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1.  Critical Role of Toll-Like Receptor 9 in Morphine and Mycobacterium tuberculosis–Induced Apoptosis in Mice 
PLoS ONE  2010;5(2):e9205.
Background
Although it is established that opioid and Mycobacterium tuberculosis are both public health problems, the mechanisms by which they affect lung functions remain elusive.
Methodology/Principal Findings
We report here that mice subjected to chronic morphine administration and M. tuberculosis infection exhibited significant apoptosis in the lung in wild type mice as demonstrated by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick end labeling assay. Morphine and M. tuberculosis significantly induced the expression of Toll-like receptor 9 (TLR9), a key mediator of innate immunity and inflammation. Interestingly, deficiency in TLR9 significantly inhibited the morphine and M. tuberculosis induced apoptosis in the lung. In addition, chronic morphine treatment and M. tuberculosis infection enhanced the levels of cytokines (TNF-α, IL-1β, and IL-6) in wild type mice, but not in TLR9 knockout (KO) mice. The bacterial load was much lower in TLR9 KO mice compared with that in wild type mice following morphine and M. tuberculosis treatment. Morphine alone did not alter the bacterial load in either wild type or TLR9 KO mice. Moreover, administration of morphine and M. tuberculosis decreased the levels of phosphorylation of Akt and GSK3β in the wild type mice, but not in TLR9 KO mice, suggesting an involvement of Akt/GSK3β in morphine and M. tuberculosis-mediated TLR9 signaling. Furthermore, administration of morphine and M. tuberculosis caused a dramatic decrease in Bcl-2 level but increase in Bax level in wild type mice, but not in TLR9 KO mice, indicating a role of Bcl-2 family in TLR9-mediated apoptosis in the lung following morphine and M. tuberculosis administration.
Conclusions/Significance
These data reveal a role for TLR9 in the immune response to opioids during M. tuberculosis infection.
doi:10.1371/journal.pone.0009205
PMCID: PMC2824811  PMID: 20174568
2.  New sub-family of lysozyme-like proteins shows no catalytic activity – crystallographic and biochemical study of STM3605 protein from Salmonella Typhimurium 
Phage viruses that infect prokaryotes integrate their genome into the host chromosome; thus, microbial genomes typically contain genetic remnants of both recent and ancient phage infections. Often phage genes occur in clusters of atypical G+C content that reflect integration of the foreign DNA. However, some phage genes occur in isolation without other phage gene neighbors, probably resulting from horizontal gene transfer. In these cases, the phage gene product is unlikely to function as a component of a mature phage particle, and instead may have been co-opted by the host for its own benefit. The product of one such gene from Salmonella enterica serovar Typhimurium, STM3605, encodes a protein with modest sequence similarity to phage-like lysozyme (N-acetylmuramidase) but appears to lack essential catalytic residues that are strictly conserved in all lysozymes. Close homologs in other bacteria share this characteristic. The structure of the STM3605 protein was characterized by X-ray crystallography, and functional assays showed that it is a stable, folded protein whose structure closely resembles lysozyme. However, this protein is unlikely to hydrolyze peptidoglycan. Instead, STM3605 is presumed to have evolved an alternative function because it shows some lytic activity and partitions to micelles.
doi:10.1007/s10969-013-9151-0
PMCID: PMC3699403  PMID: 23572252
Crystal structure; mutagenesis; oligomeric state; phage-like lysozyme; Salmonella
3.  Evaluation of Mood Disorder Questionnaire (MDQ) in Patients with Mood Disorders: A Multicenter Trial across China 
PLoS ONE  2014;9(4):e91895.
Background
The aim of this study was to test the ability of the Chinese version of the Mood Disorder Questionnaire (MDQ) to identify Bipolar Disorders (BD) in patients diagnosed with Major Depressive Disorder (MDD) or Unipolar Disorder (UD) in the clinical setting.
Methods
1,487 being treated for MDD or UD at 12 mental health centers across China, completed the MDQ and subsequently examined by the Mini International Neuropsychiatric Interview (MINI). Receiver Operating Characteristic(ROC) curves were used to determine the ability of the MDQ to differentiate between BD (BD, BD-I and BD-II) and MDD or UD and patients with BD-I from patients with BD-II.
Results
Of the 1,487 patients, 309 (20.8%) satisfied the DSM-IV criteria for BD: 118 (7.9%) for BD-I and 191 (12.8%) for BD-II. When only part one of the MDQ was used, the best cutoff was 7 between BD and UD (sensitivity 0.66, specificity 0.88, positive predictive value 0.59, negative predictive value 0.91), 6 between BD-II and UD, and 10 between BD-I and BD-II. If all three parts of the MDQ were used, the MDQ could not distinguish between BD and UD at a cutoff of 7 (or 6), and the sensitivity was only 0.22 (or 0.24).
