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1.  MTA1 Promotes STAT3 Transcription and Pulmonary Metastasis in Breast Cancer 
Cancer research  2013;73(12):3761-3770.
Overexpression of the pro-metastatic chromatin modifier protein MTA1 in human cancer contributes to tumor aggressiveness, but the role of endogenous MTA1 in cancer has not been explored. Here we report the effects of selective genetic depletion of MTA1 in a physiologically relevant spontaneous mouse model of breast cancer pulmonary metastasis. We found that MTA1 acts as a mandatory modifier of breast-to-lung metastasis without effects on primary tumor formation. The underlying mechanism involved MTA1-dependent stimulation of STAT3 transcription through action on the MTA1/ STAT3/ Pol II coactivator complex, and in turn, on the expression and functions of STAT3 target genes including Twist1. Accordingly, we documented a positive correlation between levels of MTA1 and STAT3 in publicly available breast cancer data sets. Together, our findings reveal an essential modifying role of the physiologic level of MTA1 in supporting pulmonary metastasis of breast cancer.
doi:10.1158/0008-5472.CAN-12-3998
PMCID: PMC3686857  PMID: 23580571
MTA1; Coactivator; STAT3 Transcription; Metastasis
2.  Cdc42 and aging of hematopoietic stem cells 
Current opinion in hematology  2013;20(4):295-300.
Purpose of review
Hematopoietic stem cells (HSCs) continuously provide mature blood cells during the lifespan of a mammal. The functional decline in hematopoiesis in the elderly, which involves a progressive reduction in the immune response and an increased incidence of myeloid malignancy, is partly linked to HSC aging. Molecular mechanisms of HSC aging remain unclear, hindering rational approaches to slow or reverse the decline of HSC function with age. Identifying conditions under which aged HSCs become equivalent to young stem cells might result in treatments for age-associated imbalances in lymphopoiesis and myelopoiesis and in blood regeneration.
Recent findings
Aging of HSCs has been for a long time thought to be an irreversible process imprinted in stem cells due to the intrinsic nature of HSC aging. Mouse model studies have found that aging is associated with elevated activity of the Rho GTPase Cdc42 in HSCs that is causative for loss of polarity, altered epigenetic modifications and functional deficits of aged HSCs. The work suggests that inhibition of Cdc42 activity in aged HSCs may reverse a number of phenotypes associated with HSC aging.
Summary
Maintaining the regenerative capacity of organs or organ systems may be a useful way to ensure healthy aging. A defined set of features phenotypically separate young from aged HSCs. Aging of HSCs has been thought to be irreversible. Recent findings support the hypothesis that functional decline of aged HSCs may be reversible by pharmacological intervention of age altered signaling pathways and epigenetic modifications.
doi:10.1097/MOH.0b013e3283615aba
PMCID: PMC4057184  PMID: 23615056
aging; Cdc42; HSC; polarity; rejuvenation
3.  Effectiveness of pharmacist dosing adjustment for critically ill patients receiving continuous renal replacement therapy: a comparative study 
Background
The impact of continuous renal replacement therapy (CRRT) on drug removal is complicated; pharmacist dosing adjustment for these patients may be advantageous. This study aims to describe the development and implementation of pharmacist dosing adjustment for critically ill patients receiving CRRT and to examine the effectiveness of pharmacist interventions.
Methods
A comparative study was conducted in an intensive care unit (ICU) of a university-affiliated hospital. Patients receiving CRRT in the intervention group received specialized pharmacy dosing service from pharmacists, whereas patients in the no-intervention group received routine medical care without pharmacist involvement. The two phases were compared to evaluate the outcome of pharmacist dosing adjustment.
Results
The pharmacist carried out 233 dosing adjustment recommendations for patients receiving CRRT, and 212 (90.98%) of the recommendations were well accepted by the physicians. Changes in CRRT-related variables (n=144, 61.81%) were the most common risk factors for dosing errors, whereas antibiotics (n=168, 72.10%) were the medications most commonly associated with dosing errors. Pharmacist dosing adjustment resulted in a US$2,345.98 ICU cost savings per critically ill patient receiving CRRT. Suspected adverse drug events in the intervention group were significantly lower than those in the preintervention group (35 in 27 patients versus [vs] 18 in eleven patients, P<0.001). However, there was no significant difference between length of ICU stay and mortality after pharmacist dosing adjustment, which was 8.93 days vs 7.68 days (P=0.26) and 30.10% vs 27.36% (P=0.39), respectively.
Conclusion
Pharmacist dosing adjustment for patients receiving CRRT was well accepted by physicians, and was related with lower adverse drug event rates and ICU cost savings. These results may support the development of strategies to include a pharmacist in the multidisciplinary ICU team.
doi:10.2147/TCRM.S59187
PMCID: PMC4051794  PMID: 24940066
pharmacist interventions; drug dosing adjustment; adverse drug event; cost saving; CRRT
4.  Efficiency of Cell-Free and Cell-Associated Virus in Mucosal Transmission of Human Immunodeficiency Virus Type 1 and Simian Immunodeficiency Virus 
Journal of Virology  2013;87(24):13589-13597.
