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2.  A distant, cis-acting enhancer drives induction of Arf by Tgfβ in the developing eye 
Developmental biology  2013;380(1):49-57.
The Arf tumor suppressor represents one of several genes encoded at the Cdkn2a and Cdkn2b loci in the mouse. Beyond its role blunting the growth of incipient cancer cells, the Arf gene also plays an essential role in development: Its gene product, p19Arf, is induced by Tgfβ2 in the developing eye to dampen proliferative signals from Pdgfrβ, which effect ultimately fosters the vascular remodeling required for normal vision in the mouse. Mechanisms underlying Arf induction by Tgfβ2 are not fully understood. Using the chr4Δ70kb/Δ70kb mouse, we now show that deletion of the coronary artery disease (CAD) risk interval lying upstream of the Cdkn2a/b locus represses developmentally-timed induction of Arf resulting in eye disease mimicking the persistent hyperplastic primary vitreous (PHPV) found in Arf-null mice and in children. Using mouse embryo fibroblasts, we demonstrate that Arf induction by Tgfβ is blocked in cis to the 70 kb deletion, but Arf induction by activated RAS and cell culture “shock” is not. Finally, we show that Arf induction by Tgfβ is derailed by preventing RNA polymerase II recruitment following Smad 2/3 binding to the promoter. These findings provide the first evidence that the CAD risk interval, located at a distance from Arf, acts as a cis enhancer of Tgfβ2-driven induction of Arf during development.
PMCID: PMC4336776  PMID: 23665474
9p21; Arf; Tgfβ; PHPV
3.  Discovery of a Potent, Covalent BTK Inhibitor for B-Cell Lymphoma 
ACS Chemical Biology  2014;9(5):1086-1091.
BTK is a member of the TEC family of non-receptor tyrosine kinases whose deregulation has been implicated in a variety of B-cell-related diseases. We have used structure-based drug design in conjunction with kinome profiling and cellular assays to develop a potent, selective, and irreversible BTK kinase inhibitor, QL47, which covalently modifies Cys481. QL47 inhibits BTK kinase activity with an IC50 of 7 nM, inhibits autophosphorylation of BTK on Tyr223 in cells with an EC50 of 475 nM, and inhibits phosphorylation of a downstream effector PLCγ2 (Tyr759) with an EC50 of 318 nM. In Ramos cells QL47 induces a G1 cell cycle arrest that is associated with pronounced degradation of BTK protein. QL47 inhibits the proliferation of B-cell lymphoma cancer cell lines at submicromolar concentrations.
PMCID: PMC4027949  PMID: 24556163
4.  Acute fatty liver of pregnancy: Over six months follow-up study of twenty-five patients 
AIM: To evaluate the prognosis of patients with acute fatty liver of pregnancy (AFLP) 6 mo or longer after discharge.
METHODS: The records of pregnant patients diagnosed with AFLP at Beijing Ditan Hospital over a 16-year period were reviewed in November 2012. Patients were monitored using abdominal ultrasound, liver and kidney functions, and routine blood examination.
RESULTS: A total of 42 patients were diagnosed with AFLP during the study period, and 25 were followed. The mean follow-up duration was 54.5 mo (range: 6.5-181 mo). All patients were in good physical condition, but one patient had gestational diabetes. The renal and liver functions normalized in all patients after recovery, including in those with pre-existing liver or kidney failure. The ultrasound findings were normal in 12 patients, an increasingly coarsened echo-pattern and increased echogenicity of the liver in 10 patients, and mild to moderate fatty liver infiltration in 3 patients. Cirrhosis or liver nodules were not observed in any patient.
CONCLUSION: Acute liver failure and acute renal failure in AFLP patients is reversible. Patients do not require any specific long-term follow-up after recovery from AFLP if their liver function tests have normalized and they remain well.
PMCID: PMC4323472
Acute fatty liver of pregnancy; Acute liver failure; Acute renal failure; Follow-up study
5.  Incidence and psychological-behavioral characteristics of refractory functional dyspepsia: A large, multi-center, prospective investigation from China 
AIM: To explore the incidence and psychological and behavioral characteristics of refractory functional dyspepsia (RFD) in China.
METHODS: The subjects of this study were 1341 new outpatients with functional dyspepsia (FD) who were diagnosed according to the Rome III criteria at four hospitals in Guangdong Province between June and September 2012, and 100 healthy volunteers. All subjects completed questionnaires and scales administered.
RESULTS: Three-hundred and twenty-seven of the 1341 patients with FD had RFD (24.4%). Patients with RFD had a longer disease duration and a more severe form of the disease than patients with non-refractory FD (NRFD). The prevalence of depression and anxiety symptoms was higher in patients with RFD than in patients with NRFD. The prevalence of unhealthy eating behaviors, lack of physical activity, and sleeping disorders was higher in patients with RFD than in patients with NRFD. Patients with RFD sought medical advice on more occasions and spent more money on treatment than patients with NRFD. Finally, patients with RFD had poorer quality of life than patients with NRFD.