Conclusion
The Chinese version of the MDQ had good psychometric features in screening bipolar disorders from depressive patients with mood disorders when part two and part three of the MDQ were ignored.
doi:10.1371/journal.pone.0091895
PMCID: PMC3976254  PMID: 24705393
4.  Molecular mechanisms responsible for the differential effects of apoE3 and apoE4 on plasma lipoprotein cholesterol levels 
Objective
The goal of this study was to understand the molecular basis for how the amino acid substitution C112R that distinguishes human apolipoprotein (apo) E4 from apoE3 causes the more pro-atherogenic plasma lipoprotein cholesterol distribution that is known to be associated with expression of apoE4.
Methods and Results
Adeno-associated viruses, serotype 8 (AAV8) were used to express different levels of human apoE3, apoE4 and several C-terminal truncation and internal deletion variants in C57BL/6 apoE-null mice which exhibit marked dysbetalipoproteinemia. Plasma obtained from these mice two weeks after the AAV8 treatment was analyzed for cholesterol and triglyceride levels as well as for the distribution of cholesterol between the lipoprotein fractions. Hepatic expression of apoE3 and apoE4 induced similar dose-dependent decreases in plasma cholesterol and triglyceride to the levels seen in control C57BL/6 mice. Importantly, at the same reduction in plasma total cholesterol, expression of apoE4 gave rise to higher very low density lipoprotein-cholesterol (VLDL-C) and lower high density lipoprotein-cholesterol (HDL-C) levels relative to the apoE3 situation. The C-terminal domain, and residues 261-272 in particular, play a critical role because deleting them markedly affected the performance of both isoforms.
Conclusions
ApoE4 possesses enhanced lipid and VLDL binding ability relative to apoE3 which gives rise to impaired lipolytic processing of VLDL in apoE4-expressing mice. These effects reduce VLDL remnant clearance from the plasma compartment and decrease the amount of VLDL surface components available for incorporation into the HDL pool, accounting for the more pro-atherogenic lipoprotein profile (higher VLDL-C/HDL-C ratio) occurring in apoE4-expressing animals compared to their apoE3 counterparts.
doi:10.1161/ATVBAHA.112.301193
PMCID: PMC3660844  PMID: 23413428
apolipoprotein E; cholesterol; high density lipoprotein; very low density lipoprotein; atherosclerosis
5.  VASP Activation via the Gα13/RhoA/PKA Pathway Mediates Cucurbitacin-B-Induced Actin Aggregation and Cofilin-Actin Rod Formation 
PLoS ONE  2014;9(4):e93547.
Cucurbitacin B (CuB), a potent antineoplastic agent of cucurbitacin triterpenoids, induces rapid disruption of actin cytoskeleton and aberrant cell cycle inhibiting carcinogenesis. However, the underlying molecular mechanism of such anticancer effects remains incompletely understood. In this study, we showed that CuB treatment rapidly induced vasodilator-stimulated phosphoprotein (VASP) phosphorylation (i.e. activation) at the Ser157 residue and generated VASP clumps which were co-localized with amorphous actin aggregates prior to the formation of highly-ordered cofilin-actin rods in melanoma cells. Knockdown of VASP or inhibition of VASP activation using PKA-specific inhibitor H89 suppressed CuB-induced VASP activation, actin aggregation and cofilin-actin rod formation. The VASP activation was mediated by cAMP-independent PKA activation as CuB decreased the levels of cAMP while MDL12330A, an inhibitor of adenylyl cyclase, had weak effect on VASP activation. Knockdown of either Gα13 or RhoA not only suppressed VASP activation, but also ameliorated CuB-induced actin aggregation and abrogated cofilin-actin rod formation. Collectively, our studies highlighted that the CuB-induced actin aggregation and cofilin-actin rod formation was mediated via the Gα13/RhoA/PKA/VASP pathway.
doi:10.1371/journal.pone.0093547
PMCID: PMC3972149  PMID: 24691407
6.  Distinct Pathways of ERK1/2 Activation by Hydroxy-Carboxylic Acid Receptor-1 
PLoS ONE  2014;9(3):e93041.
Mechanistic investigations have shown that, upon agonist activation, hydroxy-carboxylic acid receptor-1(HCA1) couples to a Gi protein and inhibits adenylate cyclase activity, leading to inhibition of liberation of free fatty acid. However, the underlying molecular mechanisms for HCA1 signaling remain largely unknown. Using CHO-K1 cells stably expressing HCA1, and L6 cells, which endogenously express rat HCA1 receptors, we found that activation of ERK1/2 by HCA1 was rapid, peaking at 5 min, and was significantly blocked by pertussis toxin. Furthermore, time course experiments with different kinase inhibitors demonstrated that HCA1 induced ERK1/2 activation via the extracellular Ca2+, PKC and IGF-I receptor transactivation-dependent pathways. In addition, we observed that pretreated the cells with M119K, an inhibitor of Gβγ subunit-dependent signaling, effectively attenuated the ERK1/2 activation triggered by HCA1, suggesting a critical role for βγ-subunits in HCA1-activated ERK1/2 phosphorylation. Furthermore, the present results also indicated that the arrestin2/3 were not required for ERK1/2 activation. In conclusion, our findings demonstrate that upon binding to agonist, HCA1 receptors initially activate Gi, leading to dissociation of the Gβγ subunit from activated Gi, and subsequently induce ERK1/2 activation via two distinct pathways: one PKC-dependent pathway and the other IGF-IR transactivation-dependent pathway. Our results provide the first in-depth evidence that defines the molecular mechanism of HCA1-mediated ERK1/2 activation.
doi:10.1371/journal.pone.0093041
PMCID: PMC3966839  PMID: 24671202
7.  Piwi Is Required in Multiple Cell Types to Control Germline Stem Cell Lineage Development in the Drosophila Ovary 
PLoS ONE  2014;9(3):e90267.
