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1.  Genome-wide association analyses identify three new susceptibility loci for primary angle closure glaucoma 
Vithana, Eranga N | Khor, Chiea-Chuen | Qiao, Chunyan | Nongpiur, Monisha E | George, Ronnie | Chen, Li-Jia | Do, Tan | Abu-Amero, Khaled | Huang, Chor Kai | Low, Sancy | Tajudin, Liza-Sharmini A | Perera, Shamira A | Cheng, Ching-Yu | Xu, Liang | Jia, Hongyan | Ho, Ching-Lin | Sim, Kar Seng | Wu, Ren-Yi | Tham, Clement C Y | Chew, Paul T K | Su, Daniel H | Oen, Francis T | Sarangapani, Sripriya | Soumittra, Nagaswamy | Osman, Essam A | Wong, Hon-Tym | Tang, Guangxian | Fan, Sujie | Meng, Hailin | Huong, Dao T L | Wang, Hua | Feng, Bo | Baskaran, Mani | Shantha, Balekudaru | Ramprasad, Vedam L | Kumaramanickavel, Govindasamy | Iyengar, Sudha K | How, Alicia C | Lee, Kelvin Y | Sivakumaran, Theru A | Yong, Victor H K | Ting, Serena M L | Li, Yang | Wang, Ya-Xing | Tay, Wan-Ting | Sim, Xueling | Lavanya, Raghavan | Cornes, Belinda K | Zheng, Ying-Feng | Wong, Tina T | Loon, Seng-Chee | Yong, Vernon K Y | Waseem, Naushin | Yaakub, Azhany | Chia, Kee-Seng | Allingham, R Rand | Hauser, Michael A | Lam, Dennis S C | Hibberd, Martin L | Bhattacharya, Shomi S | Zhang, Mingzhi | Teo, Yik Ying | Tan, Donald T | Jonas, Jost B | Tai, E-Shyong | Saw, Seang-Mei | Hon, Do Nhu | Al-Obeidan, Saleh A | Liu, Jianjun | Chau, Tran Nguyen Bich | Simmons, Cameron P | Bei, Jin-Xin | Zeng, Yi-Xin | Foster, Paul J | Vijaya, Lingam | Wong, Tien-Yin | Pang, Chi-Pui | Wang, Ningli | Aung, Tin
Nature genetics  2012;44(10):1142-1146.
Primary angle closure glaucoma (PACG) is a major cause of blindness worldwide. We conducted a genome-wide association study including 1,854 PACG cases and 9,608 controls across 5 sample collections in Asia. Replication experiments were conducted in 1,917 PACG cases and 8,943 controls collected from a further 6 sample collections. We report significant associations at three new loci: rs11024102 in PLEKHA7 (per-allele odds ratio (OR) = 1.22; P = 5.33 × 10−12), rs3753841 in COL11A1 (per-allele OR = 1.20; P = 9.22 × 10−10) and rs1015213 located between PCMTD1 and ST18 on chromosome 8q (per-allele OR = 1.50; P = 3.29 × 10−9). Our findings, accumulated across these independent worldwide collections, suggest possible mechanisms explaining the pathogenesis of PACG.
doi:10.1038/ng.2390
PMCID: PMC4333205  PMID: 22922875
2.  The histone deacetylase inhibitor SAHA sensitizes acute myeloid leukemia cells to a combination of nucleoside analogs and the DNA-alkylating agent busulfan 
Leukemia & lymphoma  2014;55(7):1625-1634.
Fludarabine (Flu), clofarabine (Clo) and busulfan (Bu) are used in allogeneic hematopoietic stem cell transplant (allo-HSCT). We reported that combining [Flu + Clo + Bu] had a synergistic cytotoxicity in AML cells. We hypothesized that combining [Flu + Clo + Bu] with the histone deacetylase inhibitor SAHA will further enhance cytotoxicity. We exposed the acute myeloid leukemia (AML) cell lines KBM3/Bu2506 and OCI-AML3 to Flu, Clo, Bu and SAHA alone and in various combinations. [Flu + Clo + Bu + SAHA] resulted in synergistic cytotoxicity, which can be attributed to (1) activated DNA-damage response and cell cycle checkpoint activation through the ATM–CHK2–P53 (or P73) pathway or ATM–CHK2–cdc25–cdc2 pathway, (2) histone modifications and (3) activated apoptosis pathway. The [Flu + Clo + Bu + SAHA] combination causes mitochondrial outer membrane permeabilization, leakage of cytochrome c and Smac/Diablo into the cytosol with caspase activation, and release of apoptosis-inducing factor (AIF) into the nucleus resulting in nuclear fragmentation and cell death. These results provide a mechanistic basis for using SAHA in future clinical trials with double nucleoside analog-busulfan combinations in pretransplant conditioning therapy.
doi:10.3109/10428194.2013.856007
PMCID: PMC4320642  PMID: 24144307
DNA alkylator; nucleoside analog; SAHA; AML; drug cytotoxicity
3.  CLIPdb: a CLIP-seq database for protein-RNA interactions 
BMC Genomics  2015;16(1):51.