CONCLUSION: RFD is not rare in clinical practice and should get attention by patients and doctors because of its long duration, severe symptoms, and associations with abnormal psychology and poor quality of life.
PMCID: PMC4323473
Refractory functional dyspepsia; Psychological-behavioral characteristics; Depression; Anxiety; Behavior; Quality of life
6.  MatrixConverter: Facilitating construction of phenomic character matrices1 
Applications in Plant Sciences  2015;3(2):apps.1400088.
• Premise of the study: While numerous software packages enable scientists to evaluate molecular data and transform them for phylogenetic analyses, few such tools exist for phenomic data. We introduce MatrixConverter, a program that helps expedite and facilitate the transformation of raw phenomic character data into discrete character matrices that can be used in most evolutionary inference programs.
• Methods and Results: MatrixConverter is an open source program written in Java; a platform-independent binary executable, as well as sample data sets and a user’s manual, are available at MatrixConverter has a simple, intuitive user interface that enables the user to immediately begin scoring phenomic characters. We demonstrate the performance of MatrixConverter on a phenomic data set from cycads.
• Conclusions: New technologies and software make it possible to obtain phenomic data from species across the tree of life, and MatrixConverter helps to transform these new data for evolutionary or ecological inference.
PMCID: PMC4332142
MatrixConverter; morphology; phenomics; phylogenetic matrix; software
7.  The Conserved Sequence Repeats of IQGAP1 mediate binding to Ezrin 
Journal of proteome research  2013;13(2):1156-1166.
Mammalian IQGAP proteins all feature multiple ~50 amino acid sequence repeats near their N-termini and little is known about the function of these “Repeats”. We have expressed and purified the Repeats from human IQGAP1 in order to identify binding partners. We used mass spectrometry to identify 42 mouse kidney proteins that associate with the IQGAP1 Repeats including the ERM proteins ezrin, radixin and moesin. ERM proteins have an N-terminal FERM domain (four point one, ezrin, radixin, moesin) through which they bind to protein targets and phosphatidylinositol 4,5-bisphosphate (PIP2), and a C-terminal actin-binding domain, and function to link the actin cytoskeleton to distinct locations on the cell cortex. Isothermal titration calorimetry (ITC) reveals that the IQGAP1 Repeats directly bind to the ezrin FERM domain while no binding is seen for full-length “autoinhibited” ezrin or a version of full-length ezrin intended to mimic the activated protein. ITC also indicates that the ezrin FERM domain binds to the Repeats from IQGAP2 but not the Repeats from IQGAP3. We conclude that IQGAP1 and IQGAP2 are positioned at the cell cortex by ERM proteins. We propose that the IQGAP3 Repeats may likewise bind to FERM domains signaling purposes.
PMCID: PMC3975686  PMID: 24294828
IQGAP1; Repeats; ezrin; FERM domain
8.  Exploiting an Allosteric Binding Site of PRMT3 Yields Potent and Selective Inhibitors 
Journal of medicinal chemistry  2013;56(5):2110-2124.
Protein arginine methyltransferases (PRMTs) play an important role in diverse biological processes. Among the nine known human PRMTs, PRMT3 has been implicated in ribosomal biosynthesis via asymmetric dimethylation of the 40S ribosomal protein S2 and in cancer via interaction with the DAL-1 tumor suppressor protein. However, few selective inhibitors of PRMTs have been discovered. We recently disclosed the first selective PRMT3 inhibitor, which occupies a novel allosteric binding site and is noncompetitive with both the peptide substrate and cofactor. Here we report comprehensive structure–activity relationship studies of this series, which resulted in the discovery of multiple PRMT3 inhibitors with submicromolar potencies. An X-ray crystal structure of compound 14u in complex with PRMT3 confirmed that this inhibitor occupied the same allosteric binding site as our initial lead compound. These studies provide the first experimental evidence that potent and selective inhibitors can be created by exploiting the allosteric binding site of PRMT3.
PMCID: PMC4319713  PMID: 23445220
9.  Effect of Tai Chi on mononuclear cell functions in patients with non-small cell lung cancer 
Tai Chi is the Chinese traditional medicine exercise for mind-body health. The objective of this study is to investigate the effect of Tai Chi Chuan (TCC) exercise on the proliferative and cytolytic/tumoricidal activities of peripheral blood mononuclear cells (PBMCs) in postsurgical non-small cell lung cancer (NSCLC) patients.
Patients (n = 27) were randomly divided into the control group (n = 13) and the TCC group (n = 14). TCC group participated in Tai Chi 24-type exercise for 16 weeks, 60-min every time, and three times a week. Peripheral blood was collected and PBMCs isolated before and after the 16-week TCC, PBMC proliferation and co-culture of PBMCs with the NSCLC cell line A549 were performed for proliferation and cell cytolysis assays. Analysis of NKT cells, NK cells, and CD123+ and CD11c + dendritic cells were also performed.
