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1.  Two unrelated patients with rare Crigler-Najjar syndrome type I: two novel mutations and a patient with loss of heterozygosity of UGT1A1 gene 
Crigler-Najjar syndrome type I (CN-I) is the most severe type of hereditary unconjugated hyperbilirubinemia. It is caused by homozygous or compound heterozygous mutations of the UDP-glycuronosyltransferase gene (UGT1A1) on chromosome 2q37. Two patients clinically diagnosed with CN-I were examined in this paper. We sequenced five exons and their flanking sequences, specifically the promoter region of UGT1A1, of the two patients and their parents. Quantitative real-time polymerase chain reaction (qRT-PCR) was used to determine the UGT1A1 gene copy number of one patient. In patient A, two mutations, c.239_245delCTGTGCC (p.Pro80HisfsX6; had not been reported previously) and c.1156G>T (p.Val386Phe), were identified. In patient B, we found that this patient had lost heterozygosity of the UGT1A1 gene by inheriting a deletion of one allele, and had a novel mutation c.1253delT (p.Met418ArgfsX5) in the other allele. In summary, we detected three UGT1A1 mutations in two CN-I patients: c.239_245delCTGTGCC (p.Pro80HisfsX6), c.1253delT (p.Met418ArgfsX5), and c.1156G>T (p.Val386Phe). The former two mutations are pathogenic; however, the pathogenic mechanism of c.1156G>T (p.Val386Phe) is unknown.
doi:10.1631/jzus.B1300233
PMCID: PMC4076604  PMID: 24793765
Crigler-Najjar syndrome type I (CN-I); Hyperbilirubinemia; UDP-glycuronosyltransferase gene (UGT1A1); Mutation; Loss of heterozygosity
2.  Effects of maternal and fetal LEP common variants on maternal glycemic traits in pregnancy 
Scientific Reports  2017;7:17710.
Previous studies suggest that leptin (LEP) has an important role in glucose metabolism in the nonpregnant state. During pregnancy, circulating maternal concentrations of leptin rise significantly, mainly due to increased secretion of leptin from maternal adipose tissue and placenta. This study aimed to analyze the impact of maternal and fetal common LEP variants on glucose homeostasis in the pregnant state. Several glycemic traits, including fasting plasma glucose, fasting plasma insulin (FPI), and plasma glucose 1 hour after a 50-g oral glucose load, were measured in 1,112 unrelated Chinese Han pregnant women at 24–28 weeks gestation. Homeostatic model assessment (HOMA) was used to assess beta cell function (HOMA1-β and HOMA2-β) and insulin resistance (HOMA1-IR and HOMA2-IR).The relationships between glycemic traits and 12 LEP variants were determined. After applying the Bonferroni correction, we detected that (1) maternal rs10954173 and fetal rs10244329 were associated with maternal FPI although the effect of fetal rs10244329 may be not independent of maternal rs10244329, and (2) maternal rs12537573 was associated with maternal FPI and HOMA2-IR. This study provides genetic evidence that both maternal and fetal LEP polymorphisms may affect maternal glucose metabolism in pregnancy.
doi:10.1038/s41598-017-18117-z
PMCID: PMC5735190  PMID: 29255202
3.  Targeted bisulfite sequencing identified a panel of DNA methylation-based biomarkers for esophageal squamous cell carcinoma (ESCC) 
Clinical Epigenetics  2017;9:129.
Background
DNA methylation has been implicated as a promising biomarker for precise cancer diagnosis. However, limited DNA methylation-based biomarkers have been described in esophageal squamous cell carcinoma (ESCC).
Methods
A high-throughput DNA methylation dataset (100 samples) of ESCC from The Cancer Genome Atlas (TCGA) project was analyzed and validated along with another independent dataset (12 samples) from the Gene Expression Omnibus (GEO) database. The methylation status of peripheral blood mononuclear cells and peripheral blood leukocytes from healthy controls was also utilized for biomarker selection. The candidate CpG sites as well as their adjacent regions were further validated in 94 pairs of ESCC tumor and adjacent normal tissues from the Chinese Han population using the targeted bisulfite sequencing method. Logistic regression and several machine learning methods were applied for evaluation of the diagnostic ability of our panel.
Results
In the discovery stage, five hyper-methylated CpG sites were selected as candidate biomarkers for further analysis as shown below: cg15830431, P = 2.20 × 10−4; cg19396867, P = 3.60 × 10−4; cg20655070, P = 3.60 × 10−4; cg26671652, P = 5.77 × 10−4; and cg27062795, P = 3.60 × 10−4. In the validation stage, the methylation status of both the five CpG sites and their adjacent genomic regions were tested. The diagnostic model based on the combination of these five genomic regions yielded a robust performance (sensitivity = 0.75, specificity = 0.88, AUC = 0.85). Eight statistical models along with five-fold cross-validation were further applied, in which the SVM model reached the best accuracy in both training and test dataset (accuracy = 0.82 and 0.80, respectively). In addition, subgroup analyses revealed a significant difference in diagnostic performance between the alcohol use and non-alcohol use subgroups.
Conclusions
Methylation profiles of the five genomic regions covering cg15830431 (STK3), cg19396867, cg20655070, cg26671652 (ZNF418), and cg27062795 (ZNF542) can be used for effective methylation-based testing for ESCC diagnosis.
Electronic supplementary material
The online version of this article (10.1186/s13148-017-0430-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13148-017-0430-7
PMCID: PMC5732523  PMID: 29270239
Esophageal squamous cell carcinoma; DNA methylation; Biomarker; Diagnosis; Targeted bisulfite sequencing
4.  Long non-coding RNA HOXA11-AS promotes the proliferation HCC cells by epigenetically silencing DUSP5 
Oncotarget  2017;8(65):109509-109521.
Hepatocellular carcinoma has been identified as the fifth most common cancer in men and the ninth in women worldwide. Despite many efforts have been made in recent years, the overall survival rate of patients with hepatocellular carcinoma still remain unsatisfied. Therefore, exploring the mechanisms underlying the progression of hepatocellular carcinoma is essential for developing novel treatments to improve patient prognosis. HOXA11-AS, transcribed from the opposite strand of the protein-coding gene HOXA11, has been identified to be associated with the malignant characteristics of several cancers. However, the biological role and molecular mechanism of HOXA11-AS in hepatocellular carcinoma still need to be further investigated. In the current study, the expression of HOXA11-AS in the hepatocellular carcinoma cell lines and tissues was measured by quantitative real-time PCR. Loss-of-function and gain-of-function approaches were applied to investigate the proliferative function of HOXA11-AS in hepatocellular carcinoma cells. Results from flow cytometric analysis of apoptosis and cell cycle distribution revealed that HOXA11-AS promoted hepatocellular carcinoma cells proliferation through regulating cell cycle and apoptosis. Gene chip technology and quantitative real-time PCR confirmed that DUSP5 was a downstream target of HOXA11-AS. RNA immune co-precipitation assays, RNA pull-down and Chromatin immunoprecipitation assays confirmed that HOXA11-AS could recruit EZH2 to the promoter region of DUSP5, which therefore suppressed the transcription of DUSP5. Collectively, these findings revealed that HOXA11-AS functions as an oncogene in hepatocellular carcinoma through interacting with polycomb-repressive complex2.
doi:10.18632/oncotarget.22723
PMCID: PMC5752538
HCC; Lnc-RNA HOXA11-AS; proliferation; EZH2; DUSP5
5.  Smoking and alcohol drinking in relation to the risk of esophageal squamous cell carcinoma: A population-based case-control study in China 
Scientific Reports  2017;7:17249.
