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1.  Inhibition of AMPK expression in skeletal muscle by systemic inflammation in COPD rats 
Respiratory Research  2014;15(1):156.
Background
Chronic obstructive pulmonary disease (COPD) is a disease characterized by airflow limitation and inflammation. Meanwhile, COPD also is associated with metabolic disorders, such as skeletal muscle weakness. Strikingly, activation of AMP-activated protein kinase (AMPK) exerts critical roles in energy metabolism. However, it remains unclear whether and how the expression levels of AMPK are affected in the COPD model rats which may lead to the dysfunction of the skeletal muscle in these rats.
Methods
Here we developed a rat model of COPD, and we investigated the morphological changes of peripheral skeletal muscle and measured the levels of tumor necrosis factor -α (TNF-α) and AMPK in skeletal muscle by using approaches that include immunohistochemistry and polymerase chain reaction (PCR).
Results
We found that the expression levels of both AMPK mRNA and protein in skeletal muscles were significantly reduced in the COPD model rats, in comparison to those from the control rats, the COPD model rats that received treatments with AICAR and resveratrol, whereas the expression levels of TNF-α were elevated in COPD rats.
Conclusion
Such findings indicate that AMPK may serve as a target for therapeutic intervention in the treatment of muscle weakness in COPD patients.
doi:10.1186/s12931-014-0156-4
PMCID: PMC4265440  PMID: 25481457
2.  Spatiotemporal Transmission Dynamics of Hemorrhagic Fever with Renal Syndrome in China, 2005–2012 
Background
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem with 90% of the total reported cases in the world. This study describes the spatiotemporal dynamics of HFRS cases in China and identifies the regions, time, and populations at highest risk, which could help the planning and implementation of key preventative measures.
Methods
Data on all reported HFRS cases at the county level from January 2005 to December 2012 were collected from Chinese Center for Disease Control and Prevention. Geographic Information System-based spatiotemporal analyses including Local Indicators of Spatial Association and Kulldorff's space-time scan statistic were performed to detect local high-risk space-time clusters of HFRS in China. In addition, cases from high-risk and low-risk counties were compared to identify significant demographic differences.
Results
A total of 100,868 cases were reported during 2005–2012 in mainland China. There were significant variations in the spatiotemporal dynamics of HFRS. HFRS cases occurred most frequently in June, November, and December. There was a significant positive spatial autocorrelation of HFRS incidence during the study periods, with Moran's I values ranging from 0.46 to 0.56 (P<0.05). Several distinct HFRS cluster areas were identified, mainly concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties.
Conclusions
This study identified significant space-time clusters of HFRS in China during 2005–2012 indicating that preventative strategies for HFRS should be particularly focused on the northeastern, central, and eastern of China to achieve the most cost-effective outcomes.
Author Summary
Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne viral disease caused by many serotypes of hantaviruses. In China, HFRS has been recognized as a severe public health problem and accounts for 90% of the reported cases in the world. We examined the spatiotemporal dynamics of HFRS cases in China during 2005–2012 and compared characteristics between cases from high-risk and low-risk counties. Several distinct HFRS cluster areas were identified, concentrated in northeastern, central, and eastern of China. Compared with cases from low-risk areas, a higher proportion of cases were younger, non-farmer, and floating residents in high-risk counties. These findings suggest preventative strategies for HFRS should be focused on the identified clusters in order to achieve the most cost-effective outcomes.
doi:10.1371/journal.pntd.0003344
PMCID: PMC4239011  PMID: 25412324
3.  Connexin 32 and 43 promoter methylation in Helicobacter pylori-associated gastric tumorigenesis 
World Journal of Gastroenterology : WJG  2014;20(33):11770-11779.
AIM: To explore the mechanism of abnormal Connexin (Cx) 32 and Cx43 expression in the gastric mucosa after Helicobacter pylori (H. pylori) infection.
METHODS: Biopsy specimens of gastric mucosa in different gastric carcinogenesis stages with H. pylori infection, that is, non-atrophic gastritis (NAG; n = 24), chronic atrophic gastritis (CAG; n = 25), intestinal metaplasia (IM; n = 28), dysplasia (DYS; n = 24), and gastric cancer (GC; n = 30), as well as specimens of normal gastric mucosa without H. pylori infection (NGM; n = 25), were confirmed by endoscopy and pathological examination. Cx32 and Cx43 mRNA expression was detected by real-time polymerase chain reaction (PCR). Cx32 and Cx43 promoter CpG island methylation status was determined by methylation-specific PCR (MSP), bisulfite PCR sequencing (BSP) and MassArray methods.
RESULTS: The relative mRNA expression levels in the gastric mucosa of patients with NGM, NAG, CAG, IM, DYS and GC were 0.146 ± 0.011, 0.133 ± 0.026, 0.107 ± 0.035, 0.039 ± 0.032, 0.037 ± 0.01 and 0.03 ± 0.011 for Cx32; and 0.667 ± 0.057, 0.644 ± 0.051, 0.624 ± 0.049, 0.555 ± 0.067, 0.536 ± 0.058 and 0.245 ± 0.121 for Cx43, respectively, which were gradually decreasing and significantly different (GC vs NGM: P < 0.001 for Cx32, P < 0.001 for Cx43). The promoter methylation levels in the gastric mucosa from NGM to GC stages by MSP were 38.8% ± 9.0%, 43.1% ± 9.4%, 56.5% ± 3.1%, 64.4% ± 9.7%, 72.5% ± 4.2% and 79.6% ± 6.8% for Cx32; and 49.0% ± 3.9%, 58.1% ± 5.0%, 66.5% ± 7.9%, 74.0% ± 8.8%, 78.3% ± 3.6% and 88.7% ± 6.2% for Cx43, respectively, which were gradually increasing and significantly different (P = 0.039, P = 0.019). The promoter methylation levels by BSP and MassArray exhibited similar trends. Cx32 and Cx43 mRNA expression was negatively correlated with promoter methylation status and gastric carcinogenesis stages (P < 0.001, P = 0.016).