Background
RNA-binding proteins (RBPs) play essential roles in gene expression regulation through their interactions with RNA transcripts, including coding, canonical non-coding and long non-coding RNAs. Large amounts of crosslinking immunoprecipitation (CLIP)-seq data (including HITS-CLIP, PAR-CLIP, and iCLIP) have been recently produced to reveal transcriptome-wide binding sites of RBPs at the single-nucleotide level.
Description
Here, we constructed a database, CLIPdb, to describe RBP-RNA interactions based on 395 publicly available CLIP-seq data sets for 111 RBPs from four organisms: human, mouse, worm and yeast. We consistently annotated the CLIP-seq data sets and RBPs, and developed a user-friendly interface for rapid navigation of the CLIP-seq data. We applied a unified computational method to identify transcriptome-wide binding sites, making the binding sites directly comparable and the data available for integration across different CLIP-seq studies. The high-resolution binding sites of the RBPs can be visualized on the whole-genome scale using a browser. In addition, users can browse and download the identified binding sites of all profiled RBPs by querying genes of interest, including both protein coding genes and non-coding RNAs.
Conclusion
Manually curated metadata and uniformly identified binding sites of publicly available CLIP-seq data sets will be a foundation for further integrative and comparative analyses. With maintained up-to-date data sets and improved functionality, CLIPdb (http://clipdb.ncrnalab.org) will be a valuable resource for improving the understanding of post-transcriptional regulatory networks.
Electronic supplementary material
The online version of this article (doi:10.1186/s12864-015-1273-2) contains supplementary material, which is available to authorized users.
doi:10.1186/s12864-015-1273-2
PMCID: PMC4326514  PMID: 25652745
CLIP-seq; RNA-binding protein; RNA; Regulatory networks; Data integration
4.  Reversal of Multidrug Resistance by the Chinese Medicine Yiqi Jianpi Huaji Decoction and the Mechanism of Action in Human Gastric Cancer SGC7901/VCR Cells 
Yiqi Jianpi Huaji Decoction (YJHD), a traditional Chinese medicinal formula composed of twelve ingredients, has recently been reported to have a good clinical curative effect. The purpose of the present study was to evaluate the effects of YJHD on SGC7901/VCR gastric cancer cells and to elucidate the possible mechanism of action. First, the effects of a low dose of YJHD in combination with chemotherapeutic agents on SGC7901/VCR cells were assessed using the CCK-8 assay and flow cytometry, and the effects of YJHD on genes and proteins involved in drug resistance (MDR1, MRP, TUBB3, STMN1, and TS) were evaluated. Furthermore, transfection of SGC7901/VCR cells with siRNAs targeting these genes inhibited their expression, and the efficacy of vincristine against the cells was dramatically improved in vitro when these genes were silenced. These results demonstrate that low-dose YJHD inhibited cell proliferation, induced apoptosis, reversed MDR, and increased sensitivity to chemotherapeutic agents in vitro by downregulating P-gp, MRP, TUBB3, and STMN1 expression. MDR can be reversed by siRNAs targeting genes involved in MDR, and this strategy for cancer treatment should be evaluated in future studies.
doi:10.1155/2015/390812
PMCID: PMC4332981
5.  Extensively drug-resistant Acinetobacter baumannii in a Thai hospital: a molecular epidemiologic analysis and identification of bactericidal Polymyxin B-based combinations 
Background
Limited knowledge of the local molecular epidemiology and the paucity of new effective antibiotics has resulted in an immense challenge in the control and treatment of extensively drug-resistant (XDR) Acinetobacter baumannii infections in Thailand. Antimicrobial combination regimens may be the only feasible treatment option in such cases. We sought to characterize the local molecular epidemiology and assess the bactericidal activity of various antibiotics individually and in combination against XDR A. baumannii in a Thai hospital.
Methods
All XDR A. baumannii isolates from Thammasat University Hospital were collected between October 2010 and May 2011. Susceptibility testing was conducted according to reference broth dilution methods. Pulse-field gel electrophoresis was used to genotype the isolates. Carbapenemase genes were detected using polymerase chain reaction. In vitro testing of clinically-relevant concentrations of imipenem, meropenem, doripenem, rifampicin and tigecycline alone and in combination with polymyxin B was conducted using multiple combination bactericidal testing.
Results
Forty-nine polymyxin B-susceptible XDR A. baumannii isolates were identified. blaOXA-23 and blaOXA-51 genes were detected in all isolates. Eight clonally related clusters were identified, resulting in the initiation of several infection control measures. Imipenem, meropenem, doripenem, rifampicin, and tigecycline in combination with PB respectively, exhibited bactericidal killing in 100%, 100%, 98.0%, 100% and 87.8% isolates respectively at 24 hours.
