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Articles by Calvin C.H. Cheng in JoVE

 JoVE Bioengineering

In vitro Synthesis of Native, Fibrous Long Spacing and Segmental Long Spacing Collagen

1Department of Chemistry, University of Toronto, 2Institute for Optical Sciences, University of Toronto


JoVE 4417

Simple and reproducible procedures are described for making three structurally distinct collagen assemblies from a common commercially available Type I collagen monomer. Native type, fibrous long spacing or segmental long spacing collagen can be constructed by varying the conditions to which the 300 nm long and 1.4 nm diameter monomer building block is exposed.

Other articles by Calvin C.H. Cheng on PubMed

[Molecular Typing of Neisseria Meningitidis Serogroup B Strains in Hubei Province]

"What Took You So Long?" The Impact of PEPFAR on the Expansion of HIV Testing and Counseling Services in Africa

HIV testing and counseling services in Africa began in the early 1990s, with limited availability and coverage. Fears of stigma and discrimination, complex laboratory systems, and lack of available care and treatment services hampered expansion. Use of rapid point-of-care tests, introduction of services to prevent mother-to-child transmission, and increasing provision of antiretroviral drugs were key events in the late 1990s and early 2000s that facilitated the expansion of HIV testing and counseling services. Innovations in service delivery included providing HIV testing in both clinical and community sites, including mobile and home testing. Promotional campaigns were conducted in many countries, and evolutions in policies and guidance facilitated expansion and uptake. Support from President's Emergency Plan for AIDS Relief and national governments, other donors, and the Global Fund for AIDS, Tuberculosis, and Malaria contributed to significant increases in the numbers of persons tested in many countries. Quality of both testing and counseling, limited number of health care workers, uptake by couples, and effectiveness of linkages and referral systems remain challenges. Expansion of antiretroviral treatment, especially in light of the evidence that treatment contributes to prevention of transmission, will require greater yet strategic coverage of testing services, especially in clinical settings and in combination with other high-impact HIV prevention strategies. Continued support from President's Emergency Plan for AIDS Relief, governments, and other donors is required for the expansion of testing needed to achieve international targets for the scale-up of treatment and universal access to knowledge of HIV status.

Direct Reprogramming of Fibroblasts into Embryonic Sertoli-like Cells by Defined Factors

Sertoli cells are considered the "supporting cells" of the testis that play an essential role in sex determination during embryogenesis and in spermatogenesis during adulthood. Their essential roles in male fertility along with their immunosuppressive and neurotrophic properties make them an attractive cell type for therapeutic applications. Here we demonstrate the generation of induced embryonic Sertoli-like cells (ieSCs) by ectopic expression of five transcription factors. We characterize the role of specific transcription factor combinations in the transition from fibroblasts to ieSCs and identify key steps in the process. Initially, transduced fibroblasts underwent a mesenchymal to epithelial transition and then acquired the ability to aggregate, formed tubular-like structures, and expressed embryonic Sertoli-specific markers. These Sertoli-like cells facilitated neuronal differentiation and self-renewal of neural progenitor cells (NPCs), supported the survival of germ cells in culture, and cooperated with endogenous embryonic Sertoli and primordial germ cells in the generation of testicular cords in the fetal gonad.

Role of Non-structural Protein 2 in the Regulation of the Replication of the Porcine Reproductive and Respiratory Syndrome Virus in MARC-145 Cells: Effect of Gene Silencing and over Expression

Porcine reproductive and respiratory syndrome (PRRS) is an economically important disease in swine-producing areas. Many vaccine strategies have been developed to control the disease, but none have yet been completely successful. The development of a cell line that can produce large yields of PRRSV vaccine is very necessary. In order to determine the role of Nsp2 in the replication of the highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) in MARC-145 cells, we used an RNA interference-based short hairpin RNA of Nsp2 and constructed cell lines expressing the HP-PRRSV Nsp2 gene. Conserved HP-PRRSV Nsp2 sequences were used to design short interfering RNAs and test their ability to silence PRRSV transcript expression and replication in cells in vitro transfection. Nsp2, ORF7, and β-actin mRNA expression were determined using semi-quantitative real-time PCR. Infection with siRNA targeting Nsp2 was found to reduce the Nsp2 expression in MARC-145 cells infected with PRRSV. Both MARC-145-TJ Nsp2 and MARC-145-TJM Nsp2 cell lines were screened by G418, which were infected with HP-PRRSV, normal MARC-145 cells for mock, and then virus titers were calculated by TCID(50) after the CPE showing up. The downregulation of Nsp2 induced a remarkable decrease in PRRSV replication, causing the reduction of structural protein. The Nsp2-targeted siRNA was found to downregulate the expression of Nsp2 in MARC-145 cells and inducing replication reduce of PRRSV in MARC-145 cells. The shRNA vectors S-1 and S-2 could effectively induce the inhibition of viral replication in MARC-145. Results showed that cells expressing the Nsp2 gene of the highly pathogenic PRRSV TJ and attenuated TJM remained stable. PRRSV replication was faster in these cells than in MARC-145 cells, especially during the early stage. This shows that Nsp2 plays a positive role in PRRSV proliferation.

Synthesis and Biological Evaluation of Cyanoguanidine Derivatives of Loratadine

Cyanoguanidine derivatives of loratadine (3a-i) were synthesized and screened for antitumor and anti-inflammatory activity. The most promising compound 3c (R=n-C(8)H(17)) possessed at least twofold higher in vitro cytotoxicity than 5-fluorouracil against mammary (MCF-7 and MDA-MB 231) as well as colon (HT-29) carcinoma cells. The mode of action, however, is so far unclear. The participation of the COX-1/2 enzymes on the cytotoxicity, however, is very unlikely. Nevertheless all compounds showed stronger in vivo anti-inflammatory activity than ibuprofen in the xylene-induced ear swelling assay in mice.

TRIM28, a New Molecular Marker Predicting Metastasis and Survival in Early-stage Non-small Cell Lung Cancer

TRIM28 is a universal corepressor for Kruppel-associated box zinc finger proteins. In this study, we demonstrated the expression of TRIM28 gene was significantly higher in cancerous tissues than in noncancerous tissues (P<0.001). TRIM28 knockdown resulted in a decrease in cell proliferation in liquid media as well as in soft agar. The proliferation rate was impaired and the cell cycle progression was inhibited after knockdown of TRIM28 in non-small cell lung cancer cell lines PAa and SK-MES-1. We used real-time polymerase chain reaction to detect circulating cancer cells in 138 non-small cell lung cancer patients. The overall positive detection rate was 30.4% (42 of 138) in peripheral blood of NSCLC patients and was 29.9% (29 of 97) in early-stage patients. In a 70-month follow-up study, 20 of 29 patients (69.0%) in TRIM28 positive group had recurrence and/or metastasis, significantly higher (P=0.004) than in the TRIM28 negative group (25 of 68, 36.8%). In addition, non-small cell lung cancer patients whose circulating cancer cells expressed TRIM28 suffered shorter tumor-specific survival compared with those with absent TRIM28 expression (P<0.001). Results of our study showed that TRIM28 provides a survival advantage to lung cancer cells and may be a new marker to predict metastasis and prognosis in early-stage non-small cell lung cancer patients.

Endoplasmic Reticulum Stress Contributes to Arsenic Trioxide-induced Apoptosis in Drug-sensitive and -resistant Leukemia Cells

This study characterized the role of endoplasmic reticulum stress (ERS)-related pathways in arsenic trioxide-induced apoptosis in multidrug-resistant leukemia K562/ADM cells. Arsenic trioxide exposure led to much significant induction of apoptosis in K562/ADM cells than the parental K562 cells, and the chaperone proteins glucose-regulated protein 78, CHOP/GADD153, X-box binding protein-1 and caspase-12 were activated to varying degrees. Furthermore, arsenic trioxide stimulation led to inhibition of P-glycoprotein and Bcl-2 expression. This study demonstrates a missing link between arsenic trioxide and ERS-induced apoptosis, and suggests that the greater effects obtained in drug-resistant K562/ADM cells may be mediated by downregulation of P-glycoprotein and Bcl-2 expression.

Association of Prolactin Haplotypes with Reproductive Traits in Tsaiya Ducks

A previous cDNA microarray study showed that the prolactin (PRL) gene may be involved in the duck ovarian follicle development and egg formation process. The purpose of this study was to investigate the relationship between PRL genotypes of single nucleotide polymorphism (SNP) and reproductive traits of Tsaiya ducks. Primer pairs for the coding regions in the PRL were designed based on the duck genomic sequence database. Polymorphisms were detected by polymerase chain reaction (PCR)-single strand polymorphism (SSCP) and were verified by DNA sequencing. Six novel SNPs (T233C, T295C, G309T, C381A, G3941T and A3975C) were identified in the 1972bp region of duck PRL gene, and all of them were located in non-coding regions. Single SNP-trait association analysis showed that each SNP was associated with at least one duck reproductive trait (P<0.05). Haplotype combinations constructed on these SNPs were associated with egg weight at 40 weeks of age (EW40), fertility rate (FR) and maximum duration of fertility (MDF) (P<0.0001). In particular, diplotype H1H2 had positive effect on EW40, whereas it had negative effect on FR and MDF (P<0.05). Positive effects of the diplotype H1H5 were observed for FR and MDF, but a negative effect was observed for EW40 (P<0.05). This suggested that the PRL gene plays an important role in the regulation of egg weight and fertility-related traits and could be a potential marker in a marker assisted selection program during duck balancing selection. Further investigations on more duck populations with large sample sizes are needed to confirm this finding.

Newly Synthesized Bis-benzimidazole Derivatives Exerting Anti-tumor Activity Through Induction of Apoptosis and Autophagy

In this study, a new series of bis-benzimidazole derivatives were designed and synthesized. Most of these new compounds showed significant anti-tumor activity in vitro compared to Hoechst 33258. Among them, the most potent compound 8 had the IC(50) values of 0.56μM for HL60 (Human promyelocytic leukemia cells) tumor cell line and 0.58μM for U937 (Human leukemic monocyte lymphoma cells) tumor cell line. Subsequent toxicity study on human peripheral blood mononuclear cells (PBMC) showed that compound 8 exhibited less toxicity than 5-FU. We also found that apoptosis and autophagy were simultaneously induced by compound 8 in HL60 cells, and inhibition of autophagy by 3-MA decreased compound 8-induced apoptosis, indicating that they acted in synergy to exert tumor cell death.

Proteomic Identification of Immunodominant Chlamydial Antigens in a Mouse Model

Chlamydia trachomatis is the most common bacterial sexually transmitted pathogen in the world. To identify new vaccine candidates a protein microarray was constructed by expressing the open reading frames (ORFs) from Chlamydia mouse pneumonitis (MoPn). C57BL/6, C3H/HeN and BALB/c mice were immunized either intranasally or intravaginally with live MoPn elementary bodies (EB). Two additional groups were immunized by the intramuscular plus subcutaneous routes with UV-treated EB, using CpG and Montanide as adjuvants to favor a Th1 response, or Alum, to elicit a Th2 response. Serum samples collected from the three strains of mice were tested in the microarray. The array included the expression of 909 proteins from the 921 ORFs of the MoPn genome and plasmid. A total of 530 ORFs were recognized by at least one serum sample. Of these, 36 reacted with sera from the three strains of mice immunized with live EB. These antigens included proteins that were previously described as immunogenic such as MOMP and HSP60. In addition, we uncovered new immunogens, including 11 hypothetical proteins. In summary, we have identified new immunodominant chlamydial proteins that can be tested for their ability to induce protection in animal models and subsequently in humans.

Biodegradation of Benzene, Toluene, Ethylbenzene, and O-xylene by the Bacterium Mycobacterium Cosmeticum Byf-4

A new strain Mycobacterium cosmeticum byf-4 able to simultaneously degrade benzene, toluene, ethylbenzene, and o-xylene (BTE(o-)X) compounds has been isolated and identified previously in our laboratory. We further report here the extent of degradation of every BTE(o-)X component, and unravel the initial mechanism involved in BTE(o-)X degradation. This organism efficiently degrades all the BTE(o-)X components when these compounds are added either individually or as a composite mixture, and has a preference for toluene followed by benzene, ethylbenzene and then o-xylene. The significantly high carbon recovery indicated that the predominant fate for BTE(o-)X compounds was mineralization and incorporation into cell materials. The presence of BTE compounds in binary or ternary mixtures consistently had a negative effect on o-xylene degradation. The initial steps involved in the degradation of BTE(o-)X were investigated by isolation of metabolites and assay of reverse transcription RT-PCR. Isolation of metabolites suggested that the BTE(o-)X compounds were initially converted by a dioxygenase to their respective catechols. The gene sequence of the PCR amplicons revealed that this isolate contained a 454-bp toluene dioxygenase (TOD) fragment. The BTE(o-)X-specific induction of the genes encoding TOD was confirmed by RT-PCR analysis. These results indicated that TOD was possibly responsible for the initial steps of BTE(o-)X catabolism in M. cosmeticum byf-4.

