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1.  Gene Expression Signatures in Tree Shrew Sclera in Response to Three Myopiagenic Conditions 
We compared gene expression signatures in tree shrew sclera produced by three different visual conditions that all produce ocular elongation and myopia: minus-lens wear, form deprivation, and dark treatment.
Six groups of tree shrews (n = 7 per group) were used. Starting 24 days after normal eye-opening (days of visual experience [DVE]), two minus-lens groups wore a monocular −5 diopter (D) lens for 2 days (ML-2) or 4 days (ML-4); two form-deprivation groups wore a monocular translucent diffuser for 2 days (FD-2) or 4 days (FD-4). A dark-treatment (DK) group was placed in continuous darkness for 11 days after experiencing a light/dark environment until 17 DVE. A normal colony-reared group was examined at 28 DVE. Quantitative PCR was used to measure the relative differences in mRNA levels for 55 candidate genes in the sclera that were selected, either because they showed differential expression changes in previous ML studies or because a whole-transcriptome analysis suggested they would change during myopia development.
The treated eyes in all groups responded with a significant myopic shift, indicating that the myopia was actively progressing. In the ML-2 group, 27 genes were significantly downregulated in the treated eyes, relative to control eyes. In the treated eyes of the FD-2 group, 16 of the same genes also were significantly downregulated and one was upregulated. The two gene expression patterns were significantly correlated (r2 = 0.90, P < 0.001). After 4 days of treatment, 31 genes were significantly downregulated in the treated eyes of the ML-4 group and three were upregulated. Twenty-nine of the same genes (26 down- and 3 up-regulated) and six additional genes (all downregulated) were significantly affected in the FD-4 group. The response patterns were highly correlated (r2 = 0.95, P < 0.001). When the DK group (mean of right and left eyes) was compared to the control eyes of the ML-4 group, the direction and magnitude of the gene expression patterns were similar to those of the ML-4 (r2 = 0.82, P < 0.001, excluding PENK). Similar patterns also were found when the treated eyes of the ML-4, FD-4, and DK groups were compared to the age-matched normal eyes.
The very similar gene expression signatures produced in the sclera by the three different myopiagenic visual conditions at different time points suggests that there is a “scleral remodeling signature” in this mammal, closely related to primates. The scleral genes examined did not distinguish between the specific visual stimuli that initiate the signaling cascade that results in axial elongation and myopia.
Three different visual conditions (minus-lens wear, form deprivation, darkness) that cause axial elongation and myopia produce very similar gene expression signatures in the sclera in 55 genes. In the sclera, the differing visual signals have merged into a single “GO” remodeling signature.
PMCID: PMC3805087  PMID: 24045991
myopia; animal models; refractive error; emmetropization; axial elongation; gene expression; sclera
2.  Evaluation of High-Resolution Precipitation Estimates from Satellites during July 2012 Beijing Flood Event Using Dense Rain Gauge Observations 
PLoS ONE  2014;9(4):e89681.
Satellite-based precipitation estimates products, CMORPH and PERSIANN-CCS, were evaluated with a dense rain gauge network over Beijing and adjacent regions for an extremely heavy precipitation event on July 21 2012. CMORPH and PEERSIANN-CSS misplaced the region of greatest rainfall accumulation, and failed to capture the spatial pattern of precipitation, evidenced by a low spatial correlation coefficient (CC). CMORPH overestimated the daily accumulated rainfall by 22.84% while PERSIANN-CCS underestimated by 72.75%. In the rainfall center, both CMORPH and PERSIANN-CCS failed to capture the temporal variation of the rainfall, and underestimated rainfall amounts by 43.43% and 87.26%, respectively. Based on our results, caution should be exercised when using CMORPH and PERSIANN-CCS as input for monitoring and forecasting floods in Beijing urban areas, and the potential for landslides in the mountainous zones west and north of Beijing.
PMCID: PMC3972163  PMID: 24691358
3.  Comparison of Predictive Value of Cardiometabolic Indices for Subclinical Atherosclerosis in Chinese Adults 
PLoS ONE  2014;9(4):e93538.
Metabolic disturbances are well-known risk factors for atherosclerosis, but it remains unclear which cardiometabolic components are the predominant determinants. This study aimed to compare and identify the key determinants of carotid atherosclerosis in asymptomatic middle-aged and elderly Chinese.
A community-based cross-sectional study including 3,162 apparently healthy residents aged 37–75 years was performed from July 2008 to June 2010 in Guangzhou, China. Carotid artery intima-media thickness (IMT) was assessed by B-mode ultrasound, and increased IMT was defined as IMT>1.00 mm. Obesity indices, blood pressure, fasting blood lipids, glucose and uric acid levels were determined. Principal components factor analysis was used to extract common factors underlying 11 metabolic factors.
