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1.  Examination of psychosocial predictors of Chinese hospital pharmacists' intention to provide clinical pharmacy services using the theory of planned behaviour: a cross-sectional questionnaire study 
BMJ Open  2016;6(10):e012775.
Objectives
Main study aim was as follows: (1) to explore the usefulness of the theory of planned behaviour (TPB) model in predicting Chinese hospital pharmacists' intention to provide clinical pharmacy services (CPSs), including auxiliary CPSs and core CPSs; (2) to identify the main factors affecting the Chinese hospital pharmacists' intention to provide core CPSs based on TPB quantitatively.
Design
Cross-sectional questionnaire study.
Setting
The study was conducted in 22 general hospitals in seven cities located in the eastern and western part of China.
Participants
416 hospital pharmacists (292 (70.2%) female) entered and completed the study.
Primary and secondary outcome measures
Quantitative responses with hospital pharmacists' intention, attitude, subjective norms (SNs) and perceived behavioural control (PBC) over provision of CPSs and their past behaviour (PB)-related CPSs.
Results
The structural equation model analysis found that attitude (p=0.0079, β=0.12), SN (p=0.038, β=0.10) and the pharmacists' intention to provide auxiliary CPSs (p=0.0001, β=0.63) significantly predicted of their intention to provide core CPSs, accounting for 54.0% of its variance. Attitude (p=0.0001, β=0.35), PBC (p=0.0182, β=0.12) and PB (p=0.0009, β=0.15) are significant predictors of pharmacists' intention, accounting for 21% of the variance in pharmacists' intention to provide auxiliary CPSs.
Conclusions
The TPB with the addition of PB is a useful framework for predicting pharmacists' intention to provide CPSs in Chinese hospital care context. Strategies to improve hospital pharmacists' intention to provide CPSs should focus on helping the individuals related medical care see the value of CPSs, altering their perception of social pressure towards core CPSs and the removal of obstacles that impede the translation of intentions into behaviour.
doi:10.1136/bmjopen-2016-012775
PMCID: PMC5073478  PMID: 27707835
Clinical Pharmacy Services; Pharmacist; Intention; Attitude; Theory of planned behavior; Structural equation model
2.  Correlation of body mass index levels with menarche in adolescent girls in Shaanxi, China: a cross sectional study 
BMC Women's Health  2016;16(1):61.
Background
Menarche is a milestone for adolescent girls. The timing of menarche is influenced by genetics, social status and nutritional status (e.g., height, weight and body mass index [BMI]) and impacts future health (e.g., obesity and breast cancer). There have been many studies on trends in age at menarche among adolescent girls in China, but few have investigated associations between growth status and the timing of menarche. This study examined the association between age at menarche and growth status among adolescent girls in Western China.
Methods
The participants in this cross sectional study came from three geographical regions of Shaanxi Province. A total of 533 adolescent girls from urban and rural areas were randomly selected. Trained investigators administered a standard questionnaire to each participant during a face-to-face interview and carried out anthropometric measurements.
Results
The average age at menarche was 13.3 years. There were statistically significant differences in BMI z-scores between pre-menarcheal and post-menarcheal girls of the same age and these differences were related to socioeconomic factors. Girls who had reached menarche, in particular those aged 13–14 years, were significantly taller (P < 0.01) and had higher BMI (P < 0.01) than girls in the same age group who had not reached menarche.
Conclusions
BMI is associated with the timing of menarche but socioeconomic factors are also important.
doi:10.1186/s12905-016-0340-4
PMCID: PMC5013571  PMID: 27599475
Adolescent girls; Body mass index; Menarche; Western China
3.  Mutual inhibition of insulin signaling and PHLPP-1 determines cardioprotective efficiency of Akt in aged heart 
Aging (Albany NY)  2016;8(5):873-887.
Insulin protects cardiomyocytes from myocardial ischemia/reperfusion (MI/R) injury through activating Akt. However, phosphatase PHLPP-1 (PH domain leucine-rich repeat protein phosphatase-1) dephosphorylates and inactivates Akt. The balanced competitive interaction of insulin and PHLPP-1 has not been directly examined. In this study, we have identified the effect of mutual inhibition of insulin signaling and PHLPP-1 on the cardioprotective efficiency of Akt in aged heart. Young (3 mon) and aged (20 mon) Sprague Dawley (SD) rats were subjected to MI/R in vivo. The PHLPP-1 level was higher in aged vs. young hearts at base. But, insulin treatment failed to decrease PHLPP-1 level during reperfusion in the aged hearts. Consequently, the cardioprotection of insulin-induced Akt activation was impaired in aged hearts, resulting in more susceptible to MI/R injury. In cultured rat ventricular myocytes, PHLPP-1 knockdown significantly enhanced insulin-induced Akt phosphorylation and reduced simulated hypoxia/reoxygenation-induced apoptosis. Contrary, PHLPP-1 overexpression terminated Akt phosphorylation and deteriorated myocytes apoptosis. Using in vivo aged animal models, we confirmed that cardiac PHLPP-1 knockdown or enhanced insulin sensitivity by exercise training dramatically increased insulin-induced Akt phosphorylation. Specifically, MI/R-induced cardiomyocyte apoptosis and infarct size were decreased and cardiac function was increased. More importantly, we found that insulin regulated the degradation of PHLPP-1 and insulin treatment could enhance the binding between PHLPP-1 and β-transducin repeat-containing protein (β-TrCP) to target for ubiquitin-dependent degradation. Altogether, we have identified a new mechanism by which insulin suppresses PHLPP-1 to enhance Akt activation. But, aged heart possesses lower insulin effectiveness and fails to decrease PHLPP-1 during MI/R, which subsequently limited Akt activity and cardioprotection. PHLPP-1 could be a promising therapeutic interventional target for elderly ischemic heart disease patients.
