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1.  IL-17 response mediates acute lung injury induced by the 2009 Pandemic Influenza A (H1N1) Virus 
Cell Research  2011;22(3):528-538.
The 2009 flu pandemic involved the emergence of a new strain of a swine-origin H1N1 influenza virus (S-OIV H1N1) that infected almost every country in the world. Most infections resulted in respiratory illness and some severe cases resulted in acute lung injury. In this report, we are the first to describe a mouse model of S-OIV virus infection with acute lung injury and immune responses that reflect human clinical disease. The clinical efficacy of the antiviral oseltamivir (Tamiflu) administered in the early stages of S-OIV H1N1 infection was confirmed in the mouse model. Moreover, elevated levels of IL-17, Th-17 mediators and IL-17-responsive cytokines were found in serum samples of S-OIV-infected patients in Beijing. IL-17 deficiency or treatment with monoclonal antibodies against IL-17-ameliorated acute lung injury induced by the S-OIV H1N1 virus in mice. These results suggest that IL-17 plays an important role in S-OIV-induced acute lung injury and that monoclonal antibodies against IL-17 could be useful as a potential therapeutic remedy for future S-OIV H1N1 pandemics.
doi:10.1038/cr.2011.165
PMCID: PMC3292301  PMID: 22025253
cytokine; acute lung injury; S-OIV H1N1
3.  Large Electric Field–Enhanced–Hardness Effect in a SiO2 Film 
Scientific Reports  2014;4:4523.
Silicon dioxide films are extensively used in nano and micro–electromechanical systems. Here we studied the influence of an external electric field on the mechanical properties of a SiO2 film by using nanoindentation technique of atomic force microscopy (AFM) and friction force microscopy (FFM). A giant augmentation of the relative elastic modulus was observed by increasing the localized electric field. A slight decrease in friction coefficients was also clearly observed by using FFM with the increase of applied tip voltage. The reduction of the friction coefficients is consistent with the great enhancement of sample hardness by considering the indentation–induced deformation during the friction measurements.
doi:10.1038/srep04523
PMCID: PMC3970131  PMID: 24681517
4.  Short Hairpin RNA against PTEN Enhances Regenerative Growth of Corticospinal Tract Axons after Spinal Cord Injury 
The Journal of Neuroscience  2013;33(39):15350-15361.
Developing approaches to promote the regeneration of descending supraspinal axons represents an ideal strategy for rebuilding neuronal circuits to improve functional recovery after spinal cord injury (SCI). Our previous studies demonstrated that genetic deletion of phosphatase and tensin homolog (PTEN) in mouse corticospinal neurons reactivates their regenerative capacity, resulting in significant regeneration of corticospinal tract (CST) axons after SCI. However, it is unknown whether nongenetic methods of suppressing PTEN have similar effects and how regenerating axons interact with the extrinsic environment. Herein, we show that suppressing PTEN expression with short-hairpin RNA (shRNA) promotes the regeneration of injured CST axons, and these axons form anatomical synapses in appropriate areas of the cord caudal to the lesion. Importantly, this model of increased CST regrowth enables the analysis of extrinsic regulators of CST regeneration in vivo. We find that regenerating axons avoid dense clusters of fibroblasts and macrophages in the lesion, suggesting that these cell types might be key inhibitors of axon regeneration. Furthermore, most regenerating axons cross the lesion in association with astrocytes, indicating that these cells might be important for providing a permissive bridge for axon regeneration. Lineage analysis reveals that these bridge-forming astrocytes are not derived from ependymal stem cells within the spinal cord, suggesting that they are more likely derived from a subset of mature astrocytes. Overall, this study reveals insights into the critical extrinsic and intrinsic regulators of axon regeneration and establishes shRNA as a viable means to manipulate these regulators and translate findings into other mammalian models.
doi:10.1523/JNEUROSCI.2510-13.2013
PMCID: PMC3782617  PMID: 24068802
5.  MAVS-MKK7-JNK2 Defines a Novel Apoptotic Signaling Pathway during Viral Infection 
PLoS Pathogens  2014;10(3):e1004020.