Four common factors, defined as “adiposity,” “blood lipids,” “triglycerides/uric acid (TG/UA)” (in men) or “triglycerides/uric acid/glucose (TG/UA/Glu)” (in women), and “blood pressure,” were retained for both sexes. After adjustment for potential covariates, the “adiposity” factor showed the strongest positive association with increased IMT in men. Comparing the extreme quartiles, ORs (95% CI) of increased IMT were 4.64 (2.04–10.59) at the CCA and 2.37 (1.54–3.64) at the BIF), followed by “blood pressure”, the corresponding OR (95% CI) was 2.85 (1.37–5.90) at the CCA. Whereas, the four common factors showed comparable and weak relationship with increased IMTs, the ORs for quartile 4 vs. quartile 1 varied from 0.89 to 3.59 in women.
Among the metabolic factors, “adiposity” and “blood pressure” play predominant roles in the presence of carotid atherosclerosis in men, but no key factor is identified in women.
PMCID: PMC3972246  PMID: 24691185
4.  Development of Lipid-Shell and Polymer Core Nanoparticles with Water-Soluble Salidroside for Anti-Cancer Therapy 
Salidroside (Sal) is a potent antitumor drug with high water-solubility. The clinic application of Sal in cancer therapy has been significantly restricted by poor oral absorption and low tumor cell uptake. To solve this problem, lipid-shell and polymer-core nanoparticles (Sal-LPNPs) loaded with Sal were developed by a double emulsification method. The processing parameters including the polymer types, organic phase, PVA types and amount were systemically investigated. The obtained optimal Sal-LPNPs, composed of PLGA-PEG-PLGA triblock copolymers and lipids, had high entrapment efficiency (65%), submicron size (150 nm) and negatively charged surface (−23 mV). DSC analysis demonstrated the successful encapsulation of Sal into LPNPs. The core-shell structure of Sal-LPNPs was verified by TEM. Sal released slowly from the LPNPs without apparent burst release. MTT assay revealed that 4T1 and PANC-1 cancer cell lines were sensitive to Sal treatment. Sal-LPNPs had significantly higher antitumor activities than free Sal in 4T1 and PANC-1 cells. The data indicate that LPNPs are a promising Sal vehicle for anti-cancer therapy and worthy of further investigation.
PMCID: PMC3975343  PMID: 24573250
salidroside; lipid-shell and polymer-core nanoparticles (LPNPs); PLGA; antitumor
5.  Over-expression of miR-98 in FFPE tissues might serve as a valuable source for biomarker discovery in breast cancer patients 
The miR-98 is thought to be associated with various cancers. This study was to evaluate the potential predictive value of miR-98 expression in formalin-fixed paraffin-embedded tissue of breast cancer patients. The expression levels of miR-98 were examined in 98 breast cancer patients and 40 cancer-free controls using real-time quantitative PCR. The comparison of miR-98 expression levels between patient and control was performed using the Mann-Whitney test. The miR-98 showed higher expression levels in breast cancer patients compared with cancer free controls (p<0.01). The expression levels of miR-98 were highly correlated with miR24/93/378 in breast cancer patients. The miR-98 exhibited great capability of discriminating between cancer patients and controls by the Receiver-operator characteristic (ROC) curve analysis. The miR-98 was found highly correlated with breast cancer by Univariable logistic regression analysis. These results suggest that over-expression of miR-98 in formalin-fixed paraffin-embedded tissues might serve as a valuable source for biomarker discovery in breast cancer patients.
PMCID: PMC3971322
Biomarkers; miR-98; breast cancer; miRNA; cancer
6.  TNF -308 G/A Polymorphism and Risk of Acne Vulgaris: A Meta-Analysis 
PLoS ONE  2014;9(2):e87806.
The -308 G/A polymorphism in the tumor necrosis factor (TNF) gene has been implicated in the risk of acne vulgaris, but the results are inconclusive. The present meta-analysis aimed to investigate the overall association between the -308 G/A polymorphism and acne vulgaris risk.
We searched in Pubmed, Embase, Web of Science and CNKI for studies evaluating the association between the -308 G/A gene polymorphism and acne vulgaris risk. Data were extracted and statistical analysis was performed using STATA 12.0 software.
A total of five publications involving 1553 subjects (728 acne vulgaris cases and 825 controls) were included in this meta-analysis. Combined analysis revealed a significant association between this polymorphism and acne vulgaris risk under recessive model (OR = 2.73, 95% CI: 1.37–5.44, p = 0.004 for AA vs. AG + GG). Subgroup analysis by ethnicity showed that the acne vulgaris risk associated with the -308 G/A gene polymorphism was significantly elevated among Caucasians under recessive model (OR = 2.34, 95% CI: 1.13–4.86, p = 0.023).
This meta-analysis suggests that the -308 G/A polymorphism in the TNF gene contributes to acne vulgaris risk, especially in Caucasian populations. Further studies among different ethnicity populations are needed to validate these findings.
