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1.  Forkhead Transcription Factor Foxq1 Promotes Epithelial–Mesenchymal Transition and Breast Cancer Metastasis 
Cancer research  2011;71(4):1292-1301.
Epithelial-mesenchymal transition (EMT) promotes cancer invasion and metastasis, but the integrative mechanisms that coordinate these processes are incompletely understood. In this study, we used a cross-species expression profiling strategy in metastatic cell lines of human and mouse origin to identify 22 up-regulated and 12 down-regulated genes that are part of an essential genetic program in metastasis. In particular, we identified a novel function in metastasis that was not previously known for the transcription factor Forkhead Box Q1 (Foxq1). Ectopic expression of Foxq1 increased cell migration and invasion in vitro, enhanced the lung metastatic capabilities of mammary epithelial cells in vivo, and triggered a marked EMT. In contrast, Foxq1 knockdown elicited converse effects on these phenotypes in vitro and in vivo. Neither ectopic expression nor knockdown of Foxq1 significantly affected cell proliferation or colony formation in vitro. Notably, Foxq1 repressed expression of the core EMT regulator E-cadherin by binding to the E-box in its promoter region. Further mechanistic investigation revealed that Foxq1 expression is regulated by TGF-β1, and that Foxq1 knockdown blocked TGF-β1-induced EMT at both morphological and molecular levels. Our findings highlight the feasibility of cross-species expression profiling as a strategy to identify metastasis-related genes, and they reveal that EMT induction is a likely mechanism underlying a novel metastasis-promoting function of Foxq1 defined here in breast cancer.
PMCID: PMC3906209  PMID: 21285253
2.  Frontal-Subcortical Volumetric Deficits in Single Episode, Medication-Naïve Depressed Patients and the Effects of 8 Weeks Fluoxetine Treatment: A VBM-DARTEL Study 
PLoS ONE  2014;9(1):e79055.
Convergent studies suggest that morphological abnormalities of frontal-subcortical circuits which involved with emotional and cognitive processing may contribute to the pathophysiology of major depressive disorder (MDD). Antidepressant treatment which has been reported to reverse the functional abnormalities of frontal-subcortical circuits in MDD may have treating effects to related brain morphological abnormalities. In this study, we used voxel-based morphometry method to investigate whole brain structural abnormalities in single episode, medication-naïve MDD patients. Furthermore, we investigated the effects of an 8 weeks pharmacotherapy with fluoxetine.
28 single episode, medication-naïve MDD participants and 28 healthy controls (HC) acquired the baseline high-resolution structural magnetic resonance imaging (sMRI) scan. 24 MDD participants acquired a follow-up sMRI scan after 8 weeks antidepressant treatment. Gray matter volumetric (GMV) difference between groups was examined.
Medication-naïve MDD had significantly decreased GMV in the right dorsolateral prefrontal cortex and left middle frontal gyrus as well as increased GMV in the left thalamus and right insula compared to HC (P<0.05, corrected). Moreover, treated MDD had significantly increased GMV in the left middle frontal gyrus and right orbitofrontal cortex compared to HC (P<0.05, corrected). No difference on GMV was detected between medication-naïve MDD group and treated MDD group.
This study of single episode, medication-naïve MDD subjects demonstrated structural abnormalities of frontal-subcortical circuitsin the early stage of MDD and the effects of 8 weeks successful antidepressant treatment, suggesting these abnormalities may play an important role in the neuropathophysiology of MDD at its onset.
PMCID: PMC3888377  PMID: 24427263
3.  Menatetrenone versus alfacalcidol in the treatment of Chinese postmenopausal women with osteoporosis: a multicenter, randomized, double-blinded, double-dummy, positive drug-controlled clinical trial 
To evaluate whether the efficacy and safety of menatetrenone for the treatment of osteoporosis is noninferior to alfacalcidol in Chinese postmenopausal women.
This multicenter, randomized, double-blinded, double-dummy, noninferiority, positive drug-controlled clinical trial was conducted in five Chinese sites. Eligible Chinese women with postmenopausal osteoporosis (N=236) were randomized to Group M or Group A and received menatetrenone 45 mg/day or alfacalcidol 0.5 μg/day, respectively, for 1 year. Additionally, all patients received calcium 500 mg/day. Posttreatment bone mineral density (BMD), new fracture onsets, and serum osteocalcin (OC) and undercarboxylated OC (ucOC) levels were compared with the baseline value in patients of both groups.
A total of 213 patients (90.3%) completed the study. After 1 year of treatment, BMD among patients in Group M significantly increased from baseline by 1.2% and 2.7% at the lumbar spine and trochanter, respectively (P<0.001); and the percentage increase of BMD in Group A was 2.2% and 1.8%, respectively (P<0.001). No difference was observed between groups. There were no changes in femoral neck BMD in both groups. Two patients (1.9%, 2/108) in Group M and four patients (3.8%, 4/105) in Group A had new fracture onsets (P>0.05). In Group M, OC and ucOC decreased from baseline by 38.7% and 82.3%, respectively (P<0.001). In Group A, OC and ucOC decreased by 25.8% and 34.8%, respectively (P<0.001). Decreases in serum OC and ucOC were more obvious in Group M than in Group A (P<0.001). The safety profile of menatetrenone was similar to alfacalcidol.