Effective strategies are needed to block mucosal transmission of human immunodeficiency virus type 1 (HIV-1). Here, we address a crucial question in HIV-1 pathogenesis: whether infected donor mononuclear cells or cell-free virus plays the more important role in initiating mucosal infection by HIV-1. This distinction is critical, as effective strategies for blocking cell-free and cell-associated virus transmission may be different. We describe a novel ex vivo model system that utilizes sealed human colonic mucosa explants and demonstrate in both the ex vivo model and in vivo using the rectal challenge model in rhesus monkeys that HIV-1-infected lymphocytes can transmit infection across the mucosa more efficiently than cell-free virus. These findings may have significant implications for our understanding of the pathogenesis of mucosal transmission of HIV-1 and for the development of strategies to prevent HIV-1 transmission.
doi:10.1128/JVI.03108-12
PMCID: PMC3838232  PMID: 24109227
5.  Mongolians core gut microbiota and its correlation with seasonal dietary changes 
Scientific Reports  2014;4:5001.
Historically, the Mongol Empire ranks among the world's largest contiguous empires, and the Mongolians developed their unique lifestyle and diet over thousands of years. In this study, the intestinal microbiota of Mongolians residing in Ulan Bator, TUW province and the Khentii pasturing area were studied using 454 pyrosequencing and q-PCR technology. We explored the impacts of lifestyle and seasonal dietary changes on the Mongolians' gut microbes. At the phylum level, the Mongolians's gut populations were marked by a dominance of Bacteroidetes (55.56%) and a low Firmicutes to Bacteroidetes ratio (0.71). Analysis based on the operational taxonomic unit (OTU) level revealed that the Mongolian core intestinal microbiota comprised the genera Prevotella, Bacteroides, Faecalibacterium, Ruminococcus, Subdoligranulum and Coprococcus. Urbanisation and life-style may have modified the compositions of the gut microbiota of Mongolians from Ulan Bator, TUW and Khentii. Based on a food frequency questionnaire, we found that the dietary structure was diverse and stable throughout the year in Ulan Bator and TUW, but was simple and varied during the year in Khentii. Accordingly, seasonal effects on intestinal microbiota were more distinct in Khentii residents than in TUW or Ulan Bator residents.
doi:10.1038/srep05001
PMCID: PMC4023135  PMID: 24833488
6.  Novel Determinants of Intestinal Colonization of Salmonella enterica Serotype Typhimurium Identified in Bovine Enteric Infection 
Infection and Immunity  2013;81(11):4311-4320.
Cattle are naturally infected with Salmonella enterica serotype Typhimurium and exhibit pathological features of enteric salmonellosis that closely resemble those in humans. Cattle are the most relevant model of gastrointestinal disease resulting from nontyphoidal Salmonella infection in an animal with an intact microbiota. We utilized this model to screen a library of targeted single-gene deletion mutants to identify novel genes of Salmonella Typhimurium required for survival during enteric infection. Fifty-four candidate mutants were strongly selected, including numerous mutations in genes known to be important for gastrointestinal survival of salmonellae. Three genes with previously unproven phenotypes in gastrointestinal infection were tested in bovine ligated ileal loops. Two of these mutants, STM3602 and STM3846, recapitulated the phenotype observed in the mutant pool. Complementation experiments successfully reversed the observed phenotypes, directly linking these genes to the colonization defects of the corresponding mutant strains. STM3602 encodes a putative transcriptional regulator that may be involved in phosphonate utilization, and STM3846 encodes a retron reverse transcriptase that produces a unique RNA-DNA hybrid molecule called multicopy single-stranded DNA. The genes identified in this study represent an exciting new class of virulence determinants for further mechanistic study to elucidate the strategies employed by Salmonella to survive within the small intestines of cattle.
doi:10.1128/IAI.00874-13
PMCID: PMC3811824  PMID: 24019407
7.  Chinese SLE Treatment and Research Group Registry: III. Association of Autoantibodies with Clinical Manifestations in Chinese Patients with Systemic Lupus Erythematosus 
Journal of Immunology Research  2014;2014:809389.
We investigated the characteristics of Chinese SLE patients by analyzing the association between specific autoantibodies and clinical manifestations of 2104 SLE patients from registry data of CSTAR cohort. Significant (P < 0.05) associations were found between anti-Sm antibody, anti-rRNP antibody, and malar rash; between anti-RNP antibody, anti-SSA antibody, and pulmonary arterial hypertension (PAH); between anti-SSB antibody and hematologic involvement; and between anti-dsDNA antibody and nephropathy. APL antibody was associated with hematologic involvement, interstitial lung disease, and a lower prevalence of oral ulcerations (P < 0.05). Associations were also found between anti-dsDNA antibody and a lower prevalence of photosensitivity, and between anti-SSA antibody and a lower prevalence of nephropathy (P < 0.05). Most of these findings were consistent with other studies in the literature but this study is the first report on the association between anti-SSA and a lower prevalence of nephropathy. The correlations of specific autoantibodies and clinical manifestations could provide clues for physicians to predict organ damages in SLE patients. We suggest that a thorough screening of autoantibodies should be carried out when the diagnosis of SLE is established, and repeated echocardiography annually in SLE patients with anti-RNP or anti-SSA antibody should be performed.
doi:10.1155/2014/809389
PMCID: PMC4017718  PMID: 24864270
8.  RhoA GTPase controls cytokinesis and programmed necrosis of hematopoietic progenitors 
The Journal of Experimental Medicine  2013;210(11):2371-2385.