PMCID: PMC3912133  PMID: 24498378
7.  TLR4 Activation Under Lipotoxic Conditions Leads to Synergistic Macrophage Cell Death Through a TRIF-Dependent Pathway1 
Macrophage dysfunction in obesity and diabetes may predispose to the development of diabetic complications such as infection and impaired healing after tissue damage. Saturated fatty acids, such as palmitate, are present at elevated concentrations in the plasma of patients with metabolic disease and may contribute to the pathogenesis of diabetes and its sequelae. To examine the effect of lipid excess on macrophage inflammatory function, we determined the influence of palmitate on LPS-mediated responses in peritoneal macrophages. Palmitate and LPS led to a profound synergistic cell death response in both primary and RAW 264.7 macrophages. The cell death had features of apoptosis and necrosis and was not dependent on ER stress, ceramide generation, or reactive oxygen species production. Instead, we uncovered a macrophage death pathway that required TLR4 signaling via TRIF, but was independent of NF-κB, MAP kinases, and IRF3. A significant decrease in macrophage lysosomal content was observed early in the death pathway, with evidence of lysosomal membrane damage occurring later in the death response. Over-expression of the transcription factor TFEB, which induces a lysosomal biogenic program, rescued the lysosomal phenotype and improved viability in palmitate and LPS treated cells. Our findings provide new evidence for crosstalk between lipid metabolism and the innate immune response that converges on the lysosome.
PMCID: PMC3552058  PMID: 23275600
8.  Targeting human CD27 with an agonist antibody stimulates T-cell activation and antitumor immunity 
Oncoimmunology  2014;3(1):e27255.
CD27 is an important co-stimulatory receptor of T cells that can potentially be exploited for immunotherapy. We developed a human IgG1 antibody that targets human CD27, and demonstrated its immunostimulatory and antineoplastic activity in various preclinical models. Currently, the antibody (1F5, CDX-1127) is being tested in patients affected by advanced malignancies.
PMCID: PMC3937191  PMID: 24605266
CD27; co-stimulation; Fc receptors; immunotherapy; monoclonal antibody
9.  DNA-dependent protein kinase catalytic subunit (DNA-PKcs)-SIN1 association mediates ultraviolet B (UVB)-induced Akt Ser-473 phosphorylation and skin cell survival 
Molecular Cancer  2013;12:172.
The exposure of skin keratinocytes to Ultraviolet (UV) irradiation leads to Akt phosphorylation at Ser-473, which is important for the carcinogenic effects of excessive sun exposure. The present study investigated the underlying mechanism of Akt Ser-473 phosphorylation by UVB radiation.
We found that DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and mammalian target of rapamycin (mTOR) complex 2 (mTORC2) were both required for UVB-induced Akt Ser-473 phosphorylation in keratinocytes. Inhibition of DNA-PKcs activity via its inhibitor NU7026, a dominant-negative kinase-dead mutation, RNA interference (RNAi) or gene depletion led to the attenuation of UVB-induced Akt Ser-473 phosphorylation. Meanwhile, siRNA silencing or gene depletion of SIN1, a key component of mTORC2, abolished Akt Ser-473 phosphorylation by UVB. Significantly, we discovered that DNA-PKcs was associated with SIN1 in cytosol upon UVB radiation, and this complexation appeared required for Akt Ser-473 phosphorylation. Meanwhile, this DNA-PKcs-SIN1 complexation by UVB was dependent on epidermal growth factor receptor (EGFR) activation, and was disrupted by an EGFR inhibitor (AG1478) or by EGFR depletion. UVB-induced complexation between DNA-PKcs and mTORC2 components was also abolished by NU7026 and DNA-PKcs mutation. Finally, we found that both DNA-PKcs and SIN1 were associated with apoptosis resistance of UVB radiation, and inhibition of them by NU7026 or genetic depletion significantly enhanced UVB-induced cell death and apoptosis.
Taken together, these results strongly suggest that DNA-PKcs-mTORC2 association is required for UVB-induced Akt Ser-473 phosphorylation and cell survival, and might be important for tumor cell transformation.
PMCID: PMC3922905  PMID: 24365180
UV irradiation; Akt Ser-473 phosphorylation; DNA-PKcs; SIN1; Skin care
10.  Research on the relationship between fibrinogen level and subtypes of the TOAST criteria in the acute ischemic stroke 
BMC Neurology  2013;13:207.
Cerebral infarction caused by different reasons seems differ in fibrinogen levels, so the current work intends to explore the relationship between the fibrinogen level and subtypes of the TOAST criteria in the acute stage of ischemic stroke.
A total of 577 case research objects were treated acute ischemic stroke patients in our hospital from December 2008 to December 2010, and blood samples within 72 hours of the onset were processed with the fibrinogen (PT-der) measurement. Classification of selected patients according to the TOAST Criteria was conducted to study the distribution of fibrinogen levels in the stroke subtypes.
The distribution of fibrinogen levels in the subtypes was observed to be statistically insignificant.
In the acute stage of ischemic stroke, fibrinogen level was not related to the subtypes of the TOAST criteria.
PMCID: PMC3878231  PMID: 24354692
Fibrinogen; Ischemic stroke; Subtypes of stroke; TOAST Criteria; Correlation
11.  The collection of NFATc1-dependent transcripts in the osteoclast includes numerous genes non-essential to physiologic bone resorption 
Bone  2012;51(5):902-912.