(1) After 16-week of TCC, cell proliferation increased significantly as compared with the control. (2) PBMCs from the TCC group also demonstrated enhanced cytolytic/oncolytic activity against A549 cells. (3) Significant differences were also found in NK cell percentage at t = 16 weeks, post-pre changes of NKT and DC11c between groups.
Regular Tai Chi exercise has the promise of enhancing PBMC proliferative and cytolytic activities in NSCLC patients. Our results affirm the value of a future trial with a larger scale and longer duration for cancer survivors.
Trial registration
PMCID: PMC4321705  PMID: 25653009
Physical activity; Peripheral blood; Immune cell; Cell proliferation; Cytolytic activity
10.  Jagged-1 signaling suppresses the IL-6 and TGF-β treatment-induced Th17 cell differentiation via the reduction of RORγt/IL-17A/IL-17F/IL-23a/IL-12rb1 
Scientific Reports  2015;5:8234.
Jagged-1 signaling has recently been reported to be involved in the Th17 cell differentiation. However, little is known about its mechanisms. Soluble Jagged-1 was used to activate the Jagged-1–Notch signaling to interfere with the IL-6 and TGF-β-induced Th17 cell skewing. Genes relevant to the autoimmunity or inflammation were screened for the first time in this system by qPCR array for the differential expressions. The 18 genes out of 84, including Clec7a, Il12b, Il12rb1, Il12rb2, Csf3, Il15, Il17a, Il17f, Il17rc, Il17rd, Il17re, Il23a, Myd88, Socs1, Stat4, Stat5a, Sykb and Tbx21, were downregulated, but only Cxcl2, Cxcl12 and Mmp3 were upregulated. The expressions of the genes, Rorγt, Il17a, Il17f, Il12rb1 and Il23a, induced by simultaneous IL-6 and TGF-β treatment were significantly suppressed by Jagged-1, followed by the reduction of RORγt, IL-17A, and IL-17F. Consistent with the attenuation of RORγt, and the reduced production and secretion of IL-17A and IL-17F in the cell supernatant and the in situ stained cells, the number of CD4+IL-17+ cells was also diminished. It is concluded that the Jagged-1–Notch signaling can suppress the IL-6 and TGF-β treatment-induced Th17 cell skewing through the attenuation of RORγt and, hence by, the down-regulation of IL-17A, IL-17F, IL-23a, and IL-12rb1.
PMCID: PMC4316398  PMID: 25648768
11.  Human intracellular ISG15 prevents interferon-α/β over-amplification and auto-inflammation 
Nature  2014;517(7532):89-93.
Intracellular ISG15 is an interferon (IFN)-α/β-inducible ubiquitin-like modifier which can covalently bind other proteins in a process called ISGylation; it is an effector of IFN-α/β-dependent antiviral immunity in mice1–4. We previously published a study describing humans with inherited ISG15 deficiency but without unusually severe viral diseases5. We showed that these patients were prone to mycobacterial disease and that human ISG15 was non-redundant as an extracellular IFN-γ-inducing molecule. We show here that ISG15-deficient patients also display unanticipated cellular, immunological and clinical signs of enhanced IFN-α/β immunity, reminiscent of the Mendelian autoinflammatory interferonopathies Aicardi–Goutières syndrome and spondyloenchondrodysplasia6–9.We further show that an absence of intracellular ISG15 in the patients’ cells prevents the accumulation of USP1810,11, a potent negative regulator of IFN-α/β signalling, resulting in the enhancement and amplification of IFN-α/β responses. Human ISG15, therefore, is not only redundant for antiviral immunity, but is a key negative regulator of IFN-α/β immunity. In humans, intracellular ISG15 is IFN-α/β-inducible not to serve as a substrate for ISGylation-dependent antiviral immunity, but to ensure USP18-dependent regulation of IFN-α/β and prevention of IFN-α/β-dependent autoinflammation.
PMCID: PMC4303590  PMID: 25307056
12.  A routine biomarker-based risk prediction model for metabolic syndrome in urban Han Chinese population 
BMC Public Health  2015;15:64.
Many MetS related biomarkers had been discovered, which provided the possibility for building the MetS prediction model. In this paper we aimed to develop a novel routine biomarker-based risk prediction model for MetS in urban Han Chinese population.
Exploring Factor analysis (EFA) was firstly conducted in MetS positive 13,345 males and 3,212 females respectively for extracting synthetic latent predictors (SLPs) from 11 routine biomarkers. Then, depending on the cohort with 5 years follow-up in 1,565 subjects (male 1,020 and female 545), a Cox model for predicting 5 years MetS was built by using SLPs as predictor; Area under the ROC curves (AUC) with 10 fold cross validation was used to evaluate its power. Absolute risk (AR) and relative absolute risk (RAR) were calculated to develop a risk matrix for visualization of risk assessment.