doi:10.18632/aging.100933
PMCID: PMC4931841  PMID: 27019292
myocardial I/R; insulin; PHLPP-1; Akt; degradation
4.  Species Abundance Distribution of Ectoparasites on Norway Rats (Rattus norvegicus) from a Localized Area in Southwest China 
Background:
The species of ectoparasites that live on a specific host in a geographical region form an ectoparasite community. Species abundance distributions describe the number of individuals observed for each different species that is encountered within a community. Based on properties of the species abundance distribution, the expected total number of species present in the community can be estimated.
Methods:
Preston’s lognormal distribution model was used to fit the expected species abundance distribution curve. Using the expected species abundance distribution curve, we estimated the total number of expected parasite species present and the amount of species that were likely missed by our sampling in the field.
Results:
In total, 8040 ectoparasites (fleas, sucking lice, gamasid mites and chigger mites) were collected from 431 Norway rats (Rattus norvegicus) from a localized area in southwest China. These ectoparasites were identified to be 47 species from 26 genera in 10 families. The majority of ectoparasite species were chigger mites (family Trombiculidae) while the majority of individuals were sucking lice in the family Polyplacidae. The expected species abundance distribution curve demonstrated the classic pattern that the majority of ectoparasite species were rare and that there were a few common species. The total expected number of ectoparasite species on R. norvegicus was estimated to be 85 species, and 38 species were likely missed by our sampling in the field.
Conclusions:
Norway rats harbor a large suite of ectoparasites. Future field investigations should sample large numbers of host individuals to assess ectoparasite populations.
PMCID: PMC4906758  PMID: 27308277
Ectoparasite; Species abundance distribution; Expected species estimation; Norway rat; Rattus norvegicus
5.  Prevalence and Spectrum of TBX5 Mutation in Patients with Lone Atrial Fibrillation 
Atrial fibrillation (AF), the most common type of cardiac rhythm disturbance encountered in clinical practice, is associated with substantially increased morbidity and mortality. Aggregating evidence demonstrates that abnormal cardiovascular development is involved in the pathogenesis of AF. A recent study has revealed that the TBX5 gene, which encodes a T-box transcription factor key to cardiovascular development, was associated with AF and atypical Holt-Oram syndrome. However, the prevalence and spectrum of TBX5 mutation in patients with lone AF remain unclear. In this study, the coding regions and splicing junction sites of TBX5 were sequenced in 192 unrelated patients with lone AF and 300 unrelated ethnically-matched healthy individuals used as controls. The causative potential of the identified TBX5 variation was evaluated by MutationTaster and PolyPhen-2. The functional effect of the mutant TBX5 was assayed by using a dual-luciferase reporter assay system. As a result, a novel heterozygous TBX5 mutation, p.H170D, was identified in a patient, with a mutational prevalence of approximately 0.52%. This mutation, which was absent in the 300 control individuals, altered the amino acid completely conserved evolutionarily across species, and was predicted to be disease-causing. Functional deciphers showed that the mutant TBX5 was associated with significantly reduced transcriptional activity when compared with its wild-type counterpart. Furthermore, the mutation significantly decreased the synergistic activation between TBX5 and NKX2-5 or GATA4. The findings expand the mutational spectrum of TBX5 linked to AF and provide new evidence that dysfunctional TBX5 may contribute to lone AF.
doi:10.7150/ijms.13264
PMCID: PMC4747871  PMID: 26917986
Atrial fibrillation; Genetics; Transcription factor; TBX5; Reporter gene assay.
6.  Applying Rank Sum Ratio (RSR) to the Evaluation of Feeding Practices Behaviors, and Its Associations with Infant Health Risk in Rural Lhasa, Tibet 
To evaluate the status of feeding practices and analyze the association between feeding practice and health status among Tibetan infants, a cross-sectional survey of 386 women with children aged under 24 months was conducted in rural areas surrounding Lhasa, Tibet. All participants were selected using simple random sampling and were interviewed face-to-face by trained interviewers. Mothers were interviewed to collect information on their feeding practices. A feeding practices index was created using the rank sum ratio method. Most of the infants had been or were being breastfed at the time of the interview. The feeding practices index was significantly and inversely associated with the prevalence of acute upper respiratory infection, and the odds ratio for the qualified feeding practices index vs. the non-qualified feeding practices index was 0.43 (95% confidence interval: 0.20–0.94). There were no measurable associations observed between acute upper respiratory infection, diarrhea, and the feeding practices index after controlling for selected factors. The method of rank sum ratio provides a flexible way to evaluate feeding practices and is easy to understand. Furthermore, appropriate infant feeding practices might play a protective role in Tibetan infants’ health.