Conclusion
Molecular epidemiologic analysis can aid the early detection of infection outbreak within the institution, resulting in the rapid containment of the outbreak. Imipenem/meropenem/rifampicin in combination with polymyxin B demonstrated consistent bactericidal effect against 49 blaOXA-23-harbouring XDR A. baumannii clinical isolates, suggesting a role of combination therapy in the treatment of these infections.
doi:10.1186/s13756-015-0043-x
PMCID: PMC4314787  PMID: 25648393
Combination therapy; Carbapenem resistance; Acinetobacter baumannii
6.  Association between epidermal growth factor receptor mutations and the expression of excision repair cross-complementing protein 1 and ribonucleotide reductase subunit M1 mRNA in patients with non-small cell lung cancer 
The present study aimed to investigate the association between epidermal growth factor receptor (EGFR) gene mutations and excision repair cross-complementing protein 1 (ERCC1) and ribonucleotide reductase subunit M1 (RRM1) mRNA expression in non-small cell lung cancer (NSCLC) tissue. The quantitative polymerase chain reaction was used to detect EGFR mutations, and ERCC1 and RRM1 mRNA expression in 257 cases of NSCLC. In the NSCLC samples the EGFR mutation rate was 49.03% (126/257). The rate was higher in females and non-smoking patients (P<0.05). High expression of ERCC1 mRNA was observed in 47.47% of the samples (122/257), while a high RRM1 mRNA expression was observed in 61.87% of the samples (159/257). In comparison with patients with NSCLC without EGFR mutations, patients with EGFR mutations had significantly lower levels of ERCC1 mRNA expression (P<0.05); however, EGFR mutations and expression levels of RRM1 mRNA were not correlated in NSCLC tissues (P>0.05). In addition, ERCC1 mRNA expression was not correlated with the expression levels of RRM1 mRNA (P>0.05). In conclusion, patients with NSCLC with EGFR mutations tend to have a low expression of ERCC1 mRNA and may potentially benefit from platinum-based chemotherapy.
doi:10.3892/etm.2015.2196
PMCID: PMC4316980  PMID: 25667646
non-small cell lung cancer; epidermal growth factor receptor; excision repair cross-complementing protein 1; ribonucleotide reductase subunit M1; molecular detection; individualized treatment
7.  Multidrug-Resistant Tuberculosis Outbreak in Gaming Centers, Singapore, 2012 
Emerging Infectious Diseases  2015;21(1):179-180.
doi:10.3201/eid2101.141159
PMCID: PMC4285258  PMID: 25531726
multidrug-resistant tuberculosis; MDR TB; outbreak; whole-genome sequencing; cyber café; contact tracing; bacteria; Singapore; gaming centers; tuberculosis and other mycobacteria
8.  When does Subliminal Affective Image Priming Influence the Ability of Schizophrenic Patients to Perceive Face Emotions? 
Background
Deficits in face emotion perception are among the most pervasive aspects of schizophrenia impairments which strongly affects interpersonal communication and social skills.
Material/Methods
Schizophrenic patients (PSZ) and healthy control subjects (HCS) performed 2 psychophysical tasks. One, the SAFFIMAP test, was designed to determine the impact of subliminally presented affective or neutral images on the accuracy of face-expression (angry or neutral) perception. In the second test, FEP, subjects saw pictures of face-expression and were asked to rate them as angry, happy, or neutral. The following clinical scales were used to determine the acute symptoms in PSZ: Positive and Negative Syndrome (PANSS), Young Mania Rating (YMRS), Hamilton Depression (HAM-D), and Hamilton Anxiety (HAM-A).
Results
On the SAFFIMAP test, different from the HCS group, the PSZ group tended to categorize the neutral expression of test faces as angry and their response to the test-face expression was not influenced by the affective content of the primes. In PSZ, the PANSS-positive score was significantly correlated with correct perception of angry faces for aggressive or pleasant primes. YMRS scores were strongly correlated with PSZ’s tendency to recognize angry face expressions when the prime was a pleasant or a neutral image. The HAM-D score was positively correlated with categorizing the test-faces as neutral, regardless of the affective content of the prime or of the test-face expression (angry or neutral).
Conclusions
Despite its exploratory nature, this study provides the first evidence that conscious perception and categorization of facial emotions (neutral or angry) in PSZ is directly affected by their positive or negative symptoms of the disease as defined by their individual scores on the clinical diagnostic scales.
doi:10.12659/MSM.893118
PMCID: PMC4282928  PMID: 25537115
Affective Symptoms; Schizophrenia; Subliminal Stimulation
9.  Systematic analysis of the clinical and biochemical characteristics of maternally inherited hypertension in Chinese Han families associated with mitochondrial 
BMC Medical Genomics  2014;7:73.
Background
Mitochondrial DNA mutations may be associated with cardiovascular disease, including the common cardiac vascular disease, hypertension.
Methods
In this study we performed segregation analysis and systematically evaluated the entire mitochondrial genome in nine maternally inherited hypertension probands from Chinese Han families. We also performed clinical, genetic and molecular characterization of 74 maternally inherited members from these families and 216 healthy controls.
Results
In the maternally inherited members, 12 had coronary heart disease (CHD), six had cerebrovascular disease, five had diabetes, nine had hyperlipidemia and three had renal disease. Laboratory tests showed that the sodium and potassium levels in blood of the maternally inherited members were higher than those of the control group (P < 0.01), while no differences were observed in fasting blood glucose (FBG), total cholesterol (TC), triglyceride, low density lipoprotein cholesterol (LDL-c) and creatinine levels (P > 0.05). The high density lipoprotein cholesterol (HDL-c) level of the maternally inherited members was lower than that of the control group (P = 0.04). The whole mitochondrial DNA sequence analysis revealed a total of 172 base changes, including 17 in ribosomal RNA (rRNA) genes, four in transfer RNA (tRNA) genes, and 22 amino acid substitutions. The remainder were synonymous changes or were located in non-coding regions. We identified seven amino acid changes in the nine maternally inherited hypertension families, including four mutations in ATPase6 and three in Cytb. More interestingly, tRNASer(UCN) 7492 T > C was absent in controls and was present in <1% of 2704 mtDNAs, indicating potential functional significance.