Brassinosteroid-induced CO(2) Assimilation is Associated with Increased Stability of Redox-sensitive Photosynthetic Enzymes in the Chloroplasts in Cucumber Plants

Brassinosteroids (BRs) play important roles in plant growth, development, photosynthesis and stress tolerance; however, the mechanism underlying BR-enhanced photosynthesis is currently unclear. Here, we provide evidence that an increase in the BR level increased the quantum yield of PSII, activities of Rubisco activase (RCA) and fructose-1,6-bisphosphatase (FBPase), and CO(2) assimilation. BRs upregulated the transcript levels of genes and activity of enzymes involved in the ascorbate-glutathione cycle in the chloroplasts, leading to an increased ratio of reduced (GSH) to oxidized (GSSG) glutathione in the chloroplasts. An increased GSH/GSSG ratio protected RCA from proteolytic digestion and increased the stability of redox-sensitive enzymes in the chloroplasts. These results strongly suggest that BRs are capable of regulating the glutathione redox state in the chloroplasts through the activation of the ascorbate-glutathione cycle. The resulting increase in the chloroplast thiol reduction state promotes CO(2) assimilation, at least in part, by enhancing the stability and activity of redox-sensitive photosynthetic enzymes through post-translational modifications.

Association of the CR1 Polymorphism with Late-onset Alzheimer's Disease in Chinese Han Populations: A Meta-analysis

It is well known that genetic variants play a critical role in the pathogenesis of Alzheimer's disease (AD). In 2009, a genome-wide association study (GWAS) demonstrated that a single nucleotide polymorphism (SNP), rs6656401, in complement receptor 1 (CR1) is significantly associated with late-onset Alzheimer's disease (LOAD) in Caucasian population. Subsequently, other researchers have attempted to validate this finding in Chinese Han populations. However, these findings in Chinese Han populations have produced both negative and positive results. To derive a more precise estimation for the relationship, we performed the present meta-analysis by analyzing three published association studies involving CR1 SNP rs6656401 through the use of the RevMan (v.5.1) program. Pooled odds ratios (ORs) were calculated for allele contrasts (A vs. G) and a dominant model [(AA+AG) vs. GG] in three studies that included 1019 cases and 1080 controls, respectively. The statistical results showed a significant difference between patients and controls for the A allele of CR1 SNP rs6656401 (P=0.005). In addition, carriers of the A allele (AA+AG) of rs6656401 had a 1.69-fold increased risk for LOAD compared with non-carriers (GG) (P=0.01). In conclusion, despite there are some limitations, this meta-analysis indicates that the A allele of the CR1 SNP rs6656401 is significantly associated with LOAD susceptibility in Chinese Han populations.

Prokineticin 2 is Involved in the Thermoregulation and Energy Expenditure

Animals have developed adaptive strategies to survive tough situations such as food shortage. However, the underlying molecular mechanism is not fully understood. Here, we provided evidence that the regulatory peptide prokineticin 2 (PK2) played an important role in such an adaptation. The PK2 expression was rapidly induced in the hypothalamic paraventricular nucleus (PVN) after fasting, which can be mimicked by 2-deoxy-d-glucose (2-DG) injection. The fasting-induced arousal was absent in the PK2-deficient (PK2(-/-)) mice. Furthermore, PK2(-/-) mice showed less energy expenditure and body weight loss than wild-type (WT) controls upon fasting. As a result, PK2(-/-) mice entered torpor after fasting. Supply of limited food (equal to 5% of body weight) daily during fasting rescued the body weight loss and hypothermal phenotype in WT mice, but not in PK2(-/-) mice, which was likely due to the higher efficiency of food utilization in PK2(-/-) mice. Our study thus demonstrated PK2 as a regulator in the thermoregulation and energy expenditure.

Comprehensive Care Improves Health Outcomes Among Elderly Taiwanese Patients With Hip Fracture

BACKGROUND: Few studies have investigated the effects of care models that combine interdisciplinary care with nutrition consultation, depression management, and fall prevention in older persons with hip fracture. The purpose of this study was to compare the effects of a comprehensive care program with those of interdisciplinary care and usual care for elderly patients with hip fracture. METHODS: A randomized experimental trial was used to explore outcomes for 299 elderly patients with hip fracture receiving three treatment care models: interdisciplinary care (n = 101), comprehensive care (n = 99), and usual care (n = 99). Interdisciplinary care included geriatric consultation, continuous rehabilitation, and discharge planning with post-hospital services. Comprehensive care consisted of interdisciplinary care plus nutrition consultation, depression management, and fall prevention. Usual care included only in-hospital rehabilitation without geriatric consultation, in-home rehabilitation, and home environmental assessment. RESULTS: Participants in the comprehensive care group had better self-care ability (odds ratio, OR = 3.19, p < .01) and less risk of depression (OR = 0.48, p < .01) than those who received usual care. The comprehensive care group had less risk of depression (OR = 0.51, p < .05) and of malnutrition (OR = 0.48, p < .05) than the interdisciplinary care group during the first year following discharge. Older persons with hip fracture benefitted more from the comprehensive care program than from interdisciplinary care and usual care. CONCLUSIONS: Older persons with hip fracture benefitted more from comprehensive care including interdisciplinary care and nutrition consultation, depression management, and fall prevention than simply interdisciplinary care.

Municipal Wastewater Treatment Plants As Pathogen Removal Systems and As a Contamination Source of Noroviruses and Enterococcus Faecalis

Municipal wastewater treatment plants play a crucial role in reducing the microbial and pathogen load of human wastes before the end-products are discharged to surface waters (final effluent) or land spread (biosolids). This study investigated the occurrence frequency of noroviruses, Enterococcus faecalis and Enterococcus faecium in influent, final effluent and biosolids from four secondary wastewater treatment plants in northwestern Ireland (plants A-D) and observed the seasonal and spatial variation of the plant treatment efficiencies in the pathogen removals. It was noted that norovirus genogroup II was more resistant to the treatment processes than the norovirus genogroup I and other active viral particles, especially those in the discharge effluents. The percolating biofilm system at plant D resulted in better effluent quality than in the extended aerated activated sludge systems (plants A and B); primary biosolids produced at plant D may pose a higher health risk to the locals. The spread of norovirus genogroup II into the environment, irrespective of the wastewater treatment process, coincides with its national clinical predominance over norovirus genogroup I. This study provides important evidence that municipal wastewater treatment plants not only achieve pathogen removal but can also be the source of environmental pathogen contamination.

Severe and Recurrent Interface Hemorrhage After Endothelial Keratoplasty

PURPOSE.: To report the occurrence and management of recurrent hemorrhage after Descemet stripping endothelial keratoplasty (DSEK) in a patient with pseudophakic bullous keratopathy. METHODS.: An 84-year-old Chinese woman on two oral antiplatelet drugs underwent DSEK in her left eye. Preoperative best-corrected visual acuity was 20/30 OD and 14/200 OS. Intraoperative bleeding was noted from the iris root. Surgery was completed uneventfully, and interface was thoroughly irrigated in the end. Slit lamp examination on the first postoperative day showed a dense interface hemorrhage and an intraocular pressure of 24 mm Hg. Repeat interface irrigation was carried out on postoperative day 4, but the hemorrhage appeared again on the following day. Donor lenticule was well apposed to the corneal stroma, and visual acuity was hand motions in the operated eye. No further surgical interventions were performed. Corticosteroid eye drops were continued four times a day in the operated eye, and the patient was advised weekly follow-up. RESULTS.: Over the next 4 weeks, the interface blood gradually started to clear from the central cornea. At the end of 4 months postoperatively, the interface hemorrhage disappeared completely. A final best-corrected visual acuity of 20/80 was achieved. Specular microscopy revealed an endothelial cell density of 1375 cells/mm. CONCLUSIONS.: Interface hemorrhage is a known complication after DSEK surgery. Recurrent hemorrhage may be expected in patients on oral antiplatelet treatment. In cases without associated graft dislocation, conservative management can still result in good visual outcome.

Upper Extremity Strength Characteristics in Female Recreational Tennis Players With and Without Lateral Epicondylalgia

Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 STUDY DESIGN: Descriptive, cross-sectional. OBJECTIVES: To compare static strength characteristics of the upper extremity musculature in female recreational tennis players who have lateral epicondylalgia with those of non-symptomatic tennis players and a control group of women who do not play tennis. BACKGROUND: A paucity of research exists describing the relationship between lateral epicondylalgia and strength characteristics of the upper extremity musculature despite the functional relationship that exists between the shoulder, elbow, and wrist. METHODS: Sixty-three females, 21 in each group, were recruited: symptomatic tennis players (STP) with lateral epicondylalgia, non-symptomatic tennis players (NSTP), and controls. Data collection was performed during a single session when strength of selected muscle groups of the dominant upper extremity was measured using a combination of force transducers. Strength ratios of selected muscle groups were calculated. RESULTS: The STP group reported median pain level of 3/10 on a numeric pain rating scale and 16 weeks symptom duration. The STP group had weaker lower trapezius (mean difference,-9.0 N; 95% CI: -13.5 to -4.4 N) and wrist extensors (-12.7 N; -24.4 to -1.1) strength and higher shoulder internal/external rotation (1.9; 0.02, 0.35) and upper/lower trapezius (1.32; 0.41, 2.23) strength ratios when compared to the NSTP group. Compared to the control group, the STP group demonstrated significantly higher shoulder internal/external rotation (0.21; 0.04, 0.38) and wrist flexion/extension (0.14; 0.01 to 0.27) strength ratios. CONCLUSIONS: In this group of recreational female tennis players, significant differences in strength and strength ratio characteristics were identified. While the design of the study precludes a cause and effect relationship to be established, the results suggest potential muscle groups of interest for further study or treatment. J Orthop Sports Phys Ther, Epub 5 September 2012. doi:10.2519/jospt.2012.4095.

Covalent Fusion Inhibitors Targeting HIV-1 Gp41 Deep Pocket

Covalent inhibitors form covalent adducts with their target, thus permanently inhibiting a physiological process. Peptide fusion inhibitors, such as T20 (Fuzeon, enfuvirtide) and C34, interact with the N-terminal heptad repeat of human immunodeficiency virus type 1 (HIV-1) gp41 glycoprotein to form an inactive hetero six-helix bundle (6-HB) to prevent HIV-1 infection of host cells. A covalent strategy was applied to peptide fusion inhibitor design by introducing a thioester group into C34-like peptide. The modified peptide maintains the specific interaction with its target N36. After the 6-HB formation, a covalent bond between C- and N-peptides was formed by an inter-helical acyl transfer reaction, as characterized by various biophysical and biochemical methods. The covalent reaction between the reactive C-peptide fusion inhibitor and its N-peptide target is highly selective, and the reaction greatly increases the thermostability of the 6-HB. The modified peptide maintains high potency against HIV-1-mediated cell-cell fusion and infection.

Genetic Diversity of Internalin Genes in the AscB -dapE Locus Among Listeria Monocytogenes Lineages III and IV Strains

Listeria monocytogenes is an important foodborne pathogen encompassing four phylogenetic lineages. Lineages III and IV are rare, but have been reported to show considerable biodiversity, providing important clues for the evolutionary history in Listeria. In this study, analysis of the ascB-dapE locus reveals genetic diversity in lineages III and IV, and is consistent with the classification of sublineages. Four of the six genetic patterns (two of sublineage IIIC and two of lineage IV) are specific to these two lineages. The ascB-dapE locus suggests a hot spot for genome diversification, and serves as an attractive molecular marker for better understanding of the biodiversity and population structure of lineages III and IV strains (© 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim).

Snail Represses the Splicing Regulator ESRP1 to Promote Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT), a tightly regulated process that is critical for development, is frequently re-activated during cancer metastasis and recurrence. We previously reported that CD44 isoform switching is critical for EMT and showed that the splicing factor ESRP1 inhibits CD44 isoform switching during EMT. However, the mechanism by which ESRP1 is regulated during EMT has not been fully understood. Here we show that the transcription repressor Snail binds to E-boxes in the ESRP1 promoter, causing repression of the ESRP1 gene. Biochemically, we define the mechanism by which ESRP1 regulates CD44 alternative splicing: ESRP1 binds to the intronic region flanking a CD44 variable exon and causes increased variable exon inclusion. We further show that ectopically expressing ESRP1 inhibits Snail-induced EMT, suggesting that downregulation of ESRP1 is required for Snail's function in EMT. Together, these data reveal how the transcription factor Snail mediates EMT through regulation of a splicing factor.

Semiconducting and Conducting Transition of Covalent-organic Polymers Induced by Defects

The chemical doping method is often adopted to obtain metal-free conducting materials. To date, it is still a great challenge to controllably prepare metal-free semiconducting and conducting materials by tuning the inherent structure of a material. In this work, a class of novel one-dimensional (1D) covalent-organic polymer (COP) has been designed, whose cross-sections are triangular, tetragonal, pentagonal and hexagonal, and their electronic properties are explored. The tetragonal 1D COP exhibits unique phenomena in electronic properties, i.e. the tetragonal COPs with mono- or trilayer defects (odd defects) show semiconducting properties, while they become conductors for the two cases of non- or bilayer defects (even defects). This observation indicates that they comply with the characteristics of semiconducting and conducting switches induced by the odd-even defects. Therefore, we infer that for the tetragonal configuration, the odd-even defects could potentially manipulate the electrical behavior of the COP material. The discovery provides a new direction for the targeted synthesis of semiconducting and conducting materials by tuning the inherent structure of materials, which is entirely different from the chemical doping method yielding metal-free conducting materials.