The piRNA pathway plays an important role in maintaining genome stability in the germ line by silencing transposable elements (TEs) from fly to mammals. As a highly conserved piRNA pathway component, Piwi is widely expressed in both germ cells and somatic cells in the Drosophila ovary and is required for piRNA production in both cell types. In addition to its known role in somatic cap cells to maintain germline stem cells (GSCs), this study has demonstrated that Piwi has novel functions in somatic cells and germ cells of the Drosophila ovary to promote germ cell differentiation. Piwi knockdown in escort cells causes a reduction in escort cell (EC) number and accumulation of undifferentiated germ cells, some of which show active BMP signaling, indicating that Piwi is required to maintain ECs and promote germ cell differentiation. Simultaneous knockdown of dpp, encoding a BMP, in ECs can partially rescue the germ cell differentiation defect, indicating that Piwi is required in ECs to repress dpp. Consistent with its key role in piRNA production, TE transcripts increase significantly and DNA damage is also elevated in the piwi knockdown somatic cells. Germ cell-specific knockdown of piwi surprisingly causes depletion of germ cells before adulthood, suggesting that Piwi might control primordial germ cell maintenance or GSC establishment. Finally, Piwi inactivation in the germ line of the adult ovary leads to gradual GSC loss and germ cell differentiation defects, indicating the intrinsic role of Piwi in adult GSC maintenance and differentiation. This study has revealed new germline requirement of Piwi in controlling GSC maintenance and lineage differentiation as well as its new somatic function in promoting germ cell differentiation. Therefore, Piwi is required in multiple cell types to control GSC lineage development in the Drosophila ovary.
doi:10.1371/journal.pone.0090267
PMCID: PMC3962343  PMID: 24658126
8.  Phenotypic Diversity of Breast Cancer-Related Mutations in Metalloproteinase-Disintegrin ADAM12 
PLoS ONE  2014;9(3):e92536.
Six different somatic missense mutations in the human ADAM12 gene have been identified so far in breast cancer. Five of these mutations involve highly conserved residues in the extracellular domain of the transmembrane ADAM12-L protein. Two of these extracellular mutations, D301H and G479E, have been previously characterized in the context of mouse ADAM12. Three other mutations, T596A, R612Q, and G668A, have been reported more recently, and their effects on ADAM12-L protein structure/function are not known. Here, we show that ADAM12-L bearing the G668A mutation is largely retained in the endoplasmic reticulum in its nascent, full-length form, with an intact N-terminal pro-domain. The T596A and R612Q mutants are efficiently trafficked to the cell surface and proteolytically processed to remove their pro-domains. However, the T596A mutant shows decreased catalytic activity at the cell surface, while the R612Q mutant is fully active and comparable to the wild-type ADAM12-L. The D301H and G479E mutants, consistent with the corresponding D299H and G477E mutants of mouse ADAM12 described earlier, are not proteolytically processed and do not exhibit catalytic activity at the cell surface. Among all six breast cancer-associated mutations in ADAM12-L, mutations that preserve the activity - R612Q and L792F - occur in triple-negative breast cancers, while loss-of-function mutations - D301H, G479E, T596A, and G668A - are found in non-triple negative cancers. This apparent association between the catalytic activity of the mutants and the type of breast cancer supports a previously postulated role of an active ADAM12-L in the triple negative breast cancer disease.
doi:10.1371/journal.pone.0092536
PMCID: PMC3961381  PMID: 24651654
9.  Polymorphism of rs873308 near the transmembrane protein 57 gene is associated with serum lipid levels 
Bioscience Reports  2014;34(2):e00095.
SNP (single-nucleotide polymorphism) of rs10903129 near the TMEM (transmembrane protein) 57 locus has been associated with TC (total cholesterol) in a previous GWAS (genome-wide association study), but the association of TMEM57 rs873308 SNP and serum lipid levels has not been previously reported. The current study was undertaken to detect the association of the TMEM57 rs873308 SNP and several environmental factors with serum lipid profiles in the Han Chinese and Mulao populations. The genotypes of the TMEM57 rs873308 SNP in 865 individuals of Han Chinese and 902 participants of Mulao nationality were determined by PCR and RFLP (restriction-fragment-length polymorphism) combined with gel electrophoresis and then confirmed by direct sequencing. The T allele frequency of TMEM57 rs873308 SNP was not different between Han and Mulao (23.18% versus 25.72%, P>0.05), but different between males and females in the two ethnic groups (P<0.05). The T allele carriers had lower serum TC, Apo (apolipoprotein) B, HDL-C (high-density lipoprotein cholesterol) levels, ApoA1/ApoB ratio in Han; and lower TAG (triacylglycerol), LDL-C (low-density lipoprotein cholesterol), ApoA1 levels and the ApoA1/ApoB ratio and higher HDL-C levels in Mulao than the T allele non-carriers. There was also different association of the TMEM57 rs873308 SNP and serum lipid profiles between males and females in the both ethnic groups. Serum lipid parameters in the two ethnic groups were also associated with several environmental factors. The association of the TMEM57 rs873308 SNP and serum lipid levels was different in the Han Chinese and Mulao populations and between males and females in the both ethnic groups. There may be a sex-specific association of the TMEM57 rs873308 SNP and serum lipid levels in our study populations.