Previous results regarding the associations between esophageal squamous-cell carcinoma (ESCC) risk and smoking/alcohol drinking in high-risk areas are inconsistent. We performed a large population-based case-control study from 2010 to 2013 in a high-incidence area of China, and enrolled 1353 ESCC cases and 1961 controls. Data regarding smoking and alcohol drinking were collected via face-to-face interviews using a structured questionnaire. Odd ratios (ORs) with 95% confidence intervals (CIs) were estimated using unconditional logistic regression models. After adjusting for alcohol drinking and other potential confounders, male heavy smokers (i.e., those who started smoked more than 20 cigarettes per day or 40 pack-years, or started smoking early), showed a moderately increased risk for ESCC; however, current smoking was not associated with an increased risk. Alcohol drinking among males significantly increased the risk for ESCC (OR = 2.20, 95%CI:1.79~2.70). We observed increasing excess ESCC risks with decreasing age at behavior initiation as well as with increasing duration and intensity of alcohol intake, which were particularly evident among current smokers. In contrast, neither smoking nor alcohol drinking was not associated with ESCC risk among females. In conclusion, alcohol drinking shows a monotonic dose-response relationship with ESCC risk among men, and this relationship is particularly evident among smokers.
doi:10.1038/s41598-017-17617-2
PMCID: PMC5722909  PMID: 29222520
6.  Protein Synthetic Machinery and mRNA in Regenerating Tips of Spinal Cord Axons in Lamprey 
The Journal of comparative neurology  2016;524(17):3614-3640.
Polyribosomes, mRNA and other elements of translational machinery have been reported in peripheral nerves and in elongating injured axons of sensory neurons in vitro, primarily in growth cones. Evidence for involvement of local protein synthesis in regenerating CNS axons is less extensive. We monitored regeneration of back-labeled lamprey spinal axons after spinal cord transection and detected mRNA in axon tips by in situ hybridization and micro-aspiration of their axoplasm. Poly(A)+mRNA was present in the axon tips, and was more abundant in actively regenerating tips than in static or retracting ones. Target-specific PCR and in situ hybridization revealed plentiful mRNA for the low molecular neurofilament subunit and β-tubulin, but very little for β-actin, consistent with the morphology of their tips, which lack filopodia and lamellipodia. Electron microscopy showed ribosomes/polyribosomes in the distal parts of axon tips and in association with vesicle-like membranes, primarily in the tip. In one instance, there were structures with the appearance of rough endoplasmic reticulum. Immunohistochemistry showed patches of ribosomal protein S6 positivity in a similar distribution. The results suggest that local protein synthesis might be involved in the mechanism of axon regeneration in the lamprey spinal cord.
Graphical abstract
Micro-aspirated tips of regenerating reticulospinal axons in transected lamprey spinal cords contained mRNA for NFL and β-tubulin, but little β-actin mRNA. Static tips contained less mRNA, while uninjured axons contained almost none. EM of injured axon tips showed polyribosomes and rough ER.
doi:10.1002/cne.24020
PMCID: PMC5050069  PMID: 27120118
7.  Elevated serum urate is a potential factor in reduction of total bilirubin: a Mendelian randomization study 
Oncotarget  2017;8(61):103864-103873.
Aim
A Mendelian randomization study (MRS) can be linked to a “natural” randomized controlled trial in order to avoid potential bias of observational epidemiology. We aimed to study the possible association between serum urate (SU) and total bilirubin (TBIL) using MRS.
Materials and Methods
An observational epidemiological study using ordinary least squares (OLS) regression and MRS using two-stage least square (TLS) regression was conducted to assess the effect of SU on TBIL. The comparison between the OLS regression and the TLS regression was analyzed by the Durbin-Hausman test. If the p value is significant, it suggests that the OLS regression cannot evaluate the relationship between exposure and outcome, and the TLS regression is precise; while if the p value is not significant, there would be no significant difference between the two regressions.
Results
A total of 3,753 subjects were analyzed. In OLS regression, there was no significant association between SU and TBIL in all subjects and subgroup analysis (all p > 0.05). However, MRS revealed a negative correlation between SU and TBIL after adjustment for confounders (beta = –0.021, p = 0.010). Further analysis was conducted in different SU subgroups, and results show that elevated SU was associated with a significant reduction in TBIL after adjustment for hyperuricemic subjects (beta = –0.053, p = 0.027). In addition, the results using the Durbin-Hausman test further confirmed a negative effect of SU on TBIL (p = 0.002 and 0.010, respectively).
Conclusions
This research shows for the first time that elevated SU was a potential causal factor in the reduction of TBIL and it provides strong evidence to resolve the controversial association between SU and TBIL.
doi:10.18632/oncotarget.21977
PMCID: PMC5732772
serum urate; total bilirubin; mendelian randomization study
8.  The Expression of AQP5 and UTs in the Sweat Glands of Uremic Patients 
BioMed Research International  2017;2017:8629783.
Purpose
To research the distribution and quantitative changes of UT-A1, UT-B1, and AQP5 in uremic skin tissue.
Methods
34 cases of uremic patients (UP) and 11 controls were recruited. Immunohistochemistry, immunofluorescence, RT-PCR, and Western Blot were used to identify the proteins in sweat glands.
Results
AQP5, UT-A1, and UT-B1 were expressed and localized in human skin basal lines, skin sweat glands, and sweat ducts, both in UP and controls. Compared to controls, AQP5 mRNA abundance was significantly decreased in UP (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly decreased (P < 0.05). By contrast, UT-A1 and UT-B1 mRNA abundance was significantly increased in the skin of UP compared with the control (P < 0.01), and, with the decrease of eGFR, the AQP5 expression was significantly increased (P < 0.05). We found that the gene changes were coincident with the corresponding target proteins. The urea transporter subtypes, UT-A1 and UT-B1, were expressed in the skin basal cell layer and exocrine sweat glands. The abundance of UT-A1 and UT-B1 in uremic sweat glands was significantly increased in UP, while the expression of AQP5 was decreased.
Conclusion
Elimination of urea through the skin by producing sweat is a potential therapeutic strategy for renal failure patients.
doi:10.1155/2017/8629783
PMCID: PMC5723962
9.  Gallic Acid Reduces Blood Pressure and Attenuates Oxidative Stress and Cardiac Hypertrophy in Spontaneously Hypertensive Rats 
Scientific Reports  2017;7:15607.