CONCLUSION: Cx32 and Cx43 mRNA expression decreased gradually during H. pylori infection-associated gastric carcinogenesis, and it is associated with hypermethylation of these genes’ promoter.
doi:10.3748/wjg.v20.i33.11770
PMCID: PMC4155367  PMID: 25206281
Gastric cancer; Helicobacter pylori; Cx32; Cx43; DNA methylation
4.  Rough Set Approach to Incomplete Multiscale Information System 
The Scientific World Journal  2014;2014:538968.
Multiscale information system is a new knowledge representation system for expressing the knowledge with different levels of granulations. In this paper, by considering the unknown values, which can be seen everywhere in real world applications, the incomplete multiscale information system is firstly investigated. The descriptor technique is employed to construct rough sets at different scales for analyzing the hierarchically structured data. The problem of unravelling decision rules at different scales is also addressed. Finally, the reduct descriptors are formulated to simplify decision rules, which can be derived from different scales. Some numerical examples are employed to substantiate the conceptual arguments.
doi:10.1155/2014/538968
PMCID: PMC4151588  PMID: 25276852
5.  δ-Cut Decision-Theoretic Rough Set Approach: Model and Attribute Reductions 
The Scientific World Journal  2014;2014:382439.
Decision-theoretic rough set is a quite useful rough set by introducing the decision cost into probabilistic approximations of the target. However, Yao's decision-theoretic rough set is based on the classical indiscernibility relation; such a relation may be too strict in many applications. To solve this problem, a δ-cut decision-theoretic rough set is proposed, which is based on the δ-cut quantitative indiscernibility relation. Furthermore, with respect to criterions of decision-monotonicity and cost decreasing, two different algorithms are designed to compute reducts, respectively. The comparisons between these two algorithms show us the following: (1) with respect to the original data set, the reducts based on decision-monotonicity criterion can generate more rules supported by the lower approximation region and less rules supported by the boundary region, and it follows that the uncertainty which comes from boundary region can be decreased; (2) with respect to the reducts based on decision-monotonicity criterion, the reducts based on cost minimum criterion can obtain the lowest decision costs and the largest approximation qualities. This study suggests potential application areas and new research trends concerning rough set theory.
doi:10.1155/2014/382439
PMCID: PMC4132342  PMID: 25147847
6.  Features and Risk Factors of Nonfatal Injury among the Rural Children: A Survey of Seven Schools in a Mountain Area in Southwest China 
PLoS ONE  2014;9(7):e102099.
Objective
We aimed to investigate the patterns and risk factors of nonfatal injuries among rural mountain-area children in southwest China.
Methods
A stratified sampling method was used to recruit rural children aged 8 to 17 years (mainly 9–14 years) from 7 schools. Self-reported injuries during the past 12 months and relevant concerns were collected from June to December 2012 by using a structured questionnaire in a class interview.
Results
The mean age of the 2,854 children was 12.2±1.5 years. The probability of annual injury was 16.7% (95% confidence interval [95% CI] 15.3–18.1%), with slightly higher injury risk for boys than girls (17.7% vs. 16.0%; P>0.05). The top 3 causes of injuries were falls (37.3%), animal-related incidents (20.6%), and burns (14.9%). The main injury risk factors included being involved in a violent episode (odds ratio [OR] 1.34, 95% CI 1.08–1.66, P = 0.007), maltreatment by parents or guardians (1.42, 1.17–1.72, P<0.001), and being from a single-child family (1.30, 1.10–1.66, P = 0.039). Older age was a protective factor (0.81, 0.76–0.87, P<0.001).
Conclusions
The incidence of nonfatal injury among rural children was high, and falls were the leading cause. Younger children and boys from poor-care and poor-living environments were at increased risk of injury, which requires urgent attention. Injury prevention programs targeting these issues are needed in this mountain area and similar rural regions of China.
doi:10.1371/journal.pone.0102099
PMCID: PMC4092098  PMID: 25010712
7.  Identification of Novel Surface-Exposed Proteins of Rickettsia rickettsii by Affinity Purification and Proteomics 
PLoS ONE  2014;9(6):e100253.