Viral infection induces innate immunity and apoptosis. Apoptosis is an effective means to sacrifice virus-infected host cells and therefore restrict the spread of pathogens. However, the underlying mechanisms of this process are still poorly understood. Here, we show that the mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for SeV (Sendai virus)-induced apoptosis. MAVS specifically activates c-Jun N-terminal kinase 2 (JNK2) but not other MAP kinases. Jnk2−/− cells, but not Jnk1−/− cells, are unable to initiate virus-induced apoptosis and SeV further fails to trigger apoptosis in MAPK kinase 7 (MKK7) knockout (Mkk7−/−) cells. Mechanistically, MAVS recruits MKK7 onto mitochondria via its 3D domain, which subsequently phosphorylates JNK2 and thus activates the apoptosis pathway. Consistently, Jnk2−/− mice, but not Jnk1−/− mice, display marked inflammatory injury in lung and liver after viral challenge. Collectively, we have identified a novel signaling pathway, involving MAVS-MKK7-JNK2, which mediates virus-induced apoptosis and highlights the indispensable role of mitochondrial outer membrane in host defenses.
Author Summary
The mitochondrial antiviral signaling protein (MAVS/VISA/Cardif/IPS-1) is critical for the innate immune response during viral infection, and its function has been well documented in mediating type I interferon production. In this study, we revealed the essential role of MAVS in virus-induced apoptosis, independent of Retinoic acid-Inducible Gene I (RIG-I) signaling. Upon viral infection, MAVS recruits MKK7 onto mitochondria, followed by MKK7 induced activation of JNK2, which subsequently initiates apoptosis. Importantly, we have clearly differentiated the roles of JNK2 versus JNK1, and MKK7 versus MKK4 in virus-induced apoptosis. Thus, we define a novel apoptotic signaling pathway, involving MAVS-MKK7-JNK2, which sheds a new perspective on the crosstalk between the antiviral and apoptotic signaling pathways in innate immunity.
doi:10.1371/journal.ppat.1004020
PMCID: PMC3961361  PMID: 24651600
6.  The Integrative Method “Suture Dragging and Simplified Vacuum Assisted Therapy” for Complex Pilonidal Sinus Disease 
Case Reports in Surgery  2014;2014:425497.
Complex and recurrent pilonidal sinuses are best treated with surgery. Different surgical modalities as complete excision of the pilonidal sinus leave the wound open or procedures like closing the wound with or without reconstructive flap are widely used. The open procedure is radical but may cause broad excision and prolonged morbidity, while risk of infection and rate of recurrence are higher in the closed techniques. Traditional Chinese surgical treatments are less invasive and more effective; they have been used to treat sinus and fistula disease successfully. In this case report, we have described a male adolescent with complex pilonidal sinus, who received traditional Chinese surgical treatment combined with modern wound healing technique. He recovered completely with short hospitalization, good tolerance, less pain, and scarring. Therefore, we recommend using this integrative method to treat complex pilonidal sinus disease.
doi:10.1155/2014/425497
PMCID: PMC3971488  PMID: 24716076
7.  Choice of Initial Antiepileptic Drug for Older Veterans: Possible Pharmacokinetic Drug Interactions With Existing Medications 
Objectives
Identify clinically-meaningful potential drug-drug interactions with antiepileptic drugs (AED-PDI), the AEDs and co-administered drugs commonly associated with AED-PDI, and characteristics of patients with increased likelihood of AED-PDI exposure.
Design
Five-year retrospective cohort study of veterans with new-onset epilepsy.
Setting
National VA and Medicare databases.
Participants
Veterans age 66 years and older with a new diagnosis of epilepsy between October 1, 1999-September 30, 2004 (N=9,682).
Measurements
We restricted AED-PDI to clinically-meaningful potential drug interactions identified by prior literature review. AED-PDI were identified using participants' date of initial AED prescription and overlapping concomitant medications. Logistic regression analysis identified factors associated with AED-PDI including demographic characteristics, chronic disease states and diagnostic setting.
Results
AED-PDI exposure was found in 45.5% (4,406/9,682); phenytoin, a drug with many potential drug interactions, was the most commonly prescribed AED. Cardiovascular drugs, lipid-lowering medications and psychotropic agents were the most commonly co-administered AED-PDI medications. Individuals at higher likelihood of AED-PDI exposure had 1) hypertension (OR=1.46, 99% CI 1.24-1.82), 2) hypercholesterolemia (OR=1.40, 99% CI 1.24-1.57) and 3) were diagnosed in emergency or primary care vs. Neurology settings (emergency OR: 1.30 99% CI=1.08-1.58; primary care OR: 1.29 99% CI 1.12-1.49).
Conclusion
Exposure to AED-PDI was substantial, but less common in epilepsy patients diagnosed in a neurology setting. Because potential outcomes associated with AED-PDI include stroke and myocardial infarction in a population already at elevated risk, clinicians should closely monitor blood pressure, coagulation, and lipid measures to minimize adverse effects of AED-PDI. Interventions to reduce AED-PDI may improve patient outcomes.
doi:10.1111/j.1532-5415.2010.02732.x
PMCID: PMC3940350  PMID: 20398114
drug-drug interaction; epilepsy; geriatrics; antiepileptic drugs
8.  Rapamycin promoted thrombosis and platelet adhesion to endothelial cells by inducing membrane remodeling 
BMC Cell Biology  2014;15:7.