Osteoclasts are specialized secretory cells of the myeloid lineage important for normal skeletal homeostasis as well as pathologic conditions of bone including osteoporosis, inflammatory arthritis and cancer metastasis. Differentiation of these multinucleated giant cells from precursors is controlled by the cytokine RANKL, which through its receptor RANK initiates a signaling cascade culminating in the activation of transcriptional regulators which induce the expression of the bone degradation machinery. The transcription factor nuclear factor of activated T-cells c1 (NFATc1) is the master regulator of this process and in its absence osteoclast differentiation is aborted both in vitro and in vivo. Differential mRNA expression analysis by microarray is used to identify genes of potential physiologic relevance across nearly all biologic systems. We compared the gene expression profile of murine wild-type and NFATc1-deficient osteoclast precursors stimulated with RANKL and identified that the majority of the known genes important for osteoclastic bone resorption require NFATc1 for induction. Here, five novel RANKL-induced, NFATc1-dependent transcripts in the osteoclast are described: Nhedc2, Rhoc, Serpind1, Adcy3 and Rab38. Despite reasonable hypotheses for the importance of these molecules in the bone resorption pathway and their dramatic induction during differentiation, the analysis of mice with mutations in these genes failed to reveal a function in osteoclast biology. Compared to littermate controls, none of these mutants demonstrated a skeletal phenotype in vivo or alterations in osteoclast differentiation or function in vitro. These data highlight the need for rigorous validation studies to complement expression profiling results before functional importance can be assigned to highly regulated genes in any biologic process.
PMCID: PMC3457000  PMID: 22985540
Osteoclast; Gene array; NFATc1; Bone resorption; NHEDC2
12.  Comparison of Dry Eye and Corneal Sensitivity between Small Incision Lenticule Extraction and Femtosecond LASIK for Myopia 
PLoS ONE  2013;8(10):e77797.
To investigate the changes in dry eye symptoms and clinical signs and corneal sensitivity after small incision lenticule extraction (SMILE) and femtosecond LASIK (femto-LASIK).
Prospective, non-randomized comparative study.
The study included a total of 71 eyes of 71 patients; the SMILE group comprised 38 eyes of 38 patients, and the femto-LASIK group comprised 33 eyes of 33 patients. Ocular Surface Disease Index (OSDI), Tear film breakup time (TBUT), the Schirmer test without anesthesia (S1T), corneal fluorescein staining, and central corneal sensation were evaluated before surgery and at 1 week, 1 month, 3 months, and 6 months after surgery.
OSDI scores in both groups were increased immediately and returned to preoperative level at 1 month after surgeries. The TBUT values in both groups were reduced after surgeries relative to their preoperative scores. Patients in SMILE group were less likely to have corneal staining compared with those in the femto-LASIK group ([odds ratio] OR = 0.50, 95% [confidence interval] CI 0.28 to 0.93, P = 0.03). Central corneal sensitivity was decreased at all postoperative time points in both groups. However, the central corneal sensation scores in the SMILE group were greater than that in the femto-LASIK group at all of the postoperative time points (all P<0.05).
SMILE surgeries resulted in a short-term increase in dry eye symptoms, tear film instability, and loss of corneal sensitivity. Furthermore, SMILE surgeries have superiority over femto-LASIK in lower risk of postoperative corneal staining and less reduction of corneal sensation.
PMCID: PMC3812215  PMID: 24204971
13.  Microdeletion and Microduplication Analysis of Chinese Conotruncal Defects Patients with Targeted Array Comparative Genomic Hybridization 
PLoS ONE  2013;8(10):e76314.
The current study aimed to develop a reliable targeted array comparative genomic hybridization (aCGH) to detect microdeletions and microduplications in congenital conotruncal defects (CTDs), especially on 22q11.2 region, and for some other chromosomal aberrations, such as 5p15-5p, 7q11.23 and 4p16.3.
Twenty-seven patients with CTDs, including 12 pulmonary atresia (PA), 10 double-outlet right ventricle (DORV), 3 transposition of great arteries (TGA), 1 tetralogy of Fallot (TOF) and one ventricular septal defect (VSD), were enrolled in this study and screened for pathogenic copy number variations (CNVs), using Agilent 8 x 15K targeted aCGH. Real-time quantitative polymerase chain reaction (qPCR) was performed to test the molecular results of targeted aCGH.
Four of 27 patients (14.8%) had 22q11.2 CNVs, 1 microdeletion and 3 microduplications. qPCR test confirmed the microdeletion and microduplication detected by the targeted aCGH.
Chromosomal abnormalities were a well-known cause of multiple congenital anomalies (MCA). This aCGH using arrays with high-density coverage in the targeted regions can detect genomic imbalances including 22q11.2 and other 10 kinds CNVs effectively and quickly. This approach has the potential to be applied to detect aneuploidy and common microdeletion/microduplication syndromes on a single microarray.
PMCID: PMC3788710  PMID: 24098474
14.  Endostatin/Collagen XVIII Is Increased in Cerebrospinal Fluid after Severe Traumatic Brain Injury 
BioMed Research International  2013;2013:402375.