Conclusions
This study showed that mutations in mtDNA may contribute to the pathogenesis of hypertension in these Chinese Han families. In the near future, identification of additional mtDNA mutations may indicate further candidate genes for hypertension.
Electronic supplementary material
The online version of this article (doi:10.1186/s12920-014-0073-x) contains supplementary material, which is available to authorized users.
doi:10.1186/s12920-014-0073-x
PMCID: PMC4331388  PMID: 25539907
mitochondrial DNA; Hypertension; Chinese; Mutations; Maternal
10.  Overexpression of MicroRNA-1 Promotes Cardiomyocyte Commitment from Human Cardiovascular Progenitors via Suppressing WNT and FGF Signaling Pathways 
Early heart development takes place through a complex series of steps, including the induction of cardiac mesoderm, formation of the cardiovascular progenitor cells and the commitment of cardiovascular lineage cells, such as cardiomyocytes (CMs), smooth muscle cells (SMCs) and endothelial cells (ECs). Recently, microRNAs, a family of endogenous, small non-coding RNAs, have been implicated as critical regulators at the posttranscriptional level in cardiogenesis as well as cardiovascular disease. Previous studies demonstrated that microRNA-1 (miR-1) could promote cardiac differentiation from mouse and human embryonic stem (ES) cells. However, the underlying mechanism largely remained unclear. We performed microRNA deep sequencing among human ES cells, ES cell derived-multipotent cardiovascular progenitors (MCPs), and MCP-specified CMs, ECs, and SMCs. A specific enrichment of miR-1 was found in CMs, not in SMCs or ECs, implying a key role of miR-1 in determining cardiovascular commitment from MCPs. When overexpressed in human pluripotent stem cells, miR-1 enhanced the expression of key cardiac transcriptional factors and sarcomeric genes. Importantly, we found miR-1 promoted CM differentiation and suppressed EC commitment from MCPs by modulating the activities of WNT and FGF signaling pathways. FZD7 and FRS2 were confirmed as miR-1 targets using luciferase reporter assay and western blot. Overall, this study reveals a switch role of miR-1 at early human cardiovascular commitment stage via suppressing both WNT and FGF signaling pathways.
doi:10.1016/j.yjmcc.2013.07.019
PMCID: PMC4268488  PMID: 23939491
MicroRNA-1; Induced pluripotent stem cells; Cardiomyocyte; Multipotent Cardiovascular Progenitors
11.  A common set of distinct features that characterize noncoding RNAs across multiple species 
Nucleic Acids Research  2014;43(1):104-114.
To find signature features shared by various ncRNA sub-types and characterize novel ncRNAs, we have developed a method, RNAfeature, to investigate >600 sets of genomic and epigenomic data with various evolutionary and biophysical scores. RNAfeature utilizes a fine-tuned intra-species wrapper algorithm that is followed by a novel feature selection strategy across species. It considers long distance effect of certain features (e.g. histone modification at the promoter region). We finally narrow down on 10 informative features (including sequences, structures, expression profiles and epigenetic signals). These features are complementary to each other and as a whole can accurately distinguish canonical ncRNAs from CDSs and UTRs (accuracies: >92% in human, mouse, worm and fly). Moreover, the feature pattern is conserved across multiple species. For instance, the supervised 10-feature model derived from animal species can predict ncRNAs in Arabidopsis (accuracy: 82%). Subsequently, we integrate the 10 features to define a set of noncoding potential scores, which can identify, evaluate and characterize novel noncoding RNAs. The score covers all transcribed regions (including unconserved ncRNAs), without requiring assembly of the full-length transcripts. Importantly, the noncoding potential allows us to identify and characterize potential functional domains with feature patterns similar to canonical ncRNAs (e.g. tRNA, snRNA, miRNA, etc) on ∼70% of human long ncRNAs (lncRNAs).
doi:10.1093/nar/gku1316
PMCID: PMC4288202  PMID: 25505163
12.  Extrinsic 2D chirality: giant circular conversion dichroism from a metal-dielectric-metal square array 
Scientific Reports  2014;4:7442.
Giant chiroptical responses routinely occur in three dimensional chiral metamaterials (MMs), but their resonance elements with complex subwavelength chiral shapes are challenging to fabricate in the optical region. Here, we propose a new paradigm for obtaining strong circular conversion dichroism (CCD) based on extrinsic 2D chirality in multilayer achiral MMs, showing that giant chiroptical response can be alternatively attained without complex structures. Our structure consists of an array of thin Au squares separated from a continuous Au film by a GaAs dielectric layer, where the Au squares occupy the sites of a rectangular lattice. This structure gives rise to a pronounced extrinsically 2D-chiral effect (CCD) in the mid-infrared (M-IR) region under an oblique incidence, where the 2D-chiral effect is due to the mutual orientation of the Au squares array and the incident light propagation direction; the large magnitude of CCD due to the large difference between left-to-left and right-to-right circularly polarized reflectance conversion efficiencies.
doi:10.1038/srep07442
PMCID: PMC4262820  PMID: 25501766
13.  Targeting and mimicking collagens via triple helical peptide assembly 
Current opinion in chemical biology  2013;17(6):10.1016/j.cbpa.2013.10.018.