Menatetrenone is an effective and safe choice in the treatment of postmenopausal osteoporosis in Chinese women.
PMCID: PMC3890406  PMID: 24426779
menatetrenone; alfacalcidol; postmenopausal; osteoporosis; bone mineral density; undercarboxylated osteocalcin
4.  TLR4 induces tumor growth and inhibits paclitaxel activity in MyD88-positive human ovarian carcinoma in vitro 
Oncology Letters  2013;7(3):871-877.
In ovarian cancer patients, chemotherapy resistance is the principal factor restricting long-term treatment. Paclitaxel (Pac) has been previously reported to be a ligand to Toll-like receptor 4 (TLR4). It was determined that TLR4 signaling is divided into the following two pathways: Myeloid differentiation factor 88 (MyD88)-dependent and MyD88-independent. The present study investigated the effect of TLR4 ligation by Pac in MyD88-positive (MyD88+) and MyD88-negative (MyD88−) human ovarian cancer cell lines. An RNA interference expression vector was specifically constructed to target TLR4 mRNA, which was stably transfected into the human ovarian cancer cell lines (SKOV3, OVCAR3, A2780 and 3AO). Cytokines, including interleukin (IL)-6 and IL-8, were detected. Cell proliferation and apoptosis were assessed in the cells transfected with scramble control and TLR4 shRNA to explore the possible functions of TLR4 in ovarian cancer cell growth. It was found that lipopolysaccharide and Pac significantly increase the secretion of IL-6 and IL-8 in the SKOV3 cell line. Similarly, Pac resulted in a significant upregulation of IL-6 and IL-8 in OVCAR3 cells, but not in A2780 and 3AO cells. These results suggested that in MyD88+ ovarian cancer cell lines, TLR4 depletion shows increased sensitivity to Pac treatment in inhibiting cell proliferation compared with in cells without TLR4 knockdown. On the contrary, such changes were not found in MyD88− cells (A2780 and 3AO). TLR4 negatively regulates Pac chemotherapy, particularly in terms of cell proliferation, and TLR4 may be a novel treatment target in Pac-resistant ovarian cancer.
PMCID: PMC3919821  PMID: 24527095
ovarian cancer; TLR4; MyD88; paclitaxel; chemotherapy
5.  Angiostrongylus cantonensis: Scanning Electron Microscopic Observations on the Cuticle of Moulting Larvae 
Angiostrongylus cantonensis is a parasitic nematode that needs to develop in different hosts in different larval stages. Freshwater snails, such as Pomacea canaliculata, are the intermediate host, and rats are the definitive host. Periodic shedding of the cuticle (moulting) is an important biological process for the survival and development of the parasite in the intermediate and definitive hosts. However, there are few studies on the cuticle alterations between different stages of this parasite. In this study, we observed the ultrastructural appearance and changes of the cuticle of the 2nd/3rd stage larvae (L2/L3) and the 3rd/4th stage larvae (L3/L4) using a scanning electron microscope. We also first divided L2/L3 into late L2 and early L3. The late L2 lacked alae, but possessed a pull-chain-like fissure. Irregular alignment of spherical particles on the cuticle were noted compared to the L3. Alae appeared in the early L3. The old cuticle turned into a thin film-like structure which adhered to the new cuticle, and spherical particles were seen regularly arranged on the surface of this structure. Regular rectangular cavities were found on the surface of L3/L4. The caudal structure of L3/L4 was much larger than that of L3, but caudal inflation, such as seen in L4, was not observed. These results are the first to reveal the ultrastructural changes of the cuticle of A. cantonensis before and after moulting of L2/L3 and L3/L4.
PMCID: PMC3916450  PMID: 24516266
Angiostrongylus cantonensis; moulting larva; scanning electron microscopy
6.  Functional connectivity between the amygdala and prefrontal cortex in medication-naive individuals with major depressive disorder 
Convergent evidence suggests dysfunction within the prefrontal cortex (PFC) and amygdala, important components of a neural system that subserves emotional processing, in individuals with major depressive disorder (MDD). Abnormalities in this system in the left hemisphere and during processing of negative emotional stimuli are especially implicated. In this study, we used functional magnetic resonance imaging (fMRI) to investigate amygdala–PFC functional connectivity during emotional face processing in medication-naive individuals with MDD.
Individuals with MDD and healthy controls underwent fMRI scanning while processing 3 types of emotional face stimuli. We compared the strength of functional connectivity from the amygdala between the MDD and control groups.
Our study included 28 individuals with MDD and 30 controls. Decreased amygdala–left rostral PFC (rPFC) functional connectivity was observed in the MDD group compared with controls for the fear condition (p < 0.05, corrected). No significant differences were found in amygdala connectivity to any cerebral regions between the MDD and control groups for the happy or neutral conditions.