Recent studies have suggested that endogenous angiogenesis inhibitor endostatin/collagen XVIII might play an important role in the secondary brain injury following traumatic brain injury (TBI). In this study, we measured endostatin/collagen XVIII concentrations serially for 1 week after hospitalization by using the enzyme-linked immunosorbent assay method in the cerebrospinal fluid (CSF) of 30 patients with TBI and a Glasgow Coma Scale (GCS) score of 8 or less on admission. There was a significant trend toward increased CSF levels of endostatin after TBI versus control from 72 h after injury. In patients with GCS score of 3–5, CSF endostatin concentration was substantially higher at 72 h after injury than that in patients with GCS score of 6–8 (P < 0.05) and peaked rapidly at day 5 after injury, but decreased thereafter. The CSF endostatin concentration in 12 patients with an unfavorable outcome was significantly higher than that in 18 patients with a favorable outcome at day 5 (P = 0.043) and day 7 (P = 0.005) after trauma. Receiver operating characteristic curve analysis suggested a reliable operating point for the 7-day CSF endostatin concentration predicting poor prognosis to be 67.29 pg/mL. Our preliminary findings provide new evidence that endostatin/collagen XVIII concentration in the CSF increases substantially in patients with sTBI. Its dynamic change may have some clinical significance on the judgment of brain injury severity and the assessment of prognosis. This trial is registered with the Identifier: NCT01846546.
PMCID: PMC3780551  PMID: 24089677
15.  Clinicopathological and molecular markers associated with prognosis and treatment effectiveness of endometrial stromal sarcoma: a retrospective study in China 
To evaluate the clinicopathological and immunophenotypic characteristics of endometrial stromal sarcoma (ESS) in China.
Methods and materials
Seventy-two consecutive ESS cases treated between 1995 and 2009 were retrospectively reviewed.
Sixty-three patients received surgical treatment. Forty-one patients underwent pelvic lymphadenectomy. In paraffin-embedded specimens, expression of the following molecular markers was detected: CD10 (27/36), vimentin (37/38), HHF35 (3/32), S-100 (0/25), desmin (2/29), CD117 (0/23), CD34 (2/24), alpha-inhibin (0/17), CK (1/34), CD99 (4/9), smooth muscle actin (5/25), EMA (0/7), estrogen receptor (13/16) and progesterone receptor (13/16). CD10 and vimentin were expressed more frequently in these specimens. Tumor classification, CD10 and surgical procedures were significantly associated with disease-free survival (DFS). Surgical procedures were significantly associated with overall survival (OS). Tumor stage (P = 0.024) and surgical procedure (P = 0.042) were found to be significant independent prognostic factors for DFS. No complete or partial response was observed among patients who received radiotherapy or chemotherapy.
Our results indicate that total hysterectomy with bilateral salpingo-oophorectomy followed by pelvic lymphadenectomy is associated with an improved treatment outcome. CD10-negative expression may contribute to the malignant characteristics and recurrence associated with ESS.
PMCID: PMC3894427  PMID: 23959089
Endometrial stromal sarcoma; Pelvic lymphadenectomy; CD10; Prognosis
16.  Comparison of Various Anthropometric and Body Fat Indices in Identifying Cardiometabolic Disturbances in Chinese Men and Women 
PLoS ONE  2013;8(8):e70893.
Although many adiposity indices may be used to predict obesity-related health risks, uncertainty remains over which of them performs best.
This study compared the predictive capability of direct and indirect adiposity measures in identifying people at higher risk of metabolic abnormalities.
This population-based cross-sectional study recruited 2780 women and 1160 men. Body weight and height, waist circumference (WC), and hip circumference (HC) were measured and body mass index (BMI), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR) were calculated. Body fat (and percentage of fat) over the whole body and the trunk were determined by bioelectrical impedance analysis (BIA). Blood pressure, fasting lipid profiles, and glucose and urine acid levels were assessed.
In women, the ROC and the multivariate logistic regression analyses both showed that WHtR consistently had the best performance in identifying hypertension, dyslipidemia, hyperuricemia, diabetes/IFG, and metabolic syndrome (MetS). In men, the ROC analysis showed that WHtR was the best predictor of hypertension, WHtR and WC were equally good predictors of dyslipidemia and MetS, and WHtR was the second-best predictor of hyperuricemia and diabetes/IFG. The multivariate logistic regression also found WHtR to be superior in discriminating between MetS, diabetes/IFG, and dyslipidemia while BMI performed better in predicting hypertension and hyperuricemia in men. The BIA-derived indices were the second-worst predictors for all of the endpoints, and HC was the worst.
WHtR was the best predictor of various metabolic abnormalities. BMI may be used as an alternative measure of obesity for identifying hypertension in both sexes.
PMCID: PMC3741370  PMID: 23951031
17.  Aberrant Functional Connectivity of Resting State Networks in Transient Ischemic Attack 
PLoS ONE  2013;8(8):e71009.
Transient ischemic attack (TIA) is usually defined as a neurologic ischemic disorder without permanent cerebral infarction. Studies have showed that patients with TIA can have lasting cognitive functional impairment. Inherent brain activity in the resting state is spatially organized in a set of specific coherent patterns named resting state networks (RSNs), which epitomize the functional architecture of memory, language, attention, visual, auditory and somato-motor networks. Here, we aimed to detect differences in RSNs between TIA patients and healthy controls (HCs).