Background
Recently, evidence indicated that the rapamycin-eluting stent which was used worldwide may contribute to an increased risk for thrombosis. On the contrary, other researchers found it was safe. Thus, it is necessary to clarify the effect of rapamycin on thrombosis and the corresponding mechanisms.
Results
The effects of rapamycin in vivo were evaluated by modified deep vein thrombosis animal model. The platelets were from healthy volunteers and the platelet-endothelium (purchased from ATCC) adhesion in cultured endothelial cells was assessed. Membrane rufflings in endothelial cells were examined by confocal and electron microscope. Thrombus formation increased in rats that were injected with rapamycin. Electron microscope analysis exhibited microvilli on the rapamycin-treated endothelium in rats. Rapamycin enhanced membrane ruffling in human umbilical vein endothelial cells (HUVECs) and adhesion of platelets to HUVECs. The platelet-HUVECs adhesion was attenuated when cells were treated with cytochalacin B. Inhibition of autophagy by 3-methyladenine led to suppression of membrane ruffles in HUVECs and augmentation of platelet-endothelial adhesion.
Conclusions
In conclusion, we found that endothelial membrane remodeling induced by rapamycin is crucial for the adhesion of platelets to endothelial cells and thereby for thrombosis in vivo, and that the endothelial membrane remodeling is autophagy dependent.
doi:10.1186/1471-2121-15-7
PMCID: PMC3936831  PMID: 24564184
Thrombosis; Membrane remodeling; Endothelial cell; Platelet
9.  Vitamin D deficiency and risk of acute lung injury in severe sepsis and severe trauma: a case-control study 
Background
The aim of this study was to determine the association between 25-hydroxyvitamin D (25-OHD) levels at the onset of critical illness and the development of acute lung injury/acute respiratory distress syndrome (ALI/ARDS) in patients with sepsis or trauma.
Methods
We performed two nested case-control studies of 478 patients with sepsis and trauma with or without ALI/ARDS admitted to the medical, surgical and trauma ICUs of a tertiary-care center. Cases consisted of patients with either sepsis or trauma and ALI/ARDS; controls consisted of equivalent numbers of matched patients with either sepsis or trauma alone. We measured serum 25-OHD levels the morning after ICU admission and used multivariable regression to assess the relationship between 25-OHD and diagnosis of ALI/ARDS during the first four ICU days, controlling for age, gender, diabetes, smoking status and season.
Results
25-OHD levels did not differ between cases with ALI/ARDS and controls in either the sepsis or trauma cohorts. Using a conditional logistic regression model, sepsis patients during the winter season with higher 25-OHD levels were more likely to develop acute lung injury (odds ratio 1.68, 95% confidence interval of 1.05 to 2.69, P = 0.03). This association did not hold for the trauma cohort in either season. Sepsis and trauma patients had a lower risk of hospital mortality at higher 25-OHD levels but neither relationship reached significance. Higher one-year mortality after trauma was associated with lower 25-OHD levels (HR 0.50, CI 0.35,0.72 P = 0.001).
Conclusions
Serum 25-OHD measured early after admission to intensive care is not associated with the development of acute lung injury, hospital or one-year mortality in critically ill patients with sepsis although lower 25-OHD levels were associated with higher one-year mortality in patients with severe trauma.
doi:10.1186/2110-5820-4-5
PMCID: PMC3944729  PMID: 24559079
Vitamin D; Sepsis; Trauma; Acute lung injury; Critical illness
10.  Clinical Presentation of a Patient with Congenital Cutis Laxa and Abnormal Thyroid Hormone Levels 
Case Reports in Dermatology  2014;6(1):43-48.