As the major structural component of the extracellular matrix, collagen plays a crucial role in tissue development and regeneration. Since structural and metabolic abnormalities of collagen are associated with numerous debilitating diseases and pathologic conditions, the ability to target collagens of diseased tissues could lead to new diagnostics and therapeutics. Collagen is also a natural biomaterial widely used in drug delivery and tissue engineering, and construction of synthetic collagen-like materials is gaining interests in the biomaterials community. The unique triple helical structure of collagen has been explored for targeting collagen strands, and for engineering collagen-like functional assemblies and conjugates. This review focuses on the forefront of research activities in the use of the collagen mimetic peptide for both targeting and mimicking collagens via its triple helix mediated strand hybridization and higher order assembly.
doi:10.1016/j.cbpa.2013.10.018
PMCID: PMC3863647  PMID: 24210894
14.  Aberrant Topoisomerase-1-DNA Lesions are Pathogenic in Neurodegenerative Genome Instability Syndromes 
Nature neuroscience  2014;17(6):813-821.
DNA damage is considered a prime factor in multiple spinocerebellar neurodegenerative diseases; however, the DNA lesions underpinning disease etiology are unknown. Here we identify the endogenous accumulation of pathogenic topoisomerase-1-DNA cleavage complexes (Top1cc) in murine models of ataxia telangiectasia and spinocerebellar ataxia with axonal neuropathy 1. We also show that the defective DNA damage response factors in these two diseases cooperatively modulate Top1cc turnover in a non-epistatic and ATM kinase-independent manner. Furthermore, coincident neural inactivation of ATM and DNA single strand break repair factors including tyrosyl-DNA phosphodiesterase-1 or XRCC1 result in increased Top1cc formation and excessive DNA damage and neurodevelopmental defects. Importantly, direct topoisomerase-1 poisoning to elevate Top1cc levels phenocopies the neuropathology of the mouse models above. Our study identifies a critical endogenous pathogenic lesion associated with neurodegenerative syndromes arising from DNA repair deficiency, indicating the essential role that genome integrity plays in preventing disease in the nervous system.
doi:10.1038/nn.3715
PMCID: PMC4074009  PMID: 24793032
15.  Diffusion Tensor Imaging Based Network Analysis Detects Alterations of Neuroconnectivity in Patients with Clinically Early Relapsing Remitting Multiple Sclerosis 
Human brain mapping  2012;34(12):3376-3391.
Although it is inarguable that conventional MRI (cMRI) has greatly contributed to the diagnosis and assessment of Multiple Sclerosis (MS), cMRI does not show close correlation with clinical findings or pathologic features, and is unable to predict prognosis or stratify disease severity. To this end, diffusion tensor imaging (DTI) with tractography and neuroconnectivity analysis may assist disease assessment in MS. We therefore attempted this pilot study for initial assessment of early relapsing remitting (RR) MS. Neuroconnectivity analysis was employed for evaluation of 24 early RRMS patients within two years of presentation, and compared to the network measures of a group of 30 age-and-gender-matched normal control subjects. To account for the situation that the connections between two adjacent regions may be disrupted by an MS lesion, a new metric, network communicability, was adopted to measure both direct and indirect connections. For each anatomical area, the brain network communicability and average path length (APL) were computed and compared to characterize the network changes in efficiencies. Statistically significant (p < 0.05) loss of communicability was revealed in our RRMS cohort, particularly in the frontal and hippocampal/parahippocampal regions as well as the motor strip and occipital lobes. Correlation with the 25 foot walk test with communicability measures in the left superior frontal (r = -0.71) as well as the left superior temporal gyrus (r = -0.43) and left postcentral gyrus (r = -0.41) were identified. Additionally identified were increased communicability between the deep gray matter (GM) structures (left thalamus and putamen) with the major inter-hemispheric and intra-hemispheric white matter tracts, the corpus callosum and cingulum respectively. These foci of increased communicability are thought to represent compensatory changes. The proposed DTI based neuroconnectivity analysis demonstrated quantifiable, structurally relevant alterations of fiber tract connections in early relapsing remitting MS and paves the way for longitudinal studies in larger patient groups.
doi:10.1002/hbm.22158
PMCID: PMC4131751  PMID: 22987661
16.  Moderate Dynamic Compression Inhibits Pro-Catabolic Response of Cartilage to Mechanical Injury, TNF-α and IL-6, but Accentuates Degradation Above a Strain Threshold 
Objective
Traumatic joint injury can initiate early cartilage degeneration in the presence of elevated inflammatory cytokines (e.g., TNF-α and IL-6). The positive/negative effects of post-injury dynamic loading on cartilage degradation and repair in vivo is not well-understood. This study examined the effects of dynamic strain on immature bovine cartilage in vitro challenged with TNF-α + IL-6 and its soluble receptor (sIL-6R) with/without initial mechanical injury.