The GTPase RhoA is required for the appropriate division and survival of hematopoietic progenitor cells.
Hematopoietic progenitor cells (HPCs) are central to hematopoiesis as they provide large numbers of lineage-defined blood cells necessary to sustain blood homeostasis. They are one of the most actively cycling somatic cells, and their precise control is critical for hematopoietic homeostasis. The small GTPase RhoA is an intracellular molecular switch that integrates cytokine, chemokine, and adhesion signals to coordinate multiple context-dependent cellular processes. By using a RhoA conditional knockout mouse model, we show that RhoA deficiency causes a multilineage hematopoietic failure that is associated with defective multipotent HPCs. Interestingly, RhoA−/− hematopoietic stem cells retained long-term engraftment potential but failed to produce multipotent HPCs and lineage-defined blood cells. This multilineage hematopoietic failure was rescued by reconstituting wild-type RhoA into the RhoA−/− Lin−Sca-1+c-Kit+ compartment. Mechanistically, RhoA regulates actomyosin signaling, cytokinesis, and programmed necrosis of the HPCs, and loss of RhoA results in a cytokinesis failure of HPCs manifested by an accumulation of multinucleated cells caused by failed abscission of the cleavage furrow after telophase. Concomitantly, the HPCs show a drastically increased death associated with increased TNF–RIP-mediated necrosis. These results show that RhoA is a critical and specific regulator of multipotent HPCs during cytokinesis and thus essential for multilineage hematopoiesis.
doi:10.1084/jem.20122348
PMCID: PMC3804933  PMID: 24101377
9.  ‘Druggable’ alterations detected by Ion Torrent in metastatic colorectal cancer patients 
Oncology Letters  2014;7(6):1761-1766.
The frequency and poor prognosis of patients with metastatic colorectal cancer (mCRC) emphasizes the requirement for improved biomarkers for use in the treatment and prognosis of mCRC. In the present study, somatic variants in exonic regions of key cancer genes were identified in mCRC patients. Formalin-fixed, paraffin-embedded tissues obtained by biopsy of the metastases of mCRC patients were collected, and the DNA was extracted and sequenced using the Ion Torrent Personal Genome Machine. For the targeted amplification of known cancer genes, the Ion AmpliSeq™ Cancer Panel, which is designed to detect 739 Catalogue of Somatic Mutations in Cancer (COSMIC) mutations in 604 loci from 46 oncogenes and tumor suppressor genes using as little as 10 ng of input DNA, was used. The sequencing results were then analyzed using the Ampliseq™ Variant Caller plug-in within the Ion Torrent Suite software. In addition, Ingenuity Pathway software was used to perform a pathway analysis. The Cox regression analysis was also conducted to investigate the potential correlation between alteration numbers and clinical factors, including response rate, disease-free survival and overall survival. Among 10 specimens, 65 genetic alterations were identified in 24 genes following the exclusion of germline mutations using the SNP database, whereby 41% of the alterations were also present in the COSMIC database. No clinical factors were found to significantly correlate with the alteration numbers in the patients by statistical analysis. However, pathway analysis identified ‘colorectal cancer metastasis signaling’ as the most commonly mutated canonical pathway. This analysis further revealed mutated genes in the Wnt, phosphoinositide 3-kinase (PI3K)/AKT and transforming growth factor (TGF)-β/SMAD signaling pathways. Notably, 11 genes, including the expected APC, BRAF, KRAS, PIK3CA and TP53 genes, were mutated in at least two samples. Notably, 90% (9/10) of mCRC patients harbored at least one ‘druggable’ alteration (range, 1–6 alterations) that has been linked to a clinical treatment option or is currently being investigated in clinical trials of novel targeted therapies. These results indicated that DNA sequencing of key oncogenes and tumor suppressors enables the identification of ‘druggable’ alterations for individual colorectal cancer patients.