We describe a case of generalized cutis laxa (CL) in a 7-year-old female child. At 2 months of age, she was found to have a hoarse voice, and at 3 years, she was much smaller than her peers. Her aging face and short stature caught our attention, and the treatment of the patient was accepted by our hospital. She underwent a thorough examination. X-ray of the wrist bone showed a markedly delayed bone age, and thyroid function tests revealed significantly elevated free triiodothyronine 3 and free thyroxine 4 levels, but thyrotropin was within the normal range. Thyroid dysfunction and CL can be associated with lagged growth and development. Whether her abnormal development was due to thyroid dysfunction or CL could not be ascertained. CL is possibly more complex than it has been supposed so far, and is therefore worth to be further studied.
doi:10.1159/000360125
PMCID: PMC3975211
Congenital cutis laxa; Thyroid function; Growth retardation
11.  Puerarin Attenuates Cerebral Damage by Improving Cerebral Microcirculation in Spontaneously Hypertensive Rats 
Puerariae Lobatae Radix (Gegen in Chinese) is the dried root of Pueraria lobata, a semiwoody, perennial, and leguminous vine native to China. Puerarin is one of the effective components of isoflavones isolated from the root of Pueraria lobata. Previous studies showed that extracts derived from the root of Pueraria lobata possessed antihypertensive effect. Our study is to investigate whether puerarin contributes to prevention of stroke by improving cerebral microcirculation in rats. Materials and Methods. Video microscopy and laser Doppler perfusion imaging on the pia mater were used to measure the diameter of microvessel and blood perfusion in 12-week old spontaneously hypertensive rats (SHRs) and age-matched normotensive WKY rats. Histological alterations were observed by hematoxylin and eosin staining, and microvessel density in cerebral tissue was measured by immunohistochemical analysis with anti-Factor VIII antibody. Cell proliferation was detected by [3H]-TdR incorporation, and activities of p42/44 mitogen activated protein kinases (p42/44 MAPKs) were detected by western blot analysis in cultured cerebral microvascular endothelial cells (MECs). Results. Intravenous injection of puerarin relaxed arterioles and increased the blood flow perfusion in the pia mater in SHRs. Puerarin treatment for 14 days reduced the blood pressure to a normal level in SHRs (P < 0.05) and increased the arteriole diameter in the pia mater significantly as compared with vehicle treatment. Arteriole remodeling, edema, and ischemia in cerebral tissue were attenuated in puerarin-treated SHRs. Microvessel density in cerebral tissue was greater with puerarin than with vehicle treatment. Puerarin-treated MECs showed greater proliferation and p42/44 MAPKs activities than vehicle treatment. Conclusions. Puerarin possesses effects of antihypertension and stroke prevention by improved microcirculation in SHRs, which results from the increase in cerebral blood perfusion both by arteriole relaxation and p42/44 MAPKs-mediated angiogenesis.
doi:10.1155/2014/408501
PMCID: PMC3971448  PMID: 24715930
12.  Grapevine microRNAs responsive to exogenous gibberellin 
BMC Genomics  2014;15:111.
Background
MicroRNAs (miRNAs), involving in various biological and metabolic processes, have been discovered and analyzed in quite a number of plants species, such as Arabidopsis, rice and other plants. However, there have been few reports about grapevine miRNAs in response to gibberelline (GA3).
Results
Solexa technology was used to sequence small RNA libraries constructed from grapevine berries treated with GA3 and the control. A total of 122 known and 90 novel grapevine miRNAs (Vvi-miRNAs) were identified. Totally, 137 ones were found to be clearly responsive to GA3, among which 58 were down-regulated, 51 were up-regulated, 21 could only be detected in the control, and seven were only detected in the treatment. Subsequently, we found that 28 of them were differentially regulated by GA3, with 12 conserved and 16 novel Vvi-miRNAs, based on the analysis of qRT-PCR essays. There existed some consistency in expression levels of GA3-responsive Vvi-miRNAs between high throughput sequencing and qRT-PCR essays. In addition, 117 target genes for 29 novel miRNAs were predicted.
Conclusions
Deep sequencing of short RNAs from grapevine berries treated with GA3 and the control identified 137 GA3-responsive miRNAs, among which 28 exhibited different expression profiles of response to GA3 in the diverse developmental stages of grapevine berries. These identified Vvi-miRNAs might be involved in the grapevine berry development and response to environmental stresses.
doi:10.1186/1471-2164-15-111
PMCID: PMC3937062  PMID: 24507455
Grapevine; Berry; microRNAs; Exogenous gibberellin; High throughput sequencing
13.  Proteomic Profiling of Tissue-Engineered Blood Vessel Walls Constructed by Adipose-Derived Stem Cells 
Tissue Engineering. Part A  2012;19(3-4):415-425.