Methods
Groups of mechanically injured or non-injured explants were cultured in TNF-α + IL-6/sIL-6R for 8 days. Intermittent dynamic compression was applied concurrently at 10%, 20%, or 30% strain amplitude. Outcome measures included sGAG loss (DMMB), aggrecan biosynthesis (35S-incorporation), aggrecanase activity (Western blot), chondrocyte viability (fluorescence staining) and apoptosis (nuclear blebbing via light microscopy), and gene expression (qPCR).
Results
In bovine explants, cytokine-alone and injury-plus-cytokine treatments markedly increased sGAG loss and aggrecanase activity, and induced chondrocyte apoptosis. These effects were abolished by moderate 10% and 20% strains. However, 30% strain-amplitude greatly increased apoptosis and had no inhibitory effect on aggrecanase activity. TNF+IL-6/sIL-6R downregulated matrix gene expression and upregulated expression of inflammatory genes, effects that were rescued by moderate dynamic strains but not by 30% strain.
Conclusions
Moderate dynamic compression inhibits the pro-catabolic response of cartilage to mechanical injury and cytokine challenge, but there is a threshold strain-amplitude above which loading becomes detrimental to cartilage. Our findings support the concept of appropriate loading for post-injury rehabilitation.
doi:10.1016/j.joca.2013.08.021
PMCID: PMC3855909  PMID: 24007885
Dynamic Compression; Cartilage; Injury; Cytokines; Apoptosis; Rehabilitation post-injury
17.  An Electrochemical Microsensor Based on a AuNPs-Modified Microband Array Electrode for Phosphate Determination in Fresh Water Samples † 
Sensors (Basel, Switzerland)  2014;14(12):24472-24482.
This work describes the fabrication, characterization, and application of a gold microband array electrode (MAE) for the determination of phosphate in fresh water samples. The working principle of this MAE is based on the reduction of a molybdophosphate complex using the linear sweep voltammetric (LSV) method. The calibration of this microsensor was performed with standard phosphate solutions prepared with KH2PO4 and pH adjusted to 1.0. The microsensor consists of a platinum counter electrode, a gold MAE as working electrode, and an Ag/AgCl electrode as reference electrode. The microelectrode chips were fabricated by the Micro Electro-Mechanical System (MEMS) technique. To improve the sensitivity, gold nanoparticles (AuNPs) were electrodeposited on the working electrode. With a linear range from 0.02 to 0.50 mg P/L, the sensitivity of the unmodified microsensor is 2.40 μA per (mg P/L) (R2 = 0.99) and that of the AuNPs-modified microsensor is 7.66 μA per (mg P/L) (R2 = 0.99). The experimental results showed that AuNPs-modified microelectrode had better sensitivity and a larger current response than the unmodified microelectrode.
doi:10.3390/s141224472
PMCID: PMC4299121  PMID: 25536001
electrochemical; microband array electrode; gold nanoparticles; phosphate; fresh water samples
18.  Intra-Articular Adhesion Reduction after Knee Surgery in Rabbits by Calcium Channel Blockers 
Background
Intra-articular adhesion after knee surgery is a common and serious complication that presents a challenging problem for orthopedic surgeons. Verapamil (VP), a widely used calcium channel blocker, has been shown to prevent synthesis/secretion of extracellular matrix molecules. The object of this study was to investigate the effects of VP on the prevention of joint adhesion in post-surgery rabbits.
Material/Methods
A controlled double-blinded study was conducted in 40 healthy New Zealand white rabbits divided randomly into 4 groups according to the treatment method, with 10 in each group: 1) 1 mg/ml VP treatment group; 2) 2.5 mg/ml VP treatment group; 3) 5 mg/ml VP treatment group; 4) control group. Rabbits underwent surgery through the medial parapatellar approach and both lateral sides and the medial of the femoral condyle were surgically exposed. After treatment, the surgical limbs were subjected to extra-articular knee-joint immobilization in the full flexed position employing Kirschner wires for 4 weeks.
Results
The knee surgery was successfully performed on all rabbits. The rabbits were killed 4 weeks post-operatively. The histological evaluation, hydroxyproline content, visual score, fibroblasts density, and vimentin expressional levels were conducted to assess the effect of VP on preventing joint adhesion.
Conclusions
In our rabbit model of knee surgery, intra-articular application of VP was able to decrease intra-articular adhesion formation after surgery. VP could prevent rabbit intra-articular adhesion in a dose-dependent manner and the highest concentration used in the study (5 mg/ml) proved to be the most effective.
doi:10.12659/MSM.892957
PMCID: PMC4259520  PMID: 25430622
Knee Joint; Rabbits; Tissue Adhesions; Verapamil
19.  Photodiode-Like Behavior and Excellent Photoresponse of Vertical Si/Monolayer MoS2 Heterostructures 
Scientific Reports  2014;4:7186.