doi:10.3390/ijerph121214976
PMCID: PMC4690912  PMID: 26633444
rank sum ratio; feeding practices index; infant health; Tibet
7.  Domain Motions and Functionally-Key Residues of l-Alanine Dehydrogenase Revealed by an Elastic Network Model 
Mycobacterium tuberculosis l-alanine dehydrogenase (l-MtAlaDH) plays an important role in catalyzing l-alanine to ammonia and pyruvate, which has been considered to be a potential target for tuberculosis treatment. In the present work, the functional domain motions encoded in the structure of l-MtAlaDH were investigated by using the Gaussian network model (GNM) and the anisotropy network model (ANM). The slowest modes for the open-apo and closed-holo structures of the enzyme show that the domain motions have a common hinge axis centered in residues Met133 and Met301. Accompanying the conformational transition, both the 1,4-dihydronicotinamide adenine dinucleotide (NAD)-binding domain (NBD) and the substrate-binding domain (SBD) move in a highly coupled way. The first three slowest modes of ANM exhibit the open-closed, rotation and twist motions of l-MtAlaDH, respectively. The calculation of the fast modes reveals the residues responsible for the stability of the protein, and some of them are involved in the interaction with the ligand. Then, the functionally-important residues relevant to the binding of the ligand were identified by using a thermodynamic method. Our computational results are consistent with the experimental data, which will help us to understand the physical mechanism for the function of l-MtAlaDH.
doi:10.3390/ijms161226170
PMCID: PMC4691113  PMID: 26690143
Mycobacterium tuberculosisl-alanine dehydrogenase; domain motions; functionally-key residues; Gaussian network model; anisotropy network model; thermodynamic cycle method
8.  ShRNA-mediated silencing of the ubiquitin-specific protease 22 gene restrained cell progression and affected the Akt pathway in nasopharyngeal carcinoma 
Cancer Biology & Therapy  2014;16(1):88-96.
Ubiquitin-specific protease 22 (USP22) is closely related with poor prognosis of cancer patients. However, the role of USP22 expression in nasopharyngeal carcinoma (NPC) has not been determined. The main aim of this study was to determine the role of USP22 in the pathologic processes of NPC. Immunohistochemistry (IHC), western blot (WB), and real-time polymerase chain reaction (RT-PCR) were used to measure the expression of USP22 in cell lines and tissues of NPC in comparison with expression in non-cancerous cells and tissues. USP22-specific short hairpin RNA (shRNA) was used to knock down USP22 expression in the NPC cell line CNE-1 and CNE-2. Furthermore, the impact of USP22 in cellular proliferation, growth, and cell cycle were detected respectively. WB was used to determine the role of USP22 in the AKT/GSK-3/Cyclin signaling pathway. The expression levels of USP22 were remarkably higher in NPC cell lines and tissues. With cell counting and the MTS assay, cellular growth and proliferation progression of USP22 knockdown cell line was shown to be effectively restrained. The USP22 silencing both in CNE-1 and CNE-2 cells caused them to accumulate in the G0/G1 phase of the cell cycle. USP22 knockdown was also found to modulate the AKT/GSK-3/Cyclin pathway, resulting in downregulation of p-AKT, p-GSK-3β, and cyclinD1. This study suggests that USP22 plays a critical regulatory role in the pathologic processes of NPC, and that it may be a potential biological treatment target in the future.
doi:10.4161/15384047.2014.987029
PMCID: PMC4623022  PMID: 25482932
Nasopharyngeal carcinoma; USP22; cell growth; cell proliferation; cell cycle; AKT/GSK-3/Cyclin pathway
9.  Conformational Motions and Functionally Key Residues for Vitamin B12 Transporter BtuCD–BtuF Revealed by Elastic Network Model with a Function-Related Internal Coordinate 
BtuCD–BtuF from Escherichia coli is a binding protein-dependent adenosine triphosphate (ATP)-binding cassette (ABC) transporter system that uses the energy of ATP hydrolysis to transmit vitamin B12 across cellular membranes. Experimental studies have showed that during the transport cycle, the transporter undergoes conformational transitions between the “inward-facing” and “outward-facing” states, which results in the open–closed motions of the cytoplasmic gate of the transport channel. The opening–closing of the channel gate play critical roles for the function of the transporter, which enables the substrate vitamin B12 to be translocated into the cell. In the present work, the extent of opening of the cytoplasmic gate was chosen as a function-related internal coordinate. Then the mean-square fluctuation of the internal coordinate, as well as the cross-correlation between the displacement of the internal coordinate and the movement of each residue in the protein, were calculated based on the normal mode analysis of the elastic network model to analyze the function-related motions encoded in the structure of the system. In addition, the key residues important for the functional motions of the transporter were predicted by using a perturbation method. In order to facilitate the calculations, the internal coordinate was introduced as one of the axes of the coordinate space and the conventional Cartesian coordinate space was transformed into the internal/Cartesian space with linear approximation. All the calculations were carried out in this internal/Cartesian space. Our method can successfully identify the functional motions and key residues for the transporter BtuCD–BtuF, which are well consistent with the experimental observations.
doi:10.3390/ijms160817933
PMCID: PMC4581229  PMID: 26247943
ABC transporter; BtuCD–BtuF; functional motions; key residues; elastic network model; internal coordinate; normal mode analysis; perturbation method
10.  PITX2 Loss-of-Function Mutation Contributes to Congenital Endocardial Cushion Defect and Axenfeld-Rieger Syndrome 
PLoS ONE  2015;10(4):e0124409.