All participants with MDD were experiencing acute episodes, therefore the findings could not be generalized to the entire MDD population.
Medication-naive individuals with MDD showed decreased amygdala–left rPFC functional connectivity in response to negative emotional stimuli, suggesting that abnormalities in amygdala–left rPFC neural circuitry responses to negative emotional stimuli might play an important role in the pathophysiology of MDD.
PMCID: PMC3819156  PMID: 24148846
7.  Evaluation of the Impacts of Land Use on Water Quality: A Case Study in The Chaohu Lake Basin 
The Scientific World Journal  2013;2013:329187.
It has been widely accepted that there is a close relationship between the land use type and water quality. There have been some researches on this relationship from the perspective of the spatial configuration of land use in recent years. This study aims to analyze the influence of various land use types on the water quality within the Chaohu Lake Basin based on the water quality monitoring data and RS data from 2000 to 2008, with the small watershed as the basic unit of analysis. The results indicated that there was significant negative correlation between forest land and grassland and the water pollution, and the built-up area had negative impacts on the water quality, while the influence of the cultivated land on the water quality was very complex. Besides, the impacts of the landscape diversity on the indicators of water quality within the watershed were also analyzed, the result of which indicated there was a significant negative relationship between them. The results can provide important scientific reference for the local land use optimization and water pollution control and guidance for the formulation of policies to coordinate the exploitation and protection of the water resource.
PMCID: PMC3736410  PMID: 23970833
8.  Community and Proteomic Analysis of Methanogenic Consortia Degrading Terephthalate 
Degradation of terephthalate (TA) through microbial syntrophy under moderately thermophilic (46 to 50°C) methanogenic conditions was characterized by using a metagenomic approach (A. Lykidis et al., ISME J. 5:122–130, 2011). To further study the activities of key microorganisms responsible for the TA degradation, community analysis and shotgun proteomics were used. The results of hierarchical oligonucleotide primer extension analysis of PCR-amplified 16S rRNA genes indicated that Pelotomaculum, Methanosaeta, and Methanolinea were predominant in the TA-degrading biofilms. Metaproteomic analysis identified a total of 482 proteins and revealed a distinctive distribution pattern of microbial functions expressed in situ. The results confirmed that TA was degraded by Pelotomaculum spp. via the proposed decarboxylation and benzoyl-coenzyme A-dependent pathway. The intermediate by-products, including acetate, H2/CO2, and butyrate, were produced to support the growth of methanogens, as well as other microbial populations that could further degrade butyrate. Proteins related to energy production and conservation, and signal transduction mechanisms (that is, chemotaxis, PAS/GGDEF regulators, and stress proteins) were highly expressed, and these mechanisms were important for growth in energy-limited syntrophic ecosystems.
PMCID: PMC3536119  PMID: 23064332
9.  The Characteristics and Significance of Locally Infiltrating B Cells in Lupus Nephritis and Their Association with Local BAFF Expression 
Introduction. Dysfunction of the B lymphocyte is considered to be involved in the pathogenesis of lupus nephritis (LN). Intrarenal B cells have been found in several forms of inflammatory kidney disease. B-cell activating factor (BAFF) regulates B lymphocyte proliferation and survival, and contributes to human autoimmune disease. Their role in renal inflammation is not well defined. Methods. Clinical parameters and renal biopsies from 62 LN patients were prospectively analyzed. We performed standard immunohistochemistry on serial paraffin tissue sections using monoclonal antibodies to CD20 and BAFF to investigate the characteristics and significance of locally infiltrating B cells and local BAFF expression in patients with LN. Results. Intrarenal B cells and/or BAFF were mainly distributed in the renal interstitium. Compared to the LN-non-B-cell/BAFF expression group, proteinuria (g/24 hour), blood urea nitrogen, serum creatinine levels, LN renal activity, and chronicity indices, were all significantly greater in the LN-B-cell/BAFF expression groups. The expression of BAFF was strongly associated with the quantity of B-cell infiltrate in the interstitium. Conclusion. As BAFF expression was strongly associated with B-cell infiltration, we hypothesize that altered B-cell differentiation and tolerance induced by excess BAFF may be central to the pathogenesis of LN.
PMCID: PMC3694495  PMID: 23843794
10.  Atypical chemokine receptor D6 inhibits human non-small cell lung cancer growth by sequestration of chemokines 
Oncology Letters  2013;6(1):91-95.
Chemokines and their receptors have been shown to play a vital role in lung cancer progression. D6 is an atypical chemokine receptor which is able to internalize and degrade chemokines. To investigate the potential role of D6 in lung cancer, we established D6-overexpressing A549 lung cancer cell lines by the transfection of human D6 cDNA. Results showed that D6 inhibited the proliferation of cancer cells in vitro and tumorigenesis in vivo. We also determined chemokine levels in the supernatant and showed that a number of chemokines (CCL2/4/5) had significantly decreased protein levels in D6-overexpressing cells compared with the controls, whereas no significant changes in mRNA expression levels of these chemokines were detected. The cell cycle distribution and expression of certain growth factors and their receptors did not change in the D6-overexpressing cells compared with parental cells. Thus, our results suggest that D6 is a negative regulator of growth in lung cancer, mainly by the sequestration of specific chemokines.