doi:10.3892/ol.2014.2047
PMCID: PMC4049685  PMID: 24932229
druggable alterations; Ion Torrrent; metastasic colorectal cancer; formalin-fixed paraffin-embedded
10.  Tandem alternative polyadenylation events of genes in non-eosinophilic nasal polyp tissue identified by high-throughput sequencing analysis 
Nasal polyps (NP) is highly associated with the disorder of immune cells. Alternative polyadenylation (APA) produces mRNA isoforms with different length of 3′-untranslated region (UTR) and regulates gene expression. It has been proven that this APA-mediated regulation of 3′UTR length is an immune-associated phenomenon. The aim of this study was to investigate the genome-wide alternative tandem 3′UTR length switching events in non-eosinophilic nasal polyp tissue. Thirteen patients diagnosed as having non-eosinophilic nasal polyps were included in this study. Nasal polyp tissue and control mucosa were collected during surgery. The 3′ end library of cDNA was constructed. The recovered libraries were sequenced with second sequencing technology, and the sequencing data were analyzed by an in-house bioinformatics pipeline. Tandem 3′UTR length switching between samples was detected by a test of linear trend alternative to independence. We found a significant alteration in the tandem 3′UTR length in 1,920 genes in nasal polyp samples. Functional annotation results showed that several gene ontology (GO) terms were enriched in the list of genes with switched APA sites, including regulation of transcription, macromolecule catabolic localization and mRNA processing. The results suggested that APA-mediated alternative 3′UTR regulation plays an important role in the post-transcriptional regulation of gene expression in non-eosinophilic nasal polyps.
doi:10.3892/ijmm.2014.1734
PMCID: PMC4055440  PMID: 24715051
chronic rhinosinusitis; nasal polyps; alternative polyadenylation site; 3′ untranslated region
11.  Personal electronics printing via tapping mode composite liquid metal ink delivery and adhesion mechanism 
Scientific Reports  2014;4:4588.
Printed electronics is becoming increasingly important in a variety of newly emerging areas. However, restricted to the rather limited conductive inks and available printing strategies, the current electronics manufacture is usually confined to industry level. Here, we show a highly cost-effective and entirely automatic printing way towards personal electronics making, through introducing a tapping-mode composite fluid delivery system. Fundamental mechanisms regarding the reliable printing, transfer and adhesion of the liquid metal inks on the substrate were disclosed through systematic theoretical interpretation and experimental measurements. With this liquid metal printer, a series of representative electronic patterns spanning from single wires to desired complex configurations such as integrated circuit (IC), printed-circuits-on-board (PCB), electronic paintings, or more do-it-yourself (DIY) devices, were demonstrated to be printed out with high precision in a moment. And the total machine cost already reached personally affordable price. This is hard to achieve by a conventional PCB technology which generally takes long time and is material, water and energy consuming, while the existing printed electronics is still far away from the real direct printing goal. The present work opens the way for large scale personal electronics manufacture and is expected to generate important value for the coming society.
doi:10.1038/srep04588
PMCID: PMC3975221  PMID: 24699375
12.  Characterization of Fecal Microbiota across Seven Chinese Ethnic Groups by Quantitative Polymerase Chain Reaction 
PLoS ONE  2014;9(4):e93631.
The human gut microbiota consists of complex microbial communities, which possibly play crucial roles in physiological functioning and health maintenance. China has evolved into a multicultural society consisting of the major ethnic group, Han, and 55 official ethnic minority groups. Nowadays, these minority groups inhabit in different Chinese provinces and some of them still keep their unique culture and lifestyle. Currently, only limited data are available on the gut microbiota of these Chinese ethnic groups. In this study, 10 major fecal bacterial groups of 314 healthy individuals from 7 Chinese ethnic origins were enumerated by quantitative polymerase chain reaction. Our data confirmed that the selected bacterial groups were common to all 7 surveyed ethnicities, but the amount of the individual bacterial groups varied to different degree. By principal component and canonical variate analyses of the 314 individuals or the 91 Han subjects, no distinct group clustering pattern was observed. Nevertheless, weak differences were noted between the Han and Zhuang from other ethnic minority groups, and between the Heilongjiang Hans from those of the other provinces. Thus, our results suggest that the ethnic origin may contribute to shaping the human gut microbiota.
doi:10.1371/journal.pone.0093631
PMCID: PMC3974763  PMID: 24699404
13.  Analyzing and modeling rheological behavior of liver fibrosis in rats using shear viscoelastic moduli*  
The process of liver fibrosis changes the rheological properties of liver tissue. This study characterizes and compares liver fibrosis stages from F0 to F4 in rats in terms of shear viscoelastic moduli. Here two viscoelastic models, the Zener model and Voigt model, were applied to experimental data of rheometer tests and then values of elasticity and viscosity were estimated for each fibrosis stage. The results demonstrate that moderate fibrosis (≤F2) has a good correlation with liver viscoelasticity. The mean Zener elasticity E 1 increases from (0.452±0.094) kPa (F0) to (1.311±0.717) kPa (F2), while the mean Voigt elasticity E increases from (0.618±0.089) kPa (F0) to (1.701±0.844) kPa (F2). The mean Zener viscosity increases from (3.499±0.186) Pa·s (F0) to (4.947±1.811) Pa·s (F2) and the mean Voigt viscosity increases from (3.379±0.316) Pa·s (F0) to (4.625±1.296) Pa·s (F2). Compared with viscosity, the elasticity shows smaller variations at stages F1 and F2 no matter what viscoelastic model is used. Therefore, the estimated elasticity is more effective than viscosity for differentiating the fibrosis stages from F0 to F2.