doi:10.1042/BSR20130131
PMCID: PMC3953947  PMID: 24517463
environmental factors; lipids; single-nucleotide polymorphism; transmembrane protein 57; Apo, apolipoprotein; BMI, body mass index; BP, blood pressure; CHD, coronary heart disease; GWAS, genome-wide association study; HDL-C, high-density lipoprotein cholesterol; LDL, low-density lipoprotein; LDL-C, low-density lipoprotein cholesterol; RFLP, restriction-fragment-length polymorphism; SNP, single-nucleotide polymorphism; TC, total cholesterol; TAG, triacylglycerol; TMEM, transmembrane protein
10.  Differential expressed genes of change in glucose metabolism in the liver of GCK knockout mice 
Gene  2013;516(2):248-254.
To investigate the role of liver-specific expression of GCK in the pathogenesis of hyperglycemia and identify candidate genes involved in the mechanisms for onset and progression of MODY2, we examined the differentially expression of genes in the liver of liver-specific glucokinase (GCK) knockout mice (gckw/−) model at 2 and 26 weeks by suppression subtractive hybridization (SSH). The expression levels of the ACAT2 and PEPCK genes identified by SSH, glycogen Synthase (GS) and glycogen phosphorylase (GP) genes were further examined at different ages by Real time PCR. In addition, we also characterized the expression of mouse GCK mRNA at different ages as well as the fasting blood glucose, serum insulin, GCK activity, total cholesterol (TC), triglyceride(TG) and glycogen content. The results show that, except for 2-week-old gckw/− mice, the fasting blood glucose levels are significantly higher for gckw/− mice (P<0.01)and the GCK activity of gckw/− mice lower about 50% than for GCK wild type(gckw/w )mice(P<0.05). The glycogen content of 4-week old and 40-week old gckw/− mice was lower than that of 4-week old and 40-week old gckw/w mice. The GP mRNA levels decrease at 40-week old gckw/− mice compared to age-matched gckw/w mice. PEPCK mRNA decreases at 2-week old gckw/− mice, but increases at 4-week old gckw/− mice(P<0.05). Changes in the expression of PEPCK genes, delayed development of GCK and impaired hepatic glycogen synthesis in liver potentially lead to onset and progression of maturity onset diabetes of the young, type 2 (MODY-2).
doi:10.1016/j.gene.2012.12.036
PMCID: PMC3642073  PMID: 23291412 CAMSID: cams2937
glucokinase; MODY2; differentially expressed genes
11.  Phylogenetic Diversity and Biological Activity of Actinobacteria Isolated from the Chukchi Shelf Marine Sediments in the Arctic Ocean 
Marine Drugs  2014;12(3):1281-1297.
Marine environments are a rich source of Actinobacteria and have the potential to produce a wide variety of biologically active secondary metabolites. In this study, we used four selective isolation media to culture Actinobacteria from the sediments collected from the Chukchi Shelf in the Arctic Ocean. A total of 73 actinobacterial strains were isolated. Based on repetitive DNA fingerprinting analysis, we selected 30 representatives for partial characterization according to their phylogenetic diversity, antimicrobial activities and secondary-metabolite biosynthesis genes. Results from the 16S rRNA gene sequence analysis indicated that the 30 strains could be sorted into 18 phylotypes belonging to 14 different genera: Agrococcus, Arsenicicoccus, Arthrobacter, Brevibacterium, Citricoccus, Janibacter, Kocuria, Microbacterium, Microlunatus, Nocardioides, Nocardiopsis, Saccharopolyspora, Salinibacterium and Streptomyces. To our knowledge, this paper is the first report on the isolation of Microlunatus genus members from marine habitats. Of the 30 isolates, 11 strains exhibited antibacterial and/or antifungal activity, seven of which have activities against Bacillus subtilis and Candida albicans. All 30 strains have at least two biosynthetic genes, one-third of which possess more than four biosynthetic genes. This study demonstrates the significant diversity of Actinobacteria in the Chukchi Shelf sediment and their potential for producing biologically active compounds and novel material for genetic manipulation or combinatorial biosynthesis.
doi:10.3390/md12031281
PMCID: PMC3967210  PMID: 24663116
marine Actinobacteria; phylogenetic diversity; biological activity; Arctic Ocean
12.  Cucurbitacin IIb Exhibits Anti-Inflammatory Activity through Modulating Multiple Cellular Behaviors of Mouse Lymphocytes 
PLoS ONE  2014;9(2):e89751.