Six SLPs were extracted by EFA from 11 routine health check-up biomarkers. Each of them reflected the specific pathogenesis of MetS, with inflammatory factor (IF) contributed by WBC & LC & NGC, erythrocyte parameter factor (EPF) by Hb & HCT, blood pressure factor (BPF) by SBP & DBP, lipid metabolism factor (LMF) by TG & HDL-C, obesity condition factor (OCF) by BMI, and glucose metabolism factor (GMF) by FBG with the total contribution of 81.55% and 79.65% for males and females respectively. The proposed metabolic syndrome synthetic predictor (MSP) based predict model demonstrated good performance for predicting 5 years MetS with the AUC of 0.802 (95% CI 0.776-0.826) in males and 0.902 (95% CI 0.874-0.925) in females respectively, even after 10 fold cross validation, AUC was still enough high with 0.796 (95% CI 0.770-0.821) in males and 0.897 (95% CI 0.868-0.921) in females. More importantly, the MSP based risk matrix with a series of risk warning index provided a feasible and practical tool for visualization of risk assessment in the prediction of MetS.
MetS could be explained by six SLPs in Chinese urban Han population. The proposed MSP based predict model demonstrated good performance for predicting 5 years MetS, and the MetS-based matrix provided a feasible and practical tool.
Electronic supplementary material
The online version of this article (doi:10.1186/s12889-015-1424-z) contains supplementary material, which is available to authorized users.
PMCID: PMC4320489  PMID: 25637138
Metabolic Syndrome (MetS); Routine biomarkers; Predictor model; Risk matrix
13.  Relationship between Personality Disorder Functioning Styles and the Emotional States in Bipolar I and II Disorders 
PLoS ONE  2015;10(1):e0117353.
Bipolar disorder types I (BD I) and II (BD II) behave differently in clinical manifestations, normal personality traits, responses to pharmacotherapies, biochemical backgrounds and neuroimaging activations. How the varied emotional states of BD I and II are related to the comorbid personality disorders remains to be settled.
We therefore administered the Plutchick – van Praag Depression Inventory (PVP), the Mood Disorder Questionnaire (MDQ), the Hypomanic Checklist-32 (HCL-32), and the Parker Personality Measure (PERM) in 37 patients with BD I, 34 BD II, and in 76 healthy volunteers.
Compared to the healthy volunteers, patients with BD I and II scored higher on some PERM styles, PVP, MDQ and HCL-32 scales. In BD I, the PERM Borderline style predicted the PVP scale; and Antisocial predicted HCL-32. In BD II, Borderline, Dependant, Paranoid (-) and Schizoid (-) predicted PVP; Borderline predicted MDQ; Passive-Aggressive and Schizoid (-) predicted HCL-32. In controls, Borderline and Narcissistic (-) predicted PVP; Borderline and Dependant (-) predicted MDQ.
Besides confirming the different predictability of the 11 functioning styles of personality disorder to BD I and II, we found that the prediction was more common in BD II, which might underlie its higher risk of suicide and poorer treatment outcome.
PMCID: PMC4307975  PMID: 25625553
14.  Exosomes: Novel Biomarkers for Clinical Diagnosis 
The Scientific World Journal  2015;2015:657086.
Exosomes are 30–120 nm endocytic membrane-derived vesicles that participate in cell-to-cell communication and protein and RNA delivery. Exosomes harbor a variety of proteins, nucleic acids, and lipids and are present in many and perhaps all bodily fluids. A significant body of literature has demonstrated that molecular constituents of exosomes, especially exosomal proteins and microRNAs (miRNAs), hold great promise as novel biomarkers for clinical diagnosis. In this minireview, we summarize recent advances in the research of exosomal biomarkers and their potential application in clinical diagnostics. We also provide a brief overview of the formation, function, and isolation of exosomes.
PMCID: PMC4322857
15.  Effect of hypoxia on hypoxia inducible factor-1α, insulin-like growth factor I and vascular endothelial growth factor expression in hepatocellular carcinoma HepG2 cells 
Oncology Letters  2015;9(3):1142-1148.
Hypoxic microenvironments and angiogenesis have been a focus of tumor research in previous years. The aim of the the present study was to create a hypoxic model and observe the effect of hypoxia on the expression of hypoxia inducible factor-1α (HIF-1α), insulin-like growth factor I (IGF-1) and vascular endothelial growth factor expression. The hypoxia model was generated using cobalt chloride (CoCl2) and an MTT assay was used to observe the influence of hypoxia on HepG2 cells. Reverse transcription-polymerase chain reaction, western blotting, ELISA and confocal immunofluorescence microscopy were used to detect the expression of HIF-1α, IGF-1 and VEGF in HepG2 cells, in which hypoxia was induced by various concentrations of CoCl2 and for various incubation times. The cell viability worsened with increasing concentrations of CoCl2. The expression of HIF-1α and IGF-1R was observed in hypoxic HepG2 cells, with the exception of HIF-1α mRNA. The expression of IGF-1R and VEGF mRNA and protein was correlated with the concentration of CoCl2 and the time that hypoxia was induced for. The expression of HIF-1α mRNA and protein was positively correlated with the expression of the VEGF mRNA and protein in a dose- and time-dependent manner under hypoxic conditions. Using immunofluorescence, it was observed that IGF-1R and HIF-1α were secreted from the hypoxic HepG2 cells. It was concluded that hypoxia induces the accumulation of IGF-1R and HIF-1α mRNA and protein, which regulates the expression of VEGF mRNA and protein in hypoxic HepG2 cells.