Gallic acid (GA) has been reported to have beneficial effects on cancer, vascular calcification, and diabetes-induced myocardial dysfunction. We hypothesized that GA controls hypertension via oxidative stress response regulation in an animal model for essential hypertension. Spontaneously hypertensive rats (SHRs) were administered GA for 16 weeks. GA treatment lowered elevated systolic blood pressure in SHRs through the inhibition of vascular contractility and components of the renin-angiotensin II system. In addition, GA administration reduced aortic wall thickness and body weight in SHRs. In SHRs, GA attenuated left ventricular hypertrophy and reduced the expression of cardiac-specific transcription factors. NADPH oxidase 2 (Nox2) and GATA4 mRNA expression was induced in SHR hearts and angiotensin II-treated H9c2 cells; this expression was downregulated by GA treatment. Nox2 promoter activity was increased by the synergistic action of GATA4 and Nkx2-5. GA seems to regulate oxidative stress by inhibiting the DNA binding activity of GATA4 in the rat Nox2 promoter. GA reduced the GATA4-induced Nox activity in SHRs and angiotensin II-treated H9c2 cells. GA administration reduced the elevation of malondialdehyde levels in heart tissue obtained from SHRs. These findings suggest that GA is a potential therapeutic agent for treating cardiac hypertrophy and oxidative stress in SHRs.
doi:10.1038/s41598-017-15925-1
PMCID: PMC5688141  PMID: 29142252
10.  Indoor PM2.5 exposure affects skin aging manifestation in a Chinese population 
Scientific Reports  2017;7:15329.
Traffic-related air pollution is known to be associated with skin aging manifestations. We previously found that the use of fossil fuels was associated with skin aging, but no direct link between indoor air pollutants and skin aging manifestations has ever been shown. Here we directly measured the indoor PM2.5 exposure in 30 households in Taizhou, China. Based on the directly measured PM2.5 exposure and questionnaire data of indoor pollution sources, we built a regression model to predict the PM2.5 exposure in larger datasets including an initial examination group (N = 874) and a second examination group (N = 1003). We then estimated the association between the PM2.5 exposure and skin aging manifestations by linear regression. In the initial examination group, we showed that the indoor PM2.5 exposure levels were positively associated with skin aging manifestation, including score of pigment spots on forehead (12.5% more spots per increase of IQR, P-value 0.0371), and wrinkle on upper lip (7.7% more wrinkle on upper lip per increase of IQR, P-value 0.0218). The results were replicated in the second examination group as well as in the pooled dataset. Our study provided evidence that the indoor PM2.5 exposure is associated with skin aging manifestation in a Chinese population.
doi:10.1038/s41598-017-15295-8
PMCID: PMC5681690  PMID: 29127390
11.  Genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry 
PeerJ  2017;5:e3951.
Background
Currently, there is limited knowledge about the genetics underlying pigmentary traits in East Asian populations. Here, we report the results of the first genome-wide association study of pigmentary traits (skin and iris color) in individuals of East Asian ancestry.
Methods
We obtained quantitative skin pigmentation measures (M-index) in the inner upper arm of the participants using a portable reflectometer (N = 305). Quantitative measures of iris color (expressed as L*, a* and b* CIELab coordinates) were extracted from high-resolution iris pictures (N = 342). We also measured the color differences between the pupillary and ciliary regions of the iris (e.g., iris heterochromia). DNA samples were genotyped with Illumina’s Infinium Multi-Ethnic Global Array (MEGA) and imputed using the 1000 Genomes Phase 3 samples as reference haplotypes.
Results
For skin pigmentation, we did not observe any genome-wide significant signal. We followed-up in three independent Chinese samples the lead SNPs of five regions showing multiple common markers (minor allele frequency ≥ 5%) with good imputation scores and suggestive evidence of association (p-values < 10−5). One of these markers, rs2373391, which is located in an intron of the ZNF804B gene on chromosome 7, was replicated in one of the Chinese samples (p = 0.003). For iris color, we observed genome-wide signals in the OCA2 region on chromosome 15. This signal is driven by the non-synonymous rs1800414 variant, which explains 11.9%, 10.4% and 6% of the variation observed in the b*, a* and L* coordinates in our sample, respectively. However, the OCA2 region was not associated with iris heterochromia.
Discussion
Additional genome-wide association studies in East Asian samples will be necessary to further disentangle the genetic architecture of pigmentary traits in East Asian populations.
doi:10.7717/peerj.3951
PMCID: PMC5671666
Skin pigmentation; Genome-wide association study; Iris color; East Asia
12.  DHX15 is associated with poor prognosis in acute myeloid leukemia (AML) and regulates cell apoptosis via the NF-kB signaling pathway 
Oncotarget  2017;8(52):89643-89654.
The role of DHX15, a newly identified DEAH-box RNA helicase, in leukemogenesis remains elusive. Here, we identified a recurrent mutation in DHX15 (NM_001358:c.664C>G: p.(R222G)) in one familial AML patient and 4/240 sporadic AML patients. Additionally, DHX15 was commonly overexpressed in AML patients and associated with poor overall survival (OS) (P=0.019) and relapse-free survival (RFS) (P=0.032). In addition, we found a distinct expression pattern of DHX15. DHX15 was highly expressed in hematopoietic stem cells and leukemia cells but was lowly expressed in mature blood cells. DHX15 was down-regulated when AML patients achieved disease remission or when leukemia cell lines were induced to differentiate. DHX15 silencing greatly inhibited leukemia cell proliferation and induced cell apoptosis and G1-phase arrest. In contrast, the restoration of DHX15 expression rescued cell viability and reduced cell apoptosis. In addition, we found that DHX15 was down-regulated when cell apoptosis was induced by ATO (arsenic trioxide); overexpression of DHX15 caused dramatic resistance to ATO-induced cell apoptosis, suggesting an important role for DHX15 in cell apoptosis. We further explored the mechanism of DHX15 in apoptosis and found that overexpression of DHX15 activated NF-kB transcription. Knockdown of DHX15 inhibited the nuclear translocation and activation of the NF-kB subunit P65 in leukemia cells. Several downstream targets of the NF-kB pathway were also down-regulated, and apoptosis-associated genes CASP3 and PARP were activated. In conclusion, this study represents the first demonstration that DHX15 plays an important role in leukemogenesis via the NF-kB signaling pathway and may serve as an independent prognostic marker for AML.
doi:10.18632/oncotarget.20288
PMCID: PMC5685698
DHX15; AML; NF-kB; knockdown; overexpression
13.  Bagging Nearest-Neighbor Prediction independence Test: an efficient method for nonlinear dependence of two continuous variables 
Scientific Reports  2017;7:12736.
Testing dependence/correlation of two variables is one of the fundamental tasks in statistics. In this work, we proposed an efficient method for nonlinear dependence of two continuous variables (X and Y). We addressed this research question by using BNNPT (Bagging Nearest-Neighbor Prediction independence Test, software available at https://sourceforge.net/projects/bnnpt/). In the BNNPT framework, we first used the value of X to construct a bagging neighborhood structure. We then obtained the out of bag estimator of Y based on the bagging neighborhood structure. The square error was calculated to measure how well Y is predicted by X. Finally, a permutation test was applied to determine the significance of the observed square error. To evaluate the strength of BNNPT compared to seven other methods, we performed extensive simulations to explore the relationship between various methods and compared the false positive rates and statistical power using both simulated and real datasets (Rugao longevity cohort mitochondrial DNA haplogroups and kidney cancer RNA-seq datasets). We concluded that BNNPT is an efficient computational approach to test nonlinear correlation in real world applications.
doi:10.1038/s41598-017-12783-9
PMCID: PMC5630623  PMID: 28986523
14.  Fine population structure analysis method for genomes of many 
Scientific Reports  2017;7:12608.