Cucurbitacin IIb (CuIIb) is one of the major active compounds in Hemsleyadine tablets which have been used for clinical treatment of bacillary dysentery, enteritis and acute tonsilitis. However, its action mechanism has not been completely understood. This study aimed to explore the anti-inflammatory activity of CuIIb and its underlying mechanism in mitogen-activated lymphocytes isolated from mouse mesenteric lymph nodes. The results showed that CuIIb inhibited the proliferation of concanavalin A (Con A)-activated lymphocytes in a time- and dose-dependent manner. CuIIb treatment arrested their cell cycle in S and G2/M phases probably due to the disruption of the actin cytoskeleton and the modulation of p27Kip1 and cyclin levels. Moreover, the surface expression of activation markers CD69 and CD25 on Con A-activated CD3+ T lymphocytes was suppressed by CuIIb treatment. Both Con A- and phorbol ester plus ionomycin-induced expression of TNF-α, IFN-γ and IL-6 proteins was attenuated upon exposure to CuIIb. Mechanistically, CuIIb treatment suppressed the phosphorylation of JNK and Erk1/2 but not p38 in Con A-activated lymphocytes. Although CuIIb unexpectedly enhanced the phosphorylation of IκB and NF-κB (p65), it blocked the nuclear translocation of NF-κB (p65). In support of this, CuIIb significantly decreased the mRNA levels of IκBα and TNF-α, two target genes of NF-κB, in Con A-activated lymphocytes. In addition, CuIIb downregulated Con A-induced STAT3 phosphorylation and increased cell apoptosis. Collectively, these results suggest that CuIIb exhibits its anti-inflammatory activity through modulating multiple cellular behaviors and signaling pathways, leading to the suppression of the adaptive immune response.
doi:10.1371/journal.pone.0089751
PMCID: PMC3934946  PMID: 24587010
13.  Surface-Based Regional Homogeneity in First-Episode, Drug-Naïve Major Depression: A Resting-State fMRI Study 
BioMed Research International  2014;2014:374828.
Background. Previous volume-based regional homogeneity (ReHo) studies neglected the intersubject variability in cortical folding patterns. Recently, surface-based ReHo was developed to reduce the intersubject variability and to increase statistical power. The present study used this novel surface-based ReHo approach to explore the brain functional activity differences between first-episode, drug-naïve MDD patients and healthy controls. Methods. Thirty-three first-episode, drug-naïve MDD patients and 32 healthy controls participated in structural and resting-state fMRI scans. MDD patients were rated with a 17-item Hamilton Rating Scale for Depression prior to the scan. Results. In comparison with the healthy controls, MDD patients showed reduced surface-based ReHo in the left insula. There was no increase in surface-based ReHo in MDD patients. The surface-based ReHo value in the left insula was not significantly correlated with the clinical information or the depressive scores in the MDD group. Conclusions. The decreased surface-based ReHo in the left insula in MDD may lead to the abnormal top-down cortical-limbic regulation of emotional and cognitive information. The surface-based ReHo may be a useful index to explore the pathophysiological mechanism of MDD.
doi:10.1155/2014/374828
PMCID: PMC3955658  PMID: 24719857
14.  Adverse Drug Reactions of Spontaneous Reports in Shanghai Pediatric Population 
PLoS ONE  2014;9(2):e89829.
Background
Knowledge of drug safety in the pediatric population of China is limited. This study was designed to evaluate ADRs in children reported to the spontaneous reporting system (SRS) of Shanghai in 2009.
Methodology and Principal Findings
Crude ADR reports submitted to Shanghai SRS in 2009 for individuals aged from birth to 17 years (including 17 years) were included. Data were analyzed with respect to age, gender, category of ADR (System Organ Class [SOC]), the severity of reports and type of reporter.
Results
A male overrepresentation was observed regarding the total number of reports. The most frequently reported group of drugs were vaccines (42.15%). Skin rash and fever were the commonest symptoms reported in the total pediatric dataset. The proportion of children that suffered from a serious ADR was 2.16% and that for drug related deaths was 0.34%. And we found that the multiple drug exposure experienced a high proportion of serious ADRs compared with the single drug use (χ2 = 15.99, P<0.0001). Sixty-five percent of ADRs were for children less than 6 years of age. And more than half of reports were from doctors.
Conclusions
In our study, consumers were more likely to report new ADRs though they appear to contribute a relatively small percentage of total reports. We propose that patients would take an active role in reporting ADRs. More researches are needed in order to achieve better understanding the characteristics of ADRs in pediatric population of China.
doi:10.1371/journal.pone.0089829
PMCID: PMC3933652  PMID: 24587066
15.  Immune cell trafficking from the brain maintains CNS immune tolerance 
The Journal of Clinical Investigation  2014;124(3):1228-1241.