Adipose-derived stem cells (ASCs) can differentiate into smooth muscle cells and have been engineered into elastic small diameter blood vessel walls in vitro. However, the mechanisms involved in the development of three-dimensional (3D) vascular tissue remain poorly understood. The present study analyzed protein expression profiles of engineered blood vessel walls constructed by human ASCs using methods of two-dimensional gel electrophoresis (2DE) and mass spectrometry (MS). These results were compared to normal arterial walls. A total of 1701±15 and 1265±26 protein spots from normal and engineered blood vessel wall extractions were detected by 2DE, respectively. A total of 20 spots with at least 2.0-fold changes in expression were identified, and 38 differently expressed proteins were identified by 2D electrophoresis and ion trap MS. These proteins were classified into seven functional categories: cellular organization, energy, signaling pathway, enzyme, anchored protein, cell apoptosis/defense, and others. These results demonstrated that 2DE, followed by ion trap MS, could be successfully utilized to characterize the proteome of vascular tissue, including tissue-engineered vessels. The method could also be employed to achieve a better understanding of differentiated smooth muscle protein expression in vitro. These results provide a basis for comparative studies of protein expression in vascular smooth muscles of different origin and could provide a better understanding of the mechanisms of action needed for constructing blood vessels that exhibit properties consistent with normal blood vessels.
doi:10.1089/ten.tea.2011.0532
PMCID: PMC3542882  PMID: 22963350
14.  Comparison of Patients Hospitalized With Influenza A Subtypes H7N9, H5N1, and 2009 Pandemic H1N1 
Hospitalization with H7N9 virus infection is associated with older age and chronic heart disease, and patients have a longer duration of hospitalization than patients with H5N1 or pH1N1. This suggests that host factors are an important contributor to H7N9 severity.
Background. Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections.
Methods. We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population.
Results. The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24–17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154).
Conclusions. The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.
doi:10.1093/cid/ciu053
PMCID: PMC3967826  PMID: 24488975
influenza A(H7N9); influenza A(H5N1); clinical epidemiology
15.  Polymerization or Cyclic Dimerization: Solvent Dependent Homo-Coupling of Terminal Alkynes at HOPG Surface 
Scientific Reports  2014;4:3899.
Surface reactivity has become one of the most important issues in surface chemistry over the past few years. In this work, we, for the first time, have investigated the homo-coupling of a special terminal alkyne derivative on the highly oriented pyrolitic graphite (HOPG) surface. Using scanning tunneling microscopy (STM) technique, we have found that such coupling reaction seriously depends on the supramolecular assembly of the monomer on the studied substrate, whereas the latter appears an obvious solvent effect. As a result, the reaction in our system undergoes polymerization and cyclic dimerization process in 1-phenyloctane and 1,2,4-trichlorobenzene, respectively. That is to say, the solvent effect can be extended from the two-dimensional (2D) supramolecular self-assembly to surface chemical reactions, and the selective homo-coupling has been successfully achieved at the solid/liquid interface.
doi:10.1038/srep03899
PMCID: PMC3904147  PMID: 24469357
16.  Reconstruction of Transcription Regulatory Networks by Stability-Based Network Component Analysis 
Reliable inference of transcription regulatory networks is still a challenging task in the field of computational biology. Network component analysis (NCA) has become a powerful scheme to uncover the networks behind complex biological processes, especially when gene expression data is integrated with binding motif information. However, the performance of NCA is impaired by the high rate of false connections in binding motif information and the high level of noise in gene expression data. Moreover, in real applications such as cancer research, the performance of NCA in simultaneously analyzing multiple candidate transcription factors (TFs) is further limited by the small sample number of gene expression data. In this paper, we propose a novel scheme, stability-based NCA, to overcome the above-mentioned problems by addressing the inconsistency between gene expression data and motif binding information (i.e., prior network knowledge). This method introduces small perturbations on prior network knowledge and utilizes the variation of estimated TF activities to reflect the stability of TF activities. Such a scheme is less limited by the sample size and especially capable to identify condition-specific TFs and their target genes. Experiment results on both simulation data and real breast cancer data demonstrate the efficiency and robustness of the proposed method.
PMCID: PMC3652899  PMID: 24407294
transcription regulatory network; network component analysis; stability analysis; transcription factor activity; target genes identification
17.  Genome-Wide Analysis of DNA Methylation in Five Tissues of Zhikong Scallop, Chlamys farreri 
PLoS ONE  2014;9(1):e86232.