Congenital heart disease (CHD), the most common type of birth defect, is still the leading non-infectious cause of infant morbidity and mortality in humans. Aggregating evidence demonstrates that genetic defects are involved in the pathogenesis of CHD. However, CHD is genetically heterogeneous and the genetic components underpinning CHD in an overwhelming majority of patients remain unclear. In the present study, the coding exons and flanking introns of the PITX2 gene, which encodes a paired-like homeodomain transcription factor 2essential for cardiovascular morphogenesis as well as maxillary facial development, was sequenced in 196 unrelated patients with CHD and subsequently in the mutation carrier’s family members available. As a result, a novel heterozygous PITX2 mutation, p.Q102X for PITX2a, or p.Q148X for PITX2b, or p.Q155X for PITX2c, was identified in a family with endocardial cushion defect (ECD) and Axenfeld-Rieger syndrome (ARS). Genetic analysis of the pedigree showed that the nonsense mutation co-segregated with ECD and ARS transmitted in an autosomal dominant pattern with complete penetrance. The mutation was absent in 800 control chromosomes from an ethnically matched population. Functional analysis by using a dual-luciferase reporter assay system revealed that the mutant PITX2 had no transcriptional activity and that the mutation eliminated synergistic transcriptional activation between PITX2 and NKX2.5, another transcription factor pivotal for cardiogenesis. To our knowledge, this is the first report on the association of PITX2 loss-of-function mutation with increased susceptibility to ECD and ARS. The findings provide novel insight into the molecular mechanisms underpinning ECD and ARS, suggesting the potential implications for the antenatal prophylaxis and personalized treatment of CHD and ARS.
doi:10.1371/journal.pone.0124409
PMCID: PMC4404345  PMID: 25893250
11.  AB98. The study of cell proliferation and apoptosis and autophagy in renal cell carcinoma cells influence by the PI3K/AKT/mTor inhibitor NVP-BEZ235 
Translational Andrology and Urology  2014;3(Suppl 1):AB98.
Objective
The research is to study the cell proliferation and apoptosis and autophagy in renal cell carcinoma cells influence by the PI3K/AKT/mTor inhibitor NVP-BEZ235. Looking for a new treatment strategy of renal cell carcinoma.
Methods
we test the effect of NVP on survival rate, apoptosis and autophagy in the RCC cell line, 786-0. We also explore the hypothesis that NVP, in combination with autophagy inhibitors, leads to apoptosis enhancement in 786-0 cells.
Results
the PI3K/AKT/mTOR pathway proteins p-AKT and p-P70S6K were highly expressed in RCC tissue. We also showed that NVP inhibited cell growth and induced apoptosis and autophagy in RCC cells. The combination treatment of NVP with autophagy inhibitors enhanced the effect of NVP on suppressing 786-0 growth and induction of apoptosis.
Conclusions
PI3K/AKT/mTOR signaling pathways protein in renal cell carcinoma tissues expression levels; PI3K/mTOR inhibitor NVP-BEZ235 can significantly inhibit renal cell 786-0 cell proliferation and promote the occurrence of apoptosis; Autophagy inhibitor can significantly improve the NVP-BEZ235 cause 786-0 proliferation inhibition and apoptosis.
doi:10.3978/j.issn.2223-4683.2014.s098
PMCID: PMC4708368
Renal cell carcinoma; NVP-BEZ235; autophagy; apoptosis
12.  Involvement of the Akt/NF-κB Pathways in the HTNV-Mediated Increase of IL-6, CCL5, ICAM-1, and VCAM-1 in HUVECs 
PLoS ONE  2014;9(4):e93810.
Background
Hantaan virus (HTNV) infection causes a severe form of HFRS(hemorrhagic fever with renal syndrome)in Asia. Although HTNV has been isolated for nearly forty years, the pathogenesis of HFRS is still unknown, and little is known regarding the signaling pathway that is activated by the virus.
Methodology/Principal Findings
Cardamonin was selected as a NF-κB inhibitor, and indirect immunofluorescence assays were used to detect the effect of cardamonin on HTNV-infected HUVECs. The effect of cardamonin on the HTNV-induced phosphorylation of Akt and DNA-binding activity of NF-κB were determined using Western blot analysis and electrophoretic mobility shift assays (EMSAs), respectively. Then, flow cytometric and quantitative real-time PCR analyses were performed to quantify the expression levels of the adhesion molecules ICAM-1 and VCAM-1, and the concentrations of IL-6, IL-8, and CCL5 in HUVEC supernatants were examined using ELISA. The results showed that cardamonin did not effect the proliferation of HUVECs or the replication of HTNV in HUVECs. Instead, cardamonin inhibited the phosphorylation of Akt and nuclear transduction of NF-κB and further reduced the expression of the adhesion molecules ICAM-1 and VCAM-1 in HTNV-infected HUVECs. Cardamonin also inhibited the secretion of IL-6 and CCL5, but not IL-8.
Conclusion/Significance
HTNV replication may not be dependent upon the ability of the virus to activate NF-κB in HUVECs. The Akt/NF-κB pathways may be involved in the pathogenesis of HFRS; therefore, cardamonin may serve as a potential beneficial agent for HFRS therapy.
doi:10.1371/journal.pone.0093810
PMCID: PMC3979720  PMID: 24714064
13.  Stability and Synchronization for Discrete-Time Complex-Valued Neural Networks with Time-Varying Delays 
PLoS ONE  2014;9(4):e93838.
In this paper, the synchronization problem for a class of discrete-time complex-valued neural networks with time-varying delays is investigated. Compared with the previous work, the time delay and parameters are assumed to be time-varying. By separating the real part and imaginary part, the discrete-time model of complex-valued neural networks is derived. Moreover, by using the complex-valued Lyapunov-Krasovskii functional method and linear matrix inequality as tools, sufficient conditions of the synchronization stability are obtained. In numerical simulation, examples are presented to show the effectiveness of our method.
doi:10.1371/journal.pone.0093838
PMCID: PMC3979734  PMID: 24714386
14.  Identification of latent tuberculosis infection-related microRNAs in human U937 macrophages expressing Mycobacterium tuberculosis Hsp16.3 
BMC Microbiology  2014;14:37.