In the CNS, no pathway dedicated to immune surveillance has been characterized for preventing the anti-CNS immune responses that develop in autoimmune neuroinflammatory disease. Here, we identified a pathway for immune cells to traffic from the brain that is associated with the rostral migratory stream (RMS), which is a forebrain source of newly generated neurons. Evaluation of fluorescently labeled leukocyte migration in mice revealed that DCs travel via the RMS from the CNS to the cervical LNs (CxLNs), where they present antigen to T cells. Pharmacologic interruption of immune cell traffic with the mononuclear cell-sequestering drug fingolimod influenced anti-CNS T cell responses in the CxLNs and modulated experimental autoimmune encephalomyelitis (EAE) severity in a mouse model of multiple sclerosis (MS). Fingolimod treatment also induced EAE in a disease-resistant transgenic mouse strain by altering DC-mediated Treg functions in CxLNs and disrupting CNS immune tolerance. These data describe an immune cell pathway that originates in the CNS and is capable of dampening anti-CNS immune responses in the periphery. Furthermore, these data provide insight into how fingolimod treatment might exacerbate CNS neuroinflammation in some cases and suggest that focal therapeutic interventions, outside the CNS have the potential to selectively modify anti-CNS immunity.
doi:10.1172/JCI71544
PMCID: PMC3934177  PMID: 24569378
16.  Effects of experimental conditions on the morphologies, structures and growth modes of pulsed laser-deposited CdS nanoneedles 
CdS nanoneedles with different morphologies, structures, and growth modes have been grown on Ni-coated Si(100) surface under different experimental conditions by pulsed laser deposition method. The effects of catalyst layer, substrate temperature, and laser pulse energy on the growth of the CdS nanoneedles were studied in detail. It was confirmed that the formation of the molten catalyst spheres is the key to the nucleation of the CdS nanoneedles by observing the morphologies of the Ni catalyst thin films annealed at different substrate temperatures. Both the substrate temperature and laser pulse energy strongly affected the growth modes of the CdS nanoneedles. The secondary growth of the smaller nanoneedles on the top of the main nanoneedles was found at appropriate conditions. A group of more completed pictures of the growth modes of the CdS nanoneedles were presented.
doi:10.1186/1556-276X-9-91
PMCID: PMC3941934  PMID: 24559455
CdS nanoneedles; Substrate temperature; Laser pulse energy; Growth mode; 61.46.-w; 61.46.Km; 68.37.Lp
17.  Genetic variant in SWI/SNF complexes influences hepatocellular carcinoma risk: a new clue for the contribution of chromatin remodeling in carcinogenesis 
Scientific Reports  2014;4:4147.
Chromatin remodeling has been newly established as an important cancer genome characterization and recent exome and whole-genome sequencing studies of hepatocellular carcinoma (HCC) showed that recurrent inactivating mutations in SWI/SNF subunits involved in the molecular basis of hepatocarcinogenesis. To test the hypothesis that genetic variants in the key subunits of SWI/SNF complexes may contribute to HCC susceptibility, we systematically assessed associations of genetic variants in SWI/SNF complexes with HCC risk using a two-staged case-control study in Chinese population. A set of 24 single nucleotide polymorphisms (SNPs) in SWI/SNF complexes were examined in stage 1 with 502 HCC patients and 487 controls and three promising SNPs (SMARCA4 rs11879293, rs2072382 and SMARCB1 rs2267032) were further genotyped in stage 2 comprising 501 cases and 545 controls for validation. SMARCA4 rs11879293 presented consistently significant associations with the risk of HCC at both stages, with an OR of 0.73 (95% CI: 0.62–0.87) using additive model in combined analysis. Moreover, the decreased risk of HCC associated with SMARCA4 rs11879293 AG/AA was more evident among HBsAg positive individuals (OR = 0.47, 95% CI: 0.27–0.80) in combined analysis. The study highlighted the potential role of the SWI/SNF complexes in conferring susceptibility to HCC, especially modified HCC risk by HBV infection.
doi:10.1038/srep04147
PMCID: PMC3930892  PMID: 24556940
18.  Chinese Herbal Medicine for Aspirin Resistance: A Systematic Review of Randomized Controlled Trials 
Aspirin resistance (AR) is a prevalent phenomenon and leads to significant clinical consequences, but the current evidence for effective interventional strategy is insufficient. The objective of this systematic review is thus to assess the efficacy and safety of Chinese herbal medicine (CHM) for AR. A systematical literature search was conducted in 6 databases until December 2012 to identify randomized controlled trials (RCTs) of CHM for AR. As a result, sixteen RCTs with a total of 1011 subjects were identified, suggesting that the interests of the medical profession and the public in the use of CHM for AR have grown considerably in the recent years. Tongxinluo capsule and Danshen-based prescriptions were the most frequently used herbal prescriptions, while danshen root, milkvetch root, Leech, and Rosewood were the most frequently used single herbs. Despite the apparent reported positive findings, it is premature to determine the efficacy and safety of CHM for the treatment of AR due to poor methodological quality and insufficient safety data. However, CHMs appeared to be well tolerated in all included studies. Thus, CHM as a promising candidate is worthy of improvement and development for further clinical AR trials. Large sample-size and well-designed rigorous RCTs are needed.
doi:10.1155/2014/890950
PMCID: PMC3950618
19.  Lignans from the bark of Eucommia ulmoides inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells 
Chinese Medicine  2014;9:8.