Fine population structure can be examined through the clustering of individuals into subpopulations. The clustering of individuals in large sequence datasets into subpopulations makes the calculation of subpopulation specific allele frequency possible, which may shed light on selection of candidate variants for rare diseases. However, as the magnitude of the data increases, computational burden becomes a challenge in fine population structure analysis. To address this issue, we propose fine population structure analysis (FIPSA), which is an individual-based non-parametric method for dissecting fine population structure. FIPSA maximizes the likelihood ratio of the contingency table of the allele counts multiplied by the group. We demonstrated that its speed and accuracy were superior to existing non-parametric methods when the simulated sample size was up to 5,000 individuals. When applied to real data, the method showed high resolution on the Human Genome Diversity Project (HGDP) East Asian dataset. FIPSA was independently validated on 11,257 human genomes. The group assignment given by FIPSA was 99.1% similar to those assigned based on supervised learning. Thus, FIPSA provides high resolution and is compatible with a real dataset of more than ten thousand individuals.
doi:10.1038/s41598-017-12319-1
PMCID: PMC5626719  PMID: 28974706
15.  RANKL-mediated harmonious dialogue between fetus and mother guarantees smooth gestation by inducing decidual M2 macrophage polarization 
Cell Death & Disease  2017;8(10):e3105-.
Decidual macrophages (dMφ) contribute to maternal–fetal tolerance. However, the mechanism of dMφ differentiation during pregnancy is still largely unknown. Here, we report that receptor activator for nuclear factor-κ B ligand (RANKL), secreted by human embryonic trophoblasts and maternal decidual stromal cells (DSCs), polarizes dMφ toward a M2 phenotype. This polarization is mediated through activation of Akt/signal transducer and activator of transcription 6 (STAT6) signaling, which is associated with the upregulation of histone H3 lysine-27 demethylase Jmjd3 and IRF4 in dMφ. Such differentiated dMφ can induce a Th2 bias that promotes maternal–fetal tolerance. Impaired expression of RANKL leads to dysfunction of dMφ in vivo and increased rates of fetal loss in mice. Transfer of RANK+Mφ reverses mouse fetal loss induced by Mφ depletion. Compared with normal pregnancy, there are abnormally low levels of RANKL/RANK in villi and decidua from miscarriage patients. These results suggest that RANKL is a pivotal regulator of maternal–fetal tolerance by licensing dMφ to ensure a successful pregnancy outcome. This observation provides a scientific basis on which a potential therapeutic strategy can be targeted to prevent pregnancy loss.
doi:10.1038/cddis.2017.505
PMCID: PMC5682671  PMID: 29022922
16.  Tissue-resident stem cell activity: a view from the adult Drosophila gastrointestinal tract 
The gastrointestinal tract serves as a fast-renewing model for unraveling the multifaceted molecular mechanisms underlying remarkably rapid cell renewal, which is exclusively fueled by a small number of long-lived stem cells and their progeny. Stem cell activity is the best-characterized aspect of mucosal homeostasis in mitotically active tissues, and the dysregulation of regenerative capacity is a hallmark of epithelial immune defects. This dysregulation is frequently associated with pathologies ranging from chronic enteritis to malignancies in humans. Application of the adult Drosophila gastrointestinal tract model in current and future studies to analyze the immuno-physiological aspects of epithelial defense strategies, including stem cell behavior and re-epithelialization, will be necessary to improve our general understanding of stem cell participation in epithelial turnover. In this review, which describes exciting observations obtained from the adult Drosophila gastrointestinal tract, we summarize a remarkable series of recent findings in the literature to decipher the molecular mechanisms through which stem cells respond to nonsterile environments.
doi:10.1186/s12964-017-0184-z
PMCID: PMC5604405  PMID: 28923062
Drosophila; Gastrointestinal tract; Stem cells; Proliferation and differentiation; Homeostasis
17.  Increased half-life and enhanced potency of Fc-modified human PCSK9 monoclonal antibodies in primates 
PLoS ONE  2017;12(8):e0183326.
Blocking proprotein convertase subtilisin kexin type 9 (PCSK9) binding to low-density lipoprotein receptor (LDLR) can profoundly lower plasma LDL levels. Two anti-PCKS9 monoclonal antibodies (mAbs), alirocumab and evolocumab, were approved by the FDA in 2015. The recommended dose is 75 mg to 150 mg every two weeks for alirocumab and 140mg every two weeks or 420 mg once a month for evolocumab. This study attempted to improve the pharmacokinetic properties of F0016A, an IgG1 anti-PCKS9 mAb, to generate biologically superior molecules. We engineered several variants with two or three amino acid substitutions in the Fc fragment based on prior knowledge. The Fc-modified mAbs exhibited increased binding to FcRn, resulting in prolonged serum half-life and enhanced efficacy in vivo. These results demonstrate that Fc-modified anti-PCKS9 antibodies may enable less frequent or lower dosing of antibodies by improved recycling into the blood.
doi:10.1371/journal.pone.0183326
PMCID: PMC5560549  PMID: 28817679
18.  Detecting Chronic Post-Traumatic Osteomyelitis of Mouse Tibia via an IL-13Rα2 Targeted Metallofullerene Magnetic Resonance Imaging Probe 
Bioconjugate chemistry  2017;28(2):649-658.
Differential diagnosis of chronic post-traumatic osteomyelitis (CPO) from aseptic inflammation remains challenging, since both pathological processes share similar clinical symptoms. Here we utilized a novel targeted metallofullerene nanoparticle based magnetic resonance imaging (MRI) probe IL-13-TAMRA-Gd3N@C80(OH)30− (CH2CH2COOH)20 to detect CPO in mouse tibia via overexpressed IL-13Rα2 receptors. The functionalized metallofullerene was characterized by X-ray photoelectron spectroscopy. Upon lipopolysaccharide (LPS) stimulation, macrophage Raw 264.7 cells showed elevated IL-13Rα2 expression via immunofluorescence staining and increased MRI probe binding via built-in TAMRA fluorescence imaging. Trauma was induced in both tibia of mice and bacteria soaked suture was inserted into the right tibia to initiate infection. During the acute phase (1.5 weeks), luminol-bioluminescence imaging revealed much higher myeloperoxidase activity in the infected tibia compared to the sham. In the chronic phase (4 weeks), X-ray radiography illustrated bone deformation in the infected tibia compared to the sham. With T1 weighted sequences, the probe clearly exhibited hyperintensity in the infection foci at both acute and chronic phases, which was not observed in the sham tibia. Histological analysis revealed severe bone structural destruction and massive inflammatory cell infiltration in the infected tibia. Immunohistochemistry confirmed abundant expression of IL-13Rα2 in the infection site. In summary, we developed a noninvasive imaging approach to detect and differentiate CPO from aseptic inflammation using a new IL-13Rα2 targeted metallofullerene MRI probe. In addition, for the first time, IL-13Rα2 was investigated as a unique biomarker in the context of osteomyelitis. Our data established a foundation for the translational application of this MRI probe in the clinical differentiation of CPO.
Graphical abstract
doi:10.1021/acs.bioconjchem.6b00708
PMCID: PMC5317096  PMID: 28061526
19.  Mitochondrial DNA sequencing and large-scale genotyping identifies MT-ND4 gene mutation m.11696G>A associated with idiopathic oligoasthenospermia 
Oncotarget  2017;8(32):52975-52982.