Background
Latent tuberculosis infection (LTBI) relies on a homeostasis of macrophages and Mycobacterium tuberculosis (Mtb). The small heat shock protein, Mtb Hsp16.3 (also known as latency-associated antigen), plays an important role in Mtb persistence within macrophages. However, the mechanism of LTBI remains elusive. The aim of this study was to delineate LTBI-related miRNA expression in U937 macrophages expressing Mtb Hsp16.3 protein. U937 macrophages were infected with an integrase-deficient Lentivirus vector to transiently express Mtb Hsp16.3, and green fluorescent protein (GFP) as a control. We used a microRNA (miRNA) microarray chip containing more than 1000 probes to identify the significant differentially expressed miRNAs in the infected U937 cells, and employed real-time quantitative polymerase chain reaction (qRT-PCR) for validation. Furthermore, we confirmed these candidate LTBI-related miRNAs in peripheral blood mononuclear cells from subjects with LTBI and in healthy control individuals. Functional annotation prediction of miRNA target genes and pathway enrichment analyses were used to explore the putative links between these miRNAs and LTBI.
Results
Analysis of the miRNA expression profile identified 149 miRNAs that were differentially expressed in U937 macrophages expressing Mtb Hsp16.3 compared with the control expressing GFP. The expression level of seven miRNAs (miR-424-5p, miR-493-5p, miR-296-5p, miR-27b-3p, miR-377-5p, miR-3680-5p, miR-191-5p) were validated by qRT-PCR. The expression level of four miRNAs (miR-424-5p, miR-27b-3p, miR-377-5p, miR-3680-5p) in the peripheral blood mononuclear cells samples from LTBI and healthy participants reflected the altered patterns observed in the microarray profile. The bioinformatic analyses suggest that the miRNAs may regulate Mtb latent infection by affecting the development of macrophage cells.
Conclusions
The results suggest that miRNA expression may play a considerable role in the pathogenesis of LTBI, and this would increase our understanding of the molecular basis of Hsp16.3-facilitated Mtb survival in macrophages.
doi:10.1186/1471-2180-14-37
PMCID: PMC3925440  PMID: 24521422
microRNAs; Macrophages; Mycobacterium; Tuberculosis; Small heat shock protein; Latent tuberculosis infection
15.  Analysis of an Outbreak of Hemorrhagic Fever with Renal Syndrome in College Students in Xi’an, China 
Viruses  2014;6(2):507-515.
The aim of the present study was to analyze an outbreak of hemorrhagic fever with renal syndrome (HFRS), caused by a Hantavirus, in college students in the northern urban area of Xi’an in 2012. The outbreak affected six students and included two deaths. The epidemiological survey revealed that both of the deceased cases were misdiagnosed initially, and treatment was delayed. Furthermore, a higher rodent population density and lower HFRS vaccine coverage were observed in the affected area, which indicates a possible role in the outbreak. Rattus norvegicus (Rn) and Mus musculus (Mm) were the predominant host populations in the area. Genotyping revealed that all HVs from patients and rodents were Hantaan virus (HTNV). Sequence analysis of the S segments revealed that the HTNVs reported in this study had high similarity with strains reported in 2011 and 1985, but these viruses diverged from a strain isolated in 1984 and the HTNV prototype strain 76-118. Detection of anti-HV IgG and amplification of the S segment of HTNV from a non-natural HTNV reservoir indicates that further investigations by increased rodent trapping are necessary.
doi:10.3390/v6020507
PMCID: PMC3939468  PMID: 24481251
Hantaan virus; hemorrhagic fever with renal syndrome; outbreak; Xi’an City
16.  Mutation spectrum of GATA4 associated with congenital atrial septal defects 
Introduction
Congenital atrial septal defect (ASD) is the second commonest form of cardiac developmental anomaly, responsible for substantial morbidity and mortality in affected individuals. Previous studies have implicated genetic defects in the pathogenesis of ASD. However, ASD is largely a genetically heterogeneous disease and the genetic determinants for ASD in the majority of patients remain to be identified.
Material and methods
The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 220 unrelated patients with ASD. The available relatives of the patients harboring the identified mutations and 200 unrelated ethnicity-matched control individuals were genotyped.
Results
Four heterozygous missense GATA4 mutations, p.P36S, p.H190R, p.S262A, and p.V399G, were identified in four unrelated patients with ASD, respectively. These mutations were neither detected in 200 control individuals nor described in the human SNP database. Alignment of multiple GATA4 protein sequences across species indicated that the affected amino acids were highly conserved evolutionarily. Genetic analysis of the available relatives of the mutation carriers showed that in each family the mutation co-segregated with ASD.
Conclusions
The findings expand the spectrum of mutations in GATA4 linked to ASD and provide new insight into the molecular etiology associated with ASD, suggesting the potential implications for the genetic diagnosis and gene-specific therapy for this prevalent cardiovascular abnormality in humans.
doi:10.5114/aoms.2013.39788
PMCID: PMC3902718  PMID: 24482639
atrial septal defect; transcription factor; genetics
17.  Impaired Cardiac SIRT1 Activity by Carbonyl Stress Contributes to Aging-Related Ischemic Intolerance 
PLoS ONE  2013;8(9):e74050.