doi:10.1631/jzus.B1300121
PMCID: PMC3989156  PMID: 24711358
Biological mechanics; Rheological properties; Liver fibrosis; Viscoelasticity; Shear modulus; Elasticity; Viscosity; Zener model; Voigt model
14.  Genome-Wide Identification, Evolution and Expression Analysis of the Grape (Vitis vinifera L.) Zinc Finger-Homeodomain Gene Family 
Plant zinc finger-homeodomain (ZHD) genes encode a family of transcription factors that have been demonstrated to play an important role in the regulation of plant growth and development. In this study, we identified a total of 13 ZHD genes (VvZHD) in the grape genome that were further classified into at least seven groups. Genome synteny analysis revealed that a number of VvZHD genes were present in the corresponding syntenic blocks of Arabidopsis, indicating that they arose before the divergence of these two species. Gene expression analysis showed that the identified VvZHD genes displayed distinct spatiotemporal expression patterns, and were differentially regulated under various stress conditions and hormone treatments, suggesting that the grape VvZHDs might be also involved in plant response to a variety of biotic and abiotic insults. Our work provides insightful information and knowledge about the ZHD genes in grape, which provides a framework for further characterization of their roles in regulation of stress tolerance as well as other aspects of grape productivity.
doi:10.3390/ijms15045730
PMCID: PMC4013592  PMID: 24705465
synteny analysis; phylogenetic analysis; gene expression; grape; zinc finger-homeodomain
15.  Hair Cell Overexpression of Islet1 Reduces Age-Related and Noise-Induced Hearing Loss 
The Journal of Neuroscience  2013;33(38):15086-15094.
Isl1 is a LIM-homeodomain transcription factor that is critical in the development and differentiation of multiple tissues. In the mouse inner ear, Isl1 is expressed in the prosensory region of otocyst, in young hair cells and supporting cells, and is no longer expressed in postnatal auditory hair cells. To evaluate how continuous Isl1 expression in postnatal hair cells affects hair cell development and cochlear function, we created a transgenic mouse model in which the Pou4f3 promoter drives Isl1 overexpression specifically in hair cells. Isl1 overexpressing hair cells develop normally, as seen by morphology and cochlear functions (auditory brainstem response and otoacoustic emissions). As the mice aged to 17 months, wild-type (WT) controls showed the progressive threshold elevation and outer hair cell loss characteristic of the age-related hearing loss (ARHL) in the background strain (C57BL/6J). In contrast, the Isl1 transgenic mice showed significantly less threshold elevation with survival of hair cells. Further, the Isl1 overexpression protected the ear from noise-induced hearing loss (NIHL): both ABR threshold shifts and hair cell death were significantly reduced when compared with WT littermates. Our model suggests a common mechanism underlying ARHL and NIHL, and provides evidence that hair cell-specific Isl1 expression can promote hair cell survival and therefore minimize the hearing impairment that normally occurs with aging and/or acoustic overexposure.
doi:10.1523/JNEUROSCI.1489-13.2013
PMCID: PMC3776061  PMID: 24048839
16.  The Association of Transporter Genes Polymorphisms and Lung Cancer Chemotherapy Response 
PLoS ONE  2014;9(3):e91967.
Lung cancer is one of the most common cancers and is the leading cause of death worldwide. Platinum-based chemotherapy is the main treatment method in lung cancer patients. Our previous studies indicated that single nucleotide polymorphisms (SNPs) in some transporter genes played important role in platinum-based chemotherapy efficacy. The aim of this study was to investigate the association of SNPs in transporter genes and platinum-based chemotherapy efficacy. The main polymorphisms on transporters OCT2, LRP, AQP2, AQP9 and TMEM205 genes were genotyped in 338 lung cancer patients. The rs195854 in genotypic model, rs896412 in genotypic and recessive models for all subjects showed significant association with chemotherapy response. In stratification analysis, TMEM205 rs896412, OCT2 rs1869641 and rs195854, AQP9 rs1516400 and AQP2 rs7314734 showed significant relation to chemotherapy response. In conclusion, the genetic polymorphisms in OCT2, AQP2, AQP9 and TMEM205 may contribute to chemotherapy response in lung cancer patients.
doi:10.1371/journal.pone.0091967
PMCID: PMC3958404  PMID: 24643204
17.  Interaction of Herpes Simplex Virus ICP0 with ND10 Bodies: a Sequential Process of Adhesion, Fusion, and Retention 
Journal of Virology  2013;87(18):10244-10254.