Genetic variants of mitochondrial DNA (mtDNA) were implicated to be associated with male infertility. Our previous whole mitochondrial genome sequencing and association study has identified two susceptibility mtDNA variants for oligoasthenospermia in Han Chinese men. In this study, we tested promising associations in an extended validation using 670 idiopathic oligoasthenospermia cases and 793 healthy controls to identify additional risk variants. We found that the genetic variant of m.11696G>A showed significantly higher frequency in the case group than that in the control group (odds ratio (OR) 2.21, 95% CI 1.21-4.04) (P=7.90×10−3). To elucidate the exact role of the genetic variants in spermatogenesis, two main sperm parameters (sperm count and motility) were taken into account. We found that m.11696G>A was associated with low sperm motility, with the OR of 2.38 (95 % CI 1.27-4.46) (P =5.22×10−3). These results advance our understanding of the genetic susceptibility to oligoasthenospermia and more functional studies are needed to provide insights into its pathogenic mechanism.
doi:10.18632/oncotarget.17675
PMCID: PMC5581086
oligoasthenospermia; mitochondrial DNA; genetic variant; haplogroup
20.  Advances in single-cell RNA sequencing and its applications in cancer research 
Oncotarget  2017;8(32):53763-53779.
Unlike population-level approaches, single-cell RNA sequencing enables transcriptomic analysis of an individual cell. Through the combination of high-throughput sequencing and bioinformatic tools, single-cell RNA-seq can detect more than 10,000 transcripts in one cell to distinguish cell subsets and dynamic cellular changes. After several years’ development, single-cell RNA-seq can now achieve massively parallel, full-length mRNA sequencing as well as in situ sequencing and even has potential for multi-omic detection. One appealing area of single-cell RNA-seq is cancer research, and it is regarded as a promising way to enhance prognosis and provide more precise target therapy by identifying druggable subclones. Indeed, progresses have been made regarding solid tumor analysis to reveal intratumoral heterogeneity, correlations between signaling pathways, stemness, drug resistance, and tumor architecture shaping the microenvironment. Furthermore, through investigation into circulating tumor cells, many genes have been shown to promote a propensity toward stemness and the epithelial-mesenchymal transition, to enhance anchoring and adhesion, and to be involved in mechanisms of anoikis resistance and drug resistance. This review focuses on advances and progresses of single-cell RNA-seq with regard to the following aspects:
1. Methodologies of single-cell RNA-seq
2. Single-cell isolation techniques
3. Single-cell RNA-seq in solid tumor research
4. Single-cell RNA-seq in circulating tumor cell research
5. Perspectives
doi:10.18632/oncotarget.17893
PMCID: PMC5581148
single cell; RNA sequencing; tumor; circulating tumor cell
21.  Interactions between household air pollution and GWAS-identified lung cancer susceptibility markers in the Female Lung Cancer Consortium in Asia (FLCCA) 
Human genetics  2015;134(3):333-341.
We previously carried out a multi-stage genome-wide association study (GWAS) on lung cancer among never smokers in the Female Lung Cancer Consortium in Asia (FLCCA) (6,609 cases, 7,457 controls) that identified novel susceptibility loci at 10q25.2, 6q22.2, and 6p21.32, and confirmed two previously identified loci at 5p15.33 and 3q28. Household air pollution (HAP) attributed to solid fuel burning for heating and cooking, is the leading cause of the overall disease burden in Southeast Asia, and is known to contain lung carcinogens. To evaluate the gene-HAP interactions associated with lung cancer in loci independent of smoking, we analyzed data from studies participating in FLCCA with fuel use information available (n=3; 1,731 cases; 1,349 controls). Coal use was associated with a 30% increased risk of lung cancer (OR=1.3, 95%CI=1.0-1.6). Among the five a priori SNPs identified by our GWAS, two showed a significant interaction with coal use (HLA Class II rs2395185, p=0.02; TP63 rs4488809(rs4600802), p=0.04). The risk of lung cancer associated with coal exposure varied with the respective alleles for these two SNPs. Our observations provide evidence that genetic variation in HLA Class II and TP63 may modify the association between HAP and lung cancer risk. The roles played in the cell-cycle and inflammation pathways by the proteins encoded by these two genes provide biological plausibility for these interactions; however, additional replication studies are needed in other non-smoking populations.
doi:10.1007/s00439-014-1528-z
PMCID: PMC5537621  PMID: 25566987
GWAS; Asia; female; lung cancer; solid fuel use; risk factors
22.  IL-33 restricts invasion and adhesion of trophoblast cell line JEG3 by downregulation of integrin α4β1 and CD62L 
Molecular Medicine Reports  2017;16(4):3887-3893.
Interleukin-33 (IL-33) promotes migration of cancer cells through downregulating the expression of E-cadherin. Previous studies have demonstrated that IL-33 stimulates the proliferation of trophoblasts. However, the effect of IL-33 on the adhesion and invasion of trophoblasts has not been investigated in detail. In the present study, the expression of IL-33 and its receptor, IL-1 receptor-like 1 (ST2), was examined in villi from women during early pregnancy using immunohistochemistry. ST2 expression on human trophoblast and choriocarcinoma cell lines JAR, BeWo, JEG3 and HTR8 was confirmed by flow cytometry (FCM) assay. The effect of recombinant human IL-33 (rhIL-33) on adhesion, invasion and associated molecules was analyzed by cell adhesion, Matrigel invasion and FCM assays. The current study identified that human trophoblasts expressed IL-33 and ST2. RhIL-33 inhibited trophoblast invasion and adhesion, and decreased adhesion and invasion-associated molecules such as integrin α4β1 and CD62L. Therefore, these results suggest that IL-33 may serve an important role in limiting invasion and implantation of trophoblasts by adhesion and invasion-associated molecules, contributing to the formation of the placenta and maintenance of normal pregnancy during early pregnancy.
doi:10.3892/mmr.2017.7085
PMCID: PMC5646966  PMID: 28765940
interleukin-33; interleukin 1 receptor-like 1; trophoblasts; JEG3 cell line; invasion; adhesion
23.  A TBX5 3′UTR variant increases the risk of congenital heart disease in the Han Chinese population 
Cell Discovery  2017;3:17026-.
TBX5 is a vital transcription factor involved in cardiac development in a dosage-dependent manner. But little is known about the potential association of TBX5 3′ untranslated region (UTR) variations with congenital cardiac malformations. This study aimed to investigate the relationship between TBX5 3′UTR variants and risk for congenital heart disease (CHD) susceptibility in two Han Chinese populations, and to reveal its molecular mechanism. The relationship between TBX5 3′UTR variants and CHD susceptibility was examined in 1 177 CHD patients and 990 healthy controls in two independent case–control studies. Variant rs6489956 C>T was found to be associated with increased CHD susceptibility in both cohorts. The combined CHD risk for the CT and TT genotype carriers was 1.83 times higher than that of CC genotype, while the risk for CT or TT genotype was 1.94 times and 2.31 times higher than that of CC carriers, respectively. Quantitative real-time PCR and western blot analysis showed that T allele carriers exhibited reduced TBX5 mRNA and protein levels in CHDs tissues. Compared with C allele, T allele showed increased binding affinity to miR-9 and miR-30a in both luciferase assays and surface plasmon resonance analysis. Functional analysis confirmed that miR-9 and miR-30a downregulated TBX5 expression at the transcriptional and translational levels, respectively. The assays in zebrafish model were in support of the interaction of miR-9/30a and TBX5 3′UTR (C and T allele). We concluded that TBX5 3′UTR variant rs6489956 increased susceptibility of CHD in the Han Chinese population because it changes the binding affinity of two target miRNAs that specifically mediate TBX5 expression.
doi:10.1038/celldisc.2017.26
PMCID: PMC5527299  PMID: 28761722
congenital heart disease; TBX5; variant; 3′UTR; microRNAs
24.  MiR-221 Attenuates the Osteogenic Differentiation of Human Annulus Fibrosus Cells 
Background
In the moderate and end stages of intervertebral disc (IVD) degeneration, endochondral ossifications are found in the IVD.