PMCID: PMC4315007  PMID: 25663870
hepatocellular carcinoma; hypoxia; hypoxia inducible factor-1α; insulin-like growth factor I; vascular endothelial growth factor
16.  PGC TagSNP and Its Interaction with H. pylori and Relation with Gene Expression in Susceptibility to Gastric Carcinogenesis 
PLoS ONE  2014;9(12):e115955.
Pepsinogen C (PGC) plays an important role in sustaining the cellular differentiation during the process of gastric carcinogenesis. This study aimed to assess the role of PGC tagSNPs and their interactions with Helicobacter pylori (H. pylori) in the development of gastric cancer and its precursor, atrophic gastritis.
Four PGC tagSNPs (rs6941539, rs6912200, rs3789210 and rs6939861) were genotyped by Sequenom MassARRAY platform in a total of 2311 subjects consisting of 642 gastric cancer, 774 atrophic gastritis, and 895 healthy control subjects. The mRNA and protein expression levels of PGC in gastric tissues and in serum were respectively measured by quantitative reverse transcriptase–polymerase chain reaction (qRT-PCR), immunohistochemistry, and Eenzyme-linked immunoabsorbent assay (ELISA).
We found associations between PGC rs3789210 CG/GG genotypes and reduced gastric cancer risk and between PGC rs6939861 A variant allele and increased risks of both gastric cancer and atrophic gastritis. As for the haplotypes of PGC rs6941539-rs6912200-rs3789210-rs6939861 loci, the TTCA and TTGG haplotypes were respectively associated with increased and reduced risks of both gastric cancer and atrophic gastritis; additionally, the CTCA haplotype was associated with increased atrophic gastritis risk. Very interestingly, rs6912200 CT/TT genotypes had a positive interaction with H. pylori, synergistically elevating the gastric cancer risk. Moreover, healthy subjects who carried rs6912200 CT, TT and CT/TT variant genotypes had lower histological and serum expression levels of PGC protein.
Our findings highlight an important role of PGC rs3789210 and rs6939861 in altering susceptibility to atrophic gastritis and/or gastric cancer. Moreover, people who carry rs6912200 variant genotypes exhibit higher gastric cancer risk in case of getting H. pylori infection, which strongly suggest a necessity of preventing and/or eliminating H. pylori infection in those individuals.
PMCID: PMC4281127  PMID: 25551587
17.  LC3A‐Positive “Stone‐Like” Structures Predict an Adverse Prognosis of Gastric Cancer 
Microtubule‐associated protein light chain 3 (LC3A) is a reliable marker of autophagy that displays three distinct patterns of immunohistochemical staining in solid tumors: diffuse cytoplasmic staining, juxtanuclear staining, and staining of “stone‐like” structures. These three patterns have a different prognostic significance in many solid tumors, but little is known about their influence in gastric cancer (GC). This study was a retrospective analysis of 188 GC patients from stages I to IV. The pattern of LC3A expression was examined in tumor and nontumor tissues by immunohistochemistry. Then, the association between the pattern of LC3A expression in GC and the prognosis was investigated by Kaplan‐Meier analysis and the Cox proportional hazards model. Two distinct patterns of LC3A immunostaining (diffuse cytoplasmic expression and “stone‐like” structures) were observed in GC tissues. LC3A‐positive “stone‐like” structures were found only in the tumors, and the number of such structures was correlated with both the tumor type and tumor stage. In addition, a high number of LC3A‐positive “stone‐like” structures was closely associated with an increased risk of recurrence after radical resection of stages I–III cancer (P < 0.001; HR = 0.205) and was associated with a lower overall survival rate for stage IV cancer (P < 0.001; HR = 0.364). Taken together, our data demonstrate that LC3A‐positive “stone‐like” structures can be used as an independent biomarker for an adverse prognosis of GC, suggesting that “stone‐like” structures are correlated with the malignancy of this disease. Anat Rec, 297:653–662, 2014. © 2014 The Authors The Anatomical Record: Advances in Integrative Anatomy and Evolutionary Biology Published by Wiley Periodicals, Inc.
PMCID: PMC4279981  PMID: 24532538
gastric cancer; autophagy; LC3A; stone‐like structure; prognosis
18.  Unilateral Muscle Overuse Causes Bilateral Changes in Muscle Fiber Composition and Vascular Supply 
PLoS ONE  2014;9(12):e116455.