On entry into the nucleus, herpes simplex virus 1 (HSV-1) DNA localizes to nuclear bodies known as ND10. Gene repression imposed by ND10 is released by a viral protein, ICP0, via degradation of the ND10 constituents promyelocytic leukemia protein (PML) and Sp100 and the subsequent dispersal of ND10 bodies. In order to understand the dynamic interaction between ICP0 and ND10, we carried out deletion mapping to identify the domains of ICP0 responsible for its association with ND10. Here, we report the following. (i) An ND10 entry signal (ND10-ES), located between residues 245 and 474, is required for ICP0 to penetrate and fuse with ND10. ICP0 lacking ND10-ES adheres to the surface of ND10 but fails to enter. (ii) In the absence of ND10-ES, the E3 ubiquitin ligase of ICP0 facilitates the transient adhesion of the truncated ICP0 to the ND10 surface, whereas the presence of ND10-ES in ICP0 renders ND10 fusion regardless of the E3 ligase activity. (iii) The C terminus of ICP0 is required for retention of ICP0 in ND10 but plays no role in the recruitment process. (iv) The adverse effects of an inactive RING domain on viral replication are partially reversed by deleting either ND10-ES or the C-terminal retention domain, suggesting that additional ICP0 functions require the release of ICP0 from ND10. Based on these results, we conclude that association of ICP0 and ND10 is a dynamic process, in which three sequential steps—adhesion, fusion, and retention—are adopted to stabilize the interaction. A faithful execution of these steps defines the ultimate productivity of the virus.
doi:10.1128/JVI.01487-13
PMCID: PMC3753982  PMID: 23864622
18.  Association between Soy Isoflavone Intake and Breast Cancer Risk for Pre- and Post-Menopausal Women: A Meta-Analysis of Epidemiological Studies 
PLoS ONE  2014;9(2):e89288.
Background
Conclusions drawn from meta-analyses on the association between soy isoflavone intake and breast cancer risk for pre- and post-menopausal women are not fully consistent. These meta-analyses did not explore the influence of different study designs on the pooled results on the basis of distinguishing between pre- and post-menopausal women.
Methodology and Principal Findings
We performed a meta-analysis of 35 studies which reported results of association between soy isoflavone intake and breast cancer risk for pre- and/or post-menopausal women, calculated pooled odds ratios and their 95% confidence intervals of pre- and post-menopausal women respectively, and further explored soy isoflavone-breast cancer association on the basis of considering different study regions and designs. Summary results suggested that soy isoflavone intake has a protective effect against breast cancer for both pre- and post-menopausal women. However, they are influenced by study design and region. Pooled ORs of studies carried out in Asian countries suggested that soy isoflavone’s protective effect exist in both pre- and post-menopausal women (OR = 0.59, 95%CI: 0.48–0.69 for premenopausal women; OR = 0.59, 95%CI: 0.44–0.74 for postmenopausal women). However, there are some differences between the results pooled from different study designs for women in Asian countries (test for consistency, P = 0.04). Pooled OR of studies on postmenopausal women in Western countries suggested that soy isoflavone intake has a marginally significant protective effect (OR = 0.92; 95%CI: 0.83∼1.00), but further analyses stratifying by study design found no statistically significant association.
Conclusions
We meta-analyzed more and newer research results, and separated women according to menopausal status to explore soy isoflavone-breast cancer association. We founded that soy isoflavone intake could lower the risk of breast cancer for both pre- and post-menopausal women in Asian countries. However, for women in Western countries, pre- or post-menopausal, there is no evidence to suggest an association between intake of soy isoflavone and breast cancer.
doi:10.1371/journal.pone.0089288
PMCID: PMC3930722  PMID: 24586662
19.  Endotoxin, Ergosterol, Fungal DNA and Allergens in Dust from Schools in Johor Bahru, Malaysia- Associations with Asthma and Respiratory Infections in Pupils 
PLoS ONE  2014;9(2):e88303.
There are few studies on associations between respiratory health and allergens, fungal and bacterial compounds in schools in tropical countries. The aim was to study associations between respiratory symptoms in pupils and ethnicity, chemical microbial markers, allergens and fungal DNA in settled dust in schools in Malaysia. Totally 462 pupils (96%) from 8 randomly selected secondary schools in Johor Bahru, Malaysia, participated. Dust was vacuumed from 32 classrooms and analysed for levels of different types of endotoxin as 3-hydroxy fatty acids (3-OH), muramic acid, ergosterol, allergens and five fungal DNA sequences. Multiple logistic regression was applied. Totally 13.1% pupils reported doctor’s diagnosed asthma, 10.3% wheeze and 21.1% pollen or pet allergy. Indian and Chinese children had less atopy and asthma than Malay. Carbon dioxide levels were low (380–690 ppm). No cat (Fel d1), dog (Can f 1) or horse allergens (Ecu cx) were detected. The levels of Bloomia tropicalis (Blo t), house dust mite allergens (Der p 1, Der f 1, Der m 1) and cockroach allergens (Per a 1 and Bla g 1) were low. There were positive associations between levels of Aspergillus versicolor DNA and daytime breathlessness, between C14 3-OH and respiratory infections and between ergosterol and doctors diagnosed asthma. There were negative (protective) associations between levels of C10 3-OH and wheeze, between C16 3-OH and day time and night time breathlessness, between cockroach allergens and doctors diagnosed asthma. Moreover there were negative associations between amount of fine dust, total endotoxin (LPS) and respiratory infections. In conclusion, endotoxin at school seems to be mainly protective for respiratory illness but different types of endotoxin could have different effects. Fungal contamination measured as ergosterol and Aspergillus versicolor DNA can be risk factors for respiratory illness. The ethnical differences for atopy and asthma deserve further attention.
doi:10.1371/journal.pone.0088303
PMCID: PMC3921143  PMID: 24523884
20.  Effects of Thapsigargin on the Proliferation and Survival of Human Rheumatoid Arthritis Synovial Cells 
The Scientific World Journal  2014;2014:605416.