Reactive aldehydes can initiate protein oxidative damage which may contribute to heart senescence. Sirtuin 1 (SIRT1) is considered to be a potential interventional target for I/R injury management in the elderly. We hypothesized that aldehyde mediated carbonyl stress increases susceptibility of aged hearts to ischemia/reperfusion (I/R) injury, and elucidate the underlying mechanisms with a focus on SIRT1. Male C57BL/6 young (4-6 mo) and aged (22-24 mo) mice were subjected to myocardial I/R. Cardiac aldehyde dehydrogenase (ALDH2), SIRT1 activity and protein carbonyls were assessed. Our data revealed that aged heart exhibited increased endogenous aldehyde/carbonyl stress due to impaired ALDH2 activity concomitant with blunted SIRT1 activity (P<0.05). Exogenous toxic aldehydes (4-HNE) exposure in isolated cardiomyocyte verified that aldehyde-induced carbonyl modification on SIRT1 impaired SIRT1 activity leading to worse hypoxia/reoxygenation (H/R) injury, which could all be rescued by Alda-1 (ALDH2 activator) (all P<0.05). However, SIRT1 inhibitor blocked the protective effect of Alda-1 on H/R cardiomyocyte. Interestingly, myocardial I/R leads to higher carbonylation but lower activity of SIRT1 in aged hearts than that seen in young hearts (P<0.05). The application of Alda-1 significantly reduced the carbonylation on SIRT1 and markedly improved the tolerance to in vivo I/R injury in aged hearts, but failed to protect Sirt1+/− knockout mice against myocardial I/R injury. This was verified by Alda-1 treatment improved postischemic contractile function recovery in ex vivo perfused aged but not in Sirt1+/− hearts. Thus, aldehyde/carbonyl stress is accelerated in aging heart. These results provide a new insight that impaired cardiac SIRT1 activity by carbonyl stress plays a critical role in the increased susceptibility of aged heart to I/R injury. ALDH2 activation can restore this aging-related myocardial ischemic intolerance.
doi:10.1371/journal.pone.0074050
PMCID: PMC3769351  PMID: 24040162
18.  Ginsenoside Rd Attenuates Myocardial Ischemia/Reperfusion Injury via Akt/GSK-3β Signaling and Inhibition of the Mitochondria-Dependent Apoptotic Pathway 
PLoS ONE  2013;8(8):e70956.
Evidence suggests Ginsenoside Rd (GSRd), a biologically active extract from the medical plant Panax Ginseng, exerts antioxidant effect, decreasing reactive oxygen species (ROS) formation. Current study determined the effect of GSRd on myocardial ischemia/reperfusion (MI/R) injury (a pathological condition where ROS production is significantly increased) and investigated the underlying mechanisms. The current study utilized an in vivo rat model of MI/R injury and an in vitro neonatal rat cardiomyocyte (NRC) model of simulated ischemia/reperfusion (SI/R) injury. Infarct size was measured by Evans blue/TTC double staining. NRC injury was determined by MTT and lactate dehydrogenase (LDH) leakage assay. ROS accumulation and apoptosis were assessed by flow cytometry. Mitochondrial membrane potential (MMP) was determined by 5, 5′, 6, 6′-tetrachloro-1, 1′, 3, 3′-tetrathylbenzimidazol carbocyanine iodide (JC-1). Cytosolic translocation of mitochondrial cytochrome c and expression of caspase-9, caspase-3, Bcl-2 family proteins, and phosphorylated Akt and GSK-3β were determined by western blot. Pretreatment with GSRd (50 mg/kg) significantly augmented rat cardiac function, as evidenced by increased left ventricular ejection fraction (LVEF) and ±dP/dt. GSRd reduced myocardial infarct size, apoptotic cell death, and blood creatine kinase/lactate dehydrogenase levels after MI/R. In NRCs, GSRd (10 µM) inhibited SI/R-induced ROS generation (P<0.01), decreased cellular apoptosis, stabilized the mitochondrial membrane potential (MMP), and attenuated cytosolic translocation of mitochondrial cytochrome c. GSRd inhibited activation of caspase-9 and caspase-3, increased the phosphorylated Akt and GSK-3β, and increased the Bcl-2/Bax ratio. Together, these data demonstrate GSRd mediated cardioprotective effect against MI/R–induced apoptosis via a mitochondrial-dependent apoptotic pathway.
doi:10.1371/journal.pone.0070956
PMCID: PMC3745454  PMID: 23976968
19.  GATA5 loss-of-Function Mutations Underlie Tetralogy of Fallot 
Tetraology of Fallot (TOF) is the most common form of cyanotic congenital heart disease and is a major cause of significant morbidity and mortality. Emerging evidence demonstrates that genetic risk factors are involved in the pathogenesis of TOF. However, TOF is genetically heterogeneous and the genetic defects responsible for TOF remain largely unclear. In the present study, the whole coding region of the GATA5 gene, which encodes a zinc-finger transcription factor essential for cardiogenesis, was sequenced in 130 unrelated patients with TOF. The relatives of the index patients harboring the identified mutations and 200 unrelated control individuals were subsequently genotyped. The functional characteristics of the mutations were analyzed using a luciferase reporter assay system. As a result, 2 novel heterozygous GATA5 mutations, p.R187G and p.H207R, were identified in 2 families with autosomal dominantly inherited TOF, respectively. The variations were absent in 400 control alleles and the altered amino acids were completely conserved evolutionarily. Functional analysis showed that the GATA5 mutants were associated with significantly decreased transcriptional activation compared with their wild-type counterpart. To our knowledge, this is the first report on the association of GATA5 loss-of-function mutations with TOF, suggesting potential implications for the early prophylaxis and allele-specific therapy of human TOF.
doi:10.7150/ijms.5270
PMCID: PMC3534875  PMID: 23289003
Congenital heart disease; Tetralogy of Fallot; Genetics; Transcription factor; GATA5.