Unilateral strength training can cause cross-transfer strength effects to the homologous contralateral muscles. However, the impact of the cross-over effects on the muscle tissue is unclear. To test the hypothesis that unilateral muscle overuse causes bilateral alterations in muscle fiber composition and vascular supply, we have used an experimental rabbit model with unilateral unloaded overstrain exercise via electrical muscle stimulation (E/EMS). The soleus (SOL) and gastrocnemius (GA) muscles of both exercised (E) and contralateral non-exercised (NE) legs (n = 24) were morphologically analyzed after 1w, 3w and 6w of EMS. Non-exercised rabbits served as controls (n = 6). After unilateral intervention the muscles of both E and NE legs showed myositis and structural and molecular tissue changes that to various degrees mirrored each other. The fiber area was bilaterally smaller than in controls after 3w of E/EMS in both SOL (E 4420 and NE 4333 µm2 vs. 5183 µm2, p<0.05) and GA (E 3572 and NE 2983 µm2 vs. 4697 µm2, p<0.02) muscles. After 6w of E/EMS, the percentage of slow MyHCI fibers was lower than in controls in the NE legs of SOL (88.1% vs. 98.1%, p<0.009), while the percentage of fast MyHCIIa fibers was higher in the NE legs of GA (25.7% vs. 15.8%, p = 0.02). The number of capillaries around fibers in the E and NE legs was lower (SOL 13% and 15%, respectively, GA 25% and 23%, respectively, p<0.05) than in controls. The overall alterations were more marked in the fast GA muscle than in the slow SOL muscle, which on the other hand showed more histopathological muscle changes. We conclude that unilateral repetitive unloaded overuse exercise via EMS causes myositis and muscle changes in fiber type proportions, fiber area and fiber capillarization not only in the exercised leg, but also in the homologous muscles in the non-exercised leg.
PMCID: PMC4278887  PMID: 25545800
19.  Effect of Single Nucleotide Polymorphism Rs189037 in ATM Gene on Risk of Lung Cancer in Chinese: A Case-Control Study 
PLoS ONE  2014;9(12):e115845.
Accumulated evidence has indicated that ataxia-telangiectasia mutated (ATM) gene polymorphisms are closely related to lung cancer. We aimed to explore the prognostic value of rs189037 (G>A), one of ATM single nucleotide polymorphisms (SNPs), and detect whether it involves in the risk of lung cancer in Chinese Han people.
In this hospital-based matched case-control study, 852 lung cancer patients and 852 healthy controls have been put into comparison to analyze the association between rs189037 and lung cancer risk in Chinese. The single nucleotide polymorphisms were determined by TaqMan real-time PCR and we used SPSS software to perform the statistical analyses.
Individuals carrying variant AA genotype of rs189037 had higher lung cancer risk (adjusted OR: 1.56) than those carrying GG genotype. After analyzing data respectively from different groups divided by genders and smoking status, we observed that the risk effect of AA genotype on the lung cancer was significant in females, non-smokers and female non-smokers, as well as the risk effect of GA genotype in male smokers. Compared with non-smokers carrying GG genotype, smokers carrying at least one A allele had higher risk of developing lung cancer than those with GG genotype (adjusted OR: 3.52 vs. adjusted OR: 2.53).
This study suggested that rs189037 (G>A) polymorphism is associated with lung cancer risk in Chinese Han population. AA genotype and A allele may be dangerous lung cancer signals in Chinese and make contribution to diagnostic and treatment value.
PMCID: PMC4277362  PMID: 25541996
20.  Allele-Selective Inhibition of Huntingtin and Ataxin-3 Expression by RNA Duplexes Containing Unlocked Nucleic Acid (UNA) Substitutions 
Biochemistry  2013;52(51):9329-9338.
Unlocked nucleic acid (UNA) is an acyclic analog of RNA that can be introduced into RNA or DNA oligonucleotides. The increased flexibility conferred by the acyclic structure fundamentally affects the strength of base-pairing, createing opportunities for improved applications and new insights into molecular recognition. Here we test how UNA substitutions affect allele-selective inhibition of trinucleotide-repeat genes Huntingtin (HTT) and Ataxin-3 (ATX-3) expression. We find that the either the combination of mismatched bases and UNA substitutions or UNA substitutions alone can improve potency and selectivity. Inhibition is potent and selectivities of > 40-fold for inhibiting mutant versus wild-type expression can be achieved. Surprisingly, even though UNA preserves the potential for complete base-pairing, the introduction of UNA substitutions at central positions within fully complementary duplexes leads to >19-fold selectivity. Like mismatched bases, the introduction of central UNA bases disrupts the potential for cleavage of substrate by Argonaute 2 (AGO2) during gene silencing. UNA-substituted duplexes are as effective as other strategies for allele-selective silencing of trinucleotide repeat disease genes. Modulation of AGO2 activity by the introduction of UNA substitutions demonstrates that backbone flexibility is as important as base-pairing for catalysis of fully complementary duplex substrates. UNA can be used to tailor RNA silencing for optimal properties and allele-selective action.