Excision of 5-hydroxymethyluracil and 5-carboxylcytosine by the Thymine DNA Glycosylase Domain: Its Structural Basis and Implications for Active DNA Demethylation

The mammalian thymine DNA glycosylase (TDG) is implicated in active DNA demethylation via the base excision repair pathway. TDG excises the mismatched base from G:X mismatches, where X is uracil, thymine or 5-hydroxymethyluracil (5hmU). These are, respectively, the deamination products of cytosine, 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). In addition, TDG excises the Tet protein products 5-formylcytosine (5fC) and 5-carboxylcytosine (5caC) but not 5hmC and 5mC, when paired with a guanine. Here we present a post-reactive complex structure of the human TDG domain with a 28-base pair DNA containing a G:5hmU mismatch. TDG flips the target nucleotide from the double-stranded DNA, cleaves the N-glycosidic bond and leaves the C1' hydrolyzed abasic sugar in the flipped state. The cleaved 5hmU base remains in a binding pocket of the enzyme. TDG allows hydrogen-bonding interactions to both T/U-based (5hmU) and C-based (5caC) modifications, thus enabling its activity on a wider range of substrates. We further show that the TDG catalytic domain has higher activity for 5caC at a lower pH (5.5) as compared to the activities at higher pH (7.5 and 8.0) and that the structurally related Escherichia coli mismatch uracil glycosylase can excise 5caC as well. We discuss several possible mechanisms, including the amino-imino tautomerization of the substrate base that may explain how TDG discriminates against 5hmC and 5mC.

A Note on Confidence Bounds After Fixed-sequence Multiple Tests

We are concerned with the problem of estimating the treatment effects at the effective doses in a dose-finding study. Under monotone dose-response, the effective doses can be identified through the estimation of the minimum effective dose, for which there is an extensive set of statistical tools. In particular, when a fixed-sequence multiple testing procedure is used to estimate the minimum effective dose, Hsu and Berger (1999) show that the confidence lower bounds for the treatment effects can be constructed without the need to adjust for multiplicity. Their method, called the dose-response method, is simple to use, but does not account for the magnitude of the observed treatment effects. As a result, the dose-response method will estimate the treatment effects at effective doses with confidence bounds invariably identical to the hypothesized value. In this paper, we propose an error-splitting method as a variant of the dose-response method to construct confidence bounds at the identified effective doses after a fixed-sequence multiple testing procedure. Our proposed method has the virtue of simplicity as in the dose-response method, preserves the nominal coverage probability, and provides sharper bounds than the dose-response method in most cases.

Poly I:C Enhances Susceptibility to Secondary Pulmonary Infections by Gram-positive Bacteria

Secondary bacterial pneumonias are a frequent complication of influenza and other respiratory viral infections, but the mechanisms underlying viral-induced susceptibility to bacterial infections are poorly understood. In particular, it is unclear whether the host's response against the viral infection, independent of the injury caused by the virus, results in impairment of antibacterial host defense. Here, we sought to determine whether the induction of an "antiviral" immune state using various viral recognition receptor ligands was sufficient to result in decreased ability to combat common bacterial pathogens of the lung. Using a mouse model, animals were administered polyinosine-polycytidylic acid (poly I:C) or Toll-like 7 ligand (imiquimod or gardiquimod) intranasally, followed by intratracheal challenge with Streptococcus pneumoniae. We found that animals pre-exposed to poly I:C displayed impaired bacterial clearance and increased mortality. Poly I:C-exposed animals also had decreased ability to clear methicillin-resistant Staphylococcus aureus. Furthermore, we showed that activation of Toll-like receptor (TLR)3 and Retinoic acid inducible gene (RIG-I)/Cardif pathways, which recognize viral nucleic acids in the form of dsRNA, both contribute to poly I:C mediated impairment of bacterial clearance. Finally, we determined that poly I:C administration resulted in significant induction of type I interferons (IFNs), whereas the elimination of type I IFN signaling improved clearance and survival following secondary bacterial pneumonia. Collectively, these results indicate that in the lung, poly I:C administration is sufficient to impair pulmonary host defense against clinically important gram-positive bacterial pathogens, which appears to be mediated by type I IFNs.

Size- and Temperature-dependent Quantum Confined Dielectric Effect in Colloidal Pbse and CdSe Nanocrystals

A new method is proposed to calculate the Stark shift induced by surface dielectric effect in colloidal nanocrystals. The effective mass approximation model is revised according to quantum confined dielectric effect. LUMO (the lowest unoccupied molecular orbital), HOMO (the highest occupied molecular orbital), band gap and Stark shift are calculated in CdSe and PbSe nanocrystals that bear significantly different physical properties. The calculated results fit well with the experimental data. The calculation of dielectric effect-induced Stark shift indicates that the quantum confined dielectric effect in PbSe and CdSe nanocrystals is size- and temperature-dependent, which is more notable in PbSe nanocrystals with a narrower band gap and results in the gentle variation of quantum confinement energy with particle size.

Enhanced Electron Field Emission from Carbon Nanotubes Irradiated by Energetic C Ions

The field emission performance and structure of the vertically aligned multi-walled carbon nanotube arrays irradiated by energetic C ion with average energy of 40 keV have been investigated. During energetic C ion irradiation, the curves of emission current density versus the applied field of samples shift firstly to low applied fields when the irradiation doses are less than 9.6 x 10(16) cm(-2), and further increase of dose makes the curves reversing to a high applied field, which shows that high dose irradiation in carbon nanotube arrays makes their field emission performance worse. After energetic ion irradiation with a dose of 9.6 x 1016 cm(-2), the turn-on electric field and the threshold electric field of samples decreased from 0.80 and 1.13 V/microm to 0.67 and 0.98 V/microm respectively. Structural analysis of scanning electron microscopy, transmission electron microscopy and Raman spectroscopy indicates that the amorphous carbon nanowire/carbon nanotube hetero nano-structures have been fabricated in the C ion irradiated carbon nanotubes. The enhancement of electron field emission is due to the formation of amorphous carbon nanowires at the tip of carbon nanotube arrays, which is an electron emitting material with low work function.

Structures and Field Emission Properties of Silicon Nanowire Arrays Implanted with Energetic Carbon Ion Beam

Structures and field emission properties of silicon nanowire arrays (SiNWAs), which were fabricated by using of electroless-chemical etching method and post-implanted by the energetic carbon ion beam with an average energy of 20 keV at various doses, have been investigated. Structural analysis of SEM and XPS shows that SiC compound had been formed at the top of SiNWAs, and Si-C/Si composite nanostructure had been obtained. Compared to as-grown SiNWAs, the C ion implanted SiNWAs have better field emission characteristics. The turn-on field and the applied field at 100 microA/cm2 are reduced from 5.01 V/microm and 5.93 V/microm for as-grown SiNWAs to 4.45 V/microm and 5.40 V/microm for SiNWAs implanted at the dose of 1 x 10(16) cm(-2), respectively. However, large implanting amounts made serious structural damages at the top of nanowires, and impaired the field emission characteristics. The influence of energetic C ion implantation on the structures and field emission properties of SiNWAs has been discussed.

Enhanced Anti-influenza Agents Conjugated with Anti-inflammatory Activity

Influenza therapy with a single targeted compound is often limited in efficacy due to the rapidly developed drug-resistance. Moreover, the uncontrolled virus-induced cytokines could cause the high mortality of human infected by H5N1 avian influenza virus. In this study, we explored the novel dual-targeted bifunctional anti-influenza drugs formed by conjugation with anti-inflammatory agents. In particular, the caffeic acid (CA)-bearing zanamivir (ZA) conjugates ZA-7-CA (1) and ZA-7-CA-amide (7) showed simultaneous inhibition of influenza virus neuraminidase and suppression of pro-inflammatory cytokines. These ZA conjugates provided remarkable protection of cells and mice against influenza infections. Intranasal administration of low dosage (<1.2 μmol/kg/day) of ZA conjugates exhibited much greater effect than the combination therapy with ZA and the anti-inflammatory agents in protection of the lethally infected mice by H1N1 or H5N1 influenza viruses.

Inferential Dependencies in Causal Inference: A Comparison of Belief-Distribution and Associative Approaches

Causal evidence is often ambiguous, and ambiguous evidence often gives rise to inferential dependencies, where learning whether one cue causes an effect leads the reasoner to make inferences about whether other cues cause the effect. There are 2 main approaches to explaining inferential dependencies. One approach, adopted by Bayesian and propositional models, distributes belief across multiple explanations, thereby representing ambiguity explicitly. The other approach, adopted by many associative models, posits within-compound associations-associations that form between potential causes-that, together with associations between causes and effects, support inferences about related cues. Although these fundamentally different approaches explain many of the same results in the causal literature, they can be distinguished, theoretically and experimentally. We present an analysis of the differences between these approaches and, through a series of experiments, demonstrate that models that distribute belief across multiple explanations provide a better characterization of human causal reasoning than models that adopt the associative approach. (PsycINFO Database Record (c) 2012 APA, all rights reserved).

Perceptions of Neighborhood Social Environment and Drug Dependence Among Incarcerated Women and Men: a Cross-sectional Analysis

ABSTRACT: BACKGROUND: Perception of neighborhood social environment can influence an individual's susceptibility to drug dependence. However, this has never been examined with a jailed sample, where frequent transitions between local jails and disadvantaged neighborhoods are common. Understanding these associations could aid in the design of targeted programs to decrease drug dependence and recidivism among the incarcerated. METHODS: For this study, 596 women and men from three Kansas City jails were surveyed over the course of six months in 2010. Drug dependence was assessed with DSM-IV criteria. Independent variables included fear of one's neighborhood, perceived level of neighborhood violence, and social capital. All data were self-reported and were analyzed using logistic regression. RESULTS: Controlling for gender and age, fear of neighborhood violence was associated with increased odds of having drug dependence (OR = 1.27, CI 1.02, 1.58) and a higher level of social capital prior to incarceration was associated with lower odds of drug dependence (OR = 0.65, CI 0.44, 0.96). Mental health problem diagnosis and past year intimate partner violence were significant mediating factors. Gender and race/ethnicity were significant moderating factors between neighborhood disadvantage and drug dependence. CONCLUSIONS: Our study suggests that drug dependence programs for women and men who cycle between jails and communities require both individual- and community-level interventions. To be most effective, programs at the community-level should focus on helping specific groups navigate their communities, as well as address individual health needs associated with drug dependence.

MicroRNA-1 Inhibits Proliferation of Hepatocarcinoma Cells by Targeting Endothelin-1

AIMS: MicroRNA-1 (miR-1) has been demonstrated as a tumor-suppressive miRNA, which shows a down-regulated pattern in several human malignancies including hepatocellular carcinoma (HCC). However, the pathophysiologic roles of miR-1 and their mechanisms in HCC tumorigenesis are still not totally elucidated. MAIN METHODS: Pre-miR-1 was cloned into pSuper plasmid to overexpress the miR-1 in hepatoma cells. Real-time PCR and Western blot were applied to detect miR-1, ET-1 mRNA and protein levels respectively. Dual luciferase reporter assay was conducted to investigate the binding site of miR-1 on 3'UTR of ET-1 mRNA. Proliferation of hepatoma cells was evaluated by MTT assay. KEY FINDINGS: We observed that over-expression of miR-1 by miRNA-expressing plasmid transfection in HepG2 and Hep3B cells significantly reduced the proliferation of these cells. To explore the mechanism, we examined the potential target genes of miR-1 by bioinformatics. A potent mitogen, Endothelin-1 (ET-1), attracted our attention. Elevated expression of ET-1 but reduced miR-1 level was detected both in human liver cancer tissues and in hepatoma cell lines using Western Blot and miRNA real-time PCR respectively. By the over-expression and inhibition of miR-1 in HepG2 and Hep3B, we confirmed that miR-1 negatively regulated ET-1 expression in hepatoma cells. A luciferase reporter assay showed that miR-1 regulation was established by pairing to a complementary binding site within the ET-1 3'UTR. Finally, attenuated proliferation of hepatoma cells by over-expression of miR-1 could be partially restored by exogenous ET-1 treatment. SIGNIFICANCE: Our findings demonstrate that miR-1 could inhibit ET-1 expression to attenuate the proliferation of hepatoma cells.

MicroRNA-467b Targets LPL Gene in RAW 264.7 Macrophages and Attenuates Lipid Accumulation and Proinflammatory Cytokine Secretion

LPL (lipoprotein lipase) is a rate-limiting enzyme involved in the hydrolysis of triglycerides. Previous studies have shown that microRNA (miR)-467b regulates hepatic LPL expression and plays a role in the progression of steatosis or abnormal lipid retention in obese mice. Macrophage-derived LPL has been shown to promote atherosclerosis. However, if miR-476b influences macrophage LPL expression and the subsequent effects are unknown. Here, we utilized oxLDL-treatment RAW 264.7 macrophages that were transfected with miR-467b mimics or inhibitors to investigate the potential roles of macrophage miR-476b. We found that miR-467b significantly decreased lipid accumulation and IL-6, IL-1β, TNF-α and MCP-1 secretions. Furthermore, our studies suggested an additional explanation for the regulatory mechanism of miR-467b on its functional target, LPL in RAW 264.7 macrophages. Thus, our findings indicate that miR-467b may regulate lipid accumulation and proinflammatory cytokine secretion in oxLDL-stimulated RAW 264.7 macrophages by targeting the LPL gene.