20.  Novel GATA4 mutations in patients with congenital ventricular septal defects 
Summary
Background
Ventricular septal defect (VSD) is the most prevalent type of congenital heart disease and is a major cause of substantial morbidity and mortality in infants. Accumulating evidence implicates genetic defects, especially in cardiac transcription factors, in the pathogenesis of VSD. However, VSD is genetically heterogeneous and the genetic determinants for VSD in most patients remain to be identified.
Material/Methods
A cohort of 230 unrelated patients with congenital VSD was included in the investigation. A total of 200 unrelated ethnically matched healthy individuals were recruited as controls. The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced initially in 230 unrelated VSD patients. The available relatives of the mutation carriers and 200 control subjects were subsequently genotyped for the presence of identified mutations.
Results
Four heterozygous missense GATA4 mutations of p.Q55R, p.G96R, p.N197S, and p.K404R were identified in 4 unrelated patients with VSD. These mutations were not detected in 200 control individuals nor described in the human SNP database. Genetic analysis of the relatives of the mutation carriers showed that in each family the mutation co-segregated with VSD.
Conclusions
These findings expand the mutation spectrum of GATA4 linked to VSD and provide new insight into the molecular etiology responsible for VSD, suggesting potential implications for the genetic diagnosis and gene-specific therapy for VSD.
doi:10.12659/MSM.882877
PMCID: PMC3560722  PMID: 22648249
ventricular septal defect; transcription factor; genetics
21.  High expression of p300 is linked to aggressive features and poor prognosis of Nasopharyngeal Carcinoma 
Background
Increased expression of transcriptional coactivator p300 has been observed in a variety of human cancers. However, the expression status of p300 protein/mRNA in nasopharyngeal carcinoma (NPC) tissues and its clinicopathologic/prognostic implication are poorly understood.
Methods
In our study, mRNA and protein expression levels of p300 was explored by reverse transcription-polymerase chain reaction (RT-PCR), Western blotting (WB) and immunohistochemistry (IHC) in nasopharyngeal mucosal and NPC tissues. The data were analyzed by receiver operating characteristic (ROC) curve analysis, spearman’s rank correlation, Kaplan-Meier plots and Cox proportional hazards regression model.
Results
Up-regulated expression of p300 mRNA/p300 protein was detected in NPC tissues by RT-PCR and WB, when compared to nasopharyngeal mucosal tissues. Based on ROC curve analysis, the cutoff score for p300 high expression was defined when more than 35% of the tumor cells were positively stained. High expression of p300 was observed in 127/209 (60.7%) of NPCs. In NPCs, high expression of p300 was positively associated with later T classification, later N classification, distant metastasis and later clinical stage (P < 0.05). In univariate survival analysis, overexpression of p300 was found to be an indicator of progression-free (P = 0.002) and overall survival (P = 0.001) in NPCs. More importantly, p300 expression was evaluated as an independent prognostic factor for NPC in multivariate analysis (P = 0.036).
Conclusions
Our findings support that high expression of p300 protein might be important in conferring a more aggressive behavior, and is an independent molecular marker for shortened survival time of patients with NPC.
doi:10.1186/1479-5876-10-110
PMCID: PMC3484019  PMID: 22647238
Nasopharyngeal carcinoma; p300; Immunohistochemistry; Prognosis
22.  Gambogic acid inhibits TNF-α-induced invasion of human prostate cancer PC3 cells in vitro through PI3K/Akt and NF-κB signaling pathways 
Acta Pharmacologica Sinica  2012;33(4):531-541.
Aim:
To investigate the mechanisms underlying the inhibitory effect of gambogic acid (GA) on TNF-α-induced metastasis of human prostate cancer PC3 cells in vitro.
Methods:
TNF-α-mediated migration and invasion of PC3 cells was examined using migration and invasion assays, respectively. NF-κB transcriptional activity and nuclear translocation were analyzed with luciferase reporter gene assays, immunofluorescence assays and Western blots. The ability of p65 to bind the promoter of Snail, an important mesenchymal molecular marker, was detected using a chromatin immunoprecipitation (ChIP) assay. After treatment with Snail-specific siRNA, the expression of invasiveness-associated genes was measured using quantitative real-time PCR and Western blot.
Results:
GA significantly inhibited the viability of PC3 cells at 1–5 μmol/L, but did not produce cytotoxic effect at the concentrations below 0.5 μmol/L. GA (0.125–0.5 μmol/L) dose-dependently inhibited the migration and invasion of PC3 cells induced by TNF-α (10 ng/mL). Moreover, the TNF-α-mediated activation of phosphatidylinositol-3-OH kinase/protein kinase B (PI3K/Akt) and NF-κB pathways was suppressed by GA (0.5 μmol/L). Furthermore, this anti-invasion effect of GA was associated with regulation of Snail. Snail expression was significantly down-regulated by treatment with GA (0.5 μmol/L) in the TNF-α-stimulated PC3 cells.