Twenty one TIA patients suffered an ischemic event and 21 matched HCs were enrolled in the study. All subjects were investigated using cognitive tests, psychiatric tests and functional magnetic resonance imaging (fMRI). Independent component analysis (ICA) was adopted to acquire the eight brain RSNs. Then one-sample t-tests were calculated in each group to gather the spatial maps of each RSNs, followed by second level analysis to investigate statistical differences on RSNs between twenty one TIA patients and 21 controls. Furthermore, a correlation analysis was performed to explore the relationship between functional connectivity (FC) and cognitive and psychiatric scales in TIA group.
Compared with the controls, TIA patients exhibited both decreased and increased functional connectivity in default mode network (DMN) and self-referential network (SRN), and decreased functional connectivity in dorsal attention network (DAN), central-executive network (CEN), core network (CN), somato-motor network (SMN), visual network (VN) and auditory network (AN). There was no correlation between neuropsychological scores and functional connectivity in regions of RSNs.
We observed selective impairments of RSN intrinsic FC in TIA patients, whose all eight RSNs had aberrant functional connectivity. These changes indicate that TIA is a disease with widely abnormal brain networks. Our results might put forward a novel way to look into neuro-pathophysiological mechanisms in TIA patients.
PMCID: PMC3741391  PMID: 23951069
18.  The Influence of Hemocoagulation Disorders on the Development of Posttraumatic Cerebral Infarction and Outcome in Patients with Moderate or Severe Head Trauma 
BioMed Research International  2013;2013:685174.
Posttraumatic cerebral infarction (PTCI) is a severe secondary insult of head injury and often leads to a poor prognosis. Hemocoagulation disorder is recognized to have important effects on hemorrhagic or ischemic damages. We sought to assess if posttraumatic hemocoagulation disorders were associated with cerebral infarction, and evaluate their influence on outcome among patients with moderate or severe head trauma. In this study, PTCI was observed in 28 (10.57%) of the 265 patients within the first week after injury. In multivariate analysis, the thrombocytopenia (odds ratio (OR) 2.210, 95% confidence interval (CI) 1.065–4.674), abnormal prothrombin time (PT) (OR 3.241, 95% CI 1.090–7.648), D-dimer (>2 mg/L) (OR 7.260, 95% CI 1.822–28.076), or disseminated intravascular coagulation (DIC) scores (≥5) (OR 4.717, 95% CI 1.778–12.517) were each independently associated with an increased risk of PTCI. Admission Glasgow Coma Scale (GCS) score, abnormal activated partial thromboplastin time (APTT) and fibrinogen, and D-dimer (>2 mg/L) and DIC scores (≥5) showed an independent predictive effect on poor outcome. In conclusion, recognition of this important treatable cause of PTCI and the associated risk factors may help identify the group at risk and tailor management of patients with TBI.
PMCID: PMC3747364  PMID: 23984395
19.  MKK3 Was Involved in Larval Settlement of the Barnacle Amphibalanus amphitrite through Activating the Kinase Activity of p38MAPK 
PLoS ONE  2013;8(7):e69510.
The p38 mitogen-activated protein kinase (p38MAPK) plays a key role in larval settlement of the barnacle Amphibalanus amphitrite. To study the signaling pathway associated with p38MAPK during larval settlement, we sought to identify the upstream kinase of p38MAPK. Three MKKs (MKK3, MKK4 and MKK7) and three MAPKs (p38MAPK, ERK and JNK) in A. amphitrite were cloned and recombinantly expressed in E. coli. Through kinase assays, we found that MKK3, but not MKK4 or MKK7, phosphorylated p38MAPK. Furthermore, MKK3 activity was specific to p38MAPK, as it did not phosphorylate ERK or JNK. To further investigate the functional relationship between MKK3 and p38MAPK in vivo, we studied the localization of phospho-MKK3 (pMKK3) and MKK3 by immunostaining. Consistent with the patterns of p38MAPK and phospho-p38MAPK (pp38MAPK), pMKK3 and MKK3 mainly localized to the antennules of the cyprids. Western blot analysis revealed that pMKK3 levels, like pp38MAPK levels, were elevated at cyprid stage, compared to nauplii and juvenile stages. Moreover, pMKK3 levels increased after treatment with adult barnacle crude extracts, suggesting that MKK3 might mediate the stimulatory effects of adult barnacle extracts on the p38MAPK pathway.
PMCID: PMC3726695  PMID: 23922727
20.  NIBP, a Novel NIK and IKKβ-binding Protein That Enhances NF-κB Activation* 
The Journal of biological chemistry  2005;280(32):29233-29241.