Purpose
To investigate whether endochondral ossification in the late stages of disc degeneration is due to the differentiation of resident progenitor cell in the annulus fibrosus (AF) and the potential signaling pathways in vitro.
Study Design
An in vitro study of AF cell osteogenic differentiation and possible mechanisms
Methods
Normal AF (NAF) and degenerated AF (DAF) cells were isolated from tissue removed surgically from juvenile patients with idiopathic scoliosis and adult patients with degenerative scoliosis. Osteogenic differentiation was investigated using quantitative RT-PCR and histology. Effects of miR-221 on osteogenesis were measured by overexpression of miR-221 with lentivirus. BMP2 and phospho-Smad protein were detected by Western blotting.
Results
Both NAF and DAF cells underwent osteogenic differentiation, which, was confirmed by detecting mineralization of the cell cultures and by an increase in the expression mRNAs for BMP2, Runx2, ALP, and Osteocalcin. DAF cells exhibited increased osteogenic differentiation potential over the NAF cells. By contrast to the elevated phospho-Smads, the basal level of miR-221 significantly decreased in DAF cells compared with NAF cells. Cultures of both cell types in osteogenic medium showed a decrease in miR-221 expression while overexpression of miR-221 markedly decreased the level of BMP2, phospho-Smads and the expression of osteogenic genes in DAF cells. The osteogenic potential of DAF cells diminished by the overexpression of miR-221.
Conclusion
Compared to NAF cells, AF cells from degenerated discs have a greater tendency for osteogenic differentiation, which involves the BMP-Smad pathways and can be regulated by miR-221. These observations may be developed into a therapeutic to prevent the endochondral ossification.
doi:10.1016/j.spinee.2016.03.026
PMCID: PMC4970913  PMID: 26997108
intervertebral disc; miR-221; annulus fibrosus; BMP; osteogenesis
25.  World Congress Integrative Medicine & Health 2017: Part one 
Brinkhaus, Benno | Falkenberg, Torkel | Haramati, Aviad | Willich, Stefan N. | Briggs, Josephine P. | Willcox, Merlin | Linde, Klaus | Theorell, Töres | Wong, Lisa M. | Dusek, Jeffrey | Wu, Darong | Eisenberg, David | Haramati, Aviad | Berger, Bettina | Kemper, Kathi | Stock-Schröer, Beate | Sützl-Klein, Hedda | Ferreri, Rosaria | Kaplan, Gary | Matthes, Harald | Rotter, Gabriele | Schiff, Elad | Arnon, Zahi | Hahn, Eckhard | Luberto, Christina M. | Martin, David | Schwarz, Silke | Tauschel, Diethard | Flower, Andrew | Gramminger, Harsha | Gupta, Hedwig H. | Gupta, S. N. | Kerckhoff, Annette | Kessler, Christian S. | Michalsen, Andreas | Kessler, Christian S. | Kim, Eun S. | Jang, Eun H. | Kim, Rana | Jan, Sae B. | Mittwede, Martin | Mohme, Wiebke | Ben-Arye, Eran | Bonucci, Massimo | Saad, Bashar | Breitkreuz, Thomas | Rossi, Elio | Kebudi, Rejin | Daher, Michel | Razaq, Samaher | Gafer, Nahla | Nimri, Omar | Hablas, Mohamed | Kienle, Gunver Sophia | Samuels, Noah | Silbermann, Michael | Bandelin, Lena | Lang, Anna-Lena | Wartner, Eva | Holtermann, Christoph | Binstock, Maxwell | Riebau, Robert | Mujkanovic, Edin | Cramer, Holger | Lauche, Romy | Michalsen, Andres | Ward, Lesley | Cramer, Holger | Irnich, Dominik | Stör, Wolfram | Burnstock, Geoffrey | Schaible, Hans-Georg | Ots, Thomas | Langhorst, Jost | Lauche, Romy | Sundberg, Tobias | Falkenberg, Torkel | Amarell, Catherina | Amarell, Catherina | Anheyer, Melanie | Eckert, Marion | Eckert, Marion | Ogal, Mercedes | Eckert, Marion | Amarell, Catherina | Schönauer, Annette | Reisenberger, Birgit | Brand, Bernhard | Anheyer, Dennis | Dobos, Gustav | Kroez, Matthias | Martin, David | Matthes, Harald | Ammendola, Aldo | Mao, Jun J. | Witt, Claudia | Yang, Yufei | Dobos, Gustav | Oritz, Miriam | Horneber, Markus | Voiß, Petra | Reisenberger, Birgit | von Rosenstiel, Alexandra | Eckert, Marion | Ogal, Mercedes | Amarell, Catharina | Anheyer, Melanie | Schad, Friedemann | Schläppi, Marc | Kröz, Matthias | Büssing, Arndt | Bar-Sela, Gil | Matthes, Harald | Schiff, Elad | Ben-Arye, Eran | Arnon, Zahi | Avshalomov, David | Attias, Samuel | Schönauer, Annette | Haramati, Aviad | Witt, Claudia | Brinkhaus, Benno | Cotton, Sian | Jong, Miek | Jong, Mats | Scheffer, Christian | Haramati, Aviad | Tauschel, Diethard | Edelhäuser, Friedrich | AlBedah, Abdullah | Lee, Myeong Soo | Khalil, Mohamed | Ogawa, Keiko | Motoo, Yoshiharu | Arimitsu, Junsuke | Ogawa, Masao | Shimizu, Genki | Stange, Rainer | Kraft, Karin | Kuchta, Kenny | Watanabe, Kenji | Bonin, D | Büssing, Arndt | Gruber, Harald | Koch, Sabine | Gruber, Harald | Pohlmann, Urs | Caldwell, Christine | Krantz, Barbara | Kortum, Ria | Martin, Lily | Wieland, Lisa S. | Kligler, Ben | Gould-Fogerite, Susan | Zhang, Yuqing | Wieland, Lisa S. | Riva, John J. | Lumpkin, Michael | Ratner, Emily | Ping, Liu | Jian, Pei | Hamme, Gesa-Meyer | Mao, Xiaosong | Chouping, Han | Schröder, Sven | Hummelsberger, Josef | Wullinger, Michael | Brodzky, Marc | Zalpour, Christoff | Langley, Julia | Weber, Wendy | Mudd, Lanay M. | Wayne, Peter | Witt, Clauda | Weidenhammer, Wolfgang | Fønnebø, Vinjar | Boon, Heather | Steel, Amie | Bugarcic, Andrea | Rangitakatu, Melisa | Steel, Amie | Adams, Jon | Sibbritt, David | Wardle, Jon | Leach, Matthew | Schloss, Janet | Dieze, Helene | Boon, Heather | Ijaz, Nadine | Willcox, Merlin | Heinrich, Michael | Lewith, George | Flower, Andrew | Graz, Bertrand | Adam, Daniela | Grabenhenrich, Linus | Ortiz, Miriam | Binting, Sylvia | Reinhold, Thomas | Brinkhaus, Benno | Andermo, Susanne | Sundberg, Tobias | Falkenberg, Torkel | Nordberg, Johanna Hök | Arman, Maria | Bhasin, Manoj | Fan, Xueyi | Libermann, Towia | Fricchione, Gregory | Denninger, John | Benson, Herbert | Berger, Bettina | Stange, Rainer | Michalsen, Andreas | Martin, David D. | Boers, Inge | Vlieger, Arine | Jong, Miek | Brinkhaus, Benno | Teut, Michael | Ullmann, Alexander | Ortiz, Miriam | Rotter, Gabriele | Binting, Sylvia | Lotz, Fabian | Roll, Stephanie | Canella, Claudia | Mikolasek, Michael | Rostock, Matthias | Beyer, Jörg | Guckenberger, Matthias | Jenewein, Josef | Linka, Esther | Six, Claudia | Stoll, Sarah | Stupp, Roger | Witt, Claudia M. | Chuang, Elisabeth | Kligler, Ben | McKee, Melissa D. | Cramer, Holger | Lauche, Romy | Klose, Petra | Lange, Silke | Langhorst, Jost | Dobos, Gustav | Chung, Vincent C. H. | Wong, Hoi L. C. | Wu, Xin Y. | Wen, Grace Y. G. | Ho, Robin S. T. | Ching, Jessica Y. L. | Wu, Justin C. Y. | Coakley, Amanda | Flanagan, Jane | Annese, Christine | Empoliti, Joanne | Gao, Zishan | Liu, Xugang | Yu, Shuguang | Yan, Xianzhong | Liang, Fanrong | Hohmann, Christoph D. | Steckhan, Nico | Ostermann, Thomas | Paetow, Arion | Hoff, Evelyn | Michalsen, Andreas | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Hu, Xiao-Yang | Wu, Ruo-Han | Logue, Martin | Blonde, Clara | Lai, Lily Y. | Stuart, Beth | Flower, Andrew | Fei, Yu-Tong | Moore, Michael | Liu, Jian-Ping | Lewith, George | Jeitler, Michael | Zillgen, Hannah | Högl, Manuel | Steckhan, Nico | Stöckigt, Barbara | Seifert, Georg | Michalsen, Andreas | Kessler, Christian | Khadivzadeh, Talat | Bashtian, Maryam Hassanzadeh | Aval, Shapour Badiee | Esmaily, Habibollah | Kim, Jihye | Kim, Keun H. | Klocke, Carina | Joos, Stefanie | Koshak, Abdulrahman | Wie, Li | Koshak, Emad | Wali, Siraj | Alamoudi, Omer | Demerdash, Abdulrahman | Qutub, Majdy | Pushparaj, Peter | Heinrich, Michael | Kruse, Sigrid | Fischer, Isabell | Tremel, Nadine | Rosenecker, Joseph | Leung, Brenda | Takeda, Wendy | Liang, Ning | Feng, Xue | Liu, Jian-ping | Cao, Hui-juan | Luberto, Christina M. | Shinday, Nina | Philpotts, Lisa | Park, Elyse | Fricchione, Gregory L. | Yeh, Gloria | Munk, Niki | Zakeresfahani, Arash | Foote, Trevor R. | Ralston, Rick | Boulanger, Karen | Özbe, Dominik | Gräßel, Elmar | Luttenberger, Katharina | Pendergrass, Anna | Pach, Daniel | Bellmann-Strobl, Judit | Chang, Yinhui | Pasura, Laura | Liu, Bin | Jäger, Sven F. | Loerch, Ronny | Jin, Li | Brinkhaus, Benno | Ortiz, Miriam | Reinhold, Thomas | Roll, Stephanie | Binting, Sylvia | Icke, Katja | Shi, Xuemin | Paul, Friedemann | Witt, Claudia M. | Rütz, Michaela | Lynen, Andreas | Schömitz, Meike | Vahle, Maik | Salomon, Nir | Lang, Alon | Lahat, Adi | Kopylov, Uri | Ben-Horin, Shomron | Har-Noi, Ofir | Avidan, Benjamin | Elyakim, Rami | Gamus, Dorit | NG, Siew | Chang, Jessica | Wu, Justin | Kaimiklotis, John | Schumann, Dania | Buttó, Ludovica | Langhorst, Jost | Dobos, Gustav | Haller, Dirk | Cramer, Holger | Smith, Caroline | de Lacey, Sheryl | Chapman, Michael | Ratcliffe, Julie | Johnson, Neil | Lyttleton, Jane | Boothroyd, Clare | Fahey, Paul | Tjaden, Bram | van Vliet, Marja | van Wietmarschen, Herman | Jong, Miek | Tröger, Wilfried | Vuolanto, Pia | Aarva, Paulina | Sorsa, Minna | Helin, Kaija | Wenzel, Claudia | Zoderer, Iris | Pammer, Patricia | Simon, Patrick | Tucek, Gerhard | Wode, Kathrin | Henriksson, Roger | Sharp, Lena | Stoltenberg, Anna | Nordberg, Johanna Hök | Xiao-ying, Yang | Wang, Li-qiong | Li, Jin-gen | Liang, Ning | Wang, Ying | Liu, Jian-ping | Balneaves, Lynda | Capler, Rielle | Bocci, Chiara | Guffi, Marta | Paolini, Marina | Meaglia, Ilaria | Porcu, Patrizia | Ivaldi, Giovanni B. | Dragan, Simona | Bucuras, Petru | Pah, Ana M. | Badalica-Petrescu, Marius | Buleu, Florina | Hogea-Stoichescu, Gheorghe | Christodorescu, Ruxandra | Kao, Lan | Cho, Yumin | Klafke, Nadja | Mahler, Cornelia | von Hagens, Cornelia | Uhlmann, Lorenz | Bentner, Martina | Schneeweiss, Andreas | Mueller, Andreas | Szecsenyi, Joachim | Joos, Stefanie | Neri, Isabella | Ortiz, Miriam | Schnabel, Katharina | Teut, Michael | Rotter, Gabriele | Binting, Sylvia | Cree, Margit | Lotz, Fabian | Suhr, Ralf | Brinkhaus, Benno | Rossi, Elio | Baccetti, Sonia | Firenzuoli, Fabio | Monechi, Maria V. | Di Stefano, Mariella | Amunni, Gianni | Wong, Wendy | Chen, Bingzhong | Wu, Justin | Amri, Hakima | Haramati, Aviad | Kotlyanskaya, Lucy | Anderson, Belinda | Evans, Roni | Kligler, Ben | Marantz, Paul | Bradley, Ryan | Booth-LaForce, Cathryn | Zwickey, Heather | Kligler, Benjamin | Brooks, Audrey | Kreitzer, Mary J. | Lebensohn, Patricia | Goldblatt, Elisabeth | Esmel-Esmel, Neus | Jiménez-Herrera, Maria | Ijaz, Nadine | Boon, Heather | Jocham, Alexandra | Stock-Schröer, Beate | Berberat, Pascal O. | Schneider, Antonius | Linde, Klaus | Masetti, Morgana | Murakozy, Henriette | Van Vliet, Marja | Jong, Mats | Jong, Miek | Agdal, Rita | Atarzadeh, Fatemeh | Jaladat, Amir M. | Hoseini, Leila | Amini, Fatemeh | Bai, Chen | Liu, Tiegang | Zheng, Zian | Wan, Yuxiang | Xu, Jingnan | Wang, Xuan | Yu, He | Gu, Xiaohong | Daneshfard, Babak | Nimrouzi, Majid | Tafazoli, Vahid | Alorizi, Seyed M. Emami | Saghebi, Seyed A. | Fattahi, Mohammad R. | Salehi, Alireza | Rezaeizadeh, Hossein | Zarshenas, Mohammad M. | Nimrouzi, Majid | Fox, Kealoha | Hughes, John | Kostanjsek, Nenad | Espinosa, Stéphane | Lewith, George | Fisher, Peter | Latif, Abdul | Lefeber, Donald | Paske, William | Öztürk, Ali Ö. | Öztürk, Gizemnur | Boers, Inge | Tissing, Wim | Naafs, Marianne | Busch, Martine | Jong, Miek | Daneshfard, Babak | Sanaye, Mohammad R. | Dräger, Kilian | Fisher, Peter | Kreitzer, Mary J. | Evans, Roni | Leininger, Brent | Shafto, Kate | Breen, Jenny | Sanaye, Mohammad R. | Daneshfard, Babak | Simões-Wüst, Ana P. | Moltó-Puigmartí, Carolina | van Dongen, Martien | Dagnelie, Pieter | Thijs, Carel | White, Shelley | Wiesener, Solveig | Salamonsen, Anita | Stub, Trine | Fønnebø, Vinjar | Abanades, Sergio | Blanco, Mar | Masllorens, Laia | Sala, Roser | Al-Ahnoumy, Shafekah | Han, Dongwoon | He, Luzhu | Kim, Ha Yun | In Choi, Da | Alræk, Terje | Stub, Trine | Kristoffersen, Agnete | von Sceidt, Christel | Michalsen, Andreas | Bruset, Stig | Musial, Frauke | Anheyer, Dennis | Cramer, Holger | Lauche, Romy | Saha, Felix J. | Dobos, Gustav | Anheyer, Dennis | Haller, Heidemarie | Lauche, Romy | Dobos, Gustav | Cramer, Holger | Azizi, Hoda | Khadem, Nayereh | Hassanzadeh, Malihe | Estiri, Nazanin | Azizi, Hamideh | Tavassoli, Fatemeh | Lotfalizadeh, Marzieh | Zabihi, Reza | Esmaily, Habibollah | Azizi, Hoda | Shabestari, Mahmoud Mohammadzadeh | Paeizi, Reza | Azari, Masoumeh Alvandi | Bahrami-Taghanaki, Hamidreza | Zabihi, Reza | Azizi, Hamideh | Esmaily, Habibollah | Baars, Erik | De Bruin, Anja | Ponstein, Anne | Baccetti, Sonia | Di Stefano, Mariella | Rossi, Elio | Firenzuoli, Fabio | Segantini, Sergio | Monechi, Maria Valeria | Voller, Fabio | Barth, Jürgen | Kern, Alexandra | Lüthi, Sebastian | Witt, Claudia | Barth, Jürgen | Zieger, Anja | Otto, Fabius | Witt, Claudia | Beccia, Ariel | Dunlap, Corina | Courneene, Brendan | Bedregal, Paula | Passi, Alvaro | Rodríguez, Alfredo | Chang, Mayling | Gutiérrez, Soledad | Beissner, Florian | Beissner, Florian | Preibisch, Christine | Schweizer-Arau, Annemarie | Popovici, Roxana | Meissner, Karin | Beljanski, Sylvie | Belland, Laura | Rivera-Reyes, Laura | Hwang, Ula | Berger, Bettina | Sethe, Dominik | Hilgard, Dörte | Heusser, Peter | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Al-Abbadey, Miznah | Bradbury, Katherine | Carnes, Dawn | Dimitrov, Borislav | Fawkes, Carol | Foster, Jo | MacPherson, Hugh | Roberts, Lisa | Yardley, Lucy | Lewith, George | Bishop, Felicity | Holmes, Michelle | Lewith, George | Yardley, Lucy | Little, Paul | Cooper, Cyrus | Bogani, Patrizia | Maggini, Valentina | Gallo, Eugenia | Miceli, Elisangela | Biffi, Sauro | Mengoni, Alessio | Fani, Renato | Firenzuoli, Fabio | Brands-Guendling, Nadine | Guendling, Peter W. | Bronfort, Gert | Evans, Roni | Haas, Mitch | Leininger, Brent | Schulz, Craig | Bu, Xiangwei | Wang, J. | Fang, T. | Shen, Z. | He, Y. | Zhang, X. | Zhang, Zhengju | Wang, Dali | Meng, Fengxian | Büssing, Arndt | Baumann, Klaus | Frick, Eckhard | Jacobs, Christoph | Büssing, Arndt | Grünther, Ralph-Achim | Lötzke, Désirée | Büssing, Arndt | Jung, Sonny | Lötzke, Désirée | Recchia, Daniela R. | Robens, Sibylle | Ostermann, Thomas | Berger, Bettina | Stankewitz, Josephin | Kröz, Matthias | Jeitler, Mika | Kessler, Christian | Michalsen, Andreas | Cheon, Chunhoo | Jang, Bo H. | Ko, Seong G. | Huang, Ching W. | Sasaki, Yui | Ko, Youme | Cheshire, Anna | Ridge, Damien | Hughes, John | Peters, David | Panagioti, Maria | Simon, Chantal | Lewith, George | Cho, Hyun J. | Han, Dongwoon | Choi, Soo J. | Jung, Young S. | Im, Hyea B | Cooley, Kieran | Tummon-Simmons, Laura | Cotton, Sian | Luberto, Christina M. | Wasson, Rachel | Kraemer, Kristen | Sears, Richard | Hueber, Carly | Derk, Gwendolyn | Lill, JR | An, Ruopeng | Steinberg, Lois | Rodriguez, Lourdes Diaz | la Fuente, Francisca García-de | De la Vega, Miguel | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Cantarero-Villanueva, Irene | Rodriguez, Lourdes Diaz | García-De la Fuente, Francisca | Jiménez-Guerrero, Fanny | Vargas-Román, Keyla | Fernández-Ruiz, Jonatan | Galiano-Castillo, Noelia | Diaz-Saez, Gualberto | Torres-Jimenez, José I. | Garcia-Gomez, Olga | Hortal-Muñoz, Luis | Diaz-Diez, Camino | Dicen, Demijon | Diezel, Helene | Adams, Jon | Steel, Amie | Wardle, Jon | Diezel, Helene | Steel, Amie | Frawley, Jane | Wardle, Jon | Broom, Alex | Adams, Jon | Dong, Fei | Yu, He | Liu, Tiegang | Ma, Xueyan | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Gu, Xiaohong | Dong, Fei | Yu, He | Wu, Liqun | Liu, Tiegang | Ma, Xueyan | Ma, Jiaju | Yan, Liyi | Wan, Yuxiang | Zheng, Zian | Zhen, Jianhua | Gu, Xiaohong | Dubois, Julie | Rodondi, Pierre-Yves | Edelhäuser, Friedrich | Schwartze, Sophia | Trapp, Barbara | Cysarz, Dirk
doi:10.1186/s12906-017-1782-4
PMCID: PMC5498855

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