Rickettsia rickettsii, the causative agent of Rocky Mountain spotted fever, is the most pathogenic member among Rickettsia spp. Surface-exposed proteins (SEPs) of R. rickettsii may play important roles in its pathogenesis or immunity. In this study, R. rickettsii organisms were surface-labeled with sulfo-NHS-SS-biotin and the labeled proteins were affinity-purified with streptavidin. The isolated proteins were separated by two-dimensional electrophoresis, and 10 proteins were identified among 23 protein spots by electrospray ionization tandem mass spectrometry. Five (OmpA, OmpB, GroEL, GroES, and a DNA-binding protein) of the 10 proteins were previously characterized as surface proteins of R. rickettsii. Another 5 proteins (Adr1, Adr2, OmpW, Porin_4, and TolC) were first recognized as SEPs of R. rickettsii herein. The genes encoding the 5 novel SEPs were expressed in Escherichia coli cells, resulting in 5 recombinant SEPs (rSEPs), which were used to immunize mice. After challenge with viable R. rickettsii cells, the rickettsial load in the spleen, liver, or lung of mice immunized with rAdr2 and in the lungs of mice immunized with other rSEPs excluding rTolC was significantly lower than in mice that were mock-immunized with PBS. The in vitro neutralization test revealed that sera from mice immunized with rAdr1, rAdr2, or rOmpW reduced R. rickettsii adherence to and invasion of vascular endothelial cells. The immuno-electron microscopic assay clearly showed that the novel SEPs were located in the outer and/or inner membrane of R. rickettsii. Altogether, the 5 novel SEPs identified herein might be involved in the interaction of R. rickettsii with vascular endothelial cells, and all of them except TolC were protective antigens.
doi:10.1371/journal.pone.0100253
PMCID: PMC4065002  PMID: 24950252
8.  Microarray of surface-exposed proteins of rickettsia heilongjiangensis for serodiagnosis of Far-eastern spotted fever 
BMC Infectious Diseases  2014;14:332.
Background
Far-eastern spotted fever (FESF) is an important emerging infectious disease in Northeast Asia. The laboratory diagnosis of FESF in hospitals is mainly based on serological methods. However, these methods need to cultivate rickettsial cells as diagnostic antigens, which is both burdensome and dangerous.
Methods
Eleven surface-exposed proteins (SEPs) were identified in our previous study and their recombinant proteins (rSEPs) fabricated on a microarray were serologically analyzed with seventeen paired sera from patients suffered from FESF in this study.
Results
All the rSEPs showed sensitivities of between 53% and 82% to acute-phase sera and of between 65% and 82% to convalescent-phase sera, and all the rSEPs except rRplA showed specificities of between 80% and 95%. The combination assay of two, three, or four of the four rSEPs (rOmpA-2, rOmpB-3, rRpsB, and rSdhB) showed better sensitivities of between 76% and 94% to the acute-phase sera or between 82% and 100% to the convalescent-phase sera and acceptable specificities of between 75% and 90%.
Conclusions
Our results suggest that the four rSEPs are more likely candidate antigens for serological diagnosis of FESF.
doi:10.1186/1471-2334-14-332
PMCID: PMC4071148  PMID: 24938647
Far-eastern spotted fever; Rickettsia heilongjiangensis; Protein microarray; Serological diagnosis
9.  Epidemiology of bronchial asthma and asthma control assessment in Henan Province, China 
Background
Prevalence of bronchial asthma, asthma treatment assessment, and estimation of the control level among asthma patients in Henan Province, China are reported in this paper.
Methods
We selected 10 among the 109 cities and districts in Henan province using a multistage stratified cluster random sampling method. A total of 500 households from each city and district were chosen. Approximately 20,000 residents from a total of 5,000 households were randomly selected to answer a questionnaire recommended by the China Asthma Alliance. Asthma patients were asked to answer a detailed questionnaire using the symptom-based guidelines to assess the levels of disease control.
Results
The overall prevalence of asthma was 0.73% ± 0.12%. Urban and rural residents had asthma prevalence rates of 1.1% ± 0.23% (88/7,924) and 0.48% ± 0.12% (57/11,792), respectively. Among the asthma patients, only 33.8% (52) received regular medication, 25% (13) used oral glucocorticoids, and 71.1% (37) used oral theophylline. The classified control levels of patients were as follows: 33.1% controlled, 49.7% partially controlled, and 17.2% uncontrolled. A total of 38.5% and 27.5% of regularly and irregularly treated asthma patients reached controlled level, respectively. The two groups significantly differed in asthma control level.
Conclusion
Asthma prevalence is low in Henan Province, China. Urban residents have higher prevalence of asthma than rural residents do. Patients with asthma receive insufficient medication, resulting in suboptimal asthma control. Improvement in diagnosis and treatment of asthma patients is urgently needed.
doi:10.1186/2213-0802-2-5
PMCID: PMC4215820  PMID: 25505697
Prevalence; Socioeconomic status; Medications for asthma; Asthma control; Asthma guideline
10.  Lateral ventricular cystic meningioma: 2 rare case reports 
Cystic meningioma is an uncommon meningioma variant that is often difficult to distinguish from other intra-axial tumors, including necrotic gliomas. Cystic meningiomas located in the ventricle are particularly rare and may be misdiagnosed with other brain tumors, including ependymoma, choroid plexus papilloma and neurocytoma, due to its location. The present study discusses two cases of lateral ventricular meningiomas, which exhibited intratumoral or peritumoral cystic changes on magnetic resonance imaging scans. The two patients underwent surgical treatment and histological examination confirmed one case of metaplastic meningioma and the other case of psammomatous meningioma. The two patients were middle-aged females and had been misdiagnosed prior to surgery. Although this clinical entity is rare, the diagnosis of meningioma should be considered, particularly in middle-aged female patients.
doi:10.3892/etm.2014.1550
PMCID: PMC3991485  PMID: 24940445
cystic meningioma; intraventricular meningioma; magnetic resonance imaging; diagnosis
11.  Exploratory Study on Th1 Epitope-Induced Protective Immunity against Coxiella burnetii Infection 
PLoS ONE  2014;9(1):e87206.