A series of experiments have been carried out to investigate the effects of different concentrations of thapsigargin (0, 0.001, 0.1, and 1 μM) on the proliferation and survival of human rheumatoid arthritis synovial cells (MH7A). The results showed that thapsigargin can block the cell proliferation in human rheumatoid arthritis synovial cells in a time- and dose-dependent manner. Results of Hoechst staining suggested that thapsigargin may induce cell apoptosis in MH7A cells in a time- and dose-dependent manner, and the percentages of cell death reached 44.6% at thapsigargin concentration of 1 μM treated for 4 days compared to the control. The protein and mRNA levels of cyclin D1 decreased gradually with the increasing of thapsigargin concentration and treatment times. Moreover, the protein levels of mTORC1 downstream indicators pS6K and p4EBP-1 were reduced by thapsigargin treatment at different concentrations and times, which should be responsible for the reduced cyclin D1 expressions. Our results revealed that thapsigargin may effectively impair the cell proliferation and survival of MH7A cells. The present findings will help to understand the molecular mechanism of fibroblast-like synoviocytes proliferations and suggest that thapsigargin is of potential for the clinical treatment of rheumatoid arthritis.
doi:10.1155/2014/605416
PMCID: PMC3934453  PMID: 24688409
21.  Evolution and expression analysis of the grape (Vitis vinifera L.) WRKY gene family 
Journal of Experimental Botany  2014;65(6):1513-1528.
Summary
Fifty-nine VvWRKY genes were identified. Phylogenetic tree and synteny analysis revealed the specific evolutionary relationship of these genes. Meanwhile, differential expression patterns indicated their possible roles in specific tissues and under different stresses.
WRKY proteins comprise a large family of transcription factors that play important roles in plant defence regulatory networks, including responses to various biotic and abiotic stresses. To date, no large-scale study of WRKY genes has been undertaken in grape (Vitis vinifera L.). In this study, a total of 59 putative grape WRKY genes (VvWRKY) were identified and renamed on the basis of their respective chromosome distribution. A multiple sequence alignment analysis using all predicted grape WRKY genes coding sequences, together with those from Arabidopsis thaliana and tomato (Solanum lycopersicum), indicated that the 59 VvWRKY genes can be classified into three main groups (I–III). An evaluation of the duplication events suggested that several WRKY genes arose before the divergence of the grape and Arabidopsis lineages. Moreover, expression profiles derived from semiquantitative PCR and real-time quantitative PCR analyses showed distinct expression patterns in various tissues and in response to different treatments. Four VvWRKY genes showed a significantly higher expression in roots or leaves, 55 responded to varying degrees to at least one abiotic stress treatment, and the expression of 38 were altered following powdery mildew (Erysiphe necator) infection. Most VvWRKY genes were downregulated in response to abscisic acid or salicylic acid treatments, while the expression of a subset was upregulated by methyl jasmonate or ethylene treatments.
doi:10.1093/jxb/eru007
PMCID: PMC3967086  PMID: 24510937
Evolution; expression profile analysis; grape (Vitis vinifera L.); phylogenetic analysis; synteny analysis; WRKY genes.
22.  CDC42 is Required for Structural Patterning of the Lung During Development 
Developmental biology  2012;374(1):46-57.
The formation of highly branched epithelial structures is critical for the development of many essential organs, including lung, liver, pancreas, kidney and mammary glands. Elongation and branching of these structures require precise control of complex morphogenetic processes that are dependent upon coordinate regulation of cell shape, apical-basal polarity, proliferation, migration, and interactions among multiple cell types. Herein, we demonstrate that temporal-spatial regulation of epithelial cell polarity by the small GTPase, CDC42, is essential for branching morphogenesis of the developing lung. Epithelial cell-specific deletion of CDC42 in fetal mice disrupted epithelial cell polarity, the actin cytoskeleton, intercellular contacts, directional trafficking of proteins, proliferation and mitotic spindle orientation, impairing the organization and patterning of the developing respiratory epithelium and adjacent mesenchyme. Transition from a pseudostratified to a simple columnar epithelium was impaired, consistent with coordinate dysregulation of epithelial cell polarity, mitotic spindle orientation, and repositioning of mitotic cells within the epithelium during cell cycle progression. Expression of sonic hedgehog and its receptor, patched-1, was decreased, while fibroblast growth factor 10 expression in the mesenchyme was expanded, resulting in disruption of branching morphogenesis and bronchiolar smooth muscle formation in this model. CDC42 is required for spatial positioning of proliferating epithelial cells, as well as signaling interactions between the epithelium and mesenchyme and is, therefore, essential for formation and maintenance of the respiratory tract during morphogenesis of the fetal lung.
doi:10.1016/j.ydbio.2012.11.030
PMCID: PMC3549046  PMID: 23219958
Mouse Development; Branching Morphogenesis; Rho GTPase; Targeted Deletion; Intercellular Junctions; Pulmonary Hypoplasia
23.  Efficacy of Combined Atorvastatin and Sildenafil in Promoting Recovery after Ischemic Stroke in Mice 
Objective
The aim of this study was to test the hypothesis that a combination of atorvastatin and sildenafil promotes recovery in an additive manner after ischemic stroke in mice.