Effect of Antihypertensive Therapy on Ventricular-arterial Mechanics, Coupling, and Efficiency

AimsTo investigate the effect of antihypertensive therapy on ventricular-arterial mechanics, coupling, and efficiency in early-stage hypertension.Methods and resultsWe studied 527 participants from two clinical trials assessing the effect of blood pressure lowering on diastolic function. Participants were aged ≥45 years with early-stage hypertension, no heart failure, ejection fraction (EF) ≥50%, and diastolic dysfunction using Doppler echocardiography. Effective arterial afterload and its components were assessed along with measures of left ventricular (LV) structure and function prior to and after 24-38 weeks of antihypertensive therapy. Systolic blood pressure decreased from 154 ± 18 to 137 ± 15 mmHg at follow-up. Blood pressure reduction was associated with decreases in ventricular and arterial stiffness, improvements in systemic arterial compliance and resistance, enhanced LV ejection, and reduction in cardiac work (all P < 0.001). Changes in Ea/Ees ratio were inversely correlated with those in EF (r = -0.25; P < 0.001), stroke work index (r = -0.13; P = 0.007), and LV efficiency (r = -0.98; P < 0.001); and directly related to changes in mitral E/e' (r = 0.12; P = 0.01). Adjusting for age and blood pressure change, women and obese individuals had less enhancement in ventricular-arterial coupling and efficiency compared with men and non-obese individuals (P = 0.04 and 0.007, respectively).ConclusionAntihypertensive therapy reduces arterial and ventricular stiffness, enhances ventricular-arterial coupling, reduces cardiac work, and improves LV efficiency, systolic, and diastolic function. Attenuated responses in women and among obese subjects suggest that structure-function changes may be less reversible in these groups, possibly explaining their greater susceptibility to ultimately develop heart failure.

Risk Factors Associated with Tuberculosis Infection Among Health Care Workers in Inner Mongolia, China

SETTING: Health care workers (HCWs) are at increased risk for tuberculosis (TB) infection. In China, surveys examining TB infection among HCWs have not studied general health care facilities, compared tuberculin tests conducted using local protocols against an internationally accepted test or characterised risk factors.OBJECTIVE: To measure the prevalence of and risk factors for TB infection among HCWs in Inner Mongolia, China.DESIGN: Between April and August 2010, we administered QuantiFERON(®)-TB Gold In-Tube (QFT-GIT) tests, skin tests using Chinese tuberculin (TST) and surveys among HCWs at an infectious diseases hospital and a general medical hospital. We assessed whether demographic characteristics, personal exposure and work exposure were associated with QFT-GIT and TST positivity, and assessed agreement between test results.RESULTS: Of 999 HCWs, 683 (68%) were QFT-GIT-positive, which was associated with greater age, longer HCW career, TB disease in a co-worker and greater daily patient exposure using multivariable analysis. TST reactions ≥ 5 mm occurred in 69% of the HCWs; agreement between test results was low (κ 0.22).CONCLUSIONS: The prevalence of TB infection among HCWs in Inner Mongolia is high; infection was associated with occupational exposure. Results from locally conducted TST are difficult to interpret. In China, TB infection control in health care facilities should be strengthened.

Electrospinning Preparation and Drug Delivery Properties of Eu(3+)/Tb(3+) Doped Mesoporous Bioactive Glass Nanofibers

Luminescent Eu(3+)/Tb(3+) doped mesoporous bioactive glass nanofibers (MBGNFs) with average diameter of 100-120nm were fabricated by electrospinning method. Pluronic P123 and N-cetyltrimethylammonium bromide (CTAB) were used as co-surfactants to generate porous structure of the nanofibers. N(2) adsorption-desorption measurement reveals that the MBGNF:Eu(3+) have a surface area of 188m(2)g(-1), a pore volume of 0.246cm(3)g(-1) and average pore size of 4.17nm, and the MBGNF:Tb(3+) have a surface area of 171m(2)g(-1), a pore volume of 0.186cm(3)g(-1) and average pore size of 3.65nm. Photoluminescence measurements reveal that the MBGNF:Eu(3+) show strong red emission dominated by the (5)D(0)→(7)F(2) transition of Eu(3+) at 614nm with a lifetime of 1.356ms, and MBGNF:Tb(3+) show strong green emission dominated by the (5)D(4)→(7)F(5) transition of Tb(3+) at 544nm with a lifetime of 1.982ms. The biocompatibility tests on L929 fibroblast cells using MTT assay reveal low cytotoxicity of MBGNF. These luminescent nanofibers show sustained release properties for ibuprofen (IBU) in vitro. The emission intensities of Eu(3+) in the drug delivery system vary with the released amount of IBU, thus making the drug release be easily tracked and monitored by the change of the luminescence intensity.

Epidemiology, Clinical Features, Treatment, and Outcomes of Cases of Influenza a Infection During the 2009 Influenza Pandemic in Northern Taiwan

In April 2009, confirmed cases of influenza A (H1N1) infections were reported worldwide, spreading from Mexico and southern California. In order to determine the clinical features of patients infected with this virus before vaccine implementation and evaluate the response of antiviral treatment in Taiwan, we reviewed medical charts and collected clinical data from outpatients and inpatients at the Tao-Yuan General Hospital.

A Pilot Study on the Relationship Between Thyroid Status and Neuropsychiatric Symptoms in Patients with Alzheimer Disease

Growing evidence links alternation of the thyroid function to the pathogenesis and progression of Alzheimer disease (AD). However, only a few studies evaluate the association between thyroid hormone levels and neuropsychiatric manifestations in patients with AD. This study aimed to investigate the relationship of thyroid hormone levels and neuropsychiatric symptoms in euthyroid patients with AD.

Protein C Polymorphism and Susceptibility to PTE in China

Pulmonary thromboembolism (PTE) is a common clinical problem that is associated with substantial morbidity and mortality. We investigated the role of protein C polymorphism in patients with PTE in order to find out the correlation between its polymorphism and the susceptibility of the Chinese population to develop PTE. We used a case-control study design. Sixty-three consecutive patients with PTE were enrolled as the investigated group and 86 healthy people as the control group. Two novel polymorphisms, C/T at the position of 2405 and A/G at the position of 2418in the protein C gene promoter region were detected through PCR-restriction fragment length polymorphism analysis. The results suggested that the genotype frequencies of the two single-nucleotide polymorphisms (SNPs) when combined together were not significantly different between the case and control group (P > 0.05). However, the allele frequency of the C2405T SNP was significantly different between the case and control group. The frequency of T allele in the PTE group was higher when compared to the control, whereas the frequency of C allele was lower (P < 0.05). These results suggested that there were six different kinds of genotype distribution (TA-TA, TA-CA, TA-CG, CG-CG, CA-CG, CA-CA) and three different kinds of haplotype (TA, CG, CA). Our result showed that the frequency of the TA haplotype was significantly higher in the patients suffering from PTE (P < 0.05). These results suggest that the two polymorphisms present in the control region of the protein C gene are associated with an increased susceptibility to PTE in the Chinese population. The 2405T allele may be a possible risk factor for the development of PTE, whereas the C allele may probably be a protective factor of PTE Moreover, the TA haplotype may also be associated with an increased risk for developing PTE.

Coping With Breast Cancer Survivorship in Chinese Women: The Role of Fatalism or Fatalistic Voluntarism

BACKGROUND:: The existing knowledge on fatalism in the field of cancer has arisen largely from the cancer prevention and screening literature. Little is known about the role of fatalism in cancer survivorship, particularly within Chinese population. OBJECTIVE:: This study aimed to explore the role of fatalism in coping with breast cancer survivorship in Chinese women. METHODS:: In-depth interviews were conducted on 29 participants selected from those who attended a local cancer self-help organization in China. Interview transcripts were transcribed and analyzed using qualitative content analysis. RESULTS:: Although they actively engaged in emotional regulation and self-care management to cope with survivorship, participants believed in fatalism and accepted their inability to change the final outcome of cancer. Such contradictory behavioral and cognitive aspects of coping reported by participants highlighted the role of a complex belief system involving Ming in positively influencing the interpretation of fatalism and the actual coping efforts taken. CONCLUSIONS:: Findings suggest that fatalism related to coping in the Chinese context combined 2 elements: fatalistic belief in and acceptance of the way things are as well as the exertion of personal efforts over the situation. As such, it seems more effectively depicted in terms of the emerging concept "fatalistic voluntarism." IMPLICATIONS FOR PRACTICE:: When planning intervention for Chinese population, incorporating fatalistic voluntarism as a cognitive belief system in the process of adaptation to survivorship may be more culturally relevant for facilitating their coping behaviors.

The Single Nucleotide Polymorphisms in BRAP Decrease the Risk of Metabolic Syndrome in a Chinese Young Adult Population

The single nucleotide polymorphisms (SNPs) in the gene of breast cancer suppressor protein (BRCA1)-associated protein (BRAP) are significantly associated with coronary artery disease, but the molecular mechanisms are not understood. We examined the associations of the SNPs (rs11066001 and rs3782886) in BRAP with metabolic syndrome (MetS), which is a strong predictor of cardiovascular disease, and potential associations between these SNPs and factors related to inflammation. There were significant associations of both the SNPs with MetS [rs11066001, odds ratio (OR) 0.70, 95% confidence interval (CI) 0.51-0.96, p = 0.028; rs3782886, OR 0.69, 95% CI 0.50-0.94, p = 0.020] under a dominant model after age and gender adjustment. Both SNPs were significantly associated with waist circumference, plasma glucose, glycated haemoglobin, triglycerides and nonesterified fatty acid. Our data provide evidence that the SNPs (rs11066001 and rs3782886) in BRAP decrease the risk of MetS, and associations of the SNPs with various components of MetS are different. Moreover, there are significant associations of both the SNPs with nonesterified fatty acid that could be involved in the inflammatory activity of electronegative low-density lipoprotein.

A Critical Role for P-Rex1 in Endothelial Junction Disruption and Vascular Hyper-Permeability

Rationale: The small GTPase Rac is critical to vascular endothelial functions, yet its regulation in endothelial cells remains unclear. Understanding the upstream pathway may delineate Rac activation mechanisms and its role in maintaining vascular endothelial barrier integrity. Objective: By investigating P-Rex1, one of the Rac-specific guanine nucleotide exchange factors (GEFs) previously known for G protein-coupled receptor (GPCR) signaling, we sought to determine whether Rac-GEF is a nodal for signal integration and potential target for drug intervention. Methods and Results: Using gene deletion and siRNA silencing approach, we investigated the role of P-Rex1 in lung microvascular endothelial cells (HLMVECs). TNF-α exposure led to disruption of endothelial junctions, and silencing P-Rex1 protected junction integrity. TNF-α stimulated Rac activation and ROS production in a P-Rex1-dependent manner. Removal of P-Rex1 significantly reduced ICAM-1 expression, PMN transendothelial migration and leukocyte sequestration in TNF-α challenged mouse lungs. The P-Rex1 knockout mice were also refractory to lung vascular hyper-permeability and edema in a LPS-induced sepsis model. Conclusions: These results demonstrate for the first time that P-Rex1 expressed in endothelial cells is activated downstream of TNF-α, which is not a GPCR agonist. Our data identify P-Rex1 as a critical mediator of vascular barrier disruption. Targeting P-Rex1 may effectively protect against TNF-α; and LPS-induced endothelial junction disruption and vascular hyper-permeability.

The Prevalence of Visual Impairment in Older Adults in Mainland China: A Systematic Review and Meta-Analysis

Purpose: This paper presents estimates of the prevalence of blindness and low vision among older adults over 50 years of age in mainland China. Methods: All primary reports of population-based studies that reported the prevalence or incidence of visual impairment among older populations in mainland China were identified. Twenty-four population-based studies were included in this systematic review. Blindness is defined as visual acuity of less than 3/60, or a corresponding visual-field loss to less than 10 degrees in the better eye with the best possible correction; low vision is defined as visual acuity of less than 6/18, but equal to or better than 3/60 in the better eye with the best possible correction. The pooled prevalence estimates of blindness and low vision were calculated assuming a random-effects model. Relative odds with 95% confidence intervals (95% CIs) were calculated, stratified by methodological and socioeconomic variables. Results: The overall pooled prevalence of blindness was 1.7% (95% CI 1.4-2.1). The results of the meta-regression showed the significance of a predictor variable: geographic region. The blindness rates per 100 older adults in various regions were 1.4 (0.9-2.0) in East China, and 1.4 (1.0-2.0) in Central China and 2.5 (1.9-3.2) in Western China. The overall pooled prevalence of low vision was 4.1% (3.4-5.1) and the independent pooled prevalence rates stratified by geographic region were 3.6% (2.6-5.1) in East China, 3.6% (2.4-5.2) in Central China and 5.2% (3.6-7.4) in Western China. Conclusions: Blindness or low vision affects approximately 5.8% Chinese adults older than 50 years. The prevalence of visual impairment, and especially blindness, vary greatly by the developmental status of geographic region.

Intralesional Steroid Injection for Benign Vocal Fold Disorders: A Systematic Review and Meta-analysis

OBJECTIVE: Emerging literature had documented the potential usefulness of vocal fold steroid injection (VFSI) as an alternative treatment option for benign vocal lesions. This study aims to conduct a qualitative synthesis and quantitative meta-analysis of vocal fold steroid injection STUDY DESIGN: Systematic review and meta-analysis. METHODS: Electronic databases were searched using relevant keywords. Extracted data include author, year of publication, diagnosis, steroid regimen, recurrence and side effects. Reported treatment outcomes were clustered into five categories, i.e. subjective, perceptual, acoustic, aerodynamic, and stroboscopic. Meta-analyses were performed on studies with numerical results using random effects model. RESULTS: Six articles were identified with a total of 321 patients. All the studies reported significant improvements after VFSI in each category of outcome measurements. Proposed indications for VFSI include vocal nodules, polyp/cyst, Reinke's edema, and scar. Meta-analysis demonstrated a significant increase in maximal phonation time after VFSI by 1.82 seconds (p<0.001, 95% confidence interval (CI): 0.29 ≈ 3.35) and a 27.61 points decrease in voice handicap index (p<0.001, 95% CI: 16.49 ≈ 38.73). Adverse effects include local hematoma, whitish deposition of triamcinolone, and mild vocal fold atrophy, which resolve spontaneously within 1 to 2 months. The recurrence rate after VFSI was between 4% and 31%. CONCLUSIONS: VFSI is well-tolerated under local anesthesia in the office setting. The invasiveness and morbidity of VFSI are low and the side effects are self-limited. Meta-analyses demonstrated significant improvements from both objective and subjective measurements. Further controlled studies with longer follow-up periods may evaluate the effectiveness of VFSI more reliably. Laryngoscope, 2012.