PMCID: PMC3742824  PMID: 23946783
chemokines; D6; decoy receptor; lung neoplasm; proliferation
11.  Actin Microfilament Mediates Osteoblast Cbfa1 Responsiveness to BMP2 under Simulated Microgravity 
PLoS ONE  2013;8(5):e63661.
Microgravity decreases osteoblastic activity, induces actin microfilament disruption and inhibits the responsiveness of osteoblast to cytokines, but the mechanisms remains enigmatic. The F-actin cytoskeleton has previously been implicated in manifold changes of cell shape, function and signaling observed under microgravity. Here we investigate the involvement of microfilament in mediating the effects of microgravity and BMP2 induction on Cbfa1 activity. For this purpose we constructed a fluorescent reporter cell line (OSE-MG63) of Cbfa1 activity by stably transfecting MG63 cells with a reporter consisting of six tandem copies of OSE2 and a minimal mOG2 promoter upstream of enhanced green fluorescent protein (EGFP). The fluorescence intensity of OSE-MG63 showed responsiveness to bone-related cytokines (IGF-I, vitamin D3 and BMP2) and presented an accordant tendency with alkaline phosphatase (ALP) activity. Using OSE-MG63 reporter fluorescence, we performed a semi-quantitative analysis of Cbfa1 activity after treatment with simulated microgravity, microfilament-disrupting agent (cytochalasin B, CB), microfilament-stabilizing agent (Jasplakinolide, JAS) or any combination thereof. In parallel, ALP activity, DNA binding activity of Cbfa1 to OSE2 (ChIP), F-actin structure (immunofluorescence) and EGFP mRNA expression (RT-qPCR) were analyzed. Simulated microgravity inhibited Cbfa1 activity, affected the responsiveness of Cbfa1 to cytokine BMP2, and caused a thinning and dispersed distribution of microfilament. Under normal gravity, CB significantly attenuated BMP2 induction to Cbfa1 activity as well as DNA binding activity of Cbfa1 to OSE2. The addition of JAS reversed the inhibitory effects of microgravity on the responsiveness of Cbfa1 to BMP2. Our study demonstrates that disrupting the microfilament organization by CB or simulated microgravity attenuates the responsiveness of Cbfa1 to BMP2. A stabilization of the microfilament organization by JAS reverses this inhibition. Taken together, these results suggest that actin microfilament participates in BMP2’s induction to Cbfa1 activity and that their disruption might be an important contributor to microgravity’s inhibition on BMP2’s osteogenic induction.
PMCID: PMC3651164  PMID: 23675497
12.  Spatio-temporal analysis to identify determinants of Oncomelania hupensis infection with Schistosoma japonicum in Jiangsu province, China 
Parasites & Vectors  2013;6:138.
With the successful implementation of integrated measures for schistosomiasis japonica control, Jiangsu province has reached low-endemicity status. However, infected Oncomelania hupensis snails could still be found in certain locations along the Yangtze river until 2009, and there is concern that they might spread again, resulting in the possible re-emergence of infections among people and domestic animals alike. In order to establish a robust surveillance system that is able to detect the spread of infected snails at an early stage, sensitive and reliable methods to identify risk factors for the establishment of infected snails need to be developed.
A total of 107 villages reporting the persistent presence of infected snails were selected. Relevant data on the distribution of infected snails, and human and livestock infection status information for the years 2003 to 2008 were collected. Spatio-temporal pattern analysis including spatial autocorrelation, directional distribution and spatial error models were carried out to explore spatial correlations between infected snails and selected explanatory factors.
The area where infected snails were found, as well as their density, decreased significantly between 2003 and 2008. Changes in human and livestock prevalences were less pronounced. Three statistically significant spatial autocorrelations for infected snails were identified. (i) The Moran’s I of infected snails increased from 2004 to 2007, with the snail density increasing and the area with infected snails decreasing. (ii) The standard deviations of ellipses around infected snails were decreasing and the central points of the ellipses moved from West to East. (iii) The spatial error models indicated no significant correlation between the density of infected snails and selected risk factors.
We conclude that the contribution of local infection sources including humans and livestock to the distribution of infected snails might be relatively small and that snail control may limit infected snails to increasingly small areas ecologically most suitable for transmission. We provide a method to identify these areas and risk factors for persistent infected snail presence through spatio-temporal analysis, and a suggested framework, which could assist in designing evidence based control strategies for schistosomiasis japonica elimination.
PMCID: PMC3654978  PMID: 23648203
Schistosomiasis; Infected snails; Determinants; Spatio-temporal analysis; China
13.  Escherichia coli Nissle 1917 Targets and Restrains Mouse B16 Melanoma and 4T1 Breast Tumors through Expression of Azurin Protein 
Applied and Environmental Microbiology  2012;78(21):7603-7610.