Coxiella burnetii is a Gram-negative bacterium that causes Q fever in humans. In the present study, 131 candidate peptides were selected from the major immunodominant proteins (MIPs) of C. burnetii due to their high-affinity binding capacity for the MHC class II molecule H2 I-Ab based on bioinformatic analyses. Twenty-two of the candidate peptides with distinct MIP epitopes were well recognized by the IFN-γ recall responses of CD4+ T cells from mice immunized with parental proteins in an ELISPOT assay. In addition, 7 of the 22 peptides could efficiently induce CD4+ T cells from mice immunized with C. burnetii to rapidly proliferate and significantly increase IFN-γ production. Significantly higher levels of IL-2, IL-12p70, IFN-γ, and TNF-α were also detected in serum from mice immunized with a pool of the 7 peptides. Immunization with the pool of 7 peptides, but not the individual peptides, conferred a significant protection against C. burnetii infection in mice, suggesting that these Th1 peptides could work together to efficiently activate CD4+ T cells to produce the Th1-type immune response against C. burnetii infection. These observations could contribute to the rational design of molecular vaccines for Q fever.
doi:10.1371/journal.pone.0087206
PMCID: PMC3907486  PMID: 24498044
13.  Brain structural plasticity in survivors of a major earthquake 
Background
Stress responses have been studied extensively in animal models, but effects of major life stress on the human brain remain poorly understood. The aim of this study was to determine whether survivors of a major earthquake, who were presumed to have experienced extreme emotional stress during the disaster, demonstrate differences in brain anatomy relative to individuals who have not experienced such stressors.
Methods
Healthy survivors living in an area devastated by a major earthquake and matched healthy controls underwent 3-dimentional high-resolution magnetic resonance imaging (MRI). Survivors were scanned 13–25 days after the earthquake; controls had undergone MRI for other studies not long before the earthquake. We used optimized voxel-based morphometry analysis to identify regional differences of grey matter volume between the survivors and controls.
Results
We included 44 survivors (17 female, mean age 37 [standard deviation (SD) 10.6] yr) and 38 controls (14 female, mean age 35.3 [SD 11.2] yr) in our analysis. Compared with controls, the survivors showed significantly lower grey matter volume in the bilateral insula, hippocampus, left caudate and putamen, and greater grey matter volume in the bilateral orbitofrontal cortex and the parietal lobe (all p < 0.05, corrected for multiple comparison).
Limitations
Differences in the variance of survivor and control data could impact study findings.
Conclusion
Acute anatomic alterations could be observed in earthquake survivors in brain regions where functional alterations after stress have been described. Anatomic changes in the present study were observed earlier than previously reported and were seen in prefrontal–limbic, parietal and striatal brain systems. Together with the results of previous functional imaging studies, our observations suggest a complex pattern of human brain response to major life stress affecting brain systems that modulate and respond to heightened affective arousal.
doi:10.1503/jpn.120244
PMCID: PMC3819151  PMID: 23710694
14.  Perceptual bias of patients with schizophrenia in morphed facial expression 
Psychiatry research  2010;185(0):60-65.
Limited research has specifically examined the nature of the dysfunction in emotion categorization representation in schizophrenia. The current study aimed to investigate the perception bias of morphed facial expression in subjects with schizophrenia and healthy controls in the emotion continua. Twenty-eight patients with schizophrenia and thirty-one healthy controls took part in this study. They were administered a standardized set of morphed photographs of facial expressions with varying emotional intensities between 0% and 100% of the emotion, in 10% increments to provide a range of intensities from pleasant to unpleasant and approach to withdraw. Shift points, indicating the time point that the subjects’ emotion identification begins to change, and response slopes, indicating how rapidly these changes have happened at the shift points in the emotion continuum, were measured. Patients exhibited a significantly greater response slope (i.e., patients’ perception changed more rapidly) and greater shift point (i.e., patients still perceived mild expressions of anger as happy faces) with increasing emotion signal compared with healthy controls when the facial expression morphed from happy to angry. Furthermore, patients with schizophrenia still perceived mild expressions of fear as angry faces(a greater shift point) and were less discriminative from angry to fearful emotion(a flatter response slope). They were sensitive to sadness (a smaller shift point) and the perception changed rapidly (a sharper response slope) as compared with healthy controls in the emotion continuum of happy to sad. In conclusion, patients with schizophrenia demonstrated impaired categorical perception of facial expressions, with generally ‘rapid’ but ‘late’ discrimination towards social threat-related stimuli such as angry facial expression. Compared with healthy controls, these patients have a sharper discrimination perception pattern in the emotion continua from positive valence to negative valence.
doi:10.1016/j.psychres.2010.05.017
PMCID: PMC3805827  PMID: 20646764
Emotion perception; Schizophrenia; Morphed facial expression
15.  Genetic variations of ND5 gene of mtDNA in populations of Anopheles sinensis (Diptera: Culicidae) malaria vector in China 
Parasites & Vectors  2013;6:290.
Background
Anopheles sinensis is a principal vector for Plasmodium vivax malaria in most parts of China. Understanding of genetic structure and genetic differentiation of the mosquito should contribute to the vector control and malaria elimination in China.
Methods
The present study investigated the genetic structure of An. sinensis populations using a 729 bp fragment of mtDNA ND5 among 10 populations collected from seven provinces in China.