Evaluation of New Bone Formation in Normal and Osteoporotic Rats with a 3-mm Femur Defect: Functional Assessment with Dynamic PET-CT (dPET-CT) Using 2-Deoxy-2-[(18)F]Fluoro-D-glucose ( (18)F-FDG) and (18)F-Fluoride

PURPOSE: The aim of the current study was to assess the formation of new bone in a 3-mm created defect in the femur and its adjacent bone tissue in osteoporotic and normal animals. The assessment is based on bone remodeling and glucose metabolism in a rat model with a 3-mm created defct in the femur using (18)F-fluoride and 2-deoxy-2-[(18)F]fluoro-D-glucose ((18)F-FDG) as tracers for dynamic PET-CT (dPET-CT). The (18)F-fluoride PET data were compared with those of (18)F-FDG. PROCEDURES: Osteoporosis was induced by ovariectomy and a calcium restricted diet in each rat (n = 7). Alternatively, a sham operation was performed in the control group (n = 8). After 3 months, all rats were operated to create a 3-mm defect using an oscillating saw in the distal metaphyseal femur, which was internally fixed with a metal plate. Eighteen weeks after osteoporosis induction and 6 weeks following femoral surgery, dPET-CT studies scan were performed with (18)F-FDG and (18)F-fluoride. Following PET data acquisition, standardized uptake values (SUVs) were calculated from the tracer concentration values. Then, a two-tissue compartmental learning-machine model was applied to the data for the calculation of the compartment parameters (K1-k4, VB, Ki). Furthermore, a non-compartmental model based on the fractal dimension was applied for quantitative analysis of both groups and both tracers. Finally, multivariate analysis was performed for the statistical analysis of the kinetic data. RESULTS: The values for K1 and Ki were higher in the osteoporotic rats than in the control group. Ki and K1 of (18)F-fluoride in the adjacent bone tissue differ significantly based on the Wilcoxon rank-sum test for the osteoporotic and control group (p < 0.05). The sensitivity and the negative predictive value (NPV) based on linear discriminant analysis was high with a value of 100 % for both tracers and both evaluated regions (defect and adjacent bone tissue) when comparing control and osteoporotic rats. The overall accuracy with (18)F-FDG was generally higher than that with (18)F-fluoride for both evaluated regions for the control and osteoporotic rats based on a multiparameter evaluation. CONCLUSION: In this study, the changes in tracer kinetics accurately discriminated differences in the created defect in the femur and its adjacent bone tissue between osteoporotic and control rats.

Dual-bioactivity-based Liquid Chromatography-coupled Quadrupole Time-of-flight Mass Spectrometry for NF-κB Inhibitors and β(2)AR Agonists Identification in Chinese Medicinal Preparation Qingfei Xiaoyan Wan

Traditional Chinese medicine (TCM) preparations have been used as an effective multitarget strategy for the treatment of complex diseases; however, their bioactive constituents are undefined and difficult to identify. In this study, a simple and dual-target method based on ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry combined with dual-bioactive (NF-κB and β(2)-adrenergic receptor) luciferase reporter assay systems was developed for the rapid determination of various bioactive compounds of TCM preparations. Qingfei Xiaoyan Wan, a TCM preparation used for the clinical therapy of asthma, was analyzed with this method. Potential anti-inflammatory and spasmolytic constituents were screened using NF-κB and β(2)-adrenergic receptor activity luciferase reporter assay systems and simultaneously identified according to the time-of-flight mass spectrometry data. One β(2)-adrenergic receptor agonist (ephedrine) and four structural types of NF-κB inhibitors (arctigenin derivatives, cholic acid derivatives, chlorogenic acid, and sinapic acid) were characterized. Tracheloside was considered a new NF-κB inhibitor. Further cytokine and chemokine detection confirmed the anti-inflammatory effects of the potential NF-κB inhibitors. The integration of ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry and dual-bioactive human cell functional evaluation systems proved to be a simple and effective strategy for the rapid screening of various bioactive compounds in TCM preparations used to treat complex diseases.

Intima-medial Thickness Homogeneity in the Common Carotid Artery: Measurement Method and Preliminary Clinical Study

BACKGROUND.: To propose and test in a preliminary clinical study a novel method for calculating intima-medial thickness (IMT) homogeneity (IMTH). METHODS.: IMT was measured off-line on every horizontal pixel line along the far wall of the common carotid artery, with previously validated software. IMTH was assessed by the SD, coefficient of variation, and interval distribution of obtained IMT values. This method was applied to 129 individuals (age, 40-60 years), including 49 healthy control subjects, 44 subjects at high risk of atherosclerosis, and 36 subjects with known atherosclerosis. Differences with a p value <0.05 were considered statistically significant. RESULTS.: SD and coefficient of variation were higher in the high-risk than in the control group, as well as in high-risk and control subgroups with maximal IMT = 0.8 mm or mean IMT = 0.55-0.65 mm. There were 85.7, 62.8, and 36% of IMT values in the 0.4- to 0.6-mm range and 0.89, 13.8, and 21.2% of IMT values in the 0.8- to 1.2-mm range in the control, high-risk, and atherosclerosis groups, respectively. CONCLUSIONS.: IMTH is a promising approach for the assessment of atherosclerosis, in addition to conventional IMT measurement. Further clinical studies are needed to assess its clinical usefulness. © 2012 Wiley Periodicals, Inc. J Clin Ultrasound, 2012.

Theoretical Studies of the Asymmetric Binary-Acid-Catalyzed Tert-Aminocyclization Reaction: Origins of the C sp 3H Activation and Stereoselectivity

A mechanistic study of the tert-aminocyclization reaction was performed by using DFT calculations and labeling experiments. The results showed that the reaction proceeded through a rate-limiting-, stereospecific-, and suprafacial 1,5-H-transfer pathway, followed by a barrier-less CC bond formation. The mode of stereocontrol for facial selection could be ruled out owing to the high activation energy of CN bond rotation. The intrinsic feature of this Lewis acid activation was found to be the activation of the LUMO, as well as an intermediate-stabilization effect. The catalytically active species was believed to be a 1:1 complex of phosphoric acid and MgCl(2) , which was stabilized by a H⋅⋅⋅Cl hydrogen bond. The chiral catalytic complex selectively recognizes and activates one of the two helical conformations of substrate A, required for 1,5-suprafacial H-transfer, which dictates the stereoselectivity of the forming products.

Cediranib Plus FOLFOX/CAPOX Versus Placebo Plus FOLFOX/CAPOX in Patients With Previously Untreated Metastatic Colorectal Cancer: A Randomized, Double-Blind, Phase III Study (HORIZON II)

PURPOSECediranib is a highly potent inhibitor of vascular endothelial growth factor (VEGF) signaling with activity against all three VEGF receptors. HORIZON II [Cediranib (AZD2171, RECENTIN) in Addition to Chemotherapy Versus Placebo Plus Chemotherapy in Patients With Untreated Metastatic Colorectal Cancer] assessed infusional fluorouracil, leucovorin, and oxaliplatin/capecitabine and oxaliplatin (FOLFOX/CAPOX) with or without cediranib in patients with previously untreated metastatic colorectal cancer (mCRC).Patients And methodsEligible patients were initially randomly assigned 1:1:1 to receive cediranib (20 or 30 mg per day) or placebo plus FOLFOX/CAPOX. In an early analysis of this and two other cediranib studies (HORIZON I [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Previously Treated Metastatic Colorectal Cancer] and HORIZON III [Cediranib Plus FOLFOX6 Versus Bevacizumab Plus FOLFOX6 in Patients With Untreated Metastatic Colorectal Cancer]), the 20-mg dose met the predefined criteria for continuation. Subsequent patients were randomly assigned 2:1 to the cediranib 20 mg or placebo arms. Progression-free survival (PFS) and overall survival (OS) were coprimary end points.ResultsIn all, 860 patients received cediranib 20 mg (n = 502) or placebo (n = 358). The addition of cediranib to FOLFOX/CAPOX resulted in PFS prolongation (hazard ratio [HR], 0.84; 95% CI, 0.73 to 0.98; P = .0121; median PFS, 8.6 months for cediranib v 8.3 months for placebo) but had no impact on OS (HR, 0.94; 95% CI, 0.79 to 1.12; P = .5707; median OS, 19.7 months for cediranib v 18.9 months for placebo). There were no significant differences in the secondary end points of objective response rate, duration of response, or liver resection rate. Median chemotherapy dose-intensity was decreased by approximately 10% in patients treated with cediranib. Adverse events (AEs) associated with cediranib were manageable. CONCLUSIONAddition of cediranib 20 mg to FOLFOX/CAPOX resulted in a modest PFS prolongation, but no significant difference in OS. The cediranib AE profile was consistent with those from previous studies. Because of the lack of improvement in OS, cediranib plus an oxaliplatin-based regimen cannot be recommended as a treatment for patients with mCRC.

Complete Genome Sequence of a Monosense Densovirus Infecting the Cotton Bollworm, Helicoverpa Armigera

Densoviruses (DNVs) infecting arthropods are members of the family Parvoviridae. Here we report the complete genome sequence of a novel DNV with a monosense genome that infects cotton bollworms (Helicoverpa armigera), named HaDNV-1. Alignment and phylogenetic analysis revealed that HaDNV-1 showed high identity with the genus Iteravirus.

Complete Genome Sequence of Avian Tembusu-Related Virus Strain WR Isolated from White Kaiya Ducks in Fujian, China

Avian tembusu-related virus, which was first identified in China, is an emerging virus causing serious economic loss to the Chinese poultry industry. We report here the complete genome sequences of avian tembusu-related virus strain WR, isolated from a White Kaiya duck with disease characterized by an abrupt decrease in egg laying with ovarian hemorrhage, which will help in further understanding the molecular and evolutionary characteristics and pathogenesis of avian tembusu-related virus, the new flavivirus affecting ducks in Southern China.

Examining the Factors Associated with Paid Employment of Clients Enrolled in First Episode of Psychosis Programs

Schizophrenia is one of the most debilitating mental disorders. For a significant portion of individuals who suffer from this disorder, onset occurs in young adulthood, arresting important social and educational development that is necessary for future successful labor force participation. The purpose of this paper is to contribute to the literature about clients enrolled in first episode psychosis programs and psychosocial outcomes by examining the factors associated with paid employment among young adults who have experienced their first psychotic episodes. In this paper, we consider the association of socioeconomic factors to employment. Our results suggest that in addition to treatment, socioeconomic factors such as receipt of public disability benefits and educational attainment are associated with employment status. These results can help to inform future directions for the enhancement of psychosocial programs in FEP models to promote paid employment.

Guidelines for the Use and Interpretation of Assays for Monitoring Autophagy

In 2008 we published the first set of guidelines for standardizing research in autophagy. Since then, research on this topic has continued to accelerate, and many new scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Accordingly, it is important to update these guidelines for monitoring autophagy in different organisms. Various reviews have described the range of assays that have been used for this purpose. Nevertheless, there continues to be confusion regarding acceptable methods to measure autophagy, especially in multicellular eukaryotes. A key point that needs to be emphasized is that there is a difference between measurements that monitor the numbers or volume of autophagic elements (e.g., autophagosomes or autolysosomes) at any stage of the autophagic process vs. those that measure flux through the autophagy pathway (i.e., the complete process); thus, a block in macroautophagy that results in autophagosome accumulation needs to be differentiated from stimuli that result in increased autophagic activity, defined as increased autophagy induction coupled with increased delivery to, and degradation within, lysosomes (in most higher eukaryotes and some protists such as Dictyostelium) or the vacuole (in plants and fungi). In other words, it is especially important that investigators new to the field understand that the appearance of more autophagosomes does not necessarily equate with more autophagy. In fact, in many cases, autophagosomes accumulate because of a block in trafficking to lysosomes without a concomitant change in autophagosome biogenesis, whereas an increase in autolysosomes may reflect a reduction in degradative activity. Here, we present a set of guidelines for the selection and interpretation of methods for use by investigators who aim to examine macroautophagy and related processes, as well as for reviewers who need to provide realistic and reasonable critiques of papers that are focused on these processes. These guidelines are not meant to be a formulaic set of rules, because the appropriate assays depend in part on the question being asked and the system being used. In addition, we emphasize that no individual assay is guaranteed to be the most appropriate one in every situation, and we strongly recommend the use of multiple assays to monitor autophagy. In these guidelines, we consider these various methods of assessing autophagy and what information can, or cannot, be obtained from them. Finally, by discussing the merits and limits of particular autophagy assays, we hope to encourage technical innovation in the field.