Monolayer transition metal dichalcogenides (TMDs) and their van der Waals heterostructures have been experimentally and theoretically demonstrated as potential candidates for photovoltaic and optoelectronic devices due to the suitable bandgap and excellent light absorption. In this work, we report the observation of photodiode behavior in (both n- and p- type) silicon/monolayer MoS2 vertical heterostructures. The photocurrent and photoresponsivity of heterostructures photodiodes were dependent both on the incident light wavelength and power density, and the highest photoresponsivity of 7.2 A/W was achieved in n-Si/monolayer MoS2 vertical heterostructures photodiodes. Compared with n-Si/MoS2 heterostructures, the photoresponsivity of p-Si/MoS2 heterostructure was much lower. Kelvin probe microscope (KFM) results demonstrated the more efficient separation of photogenerated excitons in n-Si/MoS2 than that in p-Si/MoS2. Coupling KFM results with band alignments of (p-, n-) Si/MoS2 heterostructures, the origins of photodiode-like phenomena of p-Si/MoS2 and n-Si/MoS2 have been unveiled, that is intrinsic built-in electric field in p-n junction, and modulated barrier height and width at the interface in n-n junction. Our work may benefit to the deep understanding of the integration of two-dimensional materials with more conventional three-dimensional semiconductors, and then contribute to the developments in the area of van der Waals heterostructures.
doi:10.1038/srep07186
PMCID: PMC4244624  PMID: 25424301
20.  An anatomically comprehensive atlas of the adult human brain transcriptome 
Nature  2012;489(7416):391-399.
Neuroanatomically precise, genome-wide maps of transcript distributions are critical resources to complement genomic sequence data and to correlate functional and genetic brain architecture. Here we describe the generation and analysis of a transcriptional atlas of the adult human brain, comprising extensive histological analysis and comprehensive microarray profiling of ~900 neuroanatomically precise subdivisions in two individuals. Transcriptional regulation varies enormously by anatomical location, with different regions and their constituent cell types displaying robust molecular signatures that are highly conserved between individuals. Analysis of differential gene expression and gene co-expression relationships demonstrates that brain-wide variation strongly reflects the distributions of major cell classes such as neurons, oligodendrocytes, astrocytes and microglia. Local neighbourhood relationships between fine anatomical subdivisions are associated with discrete neuronal subtypes and genes involved with synaptic transmission. The neocortex displays a relatively homogeneous transcriptional pattern, but with distinct features associated selectively with primary sensorimotor cortices and with enriched frontal lobe expression. Notably, the spatial topography of the neocortex is strongly reflected in its molecular topography— the closer two cortical regions, the more similar their transcriptomes. This freely accessible online data resource forms a high-resolution transcriptional baseline for neurogenetic studies of normal and abnormal human brain function.
doi:10.1038/nature11405
PMCID: PMC4243026  PMID: 22996553
Neuroscience; Genetics; Genomics; Databases
21.  Ras-related C3 botulinum toxin substrate 1 activation is involved in the pathogenesis of diabetic retinopathy 
This study used a streptozotocin (STZ)-induced rat model of diabetes to investigate whether Ras-related C3 botulinum toxin substrate 1 (Rac1) was involved in the pathogenesis of diabetic retinopathy. The effects of Rac1 inhibition on vascular endothelial (VE)-cadherin and β-catenin expression in high glucose-induced rat retinal endothelial cells (RRECs) were additionally examined. Rac1 activation in the retinas from STZ-induced diabetic rats and in high glucose-induced RRECs was measured by reverse transcription-quantitative polymerase chain reaction analysis, immunohistochemistry and western blot analysis. The expression levels of VE-cadherin and β-catenin were also examined with or without Rac1 inhibition through small interfering (si)RNA transfection. STZ-induced diabetes was associated with an increase in the vascular permeability of the retina. Furthermore, Rac1 activation was increased in the retina of STZ-induced diabetic rats and in high glucose-induced RRECs compared with that in the controls. Immunohistochemistry showed that immunostaining of Rac1 was localized in the outer plexiform, inner nuclear, inner plexiform and ganglion cell layers and in the retinal microvasculature of rats. The expression of β-catenin was increased in the retinas of the diabetic rats at four, eight and 12 weeks after the induction of diabetes compared with that in the controls. Additionally, Rac1 activation was required for the high glucose-induced VE-cadherin expression decrease and for β-catenin expression in high glucose-induced RRECs. Rac1 inhibition by Rac1-siRNA transfection effectively prevented hyperpermeability, β-catenin expression and the VE-cadherin expression decrease in high glucose-induced RRECs. In conclusion, diabetes affects the expression of Rac1 in the retina. Rac1 may be involved in the diabetes-induced damage and/or alterations to the blood-retinal barrier through changes in VE-cadherin and β-catenin expression.