Conclusion:
GA inhibits TNF-α-induced invasion of PC3 cells via inactivation of the PI3K/Akt and NF-κB signaling pathways, which may offer a novel approach for the treatment of human prostate cancer.
doi:10.1038/aps.2011.180
PMCID: PMC4003358  PMID: 22426696
gambogic acid; human prostate cancer; tumor metastasis; tumor invasion; tumor necrosis factor-α (TNF-α); PI3K/Akt signaling pathway; NF-κB signaling pathway; Snail
23.  Hemoglobin levels and anemia evaluation during pregnancy in the highlands of Tibet: a hospital-based study 
BMC Public Health  2009;9:336.
Background
Anemia is regarded as a major risk factor for unfavorable pregnancy outcomes, but there have been no previous studies describing the pattern of hemoglobin concentration during pregnancy in Tibet and the relationship between altitude and Hb concentration in the pregnant women living in Tibet still has not been clearly established. The main objectives of this study were to study the hemoglobin levels and prevalence of anemia among pregnant women living in the highlands of Tibet and to evaluate potential associations of hemoglobin and anemia with women's characteristics.
Methods
The hospital-based study was conducted in 380 pregnant women. Their blood samples were tested and related sociodemographic information was collected. Multiple linear regression model and multiple logistic regression model were used to assess the association of pregnant women's characteristics with hemoglobin level and the occurrence of anemia. Centers for Disease Control (CDC), Dirren et al. and Dallman et al. methods were used to adjust the hemoglobin measurements based on altitude for estimating the prevalence of anemia.
Results
The mean hemoglobin concentration was 127.6 g/L (range: 55.0-190.0 g/L). Prevalence rate of anemia in this study was 70.0%, 77.9% and 41.3%, respectively for three altitude-correction methods for hemoglobin (CDC method, Dirren et al. method, and Dallman et al. method). Gestational age, ethnicity, residence and income were significantly associated with the hemoglobin concentration and prevalence of anemia in the study population. Specially, the hemoglobin concentration of pregnant women decreased with increase in gestational age.
Conclusion
The hemoglobin level was low and prevalence rate of anemia was high among pregnant women in Lhasa, Tibet. Gestational age, ethnicity, residence and income were found to be significantly associated with the hemoglobin level and the occurrence of anemia in the study population.
doi:10.1186/1471-2458-9-336
PMCID: PMC2753353  PMID: 19754927
24.  Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-fluorouracil antitumor activity through activation of the PPARγ signaling pathway 
Acta Pharmacologica Sinica  2009;30(9):1316-1322.
Aim:
Resistance to 5-fluorouracil (5-FU) is a major cause of chemotherapy failure in advanced hepatocellular carcinoma (HCC).Rosiglitazone, a peroxisome proliferator-activated receptor γ (PPARγ) agonist, has a crucial role in growth inhibition and induction of apoptosis in several carcinoma cell lines. In this study, we examine rosiglitazone-induced sensitization of HCC cell lines (BEL-7402 and Huh-7 cells) to 5-FU.
Methods:
The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) assay was used to evaluate cell viability. Western blotting analysis was performed to detect the protein expression (PPARγ, PTEN, and COX-2) in BEL-7402 cells. Immunohistochemistry staining was used to examine the expression of PTEN in 100 advanced HCC tissues and paracancerous tissues. In addition, small interfering RNA was used to suppress PPARγ, PTEN, and COX-2 expression.
Results:
Rosiglitazone facilitates the anti-tumor effect of 5-FU in HCC cell lines, which is mediated by the PPARγ signaling pathway. Activation of PPARγ by rosiglitazone increases PTEN expression and decreases COX-2 expression. Since distribution of PTEN in HCC tissues is significantly decreased compared with the paracancerous tissue, over-expression of PTEN by rosiglitazone enhances 5-FU-inhibited cell growth of HCC. Moreover, down-regulation of COX-2 is implicated in the synergistic effect of 5-FU.
Conclusion:
Rosiglitazone sensitizes hepatocellular carcinoma cell lines to 5-FU antitumor activity through the activation of PPARγ. The results suggest potential novel therapies for the treatment of advanced liver cancer.
doi:10.1038/aps.2009.119
PMCID: PMC4007181  PMID: 19684609
rosiglitazone; hepatocellular carcinoma; PTEN; PPARγ; 5-fluorouracil
25.  Evaluation of a portable hemoglobin photometer in pregnant women in a high altitude area: a pilot study 
BMC Public Health  2009;9:228.
Background
Anemia is a widespread public health problem associated with an increased risk of morbidity and mortality, especially in pregnant women. This study examined the agreement between a portable hemoglobin photometer and a laboratory analyzer in determining hemoglobin level in pregnant women.
Methods
This study recruited 69 pregnant women in Tibet, China. Capillary blood samples were taken to measure hemoglobin concentration using the hemoglobin photometer and the laboratory analyzer. Limit of agreement, concordance and intraclass correlation coefficient were used to evaluate the agreement. Laboratory measurement was considered as the standard reference method. Sensitivity and specificity were calculated to assess the error in screening for anemia.
Results
Mean difference between the two methods was -2.1 g/l. wide 95% limits of agreement were found (-22.6 g/l to 18.4 g/l). The intraclass correlation coefficient was 0.795, and concordance correlation coefficient was 0.793. Sensitivity and specificity were 94.9% and 76.7% respectively. Positive predictive value was 84.1%, and negative predictive value was 92.0%.
Conclusion
This hemoglobin photometer is not recommended for determining hemoglobin concentration in pregnancy in a high altitude area.
doi:10.1186/1471-2458-9-228
PMCID: PMC2717084  PMID: 19591672

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