Background
Tree bark of Eucommia ulmoides Oliv., (commonly well-known as “Du-zhong” in China), has been used to treat hypertension, hypercholesterolemia, hyperglycemia, hepatic fibrosis and renal injury. This study aims to investigate the effects of lignans extracted from the bark of Eucommia ulmoides Oliv. on Ang II-induced proliferation and extracellular matrix biosynthesis in rat mesangial cells.
Methods
Rat mesangial cells (RMCs) were cultured in vitro and divided into six groups (control, Ang II, losartan, and low, middle and high concentration lignans groups). RMC proliferation was measured by MTT assay. RT-qPCR and western blotting were used to detect mRNA and protein expression of collagen type I (Col I), collagen type III (Col III), collagen type IV (Col IV), fibronectin and aldose reductase (AR).
Results
Cellular proliferation induced by Ang II was significantly suppressed by Eucommia lignans of different concentrations (P = 0.034, P < 0.001, and P < 0.001). Treatment of cells with Ang II increased Col I, Col III, Col IV, and fibronectin mRNA expression, which was observed at the protein level (P < 0.001, P < 0.001, P = 0.004, and P = 0.004, respectively). The increased mRNA expression and protein levels of Col I, Col III, Col IV, and fibronectin were diminished remarkably with by treatment Eucommia lignans, and elevated AR expression stimulated by Ang II was significantly inhibited by Eucommia lignans.
Conclusions
Eucommia lignans (Du-zhong) inhibited Ang II-stimulated extracellular matrix biosynthesis in mesangial cells.
doi:10.1186/1749-8546-9-8
PMCID: PMC3937011  PMID: 24524265
20.  Oleate promotes differentiation of chicken primary preadipocytes in vitro 
Bioscience Reports  2014;34(1):e00093.
In addition to providing energy and constituting cell membrane, fatty acids also play an important role in adipocyte differentiation and lipid metabolism. As an important member of monounsaturated fatty acids, oleate, together with other components, is widely used to induce chicken preadipocyte differentiation. However, it is not clear whether oleate alone can induce chicken preadipocyte differentiation. In the present study, four different treatments were designed to test this question: basal medium, IDX [insulin, dexamethasone and IBMX (isobutylmethylxanthine)], oleate and IDX plus oleate. Cytoplasmic lipid droplet accumulation and mRNA expression for adipogenesis-related genes were monitored. After treatment of oleate on chicken preadipocytes, apparent lipid droplet formation and lipid accumulation were observed, accompanied by increasing expression of PPARγ (peroxisome proliferator-activated receptor-γ) and AFABP (adipocyte fatty acid-binding protein), but decreasing level of GATA2 (GATA-binding protein 2). In contrast, for cells cultured in the basal medium with or without IDX supplementation, lipid droplet barely occurred. These results suggest that exogenous oleate alone can act as an inducer of preadipocyte differentiation into adipocytes.
Our results suggest that oleate alone can act as a direct inducer of chicken preadipocyte differentiation by elevating expression of key positive regulators and suppressing expression of negative regulator of adipogenesis.
doi:10.1042/BSR20130120
PMCID: PMC3917231  PMID: 24428793
adipogenesis; chicken; differentiation; fatty acid; inducer; preadipocyte; AFABP, adipocyte fatty acid-binding protein; DMEM/F12, Dulbecco’s modified Eagle’s medium/Ham’s nutrient mixture F-12; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GATA2, GATA-binding protein 2; IBMX, isobutylmethylxanthine; IDX, insulin, dexamethasone and isobutylmethylxanthine; PPARγ, peroxisome proliferator-activated receptor-γ
21.  Oxaliplatin-Based Chemotherapy Is More Beneficial in KRAS Mutant than in KRAS Wild-Type Metastatic Colorectal Cancer Patients 
PLoS ONE  2014;9(2):e86789.
To identify better regimens in currently available chemotherapy would be beneficial to KRAS mutant metastatic colorectal cancer (mCRC) patients because they have fewer treatment options than KRAS wild-type mCRC patients. Clinicopathologic features and overall survival (OS) of KRAS mutant and wild-type mCRC patients who had used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens were compared to those who had never-used oxaliplatin-based, irinotecan-based, bevacizumab-based, as well as cetuximab-based regimens respectively. Between 2007 and 2012, a total of 394 mCRC patients, in whom 169 KRAS mutant and 225 KRAS wild-type, were enrolled. In KRAS mutant patients who had used oxaliplatin-based regimens (N = 131), the OS was significantly longer than that in KRAS mutant patients who had never-used oxaliplatin-based regimens (N = 38). The OS was 28.8 months [95% confidence interval (CI): 23.2–34.4] in KRAS mutant patients who had used oxaliplatin-based regimens versus 17.8 months [95% CI: 6.5–29.1] in KRAS mutant patients who had never-used oxaliplatin-based regimens (P = 0.026). Notably, OS in KRAS wild-type mCRC patients who had used oxaliplatin-based regimens (N = 185) was not significantly longer than that in KRAS wild-type mCRC patients who had never-used oxaliplatin-based regimens (N = 40) (P = 0.25). Furthermore, the OS in KRAS mutant patients who had used either irinotecan-based, bevacizumab-based or cetuximab-based regimens was not significantly different than that in KRAS mutant patients who had never-used either irinotecan-based, bevacizumab-based or cetuximab-based regimens respectively. In multivariate analyses, patients who had used oxaliplatin-based regimens remains an independent prognostic factor for longer OS in KRAS mutant mCRC patients. In conclusion, oxaliplatin-based regimens are more beneficial in KRAS mutant than in KRAS wild-type mCRC patients.
doi:10.1371/journal.pone.0086789
PMCID: PMC3913571  PMID: 24505265
22.  Dewetting Properties of Metallic Liquid Film on Nanopillared Graphene 
Scientific Reports  2014;4:3938.