doi:10.3892/etm.2014.2081
PMCID: PMC4247314  PMID: 25452781
Rac1; β-catenin; VE-cadherin; diabetes; retinopathy; rat; rat retinal endothelial cell
22.  A systematic assessment of genotoxicity on pivaloylacylation-7ADCA-a wide existing antibiotic impurity 
The safety of antibiotics has been becoming an important worldwide concern. As an inevitable and widespread existing impurity of β-lactam antibiotics, pivaloylacylation-7ADCA may has potential impact on drug safety. However, due to the restriction on traditional drug production technique, purified pivaloylacylation-7ADCA cannot be acquired and thus the toxicity of pivaloylacylation-7ADCA remains completely unknown. In this study, we firstly assessed the genotoxicity of newly purified pivaloylacylation-7ADCA. A series of well-designed experiments, including bacterial reverse mutation assay (Ames assay), mouse lymphoma assay (TK gene mutation test), chromosomal aberration assay, in vivo mouse micronucleus test and single cell gel electrophoresis assay (comet assay), were performed in genotoxicity assessment of pivaloylacylation-7ADCA at three different genetic endpoints, i.e. gene mutation, chromosome aberration or breakage, and DNA strand breaks. No genotoxicity were observed at all tested genetic endpoints, suggesting that pivaloylacylation-7ADCA has no mutagenic effect. To our knowledge, this is the first systematic assessment on the toxicity of newly synthesized pivaloylacylation-7ADCA, which should be an important part of the drug safety evaluation of β-lactam antibiotics. Moreover, our study is expected to serve as a reference for the genotoxicity assessment of other antibiotic impurities, by using purified impurity as test sample and by combining a group of well-designed genotoxic assays with different species, major genetic endpoints and in vivo/vitro tests.
PMCID: PMC4276199  PMID: 25550941
Genotoxicity; risk assessment; β-lactam antibiotics; pivaloylacylation-7ADCA
23.  Acoustic rainbow trapping by coiling up space 
Scientific Reports  2014;4:7038.
We numerically realize the acoustic rainbow trapping effect by tapping an air waveguide with space-coiling metamaterials. Due to the high refractive-index of the space-coiling metamaterials, our device is more compact compared to the reported trapped-rainbow devices. A numerical model utilizing effective parameters is also calculated, whose results are consistent well with the direct numerical simulation of space-coiling structure. Moreover, such device with the capability of dropping different frequency components of a broadband incident temporal acoustic signal into different channels can function as an acoustic wavelength division de-multiplexer. These results may have potential applications in acoustic device design such as an acoustic filter and an artificial cochlea.
doi:10.1038/srep07038
PMCID: PMC4229664  PMID: 25392033
24.  Malignant gangliocytic paraganglioma of the duodenum with distant metastases and a lethal course 
World Journal of Gastroenterology : WJG  2014;20(41):15454-15461.
Gangliocytic paraganglioma (GP) is rare and has been regarded as benign in general with a good prognosis. We present a patient with duodenal GP showing a malignant and lethal clinical course. A 47-year-old male patient was found to have a duodenal tumor and enlarged regional lymph nodes. The patient initially underwent a pancreaticoduodenectomy to resect the tumor and involved lymph nodes completely. Histological and immunohistochemical analyses showed findings typical of GP. However, the distant metastatic lesions in the liver and pelvic cavity were rapidly observed after surgery. The patient underwent chemotherapy and radiotherapy, as well as a second surgery to partly remove the metastatic mass in the pelvic cavity. The histological examination revealed no significant difference in histological features between the primary duodenal tumor and the metastatic pelvic mass. However, the patient finally died of the tumor due to the recurrence of the residual pelvic lesion and increased liver mass. To our knowledge, this is the first report of lethal GP with multifocal metastases. Our case confirms that GP should be regarded as a malignant potential tumor with behavior code of “1”, rather than a benign tumor of “0”.
doi:10.3748/wjg.v20.i41.15454
PMCID: PMC4223280  PMID: 25386095
Duodenal neoplasms; Gangliocytic neoplasms; Paraganglioma; Lymphatic metastasis; Treatment outcome
25.  Silica nanoparticles induce autophagy and endothelial dysfunction via the PI3K/Akt/mTOR signaling pathway 
Although nanoparticles have a great potential for biomedical applications, there is still a lack of a correlative safety evaluation on the cardiovascular system. This study is aimed to clarify the biological behavior and influence of silica nanoparticles (Nano-SiO2) on endothelial cell function. The results showed that the Nano-SiO2 were internalized into endothelial cells in a dose-dependent manner. Monodansylcadaverine staining, autophagic ultrastructural observation, and LC3-I/LC3-II conversion were employed to verify autophagy activation induced by Nano-SiO2, and the whole autophagic process was also observed in endothelial cells. In addition, the level of nitric oxide (NO), the activities of NO synthase (NOS) and endothelial (e)NOS were significantly decreased in a dose-dependent way, while the activity of inducible (i)NOS was markedly increased. The expression of C-reactive protein, as well as the production of proinflammatory cytokines (tumor necrosis factor α, interleukin [IL]-1β, and IL-6) were significantly elevated. Moreover, Nano-SiO2 had an inhibitory effect on the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling pathway. Our findings demonstrated that Nano-SiO2 could disturb the NO/NOS system, induce inflammatory response, activate autophagy, and eventually lead to endothelial dysfunction via the PI3K/Akt/mTOR pathway. This indicates that exposure to Nano-SiO2 is a potential risk factor for cardiovascular diseases.
doi:10.2147/IJN.S71074
PMCID: PMC4227623  PMID: 25395850
silica nanoparticles; endothelial dysfunction; autophagy; nitric oxide; inflammation

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