The transcription factor NF-κB plays an important role in both physiological and pathological events in the central nervous system. Nevertheless, the mechanisms of NF-κB-mediated regulation of gene expression, and the signaling molecules participating in the NF-κB pathway in the central nervous system are, to date, poorly understood. To identify such molecules, we conducted a yeast two-hybrid screen of a human brain cDNA library using NIK as bait. As a result, we identified a novel NIK and IKKβ binding protein designated NIBP that is mainly expressed in brain, muscle, heart, and kidney. Interestingly, low levels of expression were detected in immune tissues such as spleen, thymus, and peripheral blood leukocytes, where NF-κB is known to modulate immune function. We demonstrated by immunohistochemistry that NIBP expression in the brain is localized to neurons. NIBP physically interacts with NIK IKKβ, but not IKKα or IKKγ. NIBP overexpression potentiates tumor necrosis factor-α-induced NF-κB activation through increased phosphorylation of the IKK complex and its downstream IκBα and p65 substrates. Finally, knockdown of NIBP expression by small interfering RNA reduces tumor necrosis factor-α-induced NF-κB activation, prevents nerve growth factor-induced neuronal differentiation, and decreases Bcl-xL gene expression in PC12 cells. Our data demonstrate that NIBP, by interacting with NIK and IKKβ, is a new enhancer of the cytokine-induced NF-κB signaling pathway. Because of its neuronal expression, we propose that NIBP may be a potential target for modulating the NF-κB signaling cascade in neuronal pathologies dependent upon abnormal activation of this pathway.
PMCID: PMC3707486  PMID: 15951441
21.  Low density lipoprotein cholesterol level inversely correlated with coronary flow velocity reserve in patients with Type 2 diabetes 
To evaluate the association of coronary artery endothelial function and plasma levels of low density lipoprotein cholesterol (LDL-C) and high density lipoprotein cholesterol (HDL-C) in patients with Type 2 Diabetes Mellitus (DM).
We investigated 90 participants from our institution between October 2007 to March 2010: non-DM (n = 60) and DM (n = 30). As an indicator of coronary endothelial dysfunction, we used non-invasive Doppler echocardiography to quantify coronary flow velocity reserve (CFVR) in the distal part of the left descending artery after rest and after intravenous adenosine administration.
Plasma level of LDL-C was significantly higher in patients with DM than in non-DM (3.21 ± 0.64 vs. 2.86 ± 0.72 mmo/L, P < 0.05), but HDL-C level did not differ between the groups (1.01 ± 0.17 vs. 1.05 ± 0.19 mmo/L). Furthermore, the CFVR value was lower in DM patients than non-diabetics (2.45 ± 0.62 vs. 2.98 ± 0.68, P < 0.001). Plasma levels of LDL-C were negatively correlated with CFVR in all subjects (r = −0.35, P < 0.001; 95% confidence interval (CI): −0.52 – −0.15) and in the non-DM (r = −0.29, P < 0.05; 95% CI: −0.51– −0.05), with an even stronger negative correlation in the DM group (r = −0.42, P < 0.05; 95% CI: −0.68 – −0.06). Age (β = −0.019, s = 0.007, sβ = −0.435, 95% CI: −0.033 – −0.005, P = 0.008), LDL-C (β = −0.217, s = 0.105, sβ = −0.282, 95% CI: −0.428 – −0.005, P = 0.045) remained independently correlated with CFVR in the DM group. However, we found no correlation between HDL-C level and CFVR in any group.
Diabetes may contribute to coronary artery disease (CAD) by inducing dysfunction of the coronary artery endothelium. Increased LDL-C level may adversely impair coronary endothelial function in DM. HDL-C may lose its endothelial-protective effects, in part as a result of pathological conditions, especially under abnormal glucose metabolism.
PMCID: PMC3708056  PMID: 23888176
Coronary flow velocity reserve; Low-density lipoprotein cholesterol; Endothelial function; Diabetes mellitus; High-density lipoprotein cholesterol
22.  Overexpression of Cystatin SN positively affects survival of patients with surgically resected esophageal squamous cell carcinoma 
BMC Surgery  2013;13:15.
Cystatin SN is a secreted protein and a cysteine proteinase inhibitor. It has been considered to be a tumor marker for gastrointestinal tract cancer in several functional researches. However, the clinicopathological and prognostic significance of Cystatin SN expression in esophageal squamous cell carcinoma (ESCC) has not been elucidated.
In our study, the expression of Cystatin SN was detected in 209 surgically resected ESCC tissues and 170 peritumoral normal esophageal mucosae by immunohistochemistry. The prognostic significance of Cystatin SN expression was analysed with Kaplan-Meier plots and the Cox proportional hazards regression models.
The results showed that the immunostaining of Cystatin SN in ESCC tissues was less intense than that in the normal control tissue (P < 0.001). Compared with patients with low tumoral Cystatin SN expression, ESCC patients with tumors high-expression Cystatin SN exhibited increased disease-free survival (DFS) and overall survival (OS) (P < 0.001 and P < 0.001, respectively). Furthermore, the expression level of Cystatin SN could further stratify the ESCC patients by survival (DFS and OS) in the stage II subgroup (P < 0.001 and P < 0.001, respectively). Multivariate analyses showed that Cystatin SN expression, N status and differentiation were independent and significant predictors of survival.
We concluded that ESCC patients whose tumors express high levels of Cystatin SN have favourable survival compared with those patients with low Cystatin SN expression. Tumoral Cystatin SN expression may be an independent predictor of survival for patients with resectable ESCCs.
PMCID: PMC3699386  PMID: 23711283
Esophageal squamous cell carcinoma; Cystatin SN; Immunohistochemistry; Prognosis
23.  Characterization of Two 20kDa-Cement Protein (cp20k) Homologues in Amphibalanus amphitrite 
PLoS ONE  2013;8(5):e64130.