Results
ND5 was polymorphic by single mutations within three groups of An. sinensis that were collected from 10 different geographic populations in China. Out of 140 specimens collected from 10 representative sites, 84 haplotypes and 71 variable positions were determined. The overall level of genetic differentiation of An. sinensis varied from low to moderate across China and with a FST range of 0.00065 – 0.341. Genealogy analysis clustered the populations of An. sinensis into three main clusters. Each cluster shared one main haplotype. Pairwise variations within populations were higher (68.68%) than among populations (31.32%) and with high fixation index (FST = 0.313). The results of the present study support population growth and expansion in the An. sinensis populations from China. Three clusters of An. sinensis populations were detected in this study with each displaying different proportion patterns over seven Chinese provinces. No correlation between genetic and geographic distance was detected in overall populations of An. sinensis (R2 = 0.058; P = 0.301).
Conclusions
The results indicate that the ND5 gene of mtDNA is highly polymorphic in An. sinensis and has moderate genetic variability in the populations of this mosquito in China. Demographic and spatial results support evidence of expansion in An. sinensis populations.
doi:10.1186/1756-3305-6-290
PMCID: PMC4228240  PMID: 24192424
Anopheles sinensis; Population genetics structure; mtDNA; ND5 gene
16.  Inhibition of Platelet Activation by Clopidogrel Prevents Hypertension-Induced Cardiac Inflammation and Fibrosis 
Cardiovascular Drugs and Therapy  2013;27(6):521-530.
Purpose
Platelets are essential for primary hemostasis; however, platelet activation also plays an important proinflammatory role. Inflammation promotes the development of cardiac fibrosis and heart failure induced by hypertension. In this study, we aimed to determine whether inhibiting platelet activation using clopidogrel could inhibit hypertension-induced cardiac inflammation and fibrosis.
Methods
Using a mouse model of angiotensin II (Ang II) infusion (1,500 ng/[kg·min] for 7 days), we determined the role of platelet activation in Ang II infusion-induced cardiac inflammation and fibrosis using a P2Y12 receptor inhibitor, clopidogrel (50 mg/[kg·day]).
Results
CD41 staining showed that platelets accumulated in Ang II-infused hearts. Clopidogrel treatment inhibited Ang II infusion-induced accumulation of α-SMA+ myofibroblasts and cardiac fibrosis (4.17 ± 1.26 vs. 1.46 ± 0.81, p < 0.05). Infiltration of inflammatory cells, including Mac-2+ macrophages and CD45+Ly6G+ neutrophils (30.38 ± 4.12 vs. 18.7 ± 2.38, p < 0.05), into Ang II-infused hearts was also suppressed by platelet inhibition. Real-time PCR and immunohistochemical staining showed that platelet inhibition significantly decreased the expression of interleukin-1β and transforming growth factor-β. Acute injection of Ang II or PE stimulated platelet activation and platelet-leukocyte conjugation, which were abolished by clopidogrel treatment.
Conclusion
Thus, inhibition of platelet activation by clopidogrel prevents cardiac inflammation and fibrosis in response to Ang II. Taken together, our results indicate Ang II infusion-induced hypertension stimulated platelet activation and platelet-leukocyte conjugation, which initiated inflammatory responses that contributed to cardiac fibrosis.
doi:10.1007/s10557-013-6471-z
PMCID: PMC3830206  PMID: 23887740
Clopidogrel; Platelet activation; Inflammation; Hypertension; Cardiac fibrosis
17.  Proteome Analysis and Serological Characterization of Surface-Exposed Proteins of Rickettsia heilongjiangensis 
PLoS ONE  2013;8(7):e70440.
Background
Rickettsia heilongjiangensis, the agent of Far-Eastern spotted fever (FESF), is an obligate intracellular bacterium. The surface-exposed proteins (SEPs) of rickettsiae are involved in rickettsial adherence to and invasion of host cells, intracellular bacterial growth, and/or interaction with immune cells. They are also potential molecular candidates for the development of diagnostic reagents and vaccines against rickettsiosis.
Methods
R. heilongjiangensis SEPs were identified by biotin-streptavidin affinity purification and 2D electrophoreses coupled with ESI-MS/MS. Recombinant SEPs were probed with various sera to analyze their serological characteristics using a protein microarray and an enzyme-linked immune sorbent assay (ELISA).
Results
Twenty-five SEPs were identified, most of which were predicted to reside on the surface of R. heilongjiangensis cells. Bioinformatics analysis suggests that these proteins could be involved in bacterial pathogenesis. Eleven of the 25 SEPs were recognized as major seroreactive antigens by sera from R. heilongjiangensis-infected mice and FESF patients. Among the major seroreactive SEPs, microarray assays and/or ELISAs revealed that GroEL, OmpA-2, OmpB-3, PrsA, RplY, RpsB, SurA and YbgF had modest sensitivity and specificity for recognizing R. heilongjiangensis infection and/or spotted fever.
Conclusions
Many of the SEPs identified herein have potentially important roles in R. heilongjiangensis pathogenicity. Some of them have potential as serodiagnostic antigens or as subunit vaccine antigens against the disease.
doi:10.1371/journal.pone.0070440
PMCID: PMC3720918  PMID: 23894656
18.  Translating genomic research into care for people with schizophrenia in China 
Schizophrenia research  2011;131(0):31-34.