Many studies have demonstrated that intravenously administered bacteria can target and proliferate in solid tumors and then quickly be released from other organs. Here, we employed the tumor-targeting property of Escherichia coli Nissle 1917 to inhibit mouse B16 melanoma and 4T1 breast tumors through the expression of azurin protein. For this purpose, recombinant azurin-expressing E. coli Nissle 1917 was developed. The levels of in vitro and in vivo azurin secretion in the engineered bacterium were determined by immunochemistry. Our results demonstrated that B16 melanoma and orthotopic 4T1 breast tumor growth were remarkably restrained and pulmonary metastasis was prevented in immunocompetent mice. It is worth noting that this therapeutic effect partially resulted from the antitumor activity of neutrophils and lymphocytes due to inflammatory responses caused by bacterial infections. No toxicity was observed in the animal during the experiments. This study indicates that E. coli Nissle 1917 could be a potential carrier to deliver antitumor drugs effectively for cancer therapy.
PMCID: PMC3485711  PMID: 22923405
14.  Poloxamer 188 Protects Neurons against Ischemia/Reperfusion Injury through Preserving Integrity of Cell Membranes and Blood Brain Barrier 
PLoS ONE  2013;8(4):e61641.
Poloxamer 188 (P188), a multiblock copolymer surfactant, has been shown to protect against ischemic tissue injury of cardiac muscle, testes and skeletal muscle, but the mechanisms have not been fully understood. In this study, we explored whether P188 had a protective effect against cerebral ischemia/reperfusion injury and its underlying mechanisms. The in vivo results showed that P188 significantly reduced the infarct volume, ameliorated the brain edema and neurological symptoms 24 h after ischemia/reperfusion. In the long-term outcome study, P188 markedly alleviated brain atrophy and motor impairments and increased survival rate in 3 weeks of post stroke period. Additionally, P188 protected cultured hippucampal HT22 cells against oxygen–glucose deprivation and reoxygenation (OGD/R) injury. The ability in membrane sealing was assessed with two fluorescent membrane-impermeant dyes. The results showed that P188 treatment significantly reduced the PI-positive cells following ischemia/reperfusion injury and repaired the HT22 cell membrane rupture induced by Triton X-100. In addition, P188 inhibited ischemia/reperfusion-induced activation of matrix metalloproteinase (MMP)-9 and leakage of Evans blue. Therefore, the present study concludes that P188 can protect against cerebral ischemia/reperfusion injury, and the protection involves multi-mechanisms in addition to the membrane resealing.
PMCID: PMC3628995  PMID: 23613890
15.  Extracellular matrix protein lumican regulates inflammation in a mouse model of colitis 
Inflammatory bowel diseases  2011;18(1):143-151.
Abnormal innate immune response contributes to inflammatory bowel disease (IBD) and experimental mouse colitis. Colitis studies have focused primarily on key regulators of innate immunity, like pathogen recognition receptors and cytoplasmic mediators. Extracellular matrix (ECM) proteins are emerging as modulators of inflammatory responses by virtue of their interactions with pathogen associated molecular patterns (PAMPs), cytokines, growth factors, receptors, and ECM fragments that mimic pathogens or cytokines. The ECM proteins have not been investigated in IBD at great depth from this standpoint. We have shown previously that the ECM protein lumican modulates host sensing of bacterial lipopolysaccharides (LPS) by toll like receptor (TLR) 4, and neutrophil chemotaxis via integrins. Here we investigated the role of lumican in the development of colitis mediated by intra-rectal administration of the hapten 2-4-5, trinitrobenzene sulfonic acid (TNBS) in Lum+/+ and Lum−/− mice. The TNBS-treated Lum+/+ mouse colons showed marked increases in CXCL1, TNF-α and neutrophil infiltration; while these responses were significantly dampened in the Lum−/− mice. The NF-κB transcription factor, known to regulate inflammatory genes, showed a robust increase after TNBS treatment in Lum+/+ but not in Lum−/− colons. Also, nuclear translocation of NF-κB was delayed in LPS-stimulated Lum−/− primary peritoneal macrophages. Thus, the Lum−/− mice have low innate immune and inflammatory responses, but more severe body weight loss and tissue damage, a phenomenon seen in the innate immune impaired Tlr4−/− and MyD88−/− mice. Therefore, lumican promotes intestinal homeostasis by aiding innate immune and inflammatory responses that are beneficial in the early stages of colitis.
PMCID: PMC3135758  PMID: 21484968
Extracellular matrix; lumican; TLR4; CD14; innate immune response; inflammation; murine colitis; neutrophils; tri-nitrobenzene sulfonic acid; dextran sodium sulfate
16.  Impaired interhemispheric connectivity in medication-naive patients with major depressive disorder 
Abnormalities in the anterior interhemispheric connections provided by the corpus callosum (CC) have long been implicated in major depressive disorder (MDD). The purpose of this study was to investigate interhemispheric connectivity in medication-naive patients with MDD by measuring fractional anisotropy in the CC with diffusion tensor imaging (DTI) techniques.