A Novel Polysilicon Field-enhanced Nanowire Thin-film Transistor with the TiN-hafnia-nitride-vacuum-silicon (THNVAS) Structure for Nonvolatile Memory Applications

A novel poly-Si field-enhanced nanowire (FEN) TFT memory with the TiN-hafnia-nitride-vacuum-silicon (THNVAS) structure fabricated simply via a sidewall spacer formation has been presented. The THNVAS devices with superior memory performance were demonstrated by introducing the hafnia as blocking oxide and the vacuum, the lowest-k in nature, as tunneling layer. According to the simulation results, the memory device with oxide/nitride/vacuum gate dielectric exhibited a higher local electric-field of 4.72 x 10(7) V/cm as compared to 2.55 x 10(7) V/cm for the conventional oxide/nitride/oxide counterpart. In addition, the electric-field of tunneling layer could be further increased to 7.06 x 10(7) V/cm while the blocking oxide was substituted for hafnia. The experimental data showed that THNVAS possessed a greater threshold voltage shift of 3.75 V in 10 ms at V(GS) = 12 V, whereas the shift only 2.5 V for THNOS ones. These considerable improvements for THNVAS devices could be attributed to the evident field enhancement across the vacuum tunneling layer. Furthermore, owing to the empty feature of vacuum tunneling layer, the THNVAS demonstrated much-improved endurance performance and preferable data retention property. Hence, such excellent characteristics of THNVAS will be an attractive nonvolatile memory for future system-on-panel and 3-D Flash applications.

High-performance Bottom-gate Poly-Si Polysilicon-oxide-nitride-oxide-silicon Thin Film Transistors Crystallized by Excimer Laser Irradiation for Two-bit Nonvolatile Memory Applications

High-performance bottom-gate (BG) poly-Si polysilicon-oxide-nitride-oxide-silicon (SONOS) TFTs with single grain boundary perpendicular to the channel direction have been demonstrated via simple excimer-laser-crystallization (ELC) method. Under an appropriate laser irradiation energy density, the silicon grain growth started from the thicker sidewalls intrinsically caused by the bottom-gate structure and impinged in the center of the channel. Therefore, the proposed ELC BG SONOS TFTs exhibited superior transistor characteristics than the conventional solid-phase-crystallized ones, such as higher field effect mobility of 393 cm2/V-s and steeper subthreshold swing of 0.296 V/dec. Due to the high field effect mobility, the electron velocity, impact ionization, and conduction current density could be enhanced effectively, thus improving the memory performance. Based on this mobility-enhanced scheme, the proposed ELC BG SONOS TFTs exhibited better performance in terms of relatively large memory window, high program/erase speed, long retention time, and 2-bit operation. Such an ELC BG SONOS TFT with single-grain boundary in the channel is compatible with the conventional a-Si TFT process and therefore very promising for the embedded memory in the system-on-panel applications.

The PH Sensing Characteristics of the Extended-gate Field-effect Transistors of Multi-walled Carbon-nanotube Thin Film Using Low-temperature Ultrasonic Spray Method

A novel, simple and low-temperature ultrasonic spray method was developed to fabricate the multi-walled carbon-nanotubes (MWCNTs) based extended-gate field-effect transistors (EGFETs) as the pH sensor. With an acid-treated process, the chemically functionalized two-dimensional MWCNT network could provide plenty of functional groups which exhibit hydrophilic property and serve as hydrogen sensing sites. For the first time, the EGFET using a MWCNT structure could achieve a wide sensing rage from pH = 1 to pH = 13. Furthermore, the pH sensitivity and linearity values of the CNT pH-EGFET devices were enhanced to 51.74 mV/pH and 0.9948 from pH = 1 to pH = 13 while the sprayed deposition reached 50 times. The sensing properties of hydrogen and hydroxyl ions show significantly dependent on the sprayed deposition times, morphologies, crystalline and chemical bonding of acid-treated MWCNT. These results demonstrate that the MWCNT-EGFETs are very promising for the applications in the pH and biomedical sensors.

High-performance Polycrystalline Silicon Thin-film Transistors with Two-dimensional Location Control of the Grain Boundary Via Excimer Laser Crystallization

High-performance low-temperature polycrystalline silicon (Poly-Si) thin-film transistors (TFTs) have been fabricated with two-dimensional (2-D) location-controlled grain boundaries using excimer laser crystallization (ELC). By locally increased thickness of the amorphous silicon (a-Si) film that was served as the seed crystals with a partial-melting crystallization scheme, the cross-shaped grain boundary structures were produced between the thicker a-Si grids. The Poly-Si TFTs with one parallel and one perpendicular grain boundary along the channel direction could therefore be fabricated to reach excellent field-effect mobility of 530 cm2/V-s while the conventional ones exhibited field-effect mobility of 198 cm2/V-s. Furthermore, the proposed TFTs achieved not only superior electric properties but also improved uniformity as compared with the conventional ones owing to the artificially controlled locations of grain boundaries.

Effect of the Annealing Ambient on the Electrical Characteristics of the Amorphous InGaZnO Thin Film Transistors

The influence of the thermal annealing on the amorphous indium gallium zinc oxide (a-IGZO) thin-film transistors (TFTs) under different ambient gases has been systematically addressed. The chemical bonding states and transfer characteristics of a-IGZO TFTs show evident dependence on the annealing ambient gas. For the a-IGZO TFTs in the oxygen ambient annealing at 250 degrees C for 30 mins exhibited a maximum field effect mobility (max muFE) of 9.36 cm2/V x s, on/off current ratio of 6.12 x 10(10), and a subthreshold slope (SS) of 0.21 V/decade. Respectively, the as-deposited ones without annealing possess a max muFE of 6.61 cm2/V x s, on/off current ratio of 4.58 x 10(8), and a SS of 0.46 V/decade. In contrast, the a-IGZO TFTs annealed at 250 degrees C for 30 mins in the nitrogen ambient would be degraded to have a max muFE of 0.18 cm2/V x s, on/off current ratio of 2.22 x 10(4), and a SS of 7.37 V/decade, corresponding. It is attributed to the content of the oxygen vacancies, according the x-ray photoelectron spectroscopy (XPS) analyze of the three different samples.

Field Emission Properties of Carbon Nanotube Arrays on the Thickness-controlled Flexible Substrate by the Pattern Transfer Process

A technigal with the polydimethylsiloxane (PDMS) solution infiltrated into the SiOx-coated CNTAs has been utilized to directly transfer the CNTAs away from the silicon substrate. The oxide coating layer was utilized to protect the morpholgy of as-grown patterned vertical aligmed carbon nanotube (CNTs) arrays. The high density plasma reactive ions etching (HDP-RIE) system was used to make the CNTs emerge from the surface of the flexible substrate and modify the crystallines of CNTs. After the protecting oxide was HDP-RIE-processed for 8 min, the emission current properties were enhanced to be 1.03 V/microm and 1.43 V/microm, respectively, for the turn-on field and the threshold field, as compared with 1.25 V/microm and 1.59 V/microm for the as-grown CNTs, accordingly. The Field Emission (FE) enhancement after dry etching could be attributed to the open-ended structures and better crystalline.

High-performance ZnO Thin-film Transistors with Location-controlled Crystal Grains Fabricated by Low-temperature Hydrothermal Method

In this paper, high-performance bottom-gate (BG) thin-film transistors (TFTs) with zinc oxide (ZnO) artificially location-controlled lateral grain growth have been prepared via low-temperature hydrothermal method. For the proper design of source/drain structure of ZnO/Ti/Pt thin films, the grains can be laterally grown from the under-cut ZnO beneath the Ti/Pt layer. Consequently, the single one vertical grain boundary perpendicular to the current flow will be produced in the channel region as the grown grains from the source/drain both sides are impinged. As compared with the conventional sputtered ZnO BG-TFTs, the proposed location-controlled hydrothermal ZnO BG-TFTs (W/L = 250 microm/10 microm) demonstrated the higher field-effect mobility of 6.09 cm2/V x s, lower threshold voltage of 3.67 V, higher on/off current ratio above 10(6), and superior current drivability, reflecting the high-quality ZnO thin films with less grain boundary effect in the channel region.

Hispolon Attenuates Balloon-Injured Neointimal Formation and Modulates Vascular Smooth Muscle Cell Migration Via AKT and ERK Phosphorylation

The pathological mechanism of restenosis is attributed primarily to excessive proliferation and migration of vascular smooth muscle cells (VSMC). The preventive effects of hispolon (1) on balloon injury-induced neointimal formation were investigated, and 1 showed potent activity in inhibiting fetal bovine serum-induced VSMC outgrowth. Hispolon (1) significantly inhibited VSMC migration, as shown by trans-well assays. Compound 1 decreased the expression and secretion of matrix metalloproteinase-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9). The expression of the endogenous inhibitors of these proteins, namely, tissue inhibitors of MMP (TIMP-1 and TIMP-2), increased. The inhibition by noncytotoxic doses of 1 of VSMC migration was through its negative regulatory effects on FAK phosphorylation, ERK1/2 phosphorylation, and PI3K/AKT. These results demonstrate that 1 can inhibit the migration of VSMC by reduced expression of MMP-9 through the suppression of the FAK signaling pathway and of the activity of PI3K/AKT. The data obtained suggest that 1 might block balloon injury-induced neointimal hyperplasia via the inhibition of VSMC proliferation and migration, without inducing apoptosis.

[A Case-control Study on Risk Factors That Associated with Severe Hand-foot-mouth Disease in Shanghai]

To explore the factors associated with severe hand-food-mouth disease (HFMD) case in Shanghai.

[Clinical Significance of the Wilms' Tumor 1 MRNA Expression in Childhood Myelodysplastic Syndrome]

To investigate the expression of the Wilms' tumor 1 (WT1) mRNA in childhood myelodysplastic syndrome (MDS), and to evaluate WT1 as a tool to differentiate MDS from aplastic anemia(AA).

[Preliminary Experience of Clinical Applications of the 7th UICC-AJCC TNM Staging System of Esophageal Carcinoma]

To compare the instructive value of the 6th and 7th editions of the UICC-AJCC staging system in prognosis of esophageal cancer (EC) patients.

[Surgical Treatment of Sternal Tumors: Resection of the Tumors and Reconstruction of the Chest Wall Defects]

To investigate the efficacy of surgical treatment of sternal tumors and repairing methods of the chest wall defects.

Design, Synthesis and Evaluation of Novel Metalloproteinase Inhibitors Based on L-tyrosine Scaffold

A series of novel l-tyrosine derivatives were designed, synthesized and assayed for their inhibitory activities on matrix metalloproteinase 2 (MMP-2) and histone deacetylase 8 (HDAC-8). The results showed that these l-tyrosine derivatives exhibited inhibitory profiles against MMP-2 and HDAC-8. The compounds 6h (IC(50)=0.013±0.001μM) and 6j (IC(50)=0.017±0.001μM) were equal potent MMP-2 inhibitors to the positive control NNGH (IC(50)=0.014±0.001μM). As for HDAC-8 inhibition, some of the hydroxamate compounds, such as 6d (IC(50)=3.6±0.2μM) and 6c (IC(50)=5.8±0.5μM), were equal potent to the positive control SAHA (IC(50)=1.6±0.1μM). Structure-activity relationships were also briefly discussed.

Short-Term Topical Bevacizumab in the Treatment of Stable Corneal Neovascularization

PURPOSE: To evaluate the safety and efficacy of topical bevacizumab in the treatment of corneal neovascularization. DESIGN: Prospective, nonrandomized, interventional case series. METHODS: Setting: Institutional, multicenter clinical trial. Study population: Twenty eyes from 20 patients with stable corneal neovascularization. Intervention procedures: Patients were treated with topical 1.0% bevacizumab for 3 weeks and were monitored for a total of 24 weeks. Main outcome measures: Primary outcome measures included: neovascular area, defined as the area of the corneal vessels themselves; vessel caliber, defined as the mean corneal vessel diameter; and invasion area, defined as the fraction of the total cornea into which the vessels extended. The occurrence of ocular and systemic adverse events was monitored closely. RESULTS: As compared with the baseline visit, patients exhibited a statistically significant improvement in neovascular area by week 6 (P = .007) and in vessel caliber by week 12 (P = .006). At the final visit, neovascular area, vessel caliber, and invasion area were reduced by 47.5%, 36.2%, and 20%, respectively. The decreases in neovascular area and vessel caliber were statistically significant (P < .001 and P = .003, respectively); however, the reduction in invasion area did not reach statistical significance (P = .06). There were no significant changes in the secondary outcomes, and there were no adverse events. CONCLUSIONS: Short-term topical bevacizumab treatment reduced the extent of stable corneal neovascularization as measured by neovascular area and vessel caliber with no associated adverse events. Interestingly, the degree of treatment efficacy was inversely proportional to the baseline invasion area.

[Study on the Infectious Risk Model of AIDS Among Men Who Have Sex with Men in Guangzhou]

To develop a human immune deficiency virus (HIV) infection risk appraisal model suitable for men who has sex with men (MSM) in Guangzhou, and to provide tools for follow-up the outcomes on health education and behavior intervention.