The implications of increased understanding of the genetic contribution to schizophrenia for patients and their families remain unclear. We carried out a study of Chinese patients’ (n = 118) and relatives’ (n = 78) views of illness severity, attribution of cause, concern about developing illness, and effect of schizophrenia on family planning. A comparison sample of English-survey respondents was also obtained, using the same series of questions (n = 42 patients, n = 127 relatives). Fewer Chinese patients and family members rated schizophrenia as very severe (33%) than did the predominantly North American respondents (67%, p < 0.0001). The pattern of attribution of cause differed between samples (p < 0.0001), favouring environmental alone in the Chinese sample (52%), with a low frequency of genetics alone (9%). Although comparatively fewer Chinese respondents were very concerned about developing schizophrenia themselves or about the risk of illness in their families (21%), this high level of concern was more common in family members (28%). Finally, Chinese respondents were somewhat less likley to indicate that schizophrenia impacted on family planning decisions (31%) than were English-survey respondents (45%, p = 0.02). The descriptive findings contribute to understanding schizophrenia in China. The comparative findings must be regarded as preliminary, since differences in demographics could influence results. The present findings suggest that understanding patients’ and families’ attributions of cause of schizophrenia may be important for developing a shared model of illness in order to decrease stigmatization, and improve therapeutic alliances.
doi:10.1016/j.schres.2011.05.008
PMCID: PMC3706332  PMID: 21636253 CAMSID: cams3089
schizophrenia; genetics; stigma; causal attribtions
19.  Novel ATPase Cu2+ Transporting Beta Polypeptide Mutations in Chinese Families with Wilson's Disease 
PLoS ONE  2013;8(7):e66526.
Wilson's disease (WD) is an autosomal recessive inherited disorder caused by mutations in the ATPase Cu2+ transporting beta polypeptide gene (ATP7B). The detailed metabolism of copper-induced pathology in WD is still unknown. Gene mutations as well as the possible pathways involved in the ATP7B deficiency were documented. The ATP7B gene was analyzed for mutations in 18 Chinese Han families with WD by direct sequencing. Cell viability and apoptosis analysis of ATP7B small interfering RNA (siRNA)-treated human liver carcinoma (HepG2) cells were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assay and Hoechst 33342 staining. Finally, the expression of B-cell CLL/lymphoma 2 (BCL2), BCL2-associated X protein (BAX), sterol regulatory element binding protein 1 (SREBP1), and minichromosome maintenance protein 7 (MCM7) of ATP7B siRNA-treated cells were tested by real-time polymerase chain reaction (real-time PCR) and Western blot analysis. Twenty different mutations including four novel mutations (p.Val145Phe, p.Glu388X, p.Thr498Ser and p.Gly837X) in the ATP7B gene were identified in our families. Haplotype analysis revealed that founder effects for four mutations (p.Arg778Leu, p.Pro992Leu, p.Ile1148Thr and p.Ala1295Val) existed in these families. Transfection of HepG2 cells with ATP7B siRNA resulted in decreased mRNA expression by 86.3%, 93.1% and 90.8%, and decreased protein levels by 58.5%, 85.5% and 82.1% at 24, 48 and 72 hours, respectively (All P<0.01). In vitro study revealed that the apoptotic, cell cycle and lipid metabolism pathway may be involved in the mechanism of WD. Our results revealed that the genetic cause of 18 Chinese families with WD and ATP7B deficiency-induce apoptosis may result from imbalance in cell cycle and lipid metabolism pathway.
doi:10.1371/journal.pone.0066526
PMCID: PMC3699604  PMID: 23843956
20.  Spatiotemporal Patterns of Japanese Encephalitis in China, 2002–2010 
Objective
The aim of the study is to examine the spatiotemporal pattern of Japanese Encephalitis (JE) in mainland China during 2002–2010. Specific objectives of the study were to quantify the temporal variation in incidence of JE cases, to determine if clustering of JE cases exists, to detect high risk spatiotemporal clusters of JE cases and to provide evidence-based preventive suggestions to relevant stakeholders.
Methods
Monthly JE cases at the county level in mainland China during 2002–2010 were obtained from the China Information System for Diseases Control and Prevention (CISDCP). For the purpose of the analysis, JE case counts for nine years were aggregated into four temporal periods (2002; 2003–2005; 2006; and 2007–2010). Local Indicators of Spatial Association and spatial scan statistics were performed to detect and evaluate local high risk space-time clusters.
Results
JE incidence showed a decreasing trend from 2002 to 2005 but peaked in 2006, then fluctuated over the study period. Spatial cluster analysis detected high value clusters, mainly located in Southwestern China. Similarly, we identified a primary spatiotemporal cluster of JE in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years.
Conclusion
JE in China is geographically clustered and its spatial extent dynamically changed during the last nine years in mainland China. This indicates that risk factors for JE infection are likely to be spatially heterogeneous. The results may assist national and local health authorities in the development/refinement of a better preventive strategy and increase the effectiveness of public health interventions against JE transmission.