PMCID: PMC3893079  PMID: 24266403
21.  Multiple species of wild tree peonies gave rise to the ‘king of flowers’, Paeonia suffruticosa Andrews 
The origin of cultivated tree peonies, known as the ‘king of flowers' in China for more than 1000 years, has attracted considerable interest, but remained unsolved. Here, we conducted phylogenetic analyses of explicitly sampled traditional cultivars of tree peonies and all wild species from the shrubby section Moutan of the genus Paeonia based on sequences of 14 fast-evolved chloroplast regions and 25 presumably single-copy nuclear markers identified from RNA-seq data. The phylogeny of the wild species inferred from the nuclear markers was fully resolved and largely congruent with morphology and classification. The incongruence between the nuclear and chloroplast trees suggested that there had been gene flow between the wild species. The comparison of nuclear and chloroplast phylogenies including cultivars showed that the cultivated tree peonies originated from homoploid hybridization among five wild species. Since the origin, thousands of cultivated varieties have spread worldwide, whereas four parental species are currently endangered or on the verge of extinction. The documentation of extensive homoploid hybridization involved in tree peony domestication provides new insights into the mechanisms underlying the origins of garden ornamentals and the way of preserving natural genetic resources through domestication.
PMCID: PMC4240985  PMID: 25377453
conservation; hybridization; Paeonia; RNA-seq; species tree
22.  Relationship between circulating tumor cells and tumor response in colorectal cancer patients treated with chemotherapy: a meta-analysis 
BMC Cancer  2014;14(1):976.
The prognostic value of circulating tumor cells (CTCs) in colorectal cancer (CRC) patients and their value in predicting tumor response to chemotherapy are controversial. The aim of this meta-analysis was to assess the prognostic and predictive value of CTCs in CRC patients treated with chemotherapy.
A comprehensive literature search for relevant studies was conducted in PubMed, Embase, the Cochrane Database, the Science Citation Index and the Ovid Database, and the reference lists of relevant studies were also perused for other relevant studies (up to April, 2014). Using the random-effects model in Stata software, version 12.0, the meta-analysis was performed using odds ratios (ORs), risk ratios (RRs), hazard ratios (HRs) and 95% confidence intervals (CIs) as effect measures. Subgroup and sensitivity analyses were also performed.
Thirteen eligible studies were included. Our meta-analysis indicated that the disease control rate was significantly higher in CRC patients with CTC-low compared with CTC-high (RR = 1.354, 95% CI [1.002–1.830], p = 0.048). CRC patients in the CTC-high group were significantly associated with poor progression-free survival (PFS; HR = 2.500, 95% CI [1.746–3.580], p < 0.001) and poor overall survival (OS; HR = 2.856, 95% CI [1.959–4.164], p < 0.001). Patients who converted from CTC-low to CTC-high or who were persistently CTC-high had a worse disease progression (OR = 27.088, 95% CI [4.960–147.919], p < 0.001), PFS (HR = 2.095, 95% CI [1.105–3.969], p = 0.023) and OS (HR = 3.604, 95% CI [2.096–6.197], p < 0.001) than patients who converted from CTC-high to CTC-low.
Our meta-analysis indicates that CTCs are associated with prognosis in CRC patients treated with chemotherapy. Moreover, CTCs could provide additional prognostic information to tumor radiographic imaging and might be used as a surrogate and novel predictive marker for the response to chemotherapy.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2407-14-976) contains supplementary material, which is available to authorized users.
PMCID: PMC4302148  PMID: 25519477
Circulating tumor cells; Colorectal cancer; Chemotherapy; Tumor response; Prognosis
23.  Crystal Structure of a Full-Length β-Catenin 
β-catenin plays essential roles in cell adhesion and Wnt signaling, while deregulation of β-catenin is associated with multiple diseases including cancers. Here, we report the crystal structures of full-length zebrafish β-catenin and a human β-catenin fragment that contains both the armadillo repeat and the C-terminal domains. Our structures reveal that the N-terminal region of the C-terminal domain, a key component of the C-terminal transactivation domain, forms a long α helix that packs on the C-terminal end of the armadillo repeat domain, and thus forms part of the β-catenin superhelical core. The existence of this helix redefines our view of interactions of β-catenin with some of its critical partners, including ICAT and Chibby, which may form extensive interactions with this C-terminal domain α helix. Our crystallographic and NMR studies also suggest that the unstructured N-terminal and C-terminal tails interact with the ordered armadillo repeat domain in a dynamic and variable manner.
PMCID: PMC4267759  PMID: 18334222
24.  Investigation of a new acetogen isolated from an enrichment of the tammar wallaby forestomach 
BMC Microbiology  2014;14(1):314.