We obtained DTI scans from medication-naive patients with MDD and from matched healthy controls. Fractional anisotropy values were compared using semiautomatic region of interest methods to localize the regional CC differences between these 2 groups.
We enrolled 27 patients and 27 controls in our study. Fractional anisotropy values were significantly lower in the anterior genu of the CC in the MDD group than in the control group (p = 0.009, corrected); results were not significantly different in any other CC subregions.
As patients with MDD were already experiencing acute episodes, future studies of individuals at risk for MDD are warranted to elucidate the interhemispheric connectivity abnormalities associated with the predisposition to MDD.
The findings demonstrate abnormalities in the structural integrity of the anterior genu of the CC in medication-naive individuals with MDD, which may contribute to impairment of interhemispheric connectivity in patients with this disorder.
PMCID: PMC3529218  PMID: 22498077
17.  Up-Regulation of microRNA-126 May Contribute to Pathogenesis of Ulcerative Colitis via Regulating NF-kappaB Inhibitor IκBα 
PLoS ONE  2012;7(12):e52782.
MicroRNAs (miRNAs) are important post-transcriptional regulators. Altered expression of miRNAs has recently demonstrated association with human ulcerative colitis (UC). In this study, we attempted to elucidate the roles of miR-126 in the pathogenesis of UC.
Expression of miR-126, miR-21, miR-375 and the potential targets NF-κB inhibitor alpha (IκBα, IKBA or NFKBIA), Polo-like kinase 2 (PLK2) and v-Crk sarcoma virus CT10 oncogene homolog (CRK) were assessed in 52 colonic biopsies from patients with active UC, inactive UC, irritable bowel syndrome (IBS) and from healthy subjects by quantitative RT-PCR and immunofluorescence analyses. Regulation of gene expression by miR-126 was assessed using luciferase reporter construct assays and specific miRNA mimic transfection.
We found that the expression of miR-126 and miR-21 were significantly increased in active UC group compared to the inactive UC, IBS and healthy control groups (P<0.05). In contrast, the expression of IKBA mRNA and protein was remarkably decreased in the active UC group compared with the other three groups (P<0.05). The expression of miR-126 and IKBA mRNA were inversely correlated in active UC patients (P<0.05). However the expression of miR-375, PLK2 and CRK showed no difference between each group. Furthermore, we demonstrate that endogenous miR-126 and exogenous miR-126 mimic can inhibit IκBα expression. Finally, mutating the miR-126 binding site of the IKBA 3′-UTR reporter construct restored reporter gene expression.
miR-126 may play roles in UC inflammatory activity by down-regulating the expression of IKBA, an important inhibitor of NF-κB signaling pathway.
PMCID: PMC3532399  PMID: 23285182
18.  Different Roles for Contracture and Calpain in Calcium Paradox-Induced Heart Injury 
PLoS ONE  2012;7(12):e52270.
The Ca2+ paradox represents a good model to study Ca2+ overload injury in ischemic heart diseases. We and others have demonstrated that contracture and calpain are involved in the Ca2+ paradox-induced injury. This study aimed to elucidate their roles in this model. The Ca2+ paradox was elicited by perfusing isolated rat hearts with Ca2+-free KH media for 3 min or 5 min followed by 30 min of Ca2+ repletion. The LVDP was measured to reflect contractile function, and the LVEDP was measured to indicate contracture. TTC staining and the quantification of LDH release were used to define cell death. Calpain activity and troponin I release were measured after Ca2+ repletion. Ca2+ repletion of the once 3-min Ca2+ depleted hearts resulted in almost no viable tissues and the disappearance of contractile function. Compared to the effects of the calpain inhibitor MDL28170, KB-R7943, an inhibitor of the Na+/Ca2+ exchanger, reduced the LVEDP level to a greater extent, which was well correlated with improved contractile function recovery and tissue survival. The depletion of Ca2+ for 5 min had the same effects on injury as the 3-min Ca2+ depletion, except that the LVEDP in the 5-min Ca2+ depletion group was lower than the level in the 3-min Ca2+ depletion group. KB-R7943 failed to reduce the level of LVEDP, with no improvement in the LVDP recovery in the hearts subjected to the 5-min Ca2+ depletion treatment; however, KB-R7943 preserved its protective effects in surviving tissue. Both KB-R7943 and MDL28170 attenuated the Ca2+ repletion-induced increase in calpain activity in 3 min or 5 min Ca2+ depleted hearts. However, only KB-R7943 reduced the release of troponin I from the Ca2+ paradoxic heart. These results provide evidence suggesting that contracture is the main cause for contractile dysfunction, while activation of calpain mediates cell death in the Ca2+ paradox.
PMCID: PMC3527529  PMID: 23284963
19.  Live and Let Die - The Bsister MADS-Box Gene OsMADS29 Controls the Degeneration of Cells in Maternal Tissues during Seed Development of Rice (Oryza sativa) 
PLoS ONE  2012;7(12):e51435.