DNA methylation plays a vital role in tissue development and differentiation in eukaryotes. Epigenetic studies have been seldom conducted in the extremely diverse and evolutionarily highly successful bilaterian lineage Mollusca. In the present study, we conducted the genome-wide profiling of DNA methylation for five tissues of a bivalve mollusc, Chlamys farreri using the methylation-sensitive amplification polymorphism (MSAP) technique. The methylation levels were quite similar among tissues, ranging from 20.9% to 21.7%. CG methylation was the dominant type (14.9%–16.5%) in the C. farreri genome, but CHG methylation also accounted for a substantial fraction of total methylation (5.1%–6.3%). Relatively high methylation diversity was observed within tissues. Methylation differentiation between tissues was evaluated and 460 tissue-specific epiloci were identified. Kidney differs from the other tissues in DNA methylation profiles. Our study presents the first look at the tissue-specific DNA methylation patterns in a bivalve mollusc and represents an initial step towards understanding of epigenetic regulatory mechanism underlying tissue development and differentiation in bivalves.
doi:10.1371/journal.pone.0086232
PMCID: PMC3891877  PMID: 24454962
18.  Allyl Isothiocyanate Increases MRP1 Function and Expression in a Human Bronchial Epithelial Cell Line 
Multidrug resistance-associated protein 1 (MRP1), a member of the ATP-binding cassette (ABC) superfamily of transporters, plays an important role in normal lung physiology by protecting cells against oxidative stress and toxic xenobiotics. The present study investigates the effects of allyl isothiocyanate (AITC) on MRP1 mRNA and MRP1 protein expression and transporter activity in the immortalised human bronchial epithelial cell line 16HBE14o-. MRP1 mRNA and MRP1 protein expression in 16HBE14o- cells that were treated with allyl isothiocyanate were analysed by real-time PCR assay and Western blotting. The transport of carboxyfluorescein, a known MRP1 substrate, was measured by functional flow cytometry to evaluate MRP1 activity. Treatment with AITC at concentrations of 5–40 μM increased MRP1 protein levels in a concentration-dependent manner. AITC treatments at concentrations of 1–40 μM caused concentration-dependent increases in MRP1 mRNA levels that were up to seven times greater than the levels found in control cells. Finally, AITC treatment at concentrations of 5–40 μM significantly increased MRP1-dependent efflux in 16HBE14o- cells. These results suggest that AITC can increase the expression and activity of MRP1 in 16HBE14o- cells in a concentration-dependent manner. The upregulation of MRP1 activity and expression by AITC could produce therapeutic effects in the treatment of lung disease.
doi:10.1155/2014/547379
PMCID: PMC3942196  PMID: 24672635
19.  Correction: Forever Love: The Hitherto Earliest Record of Copulating Insects from the Middle Jurassic of China 
PLoS ONE  2014;9(1):10.1371/annotation/54a6126f-eed2-456e-ba80-5a1fd2d78e8e.
doi:10.1371/annotation/54a6126f-eed2-456e-ba80-5a1fd2d78e8e
PMCID: PMC3882207
20.  Specific Multilocus Variable-Number Tandem-Repeat Analysis Genotypes of Mycoplasma pneumoniae Are Associated with Diseases Severity and Macrolide Susceptibility 
PLoS ONE  2013;8(12):e82174.
Clinical relevance of multilocus variable-number tandem-repeat (VNTR) analysis (MLVA) in patients with community-acquired pneumonia (CAP) by Mycoplasma pneumoniae (M. pneumoniae) is unknown. A multi-center, prospective study was conducted from November 2010 to April 2012. Nine hundred and fifty-four CAP patients were consecutively enrolled. M. pneumoniae clinical isolates were obtained from throat swabs. MLVA typing was applied to all isolates. Comparison of pneumonia severity index (PSI) and clinical features among patients infected with different MLVA types of M. pneumoniae were conducted. One hundred and thirty-six patients were positive with M. pneumoniae culture. The clinical isolates were clustered into 18 MLVA types. One hundred and fourteen (88.3%) isolates were resistant to macrolide, covering major MLVA types. The macrolide non-resistant rate of M. pneumoniae isolates with Mpn13-14-15-16 profile of 3-5-6-2 was significantly higher than that of other types (p≤0.001). Patients infected with types U (5-4-5-7-2) and J (3-4-5-7-2) had significantly higher PSI scores (p<0.001) and longer total duration of cough (p = 0.011). Therefore it seems that there is a correlation between certain MLVA types and clinical severity of disease and the presence of macrolide resistance.
doi:10.1371/journal.pone.0082174
PMCID: PMC3867324  PMID: 24367502
21.  Rivaroxaban for the treatment of symptomatic deep-vein thrombosis and pulmonary embolism in Chinese patients: a subgroup analysis of the EINSTEIN DVT and PE studies 
Thrombosis Journal  2013;11:25.
Background
The worldwide EINSTEIN DVT and EINSTEIN PE studies randomized 8282 patients with acute symptomatic deep-vein thrombosis (DVT) and/or pulmonary embolism (PE) and, for the first time in trials in this setting, included patients in China. This analysis evaluates the results of these studies in this subgroup of patients.