Lc3 Transgene Improves Survival and Attenuates Lung Injury Through Increasing Autophagosomal Clearance in Septic Mice

OBJECTIVE:: To clarify the role of autophagy in sepsis-induced lung injury. BACKGROUND:: The role of autophagy as a protective or maladaptive response in lung cells during sepsis has not yet been determined. The lack of specificity of the autophagic process has driven the development of new approaches that assessautophagosomes from formation to fusion with lysosomes. METHODS:: Sepsis was induced by cecal ligation and puncture (CLP). The autophagic process was manipulated using the pharmacological inhibitors of the autophagy pathway. Green fluorescent protein (GFP)-microtubule-associated protein 1 light chain 3 (LC3) transgenic mice were further used to determine the role of autophagy. RESULTS:: The formation of autophagosomal protein LC3-II progressively accumulated in the lungs over 24 hours after CLP, with the Lc3 gene expression returning to baseline levels at 24 hours. Autophagosome-lysosome fusion, however, gradually decreased from 8 to 24 hours after CLP, suggesting impaired clearance of autophagosomes rather than upregulation of autophagy in the septic lung. In contrast, transgenic mice overexpressing the Lc3 gene exhibited increased clearance of autophagosomes and improved survival after CLP. This protective effect was also seen in decreased cell death, inflammatory responses, neutrophil accumulation, albumin leakage, and edema formation. However, blockade of autophagosome-lysosome fusion with bafilomycin A1 abolished the protective effects in transgenic mice. This indicates that Lc3 transgene attenuates lung injury/inflammation in sepsis, possibly through increasing the clearance of autophagosomes. CONCLUSIONS:: Autophagy in the septic lung represents a protective response. However, autophagy, by virtue of excessive autophagosome accumulation, may play a maladaptive role in the late stage of sepsis, leading to acute lung injury.

Role of P2X7 Receptor-Mediated IL-18/IL-18R Signaling in Morphine Tolerance: Multiple Glial-Neuronal Dialogues in the Rat Spinal Cord

The glial function in morphine tolerance has been explored, but its mechanisms remain unclear. Our previous study has showed that microglia-expressed P2X7 receptors (P2X7R) contribute to the induction of tolerance to morphine analgesia in rats. This study further explored the potential downstream mechanisms of P2X7R underlying morphine tolerance. The results revealed that the blockade of P2X7 receptor by P2X7R antagonist or targeting small interfering RNA (siRNA) reduced tolerance to morphine analgesia in the pain behavioral test and spinal extracellular recordings in vivo and whole-cell recording of the spinal cord slice in vitro. Chronic morphine treatment induced an increase in the expression of interleukin (IL)-18 by microglia, IL-18 receptor (IL-18R) by astrocytes, and protein kinase Cγ (PKCγ) by neurons in the spinal dorsal horn, respectively, which was blocked by a P2X7R antagonist or targeting siRNA. Chronic morphine treatment also induced an increased release of D-serine from the spinal astrocytes. Further, both D-amino acid oxygenase (DAAO), a degrading enzyme of D-serine, and bisindolylmaleimide α (BIM), a PKC inhibitor, attenuated morphine tolerance. The present study demonstrated a spinal mechanism underlying morphine tolerance, in which chronic morphine triggered multiple dialogues between glial and neuronal cells in the spinal cord via a cascade involving a P2X7R-IL-18-D-serine-N-methyl-D-aspartate receptor (NMDAR)-PKCγ-mediated signaling pathway. PERSPECTIVE: The present study shows that glia-neuron interaction via a cascade (P2X7R-IL-18-D-serine-NMDAR-PKCγ) in the spinal cord plays an important role in morphine tolerance. This article may represent potential new therapeutic targets for preventing morphine analgesic tolerance in clinical management of chronic pain.

A Highly Sensitive Method for Molecular Diagnosis of Fungal Keratitis: A Dot Hybridization Assay

PURPOSE: Fungal keratitis (FK) is an important cause of ocular morbidity, especially for people living in the agricultural communities of the developing world. Current diagnostic methods may lack sensitivity (direct microscopy) or are time consuming (culture). The aim of this study was to develop a dot hybridization assay for sensitive and rapid diagnosis of FK. DESIGN: Evaluation of diagnostic test or technology. PARTICIPANTS AND CONTROLS: Fifty corneal scrapes (49 patients) from consecutive cases of clinically suspected microbial keratitis were analyzed prospectively. METHODS: Molecular detection of fungi in the scrapes was performed by amplification of the internal transcribed spacer region (ITS) that contained the target gene (5.8S rRNA gene) by polymerase chain reaction (PCR), followed by hybridization of the PCR product to a fungus-specific oligonucleotide probe immobilized on a nylon membrane. The results were compared with those obtained by gram-stain microscopy, culture, and gel electrophoresis of the PCR products. Discrepant results were resolved by cloning and resequencing of the amplified ITS fragments. MAIN OUTCOME MEASURES: Performance of the dot hybridization assay, including sensitivity, specificity, and positive and negative predictive values, was evaluated. RESULTS: Ten scrapes demonstrated positive results by both the dot hybridization assay and culture. However, 11 scrapes demonstrated positive results by the dot hybridization assay, but demonstrated negative results by culture, and 10 of the 11 samples were considered to be positive for FK by cloning and resequencing of the amplified ITS fragment and by a pathologic examination or clinical course review. The sensitivities for diagnosis of FK by the dot hybridization assay and culture were 100% and 50%, respectively, whereas the specificities were 96.7% and 100%, respectively. CONCLUSIONS: The dot hybridization assay is a highly sensitive and specific diagnostic tool for FK. The method provides a much higher sensitivity than that of culture (100% vs. 50%; P<0.001). The hybridization procedure can be finished within a working day. It is expected that the method can have an impact on the diagnosis and treatment of FK in the future. FINANCIAL DISCLOSURE(S): The author(s) have no proprietary or commercial interest in any materials discussed in this article.

A Graphene-based Multifunctional Affinity Probe for Selective Capture and Sequential Identification of Different Biomarkers from Biosamples

A novel multifunctional graphene-based affinity probe has been explored for selective capture of two different types of peptides from the biosamples for sequential detection.

Successful Teriparatide Treatment of Atypical Fracture After Long-term Use of Alendronate Without Surgical Procedure in a Postmenopausal Woman: a Case Report

OBJECTIVE: Bisphosphonates are used as first-line therapy for postmenopausal osteoporosis owing to their potent inhibition of bone resorption. Long-term use of bisphosphonates may lead to low-energy femoral subtrochanteric or shaft fractures in a very few patients. The aim of this study was to describe the clinical course of a patient treated with alendronate for 3 years who developed an atypical femoral fracture and to hypothesize the beneficial effects of teriparatide on the healing of the patient's atypical femoral fracture. METHODS: A 63-year-old Asian woman had a lumbar osteoporotic fracture and received 70 mg of alendronate for 3 years. Pain and soreness in the thigh presented initially and exacerbated thereafter. X-ray revealed a right femoral diaphysis stress fracture. She then received teriparatide for the treatment of osteoporosis and the femoral atypical fracture. RESULTS: Pain and tenderness improved remarkably after teriparatide treatment for 1 month, and these symptoms disappeared after teriparatide treatment for 9 months. The patient also received raloxifen as further therapy, and the fracture line had completely disappeared by 15 months after treatment. CONCLUSIONS: Even though a previous study has reported that teriparatide healed stress fractures in a rat model and even with the time course of fracture healing in our patient, we are still not certain that teriparatide played a primary role in the positive response to therapy. Vitamin D therapy, calcium, and alendronate discontinuation may have played secondary roles. This case report may serve to introduce a direction for future research into the pharmacological treatment of atypical femoral fractures. Surgical treatment of incomplete atypical femoral fractures may be a safer method.

Polymorphisms in XPC Provide Prognostic Information in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is the most common type of adult leukemia for which cytosine arabinoside-based chemotherapy is the main treatment. Single nucleotide polymorphisms within the nucleotide excision repair pathway may alter the susceptibility of leukemia cells to chemotherapy. We investigated the roles of six single nucleotide polymorphisms (ERCC5rs76871136, ERCC5rs77569659, ERCC5rs873601, XPCrs2228000, XPCrs2228001, and XPCrs1870134) in the nucleotide excision repair pathway in influencing the outcome of patients with AML treated with cytosine arabinoside-based chemotherapy. One hundred fifty-one patients with AML in a Chinese population were enrolled in this study. Genotypes were determined by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry. We found that the distribution of three genotypes of XPCrs1870134 significantly differed in the cytogenetic risk groups (P = 0.04). A statistically significant correlation between polymorphisms of XPCrs2228001 and gender was found among the gender groups (P = 0.03). Moreover, patients carrying at least one variant allele (XPCrs2228001AA+CC) were more likely to respond better than those who did not carry a variant. However, no significant association was detected between polymorphisms in ERCC5 and treatment response. These findings suggest that XPC polymorphisms are important markers for the outcome of patients with AML in the Chinese population.

Fabrication of Flexible and Freestanding Zinc Chalcogenide Single Layers

Inorganic graphene analogues (IGAs) are a conceptually new class of materials with attractive applications in next-generation flexible and transparent nanodevices. However, their species are only limited to layered compounds, and the difficulty in extension to non-layered compounds hampers their widespread applicability. Here we report the fabrication of large-area freestanding single layers of non-layered ZnSe with four-atomic thickness, using a strategy involving a lamellar hybrid intermediate. Their surface distortion, revealed by means of synchrotron radiation X-ray absorption fine structure spectroscopy, is shown to give rise to a unique electronic structure and an excellent structural stability, thus determining an enhanced solar water splitting efficiency and photostability. The ZnSe single layers exhibit a photocurrent density of 2.14 mA cm(-2) at 0.72 V versus Ag/AgCl under 300 W Xe lamp irradiation, 195 times higher than that of bulk counterpart. This work opens the door for extending atomically thick IGAs to non-layered compounds and holds promise for a wealth of innovative applications.

Highly Sensitive and Fast-responsive Fluorescent Chemosensor for Palladium: Reversible Sensing and Visible Recovery

The well-known rhodamine spiro-lactam framework offers an ideal model for the development of fluorescence-enhanced chemosensors through simple and convenient syntheses. Herein, we report a new tridentate PNO receptor, which was introduced into a rhodamine spiro-lactam system to develop Pd(2+) -chemosensor RPd4, that displayed significantly improved sensing properties for palladium. Compound RPd4 shows a very fast response time (about 5 s), high sensitivity (5 nM), and excellent specificity for Pd(2+) ions over other PGE ions (Pt(2+) , Rh(3+) , and Ru(3+) ). In addition, RPd4 displays quite different responses to different valence states of the Pd ions, that is, very fast response towards Pd(2+) ions but slow response towards Pd(0) , which may provide us with a convenient method for the selective discrimination of Pd species in different valence states. According to proof-of-concept experiments, RPd4 has potential applications in Pd(2+) -analysis in drug compounds, water, soil, and leaf samples. Owing to its good reversibility, RPd4 can also be used as a sensor material for the selective detection and visual recovery of trace Pd(2+) ions in environmental samples.

Discovery of Small-Molecule Inhibitors of the TLR1/TLR2 Complex

An important regulator of innate immunity, the protein complex of Toll-like receptors 1 and 2 (TLR1/TLR2) provides an attractive target for the treatment of various immune disorders. The novel compound CU-CPT22 can compete with the binding of the specific lipoprotein ligand to TLR1/TLR2 with high inhibitory activity and specificity. Repression of downstream signaling from TNF-α and IL-1β was also observed.

A Privacy-Preserved Analytical Method for EHealth Database with Minimized Information Loss

Digitizing medical information is an emerging trend that employs information and communication technology (ICT) to manage health records, diagnostic reports, and other medical data more effectively, in order to improve the overall quality of medical services. However, medical information is highly confidential and involves private information, even legitimate access to data raises privacy concerns. Medical records provide health information on an as-needed basis for diagnosis and treatment, and the information is also important for medical research and other health management applications. Traditional privacy risk management systems have focused on reducing reidentification risk, and they do not consider information loss. In addition, such systems cannot identify and isolate data that carries high risk of privacy violations. This paper proposes the Hiatus Tailor (HT) system, which ensures low re-identification risk for medical records, while providing more authenticated information to database users and identifying high-risk data in the database for better system management. The experimental results demonstrate that the HT system achieves much lower information loss than traditional risk management methods, with the same risk of re-identification.

OX40 Facilitates Control of a Persistent Virus Infection

During acute viral infections, clearance of the pathogen is followed by the contraction of the anti-viral T cell compartment. In contrast, T cell responses need to be maintained over a longer period of time during chronic viral infections in order to control viral replication and to avoid viral spreading. Much is known about inhibitory signals such as through PD-1 that limit T cell activity during chronic viral infection, but little is known about the stimulatory signals that allow maintenance of anti-viral T cells. Here, we show that the co-stimulatory molecule OX40 (CD134) is critically required in the context of persistent LCMV clone 13 infection. Anti-viral T cells express high levels of OX40 in the presence of their cognate antigen and T cells lacking the OX40 receptor fail to accumulate sufficiently. Moreover, the emergence of T cell dependent germinal center responses and LCMV-specific antibodies are severely impaired. Consequently, OX40-deficient mice fail to control LCMV clone 13 infection over time, highlighting the importance of this signaling pathway during persistent viral infection.

Dimorpholinium Tetra-chlorido-cobaltate(II)

In the title mol-ecular salt, (C(4)H(10)NO)(2)[CoCl(4)], the morpholinium cations adopt chair conformations and the tetra-chloridocobaltate(II) anion is significantly distorted from regular tetra-hedral geometry [Cl-Co-Cl = 102.183 (19)-117.59 (2)°]. The Co-Cl bond lengths for the chloride ions not accepting hydrogen bonds are significantly shorter than those for the chloride ions accepting such bonds. In the crystal, the components are linked by N-H⋯O and N-H⋯Cl and bifurcated N-H⋯(O,Cl) hydrogen bonds to generate (100) sheets.