Bsister genes have been identified as the closest relatives of class B floral homeotic genes. Previous studies have shown that Bsister genes from eudicots are involved in cell differentiation during ovule and seed development. However, the complete function of Bsister genes in eudicots is masked by redundancy with other genes and little is known about the function of Bsister genes in monocots, and about the evolution of Bsister gene functions. Here we characterize OsMADS29, one of three MADS-box Bsister genes in rice. Our analyses show that OsMADS29 is expressed in female reproductive organs including the ovule, ovule vasculature, and the whole seed except for the outer layer cells of the pericarp. Knock-down of OsMADS29 by double-stranded RNA-mediated interference (RNAi) results in shriveled and/or aborted seeds. Histological analyses of the abnormal seeds at 7 days after pollination (DAP) indicate that the symplastic continuity, including the ovular vascular trace and the nucellar projection, which is the nutrient source for the filial tissue at early development stages, is affected. Moreover, degeneration of all the maternal tissues in the transgenic seeds, including the pericarp, ovular vascular trace, integuments, nucellar epidermis and nucellar projection, is blocked as compared to control plants. Our results suggest that OsMADS29 has important functions in seed development of rice by regulating cell degeneration of maternal tissues. Our findings provide important insights into the ancestral function of Bsister genes.
PMCID: PMC3520895  PMID: 23251532
20.  Quantitative assessment of gait and neurochemical correlation in a classical murine model of Parkinson’s disease 
BMC Neuroscience  2012;13:142.
Gait deficits are important clinical symptoms of Parkinson’s disease (PD). However, existing behavioral tests for the detection of motor impairments in rodents with systemic dopamine depletion only measure akinesia and dyskinesia, and data focusing on gait are scarce. We evaluated gait changes in the methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced C57BL/6 murine model of PD by using a computer-assisted CatWalk system. Correlations of gait parameters with tyrosine hydroxylase (TH) protein levels in the substantia nigra (SN) were also investigated.
The gait readouts, including the walking duration, variation of walking speed, step cycle, duty cycle, stance, initial dual stance, terminal dual stance, three- and four-point supports, and the base of support between hind limbs was noted to increase significantly one week after MPTP injection. In contrast, values of the stride length, cadence, swing speed, and diagonal dual support decreased substantially following MPTP treatment (p < 0.05). All of these changes lasted for three weeks after the last MPTP administration. Except for the stance in the fore limbs and the swing speed in the hind limbs, the gait variability in the PD mice showed a closer correlation with the protein levels of TH in the SN than the walking distances in the conventional open field test. Coordination parameters of the regularity index and step pattern were not affected in mice treated with MPTP.
Data of the study suggest that the computer-assisted CatWalk system can provide reliable and objective criteria to stratify gait changes arising from MPTP-induced bilateral lesions in C57/BL6 mice. The extent of gait changes was noted to correlate with the expression of the biomarker for dopaminergic neurons. This novel analytical method may hold promise in the study of disease progression and new drug screening in a murine PD model.
PMCID: PMC3507899  PMID: 23151254
Parkinson’s disease; Gait; MPTP; Tyrosine hydroxylase; Neurochemical correlation
21.  Rapid and accurate detection of RMP- and INH- resistant Mycobacterium tuberculosis in spinal tuberculosis specimens by CapitalBio™ DNA microarray: A prospective validation study 
BMC Infectious Diseases  2012;12:303.
DNA microarrays can detect tuberculosis and its multi-drug resistant form in M. tuberculosis isolates and sputum specimens with high sensitivity and specificity. However, no performance data currently exists for its use in spinal tuberculosis specimens. This study was aimed to assess the performance of the CapitalBio™ DNA microarray in the detection of isoniazid (INH) and rifampicin (RMP) resistance in spinal tuberculosis compared with the BACT/MGIT 960 system.
From March 2009 to December 2011, 153 consecutive patients from Southwest Hospital, Chongqing with clinically and pathologically diagnosed spinal tuberculosis were enrolled into this study. Specimens collected during surgery from the tuberculosis patients were subjected to M. tuberculosis species identification and drug-resistance detection by the CapitalBio™ DNA microarray, and results were compared with those obtained from the absolute concentration drug susceptibility testing.
The CapitalBio™ DNA microarray achieved 93.55% sensitivity for the correct M. tuberculosis species identification of the 93 specimens that tested positive for spinal tuberculosis through culture. In addition, twenty-seven additional patients (45.0%) were detected by the DNA microarray to be positive for M. tuberculosis among sixty spinal tuberculosis patients who were culture negative. Moreover, the DNA microarray had a sensitivity of 88.9% and a specificity of 90.7% for RMP resistance, and the microarray had a sensitivity of 80.0% and a specificity of 91.0% for INH resistance. The mean turn-around time of M. tuberculosis species identification and drug resistance detection using the DNA microarray was 5.8 (range, 4–9) hours.
The CapitalBio™ DNA microarray is a feasible and accurate tool for the species identification of M. tuberculosis and for directly detecting RMP and INH resistance from spinal tuberculosis specimens in fewer than 9 hours.