Author Summary
Japanese encephalitis (JE) is a mosquito-borne disease, which primarily occurs in rural and suburban areas of Southeast Asia and the Western Pacific region. JE still remains a significant public health problem in mainland China, with approximately 50% of global cases annually. Few studies have explored the spatiotemporal patterns of JE cases in China. Here we reported the results of Local Indicators of Spatial Association and spatial scan statistics of JE cases in mainland China at the county level during the four periods: 2002; 2003–2005; 2006; 2007–2010. The primary spatiotemporal cluster of JE was detected in Southwestern China between July and August, with the geographical range of JE transmission increasing over the past years. The results of LISA and spatial scan statistics were consistent which indicates that these methods are reliable and could have wider applications in the fields of disease surveillance and management in China, particularly in the surveillance and monitoring of other vector-borne diseases. These findings may assist in informing prevention and control strategies and increase the effectiveness of public health interventions against JE transmission.
doi:10.1371/journal.pntd.0002285
PMCID: PMC3688550  PMID: 23819000
21.  Cortical Surface Area Correlates with STON2 Gene Ser307Pro Polymorphism in First-Episode Treatment-Naïve Patients with Schizophrenia 
PLoS ONE  2013;8(6):e64090.
Background
Evidence shows that STON2 gene is associated with synaptic function and schizophrenia. This study aims to explore the relationship between two functional polymorphisms (Ser307Pro and Ala851Ser) of STON2 gene and the cortical surface area in first-episode treatment-naïve patients with schizophrenia and healthy controls.
Methodology/Principal Findings
Magnetic resonance imaging of the whole cortical surface area, which was computed by an automated surface-based technique (FreeSurfer), was obtained from 74 first-episode treatment-naïve patients with schizophrenia and 55 healthy controls. Multiple regression analysis was performed to investigate the effect of genotype subgroups on the cortical surface area. A significant genotype-by-diagnosis effect on the cortical surface area was observed. Pro-allele carriers of Ser307Pro polymorphism had larger right inferior temporal surface area than Ser/Ser carriers in the patients with schizophrenia; however, no significant difference was found in the same area in the healthy controls. The Ala851Ser polymorphism of STON2 gene was not significantly associated with the cortical surface area in patients with schizophrenia and healthy controls.
Conclusions/Significance
The present study demonstrated that the functional variant of the STON2 gene could alter cortical surface area on the right inferior temporal and contribute to the pathogenesis of schizophrenia.
doi:10.1371/journal.pone.0064090
PMCID: PMC3681785  PMID: 23785397
22.  Spatial-temporal analysis of malaria and the effect of environmental factors on its incidence in Yongcheng, China, 2006–2010 
BMC Public Health  2012;12:544.
Background
In 2003, Plasmodium vivax malaria has re-emerged in central eastern China including Yongcheng prefecture, Henan Province, where no case has been reported for eleven years. Our goals were to detect the space-time distribution pattern of malaria and to determine significant environmental variables contributing to malaria incidence in Yongcheng from 2006 to 2010, thus providing scientific basis for further optimizing current malaria surveillance and control programs.
Methods
This study examined the spatial and temporal heterogeneities in the risk of malaria and the influencing factors on malaria incidence using geographical information system (GIS) and time series analysis. Univariate analysis was conducted to estimate the crude correlations between malaria incidence and environmental variables, such as mosquito abundance and climatic factors. Multivariate analysis was implemented to construct predictive models to explore the principal environmental determinants on malaria epidemic using a Generalized Estimating Equation (GEE) approach.
Results
Annual malaria incidence at town-level decreased from the north to south, and monthly incidence at prefecture-level demonstrated a strong seasonal pattern with a peak from July to November. Yearly malaria incidence had a visual spatial association with yearly average temperature. Moreover, the best-fit temporal model (model 2) (QIC = 16.934, P<0.001, R2 = 0.818) indicated that significant factors contributing to malaria incidence were maximum temperature at one month lag, average humidity at one month lag, and malaria incidence of the previous month.
Conclusions
Findings supported the effects of environment factors on malaria incidence and indicated that malaria control targets should vary with intensity of malaria incidence, with more public resource allocated to control the source of infections instead of large scale An. sinensis control when malaria incidence was at a low level, which would benefit for optimizing the malaria surveillance project in China and some other countries with unstable or low malaria transmission.
doi:10.1186/1471-2458-12-544
PMCID: PMC3488337  PMID: 22823998
Malaria; Anopheles; Weather; Geographic information system; Modeling
23.  Development of a class-specific polyclonal antibody-based indirect competitive ELISA for detecting fluoroquinolone residues in milk*  
Modified 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC) method was employed to synthesize the artificial antigen of norfloxacin (NOR), and New Zealand rabbits were used to produce anti-NOR polyclonal antibody (pAb). Based on the checkerboard titration, an indirect competitive enzyme-linked immunosorbent assay (icELISA) standard curve was established. This assay was sensitive and had a working range from 0.12 to 68.40 ng/ml, with the half maximal inhibitory concentration (IC50) and limit of detection (LOD) values of 2.7 ng/ml and 0.06 ng/ml, respectively. The produced pAb exhibited high cross-reactivity to fluoroquinolones (FQs) tested, and the IC50 values to enoxacin, ciprofloxacin, and pefloxacin were 3.1, 3.4, and 4.1 ng/ml, respectively. It also indicated that the concentrations of NaOH and methanol in assay buffer should not be higher than 10% and 30%. When spiked in milk at 5, 20, and 50 ng/ml, the recoveries for NOR, enoxacin, ciprofloxacin, and pefloxacin ranged 90.5%–98.0%, 84.0%–95.2%, 94.0%–106.0%, and 89.5%–100.0%, respectively. The results suggest that this class-specific pAb-based icELISA could be utilized for the primary screening of FQ residues in animal-original products.
doi:10.1631/jzus.B1200001
PMCID: PMC3390712  PMID: 22761246
Norfloxacin; Fluoroquinolones; Indirect competitive ELISA; Class-specificity; Milk
24.  Reciprocal Interaction between Macrophages and T cells Stimulates IFN-γ and MCP-1 Production in Ang II-induced Cardiac Inflammation and Fibrosis 
PLoS ONE  2012;7(5):e35506.