The barnacle, Amphibalanus amphitrite, is a common marine fouling organism. Understanding the mechanism of barnacle adhesion will be helpful in resolving the fouling problem. Barnacle cement is thought to play a key role in barnacle attachment. Although several adult barnacle cement proteins have been identified in Megabalanus rosa, little is known about their function in barnacle settlement. In this study, two homologous 20k-cement proteins (cp20k) in Amphibalanus amphitrite, named Bamcp20k-1 and Bamcp20k-2, were characterized. The two homologues share primary sequence structure with proteins from other species including Megabalanus rosa and Fistulobalanus albicostatus. The conserved structure included repeated Cys domains and abundant charged amino acids, such as histidine. In this study we demonstrated that Bamcp20k-1 localized at the α secretory cells in the cyprid cement gland, while Bamcp20k-2 localized to the β secretory cells. The differential localizations suggest differential regulation for secretion from the secretory cells. Both Bamcp20k-1 and Bamcp20k-2 from cyprids dissolved in PBS. However, adult Bamcp20k-2, which was dominant in the basal shell of adult barnacles, was largely insoluble in PBS. Solubility increased in the presence of the reducing reagent Dithiothreitol (DTT), suggesting that the formation of disulfide bonds plays a role in Bamcp20k-2 function. In comparison, Bamcp20k-1, which was enriched in soft tissue, could not be easily detected in the shell and base by Western blot and easily dissolved in PBS. These differential solubilities and localizations indicate that Bamcp20k-1 and Bamcp20k-2 have distinct functions in barnacle cementing.
PMCID: PMC3661472  PMID: 23717550
24.  Association of Weight-Adjusted Body Fat and Fat Distribution with Bone Mineral Density in Middle-Aged Chinese Adults: A Cross-Sectional Study 
PLoS ONE  2013;8(5):e63339.
Although it is well established that a higher body weight is protective against osteoporosis, the effects of body fat and fat distribution on bone mineral density (BMD) after adjustment for body weight remains uncertain.
To examine the relationship between body fat and fat distribution and BMD beyond its weight-bearing effect in middle-aged Chinese adults.
The study had a community-based cross-sectional design and involved 1,767 women and 698 men aged 50–75 years. The BMD of the lumbar spine, total hip, and whole body, and the fat mass (FM) and percentage fat mass (%FM) of the total body and segments of the body were measured by dual-energy X-ray absorptiometry. General information on the participants was collected using structured questionnaire interviews.
After adjusting for potential confounders, an analysis of covariance showed the weight-adjusted (WA-) total FM (or %FM) to be negatively associated with BMD in all of the studied sites (P<0.05) in both women and men. The unfavorable effects of WA-total FM were generally more substantial in men than in women, and the whole body was the most sensitive site related to FM, followed by the total hip and the lumbar spine, in both genders. The mean BMD of the lumbar spine, total hip, and whole body was 3.93%, 3.01%, and 3.65% (in women) and 5.02%, 5.57%, 6.03% (in men) lower in the highest quartile (vs. lowest quartile) according to the WA-total FM (all p<0.05). Similar results were noted among the groups for WA-total FM%. In women, abdominal fat had the most unfavorable association with BMD, whereas in men it was limb fat.
FM (or %FM) is inversely associated with BMD beyond its weight-bearing effect. Abdominal fat in women and limb fat in men seems to have the greatest effect on BMD.
PMCID: PMC3658980  PMID: 23700417
25.  Nonstructural Protein NS80 Is Crucial in Recruiting Viral Components to Form Aquareoviral Factories 
PLoS ONE  2013;8(5):e63737.
Replication and assembly of vertebrate reoviruses occur in specific intracellular compartments known as viral factories. Recently, NS88 and NS80, the nonstructural proteins from aquareoviruses, have been proposed to share common traits with µNS from orthoreoviruses, which are involved in the formation of viral factories.
Methodology/Principal Findings
In this study, the NS80 characteristics and its interactions with other viral components were investigated. We observed that the NS80 structure ensured its self-aggregation and selective recruitment of viral proteins to viral factories like structures (VFLS). The minimum amino acids (aa) of NS80 required for VFLS formation included 193 aa at the C-terminal. However, this truncated protein only contained one aa coil and located in the nucleus. Its N-terminal residual regions, aa 1–55 and aa 55–85, were required for recruiting viral nonstructural protein NS38 and structural protein VP3, respectively. A conserved N-terminal region of NS38, which was responsible for the interaction with NS80, was also identified. Moreover, the minimal region of C-terminal residues, aa 506–742 (Δ505), required for NS80 self-aggregation in the cytoplasm, and aa 550–742 (Δ549), which are sufficient for recruiting viral structure proteins VP1, VP2, and VP4 were also identified.
The present study shows detailed interactions between NS80 and NS38 or other viral proteins. Sequence and structure characteristics of NS80 ensures its self-aggregation to form VFLS (either in the cytoplasm or nucleus) and recruitment of viral structural or nonstructural proteins.
PMCID: PMC3646018  PMID: 23671697

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