PMCID: PMC3527135  PMID: 23151186
DNA microarray; Spinal tuberculosis; Drug resistance; Gene mutation
22.  Interplay between the Westerlies and Asian monsoon recorded in Lake Qinghai sediments since 32 ka 
Scientific Reports  2012;2:619.
Two atmospheric circulation systems, the mid-latitude Westerlies and the Asian summer monsoon (ASM), play key roles in northern-hemisphere climatic changes. However, the variability of the Westerlies in Asia and their relationship to the ASM remain unclear. Here, we present the longest and highest-resolution drill core from Lake Qinghai on the northeastern Tibetan Plateau (TP), which uniquely records the variability of both the Westerlies and the ASM since 32 ka, reflecting the interplay of these two systems. These records document the anti-phase relationship of the Westerlies and the ASM for both glacial-interglacial and glacial millennial timescales. During the last glaciation, the influence of the Westerlies dominated; prominent dust-rich intervals, correlated with Heinrich events, reflect intensified Westerlies linked to northern high-latitude climate. During the Holocene, the dominant ASM circulation, punctuated by weak events, indicates linkages of the ASM to orbital forcing, North Atlantic abrupt events, and perhaps solar activity changes.
PMCID: PMC3431539  PMID: 22943005
23.  Association of Intrarenal B-Cell Infiltrates with Clinical Outcome in Lupus Nephritis: A Study of 192 Cases 
Background. Lupus nephritis (LN) remains a major cause of morbidity and end-stage renal disease. Dysfunction of B lymphocytes is thought to be important in the pathogenesis of SLE/LN. Intrarenal B cells have been found in several forms of inflammatory kidney diseases although their role in LN renal is not well defined. Methods. Intrarenal B cells were analyzed in 192 renal biopsies from patients diagnosed with lupus nephritis. Immunohistochemical staining of serial sections was performed for each LN patient using CD20, CD3, and CD21 antibodies. Results. Intrarenal B cells were more likely to be associated with class IV LN and were mainly distributed in the renal interstitium, with very few in the glomerulus. The systemic lupus erythematosus disease activity index (SLEDAI), blood urea nitrogen, and serum creatinine levels were all significantly greater in the LN-B cell groups (all P < 0.05). LN renal activity and chronicity indices correlated with B-cells infiltrates (all P < 0.0001). Renal biopsies were classified into four distinct categories according to the organizational grade of inflammatory cell infiltrates. Germinal center- (GC-) like structures were not identified in any LN biopsies. Conclusion. It is hypothesized that intrarenal B cells enhance immunological responses and exaggerate the local immune response to persisting autoimmune damage in the tubulointerstitium.
PMCID: PMC3389683  PMID: 22792121
24.  IL-23 Receptor Regulation by Let-7f in Human CD4+ Memory T Cells 
CD4+ memory T cells include the Th17 cell population, which has been shown to be implicated in autoimmune and inflammatory diseases. These memory T cells express higher IL-23R and produce more IL-17 compared with their naive counterparts. However, the molecular mechanisms that regulate IL-23R expression in human T cells are not completely understood. MicroRNAs play important roles in a wide range of biological events through posttranscriptional suppression of target mRNAs. In this article, we provide evidence that a specific microRNA, Let-7f, inhibits IL-23R expression in human CD4+ memory T cells. Endogenous expression of Let-7f in memory T cells is significantly lower when compared with naive T cells, and Let-7f blocks IL-23R expression through its complementary target sequence within 3′ untranslated region of target gene. Furthermore, exogenous transfection of a Let-7f mimic into memory T cells results in downregulation of IL-23R and its downstream cytokine, IL-17. Our findings reveal a novel mechanism in regulating the IL-23/IL-23R pathway and subsequent downstream IL-17 production, which may provide novel therapeutics for human inflammatory and autoimmune diseases.
PMCID: PMC3133967  PMID: 21508257
25.  Aqua­(benzamidato-κN)bis­[3,5-difluoro-2-(pyridin-2-yl)phenyl-κC 1]iridium(III) methanol monosolvate 
In the title compound, [Ir(C11H6F2N)2(C7H6NO)(H2O)]·CH3OH, the IrIII ion adopts an octa­hedral geometry, and is coordinated by two 3,5-difluoro-2-(pyridin-2-yl)phenyl ligands, one mol­ecule of water and one benzamidate anion. The two 2-(4,6-difluoro­phen­yl)pyridyl ligands are arranged in a cis-C,C′ and trans-N,N′ fashion. Additionally, there is a bystanding methanol mol­ecule outside the coordination sphere of the IrIII ion. In the crystal, mol­ecules of the title compound are linked by O—H⋯O and O—H⋯N hydrogen bonds. One F atom of each ligand is equally disordered over two sites. The C atom of the solvent molecule is likewise disordered over two sites in a 0.589 (11):0.411 (11) ratio.
PMCID: PMC3297261  PMID: 22412451

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