Design
Adult C57BL/6 mice (n=67) were subjected to transient middle cerebral artery occlusion. Vehicle-control (H2O), atorvastatin (0.3mg/kg), sildenafil (0.3mg/kg), or combined atorvastatin (0.3mg/kg) and sildenafil (0.3mg/kg) were administrated via oral gavage daily for 6 days starting 24 hours after ischemia. Behavioral studies including neurological score and adhesive removal test were performed before surgery and on postoperative days 1 and 7; cylinder test was performed before surgery and on postoperative day 7. Mice were sacrificed after 7 days and brain slices were stained with Haematoxylin & Eosin to measure the infarct volume.
Results
The combination group performed significantly better in the adhesive removal test (average ± SD) (50 ± 54 seconds) as compared to the control group (147±109 seconds) (P<0.05) and to atorvastatin (144±102 seconds) (p<0.05), but did not show statistically significant improvement as compared to sildenafil (107± 115 seconds) (p=0.148). There were no significant differences among the groups in neurological score and cylinder test. There was no significant difference in the infarct volume.
Conclusions
The data suggest that combined atorvastatin and sildenafil generates a better functional outcome as compared to atorvastatin-only treatment, but not sildenafil-only treatment, in one of multiple variables tested.
doi:10.1097/PHM.0b013e3182643f1a
PMCID: PMC3675160  PMID: 22854903
Stroke; Atorvastatin; Sildenafil; Recovery; Angiogenesis
24.  Community Structure and Succession Regulation of Fungal Consortia in the Lignocellulose-Degrading Process on Natural Biomass 
The Scientific World Journal  2014;2014:845721.
The study aims to investigate fungal community structures and dynamic changes in forest soil lignocellulose-degrading process. rRNA gene clone libraries for the samples collected in different stages of lignocellulose degradation process were constructed and analyzed. A total of 26 representative RFLP types were obtained from original soil clone library, including Mucoromycotina (29.5%), unclassified Zygomycetes (33.5%), Ascomycota (32.4%), and Basidiomycota (4.6%). When soil accumulated with natural lignocellulose, 16 RFLP types were identified from 8-day clone library, including Basidiomycota (62.5%), Ascomycota (36.1%), and Fungi incertae sedis (1.4%). After enrichment for 15 days, identified 11 RFLP types were placed in 3 fungal groups: Basidiomycota (86.9%), Ascomycota (11.5%), and Fungi incertae sedis (1.6%). The results showed richer, more diversity and abundance fungal groups in original forest soil. With the degradation of lignocellulose, fungal groups Mucoromycotina and Ascomycota decreased gradually, and wood-rotting fungi Basidiomycota increased and replaced the opportunist fungi to become predominant group. Most of the fungal clones identified in sample were related to the reported lignocellulose-decomposing strains. Understanding of the microbial community structure and dynamic change during natural lignocellulose-degrading process will provide us with an idea and a basis to construct available commercial lignocellulosic enzymes or microbial complex.
doi:10.1155/2014/845721
PMCID: PMC3915490  PMID: 24574925
25.  Sonic Hedgehog Initiates Cochlear Hair Cell Regeneration through Downregulation of Retinoblastoma Protein 
Cell cycle re-entry by cochlear supporting cells and/or hair cells is considered one of the best approaches for restoring hearing loss as a result of hair cell damage. To identify mechanisms that can be modulated to initiate cell cycle re-entry and hair cell regeneration, we studied the effect of activating the sonic hedgehog (Shh) pathway. We show that Shh signaling in postnatal rat cochleae damaged by neomycin leads to renewed proliferation of supporting cells and hair cells. Further, proliferating supporting cells are likely to transdifferentiate into hair cells. Shh treatment leads to inhibition of retinoblastoma protein (pRb) by increasing phosphorylated pRb and reducing retinoblastoma gene transcription. This results in upregulation of cyclins B1, D2, and D3, and CDK1. These results suggest that Shh signaling induces cell cycle re-entry in cochlear sensory epithelium and the production of new hair cells, in part by attenuating pRb function. This study provides an additional route to modulate pRb function with important implications in mammalian hair cell regeneration.
doi:10.1016/j.bbrc.2012.11.088
PMCID: PMC3579567  PMID: 23211596
Retinoblastoma 1; hedgehog; inner ear; cochlea; hair cell; regeneration

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