Forestomach fermentation in Australian marsupials such as wallabies and kangaroos, though analogous to rumen fermentation, results in lower methane emissions. Insights into hydrogenotrophy in these systems could help in devising strategies to reduce ruminal methanogenesis. Reductive acetogenesis may be a significant hydrogen sink in these systems and previous molecular analyses have revealed a novel diversity of putative acetogens in the tammar wallaby forestomach.
Methanogen-inhibited enrichment cultures prepared from tammar wallaby forestomach contents consumed hydrogen and produced primarily acetate. Functional gene (formyltetrahydrofolate synthetase and acetyl-CoA synthase) analyses revealed a restricted diversity of Clostridiales species as the putative acetogens in the cultures. A new acetogen (growth on H2/CO2 with acetate as primary end product) designated isolate TWA4, was obtained from the cultures. Isolate TWA4 classified within the Lachnospiraceae and demonstrated >97% rrs identity to previously isolated kangaroo acetogens. Isolate TWA4 was a potent hydrogenotroph and demonstrated excellent mixotrophic growth (concomitant consumption of hydrogen during heterotrophic growth) with glycerol. Mixotrophic growth of isolate TWA4 on glycerol resulted in increased cell densities and acetate production compared to autotrophic growth. Co-cultures with an autotrophic methanogen Methanobrevibacter smithii revealed that isolate TWA4 performed reductive acetogenesis under high hydrogen concentration (>5 mM), but not at low concentrations. Under heterotrophic growth conditions, isolate TWA4 did not significantly stimulate methanogenesis in a co-culture with M. smithii contrary to the expectation for organisms growing fermentatively.
The unique properties of tammar wallaby acetogens might be contributing factors to reduced methanogen numbers and methane emissions from tammar wallaby forestomach fermentation, compared to ruminal fermentation. The macropod forestomach may be a useful source of acetogens for future strategies to reduce methane emissions from ruminants, particularly if these strategies also include some level of methane suppression and/or acetogen stimulation, for example by harnessing mixotrophic growth capabilities
Electronic supplementary material
The online version of this article (doi:10.1186/s12866-014-0314-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4275979  PMID: 25495654
Acetogen; Acetogenesis; Tammar wallaby; Rumen; Methanogenesis
25.  Aldosterone synthase inhibition: cardiorenal protection in animal disease models and translation of hormonal effects to human subjects 
Aldosterone synthase inhibition provides the potential to attenuate both the mineralocorticoid receptor-dependent and independent actions of aldosterone. In vitro studies with recombinant human enzymes showed LCI699 to be a potent, reversible, competitive inhibitor of aldosterone synthase (Ki = 1.4 ± 0.2 nmol/L in humans) with relative selectivity over 11β-hydroxylase.
Hormonal effects of orally administered LCI699 were examined in rat and monkey in vivo models of adrenocorticotropic hormone (ACTH) and angiotensin-II-stimulated aldosterone release, and were compared with the mineralocorticoid receptor antagonist eplerenone in a randomized, placebo-controlled study conducted in 99 healthy human subjects. The effects of LCI699 and eplerenone on cardiac and renal sequelae of aldosterone excess were investigated in a double-transgenic rat (dTG rat) model overexpressing human renin and angiotensinogen.
Rat and monkey in vivo models of stimulated aldosterone release predicted human dose– and exposure–response relationships, but overestimated the selectivity of LCI699 in humans. In the dTG rat model, LCI699 dose-dependently blocked increases in aldosterone, prevented development of cardiac and renal functional abnormalities independent of blood pressure changes, and prolonged survival. Eplerenone prolonged survival to a similar extent, but was less effective in preventing cardiac and renal damage. In healthy human subjects, LCI699 0.5 mg selectively reduced plasma and 24 h urinary aldosterone by 49 ± 3% and 39 ± 6% respectively (Day 1, mean ± SEM; P < 0.001 vs placebo), which was associated with natriuresis and an increase in plasma renin activity. Doses of LCI699 greater than 1 mg inhibited basal and ACTH-stimulated cortisol. Eplerenone 100 mg increased plasma and 24 h urinary aldosterone while stimulating natriuresis and increasing renin activity. In contrast to eplerenone, LCI699 increased the aldosterone precursor 11-deoxycorticosterone and urinary potassium excretion.
These results provide new insights into the cardiac and renal effects of inhibiting aldosterone synthase in experimental models and translation of the hormonal effects to humans. Selective inhibition of aldosterone synthase appears to be a promising approach to treat diseases associated with aldosterone excess.
Electronic supplementary material
The online version of this article (doi:10.1186/s12967-014-0340-9) contains supplementary material, which is available to authorized users.
PMCID: PMC4301837  PMID: 25491597
Aldosterone; Cortisol; Cushing’s disease; Double-transgenic rat; Eplerenone; Mineralocorticoid; Translational research

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