Background
The inflammatory response plays a critical role in hypertension-induced cardiac remodeling. We aimed to study how interaction among inflammatory cells causes inflammatory responses in the process of hypertensive cardiac fibrosis.
Methodology/Principal Findings
Infusion of angiotensin II (Ang II, 1500 ng/kg/min) in mice rapidly induced the expression of interferon γ (IFN-γ) and leukocytes infiltration into the heart. To determine the role of IFN-γ on cardiac inflammation and remodeling, both wild-type (WT) and IFN-γ-knockout (KO) mice were infused Ang II for 7 days, and were found an equal blood pressure increase. However, knockout of IFN-γ prevented Ang II-induced: 1) infiltration of macrophages and T cells into cardiac tissue; 2) expression of tumor necrosis factor α and monocyte chemoattractant protein 1 (MCP-1), and 3) cardiac fibrosis, including the expression of α-smooth muscle actin and collagen I (all p<0.05). Cultured T cells or macrophages alone expressed very low level of IFN-γ, however, co-culture of T cells and macrophages increased IFN-γ expression by 19.8±0.95 folds (vs. WT macrophage, p<0.001) and 20.9 ± 2.09 folds (vs. WT T cells, p<0.001). In vitro co-culture studies using T cells and macrophages from WT or IFN-γ KO mice demonstrated that T cells were primary source for IFN-γ production. Co-culture of WT macrophages with WT T cells, but not with IFN-γ-knockout T cells, increased IFN-γ production (p<0.01). Moreover, IFN-γ produced by T cells amplified MCP-1 expression in macrophages and stimulated macrophage migration.
Conclusions/Significance
Reciprocal interaction between macrophages and T cells in heart stimulates IFN-γ expression, leading to increased MCP-1 expression in macrophages, which results a forward-feed recruitment of macrophages, thus contributing to Ang II-induced cardiac inflammation and fibrosis.
doi:10.1371/journal.pone.0035506
PMCID: PMC3342394  PMID: 22567105
25.  Random repeated cross sectional study on breeding site characterization of Anopheles sinensis larvae in distinct villages of Yongcheng City, People's Republic of China 
Parasites & Vectors  2012;5:58.
Background
Characterizing the breeding site of Anopheles sinensis is of major importance for the transition from malaria control to elimination in China. However, little information is available especially regarding the characteristics and influencing factors of breeding sites of An. sinensis in Yongcheng City, a representative region of unstable malaria transmission in the Huang-Huai River region of central China. The aims of this study were to determine the breeding site characteristics of An. sinensis and related environmental and physicochemical parameters, to find out which breeding site characteristics could best explain the presence of An. sinensis larvae, and to determine whether the breeding habit of An. sinensis has changed or not.
Methods
Random repeated cross sectional study was undertaken in six villages of the Yongcheng city characterized by different levels of the historical incidence of P. vivax malaria. The potential breeding sites of An. sinensis larvae in each village were examined twice per month both in the household courtyards and the village surroundings. The larval sampling was done by the standard dipping method. Some important breeding site characterizations were recorded and characterized. The anopheline mosquito larvae and emerged adults were identified to the species level morphologically and to sub-species by the ribosomal DNA PCR technique. Chi-square analysis and logistic regression analysis were applied to determine the importance of factors for explaining the presence or absence of An. sinensis larvae.
Results
According to the ribosomal DNA PCR assay, all sampled anopheline mosquito larvae and emerged adults belonged to An. sinensis. Only 3 containers that were sampled from the household courtyards were found to contain An. sinensis larvae. There were no differences in the species composition of mosquito larvae among containers that contained water in the household courtyards (P > 0.05). An. sinensis larvae were shown to be present in a total of 60 breeding sites in the village surroundings, this included 8 (13.3%) river fringes, 26 (43.3%) ponds, 23 (38.3%) puddles, and 3 (5.0%) irrigation/drainage ditches. Logistic regression analysis revealed that the breeding site type, water depth, chemical oxygen demand (COD), ammonia nitrogen, and sulphate were found to be the key factors determining the presence of An. sinensis larvae. Approximately 94.9% of An. sinensis larvae inhabited relatively large and medium-sized water bodies, with depths between 0.5 m and 1.0 m (73.3%), COD lower than 2 mg/L (75%), ammonia nitrogen lower than 0.4 mg/L (86.7%), and sulphate lower than 150 mg/L (58.3%), respectively.
Conclusion
These results indicate that the majority of An. sinensis larval breeding sites were relatively large and medium-sized water bodies with depths between 0.5 m and 1.0 m, and containing low levels of COD, ammonia nitrogen, and sulphate, respectively. For effective An. sinensis larval control, the type of breeding site, water depth, COD, ammonia nitrogen, and sulphate should be given higher priority over other factors in areas where it is the primary vector.
doi:10.1186/1756-3305-5-58
PMCID: PMC3323357  PMID: 22444032
Breeding site; Characterization; Mosquito; Anopheles vectors; Ecology, Malaria elimination

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