In this work, we report simulation evidence that the graphene surface decorated by carbon nanotube pillars shows strong dewettability, which can give it great advantages in dewetting and detaching metallic nanodroplets on the surfaces. Molecular dynamics (MD) simulations show that the ultrathin liquid film first contracts then detaches from the graphene on a time scale of several nanoseconds, as a result of the inertial effect. The detaching velocity is in the order of 10 m/s for the droplet with radii smaller than 50 nm. Moreover, the contracting and detaching behaviors of the liquid film can be effectively controlled by tuning the geometric parameters of the liquid film or pillar. In addition, the temperature effects on the dewetting and detaching of the metallic liquid film are also discussed. Our results show that one can exploit and effectively control the dewetting properties of metallic nanodroplets by decorating the surfaces with nanotube pillars.
doi:10.1038/srep03938
PMCID: PMC3909898  PMID: 24487279
23.  Dynamic Scene Stitching Driven by Visual Cognition Model 
The Scientific World Journal  2014;2014:981724.
Dynamic scene stitching still has a great challenge in maintaining the global key information without missing or deforming if multiple motion interferences exist in the image acquisition system. Object clips, motion blurs, or other synthetic defects easily occur in the final stitching image. In our research work, we proceed from human visual cognitive mechanism and construct a hybrid-saliency-based cognitive model to automatically guide the video volume stitching. The model consists of three elements of different visual stimuli, that is, intensity, edge contour, and scene depth saliencies. Combined with the manifold-based mosaicing framework, dynamic scene stitching is formulated as a cut path optimization problem in a constructed space-time graph. The cutting energy function for column width selections is defined according to the proposed visual cognition model. The optimum cut path can minimize the cognitive saliency difference throughout the whole video volume. The experimental results show that it can effectively avoid synthetic defects caused by different motion interferences and summarize the key contents of the scene without loss. The proposed method gives full play to the role of human visual cognitive mechanism for the stitching. It is of high practical value to environmental surveillance and other applications.
doi:10.1155/2014/981724
PMCID: PMC3932260
24.  Crystallization and preliminary X-ray analysis of S-­ribosylhomocysteinase from Streptococcus mutans  
S-Ribosylhomocysteinase (LuxS) encoded by the LuxS gene from Streptococcus mutans was solubly expressed in Escherichia coli, purified and crystallized. Diffraction by the crystal extended to 2.4 Å resolution.
S-Ribosylhomocysteinase (LuxS) encoded by the luxS gene from Streptococcus mutans plays a crucial role in the quorum-sensing system. LuxS was solubly expressed in Escherichia coli with high yield. The purity of the purified target protein, which was identified by SDS–PAGE and MALDI–TOF MS analysis, was >95%. The protein was crystallized using the hanging-drop vapour-diffusion method with PEG 3350 as the primary precipitant. X-ray diffraction data were collected at Beijing Synchrotron Radiation Facility (BSRF). Diffraction by the crystal extended to 2.4 Å resolution and the crystal belonged to space group C2221, with unit-cell parameters a = 55.3, b = 148.7, c = 82.8 Å.
doi:10.1107/S1744309111054212
PMCID: PMC3274403  PMID: 22297999
Streptococcus mutans; LuxS
25.  MicroRNA-200b Is Overexpressed in Endometrial Adenocarcinomas and Enhances MMP2 Activity by Downregulating TIMP2 in Human Endometrial Cancer Cell Line HEC-1A Cells 
Nucleic Acid Therapeutics  2013;23(1):29-34.
MicroRNAs (miRNAs) play important roles in tumorigenesis and metastasis. In this study, we investigated miR-200b expression in endometrial adenocarcinomas and normal adjacent tissues and found that miR-200b is more highly expressed in cancer tissues than in normal adjacent tissues. A novel target of miR-200b, tissue inhibitor of metalloproteinase 2 (TIMP2), was predicted using a bioinformatics approach and was confirmed in human endometrial cancer cell line HEC-1A cells by luciferase assay, quantitative real-time polymerase chain reaction, western blotting, and enzyme-linked immunosorbent assay. We found that miR-200b repressed TIMP2 expression at both the messenger RNA and protein levels, although a family member, miR-200a, had no such effect. Using reverse gelatin zymography, we showed that miR-200b enhances matrix metallopeptidase 2 (MMP2) activity by downregulating TIMP2 expression in HEC-1A cells. These data suggest that miR-200b may play an important role in the metastasis of endometrial adenocarcinomas.
doi:10.1089/nat.2012.0385
PMCID: PMC3569964  PMID: 23205572

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