Methods
A total of 439 Chinese patients who had acute symptomatic DVT (n=211), or PE with or without DVT (n=228), were randomized to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or standard therapy of enoxaparin overlapping with and followed by an adjusted-dose vitamin K antagonist, for 3, 6, or 12 months. The primary efficacy outcome was symptomatic recurrent venous thromboembolism. The principal safety outcome was major or non-major clinically relevant bleeding.
Results
The primary efficacy outcome occurred in seven (3.2%) of the 220 patients in the rivaroxaban group and in seven (3.2%) of the 219 patients in the standard-therapy group (hazard ratio, 1.04; 95% confidence interval 0.36–3.0; p=0.94). The principal safety outcome occurred in 13 (5.9%) patients in the rivaroxaban group and in 20 (9.2%) patients in the standard-therapy group (hazard ratio, 0.63; 95% confidence interval 0.31–1.26; p=0.19). Major bleeding was observed in no patients in the rivaroxaban group and in five (2.3%) patients in the standard-therapy group. In fragile patients (defined as age >75 years, creatinine clearance <50 mL/min, and/or body weight ≤50 kg), the principal safety outcome occurred in four (8.9%) of the 45 patients who received rivaroxaban compared with seven (15.2%) of the 46 patients who received standard therapy.
Conclusions
In Chinese patients with acute symptomatic DVT and/or PE, rivaroxaban was as efficacious as enoxaparin followed by vitamin K antagonist therapy, with a similar safety profile. The relative efficacy and safety of rivaroxaban compared with enoxaparin/vitamin K antagonist were consistent with that found in the rest of the world.
Trial registration number
EINSTEIN PE, ClinicalTrials.gov NCT00439777; EINSTEIN DVT, ClinicalTrials.gov NCT00440193
doi:10.1186/1477-9560-11-25
PMCID: PMC3896794  PMID: 24341332
Rivaroxaban; Deep vein thrombosis; Pulmonary embolism; Venous thromboembolism; Vitamin K antagonist; Randomized trial
22.  The perinucleolar compartment associates with malignancy 
Frontiers in biology  2013;8(4):10.1007/s11515-013-1265-z.
The perinucleolar compartment (PNC) is a unique nuclear substructure, forming predominantly in cancer cells both in vitro and in vivo. PNC prevalence (percentage of cells containing at least one PNC) has been found to positively correlate with disease progression in several cancers (breast, ovarian, and colon). While there is a clear association between PNCs and cancer, the molecular function of the PNC remains unclear. Here we summarize the current understanding of the association of PNCs with cancer and its possible functions in cancer cells.
doi:10.1007/s11515-013-1265-z
PMCID: PMC3862354  PMID: 24348523
PNC; cancer; nuclear substructure; gene expression regulation; structure and function
23.  LncRNAs Expression in Preeclampsia Placenta Reveals the Potential Role of LncRNAs Contributing to Preeclampsia Pathogenesis 
PLoS ONE  2013;8(11):e81437.
Background
Long non-coding RNAs (lncRNAs) are an important class of pervasive genes involved in a variety of biological functions. They are aberrantly expressed in many types of diseases. In this study, we aimed to investigate the lncRNA profiles in preeclampsia. Preeclampsia has been observed in patients with molar pregnancy where a fetus is absent, which demonstrate that the placenta is sufficient to cause this condition. Thus, we analyzed the lncRNA profiles in preeclampsia placentas.
Methodology/Principal Findings
In this study, we described the lncRNA profiles in six preeclampsia placentas (T) and five normal pregnancy placentas (N) using microarray. With abundant and varied probes accounting for 33,045 LncRNAs in our microarray, 28,443 lncRNAs that were expressed at a specific level were detected. From the data, we found 738 lncRNAs that were differentially expressed (≥1.5-fold-change) among preeclampsia placentas compared with controls. Coding-non-coding gene co-expression networks (CNC network) were constructed based on the correlation analysis between the differentially expressed lncRNAs and mRNAs. According to the CNC network and GO analysis of differentially expressed lncRNAs/mRNAs, we selected three lncRNAs to analyze the relationship between lncRNAs and preeclampsia. LOC391533, LOC284100, and CEACAMP8 were evaluated using qPCR in 40 preeclampsia placentas and 40 controls. These results revealed that three lncRNAs were aberrantly expressed in preeclampsia placentas compared with controls.
