 1-mediated NF-κB activation in macrophages and osteoclast precursors independent of β-catenin. Moreover, recombinant Wnt4 proteins were able to alleviate osteoporotic bone loss and inflammation by inhibiting NF-κB in vivo. Taken together, our results suggest that Wnt4 might be used as a therapeutic agent for treating osteoporosis by attenuating NF-κB.
doi:10.1038/nm.3586
PMCID: PMC4159424  PMID: 25108526
22.  The fate of recent duplicated genes following a fourth-round whole genome duplication in a tetraploid fish, common carp (Cyprinus carpio) 
Scientific Reports  2015;5:8199.
Whole genome duplication (WGD) results in extensive genetic redundancy. In plants and yeast, WGD is followed by rapid gene deletions and intense expression differentiation with slow functional divergence. However, the early evolution of the gene differentiation processes is poorly understood in vertebrates because almost all studied WGDs are extremely ancient, and the genomes have returned to a diploid status. Common carp had a very recent fourth round of WGD dated to 8 million years ago. It therefore constitutes an ideal model to study early-stage functional divergence and expression differentiation in vertebrates. We identified 1,757 pairs of recently duplicated genes (RDGs) originating from this specific WGD and found that most ancestral genes were retained in duplicate. Most RDGs were conserved and under selective pressure. Gene expression analysis across six tissues revealed that 92.5% of RDG pairs were co-expressed in at least one tissue and that the expression of nearly half pairs ceased to be strongly correlated, indicating slow spatial divergence but rapid expression dissociation. Functional comparison revealed that 25% of pairs had functional divergence, of which neo- and sub-functionalization were the main outcomes. Our analysis revealed slow gene loss but rapid and intense expression and function differentiation after WGD.
doi:10.1038/srep08199
PMCID: PMC4314655  PMID: 25645996
23.  Cationic nanocarriers induce cell necrosis through impairment of Na+/K+-ATPase and cause subsequent inflammatory response 
Cell Research  2015;25(2):237-253.
Nanocarriers with positive surface charges are known for their toxicity which has limited their clinical applications. The mechanism underlying their toxicity, such as the induction of inflammatory response, remains largely unknown. In the present study we found that injection of cationic nanocarriers, including cationic liposomes, PEI, and chitosan, led to the rapid appearance of necrotic cells. Cell necrosis induced by cationic nanocarriers is dependent on their positive surface charges, but does not require RIP1 and Mlkl. Instead, intracellular Na+ overload was found to accompany the cell death. Depletion of Na+ in culture medium or pretreatment of cells with the Na+/K+-ATPase cation-binding site inhibitor ouabain, protected cells from cell necrosis. Moreover, treatment with cationic nanocarriers inhibited Na+/K+-ATPase activity both in vitro and in vivo. The computational simulation showed that cationic carriers could interact with cation-binding site of Na+/K+-ATPase. Mice pretreated with a small dose of ouabain showed improved survival after injection of a lethal dose of cationic nanocarriers. Further analyses suggest that cell necrosis induced by cationic nanocarriers and the resulting leakage of mitochondrial DNA could trigger severe inflammation in vivo, which is mediated by a pathway involving TLR9 and MyD88 signaling. Taken together, our results reveal a novel mechanism whereby cationic nanocarriers induce acute cell necrosis through the interaction with Na+/K+-ATPase, with the subsequent exposure of mitochondrial damage-associated molecular patterns as a key event that mediates the inflammatory responses. Our study has important implications for evaluating the biocompatibility of nanocarriers and designing better and safer ones for drug delivery.
doi:10.1038/cr.2015.9
PMCID: PMC4650577  PMID: 25613571
cationic nanocarriers; necrosis; Na+/K+-ATPase; inflammation; damage-associated molecular patterns
24.  LATS2 Suppresses Oncogenic Wnt Signaling by Disrupting β-catenin/BCL9 Interaction 
Cell reports  2013;5(6):1650-1663.
SUMMARY
Abnormal activation of Wnt/β-catenin-mediated transcription is associated with a variety of human cancers. Here we report that LATS2 inhibited oncogenic Wnt/β-catenin-mediated transcription by disrupting the β-catenin/BCL9 interaction. LATS2 directly interacted with β-catenin and to be present on Wnt target gene promoters. Mechanistically, LATS2 inhibited the interaction between BCL9 and β-catenin and subsequent recruitment of BCL9, independent of LATS2 kinase activity. LATS2 was down-regulated and inversely correlated with the levels of Wnt target genes in human colorectal cancers. Moreover, nocodazole, an anti-microtubule drug, potently induced LATS2 to suppress tumor growth in vivo by targeting β-catenin/BCL9. Our results suggest that LATS2 is not only a key tumor suppressor in human cancer, but may also be an important target for anti-cancer therapy.
doi:10.1016/j.celrep.2013.11.037
PMCID: PMC3897473  PMID: 24360964
25.  Evaluation of the Quality of Guidelines for Myasthenia Gravis with the AGREE II Instrument 
PLoS ONE  2014;9(11):e111796.
Background
Clinical practice guidelines (CPGs) are systematically developed statements to assist practitioners in making decisions about appropriate healthcare in specific clinical circumstances. The methodological quality of CPGs for myasthenia gravis (MG) are unclear.
Objective
To critically evaluate the methodological quality of CPGs for MG using AGREE II instrument.
Method
A systematical search strategy on PubMed, EMBASE, DynaMed, the National Guideline Clearinghouse (NGC) and the Chinese Biomedical Literature database (CBM) was performed on September 20th 2013. All guidelines related to MG were evaluated with AGREE II. The software used for analysis was SPSS 17.0.
Results
A total of 15 CPGs for MG met the inclusion criteria (12 CPGs in English, 3 CPGs in Chinese). The overall agreement among reviews was moderate or high (ICC >0.70). The mean scores (mean ± SD) for al six domains were presented as follows: scope and purpose (60.93% ±16.62%), stakeholder involvement (40.93% ±20.04%), rigor of development (37.22% ±30.46%), clarity of presentation (64.26% ±16.36%), applicability (28.19% ±20.56%) and editorial independence (27.78% ±28.28%). Compared with non-evidence-based CPGs, evidence-based CPGs had statistically significant higher quality scores for all AGREE II domains (P<0.05). All domain scores appear slightly higher for CPGs published after AGREE II instrument development and validation (P>0.05). The quality scores of CPGs developed by NGC/AAN were higher than the quality scores of CPGs developed by other organizations for all domains. The difference was statistically significant for all domains with the exception of clarity of presentation (P = 0.07).
Conclusions
The qualities of CPGs on MG were generally acceptable with several flaws. The AGREE II instrument should be adopted by guideline developers, particularly in China.
doi:10.1371/journal.pone.0111796
PMCID: PMC4234220  PMID: 25402504

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