Conclusions/Significance
Our study is the first study to determine the genome-wide lncRNAs expression patterns in preeclampsia placenta using microarray. These results revealed that clusters of lncRNAs were aberrantly expressed in preeclampsia placenta compared with controls, which indicated that lncRNAs differentially expressed in preeclampsia placenta might play a partial or key role in preeclampsia development. Misregulation of LOC391533, LOC284100, and CEACAMP8 might contribute to the mechanism underlying preeclampsia. Taken together, this study may provide potential targets for the future treatment of preeclampsia and novel insights into preeclampsia biology.
doi:10.1371/journal.pone.0081437
PMCID: PMC3842959  PMID: 24312300
24.  Epitope analysis of anti-myeloperoxidase antibodies in propylthiouracil-induced antineutrophil cytoplasmic antibody-associated vasculitis 
Arthritis Research & Therapy  2013;15(6):R196.
Introduction
Increasing evidence has suggested that linear epitopes of antineutrophil cytoplasmic antibody (ANCA) directed to myeloperoxidase (MPO) might provide clues to the pathogenesis of propylthiouracil (PTU)-induced ANCA-associated vasculitis (AAV). This study mapped epitopes of MPO-ANCA in sera from patients with PTU-induced MPO-ANCA (with or without vasculitis) and primary AAV, aiming to analyze certain epitopes associated with the development of PTU-induced AAV.
Methods
Six recombinant linear fragments, covering the whole amino acid sequence of a single chain of MPO, were produced from Escherichia coli. Sera from 17 patients with PTU-induced AAV, 17 patients with PTU-induced MPO-ANCA but without clinical evidence of vasculitis, and 64 patients with primary AAV were collected at presentation. Of the 17 patients with PTU-induced AAV, 12 also had sera at remission. The epitope specificities were detected by enzyme-linked immunosorbent assay by using the recombinant fragments as solid-phase ligands.
Results
Compared with patients with PTU-induced MPO-ANCA but without clinical vasculitis, sera from PTU-induced AAV patients showed significantly higher reactivity against the H1 fragment of MPO (optical density values: 0.17 (0.10 to 0.35) versus 0.10 (0.04 to 0.21), P = 0.038) and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.026). Compared with sera from primary AAV patients, sera from PTU-induced AAV patients had significantly higher reactivity to the P fragment and the H4 fragment (47.1% versus 14.1% P < 0.001; 41.2% versus 14.1%, P = 0.034, respectively), and could recognize a significantly higher number of fragments (two (none to four) versus one (none to two), P = 0.013]. Among the 12 PTU-induced AAV patients with sequential samples, the number of fragments recognized in remission was significantly less than that in initial onset (two (none to four) versus none (none to 0.75), P < 0.001].
Conclusions
Linear epitopes of MPO molecules might be associated closely with PTU-induced AAV. In particular, the P and H4 fragments may be important epitopes in PTU-induced AAV.
doi:10.1186/ar4386
PMCID: PMC3979166  PMID: 24252385
25.  Triptolide Induces Growth Inhibition and Apoptosis of Human Laryngocarcinoma Cells by Enhancing p53 Activities and Suppressing E6-Mediated p53 Degradation 
PLoS ONE  2013;8(11):e80784.
Triptolide, an active compound extracted from Chinese herb Leigongteng (Tripterygium wilfordii Hook F.), shows a broad-spectrum of anticancer activity through its cytotoxicity. However, the efficacy of triptolide on laryngocarcinoma rarely been evaluated, and the mechanism by which triptolide-induced cellular apoptosis is still not well understood. In this study, we found that triptolide significantly inhibited the laryngocarcinoma HEp-2 cells proliferation, migration and survivability. Triptolide induces HEp-2 cell cycle arrest at the G1 phase and apoptosis through intrinsic and extrinsic pathways since both caspase-8 and -9 are activated. Moreover, triptolide enhances p53 expression by increasing its stability via down-regulation of E6 and E6AP. Increased p53 transactivates down-stream target genes to initiate apoptosis. In addition, we found that short time treatment with triptolide induced DNA damage, which was consistent with the increase in p53. Furthermore, the cytotoxicity of triptolide is decreased by p53 knockdown or use of caspases inhibitor. In conclusion, our results demonstrated that triptolide inhibits cell proliferation and induces apoptosis in laryngocarcinoma cells by enhancing p53 expression and activating p53 functions through induction of DNA damage and suppression of E6 mediated p53 degradation. These studies indicate that triptolide is a potential anti-laryngocarcinoma drug.
doi:10.1371/journal.pone.0080784
PMCID: PMC3828261  PMID: 24244715

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