4-Chloro-1H-pyrrolo-[2,3-d]pyrimidine

The title compound, C(6)H(4)ClN(3), is essentially planar with the pyrrole and pyrimidine rings inclined to one another by 0.79 (15)°. In the crystal, mol-ecules are connected via pairs of N-H⋯N hydrogen bonds, forming inversion dimers. These dimers are linked via C-H⋯N inter-actions, forming a two-dimensional network parallel to (10-1).

FK228 from Burkholderia Thailandensis MSMB43

FK228 [systematic name: (1S,4S,7Z,10S,16E,21R)-7-ethyl-idene-4,21-di(propan-2-yl)-2-oxa-12,13-dithia-5,8,20,23-tetra-za--bicyclo[8.7.6]tricos-16-ene-3,6,9,19,22-pentone], C(24)H(36)N(4)O(6)S(2), also known as FR901228, depsipeptide, NSC 630176, romidepsin, and marketed as Istodax by Celgene Corporation, is crystallized from ethyl acetate in P2(1) as compared to the absolute configuration of FK228, first crystallized from methanol in P2(1)2(1)2(1) [Shigematsu et al. (1994 ▶). J. Anti-biot.47, 311-314]. A slight difference is observed between the absolute configuration of FK228 and the present structure. The molecular structure is stabilized by intramolecular N-H⋯O hydrogen bonds. In the crystal, molecules are linked via N-H⋯O hydrogen bonds.

Syntenic Gene Analysis Between Brassica Rapa and Other Brassicaceae Species

Chromosomal synteny analysis is important in genome comparison to reveal genomic evolution of related species. Shared synteny describes genomic fragments from different species that originated from an identical ancestor. Syntenic genes are orthologs located in these syntenic fragments, so they often share similar functions. Syntenic gene analysis is very important in Brassicaceae species to share gene annotations and investigate genome evolution. Here we designed and developed a direct and efficient tool, SynOrths, to identify pairwise syntenic genes between genomes of Brassicaceae species. SynOrths determines whether two genes are a conserved syntenic pair based not only on their sequence similarity, but also by the support of homologous flanking genes. Syntenic genes between Arabidopsis thaliana and Brassica rapa, Arabidopsis lyrata and B. rapa, and Thellungiella parvula and B. rapa were then identified using SynOrths. The occurrence of genome triplication in B. rapa was clearly observed, many genes that were evenly distributed in the genomes of A. thaliana, A. lyrata, and T. parvula had three syntenic copies in B. rapa. Additionally, there were many B. rapa genes that had no syntenic orthologs in A. thaliana, but some of these had syntenic orthologs in A. lyrata or T. parvula. Only 5,851 genes in B. rapa had no syntenic counterparts in any of the other three species. These 5,851 genes could have originated after B. rapa diverged from these species. A tool for syntenic gene analysis between species of Brassicaceae was developed, SynOrths, which could be used to accurately identify syntenic genes in differentiated but closely-related genomes. With this tool, we identified syntenic gene sets between B. rapa and each of A. thaliana, A. lyrata, T. parvula. Syntenic gene analysis is important for not only the gene annotation of newly sequenced Brassicaceae genomes by bridging them to model plant A. thaliana, but also the study of genome evolution in these species.

Glioblastoma Multiforme: Molecular Characterization and Current Treatment Strategy (Review)

Glioblastoma multiforme (GBM) is the most common and lethal malignant primary brain tumor. It is classified by the World Health Organization (WHO) in the group of diffusely infiltrating astrocytomas, representing up to 50% of all primary brain gliomas, and carries the poorest prognosis. Aberrant genetic events and signaling pathways have clearly demonstrated that GBM is highly anaplastic and a morphologically highly heterogeneous tumor. Understanding the genetic alterations, specific molecular biomarkers and proliferative pathways may promote therapeutic development for the management of GBM. Age, Karnofsky performance score, histology, position and the extent of tumor resection have been identified as potential prognostic factors for patients with GBM. In this study, we review the molecular characterization of tumor cells, the current standard of care for patients diagnosed with GBM, including gross or near-total resection of the tumor, followed by radiotherapy, stereotactic brachytherapy, chemotherapy and new targeted therapies. Thus, we conclude that multimodal approaches for the treatment of patients with GBM may significantly improve their prognoses.

Association Between the M235T Polymorphism of the AGT Gene and Cytokines in Patients with Hypertension

The aim of the present study was to explore the association between the M235T polymorphism of the angiotensinogen (AGT) gene and cytokines in patients with essential hypertension (EH). A total of 300 patients with EH and an age-matched control group of 150 individuals without EH, secondary hypertension, myocardial infarction and diabetes were enrolled in this study. Polymerase chain reaction combined with restriction fragment length polymorphism (PCR-RFLP) was used to detect variation in the target genotype, and enzyme-linked immunosorbant assay (ELISA) was used to detect the cytokine [interleukin (IL)-1, IL-6 and tumor necrosis factor-α (TNF-α)] concentrations. The AGT gene 235T allele and 235TT genotype frequencies in hypertensive patients were slightly higher than those in the controls. Furthermore, in the hypertensive subjects with the AGT gene 235T allele, the concentrations of IL-1 and TNF-α were significant higher than those in the controls. The results from our study suggest that the higher AGT gene TT genotype and 235T allele frequencies may be risk factors for hypertension. High frequencies of the AGT gene 235T allele and high cytokine concentrations (IL-1 and TNF-α) may promote the transcription and expression of AGT, particularly in hypertensive patients with the 235TT genotype.

In Vitro Effect of Adenosine on the MRNA Expression of Kir 2.1 and Kir 4.1 Channels in Rat Retinal Müller Cells at Elevated Hydrostatic Pressure

The aim of this study was to investigate the expression of Kir 2.1 and Kir 4.1 channels at an elevated hydrostatic pressure in vitro, and to determine whether adenosine may modulate the mRNA expression of Kir 2.1 and Kir 4.1 channels in retinal Müller cells at an elevated hydrostatic pressure in vitro. Müller cells treated with 1 μM adenosine at 40 mmHg/24 h, and mRNA expression of Kir 2.1 and Kir 4.1 channels were examined using real-time PCR. Müller cells significantly increased the mRNA expression of Kir 2.1 and Kir 4.1 channels at 40 mmHg/24 h. When further treated with 1 μM adenosine at 40 mmHg/24 h, the mRNA expression of the Kir 2.1 channels decreased, while the mRNA expression of the Kir 4.1 channels continued to increase. When the pressure was elevated, Müller cells were still able to take up K(+) and mediate the potassium concentration of the retina. Adenosine upregulated the expression of the Kir 4.1 channels, but weakly affected the expression of the Kir 2.1 channels.

MicroRNA Signature for Human Pancreatic Cancer Invasion and Metastasis

Pancreatic cancer has the poorest prognosis among all human malignant solid tumors, mainly due to its high invasive and metastatic biological features. microRNAs (miRNAs) are a group of endogenous and small non-coding RNA molecules 18-25 nucleotides in length, functioning as either tumor-suppressor genes or oncogenes. Evidence has shown that regulation of miRNAs in pancreatic cancer is associated with tumor growth, invasion, metastasis and resistance to therapy. Over the last decade, many studies have also found that there is a close relationship between miRNAs and biological characteristics of pancreatic cancer invasion and metastasis, such as the presence of cancer stem cells, epithelial-mesenchymal transition (EMT) phenotype, DNA methylation or epigenetic alteration, and the activation of some specific signaling pathways. Therefore, better understanding of the complex role of miRNAs in the development and progression of pancreatic cancer metastasis may provide new insights that could be of therapeutic consequence. In this brief review, we discuss the literature concerning the correlation between miRNAs and pancreatic cancer, focusing on miRNAs that contribute to pancreatic cancer invasion and metastasis, particularly on cancer stem cell characteristics, the EMT process, epigenetic modifications and tumor-associated signaling pathways.

Superselective Internal Iliac Arterial Embolization for Severe Hemorrhage Following Radical Prostatectomy

Severe hemorrhage following a prostatectomy is a rare and serious complication. A 63-year-old male with severe hemorrhage following radical prostatectomy which led to hypovolemic shock presented at our department and was treated with superselective internal iliac arterial embolization. At 6 months follow-up, the patient had recovered well, regained excellent urinary continence and the pelvic hematoma was absorbed using ultrasound examination. We concluded that rapid diagnosis by computed tomography angiography and early superselective embolization of internal iliac artery should be considered as the treatment of choice in severe hemorrhage cases following radical prostatectomy.

Identification of Paleo-events Recorded in the Yellow Sea Sediments by Sorting Coefficient of Grain Size

Identification of natural and anthropogenic events in the past is important for studying their patterns and mechanisms; and sensitive proxies in marine sediments are more reliable for identifying these events than those in terrestrial sediments, which are usually disturbed by human activities. Since the main source materials for the sediments in the Northern Yellow Sea Mud are transported by the Yellow River, sedimentary characteristics can be used to reconstruct the historical events that occurred in the Yellow River Valley. In the present study, by analyzing sorting coefficient of grain size in a 250-year sediment core from the Northern Yellow Sea Mud, we identified several major historical events: the Haiyuan Earthquake in AD 1920 and several times of relocation of the Yellow River estuary. The proxy has the potential of detecting and reconstructing historical events; in combination with historical archives, they also provide an accurate dating method.

Associations Between Partner Violence Perpetration and History of STI Among HIV-infected Substance Using Men in Russia

Abstract Studies document a significant association between victimization from intimate partner violence (IPV) and sexually transmitted infections (STIs) and HIV among substance using women in Russia and elsewhere, but no study has examined IPV perpetration and STI among Russian men or HIV-infected men in Eastern Europe. This study was designed to assess the association between lifetime history of IPV perpetration and STI (lifetime and current) among substance using HIV-infected men in Russia. Cross-sectional analyses were conducted with baseline data from 415 male participants enrolled in a randomized HIV intervention clinical trial [the HERMITAGE Study]. Participants were HIV-infected men reporting recent heavy alcohol use and unprotected sex in St. Petersburg, Russia. Baseline surveys assessed demographics, IPV perpetration, risk behaviors, and STI history. Current STI was assessed via blood testing for syphilis and urine testing for gonorrhea, Chlamydia and Trichomonas. Multiple logistic regression analyses were used to assess the association between history of IPV with lifetime and current STI. Participants were aged 20-57 years. Almost half of participants (46%) reported a history of IPV perpetration; 81% reported past 30-day binge alcohol use, and 43% reported past 30-day injection drug use. Past and current STI was 41% and 12%, respectively. Men reporting a history of IPV perpetration had significantly higher odds of reporting ever having an STI (AOR=1.6, 95% CI=1.1, 2.4) but lower odds of testing positive for a current STI (AOR=0.50, 95% CI=0.26, 0.96). These findings demonstrate that a history of male IPV perpetration is common in HIV-infected Russian men and associated with a history of STI. Programmatic work toward IPV prevention is needed in Russia and may be beneficial in mitigating STIs, but more research is needed to understand how and why the association between IPV and STI changes over time in this population.

Ets-1 is a Transcriptional Mediator of Oncogenic Nitric Oxide Signaling in Estrogen Receptor-negative Breast Cancer

ABSTRACT: INTRODUCTION: The Ets-1 transcription factor is candidate breast cancer oncogene that regulates the expression of genes involved in tumor progression and metastasis. Ets-1 signaling has also been linked to the development of a basal-like breast cancer phenotype. We recently described a nitric oxide (NO)-induced gene signature that is associated with poor disease outcome in estrogen receptor-negative (ER-) breast cancer and contains both stem cell-like and basal-like components. Thus, we examined the role of Ets-1 in NO signaling and NO-induced phenotypes in ER- human breast cancer cells. METHODS: Promoter region analyses were performed on genes upregulated in inducible nitric oxide synthase (NOS2) high expressing tumors for Ets-binding sites. In vitro mechanisms were examined in human basal-like breast cancer cells lines. NO signaling effects were studied using either forced NOS2 expression or the use of a chemical NO-donor DETANO. RESULTS: Promoter region analysis of genes that are up-regulated in human ER-negative breast tumors with high NOS2 expression revealed that the Ets-binding sequence is the only common promoter element present in all of these genes, indicating that Ets-1 is the key transcriptional factor down-stream of oncogenic NOS2-signaling. Accordingly, both forced NOS2 over-expression and exposure to NO-donors resulted in significant Ets-1 transcriptional activation in ER- breast cancer cells. Functional studies showed that NO activated Ets-1 transcriptional activity via a Ras/MEK/ERK signaling pathway by a mechanism that involved Ras S-nitrosylation. RNA knock-down of Ets-1 suppressed NO-induced expression of selected basal-like breast cancer markers such as P-cadherin, S100A8, IL-8 and -crystallin. Additionally, Ets-1 knock-down reduced NO-mediated cellular proliferation, matrix metalloproteinase and cathepsin B activities, as well as matrigel invasion. CONCLUSIONS: These data show that Ets-1 is a key transcriptional mediator of oncogenic NO signaling that promotes the development of an aggressive disease phenotype in ER- breast cancer in an Ets-1 and Ras-dependent manner, providing novel clues of how NOS2 expression in human breast tumors is functionally linked to poor patient survival.

Norepinephrine Regulates Prophenoloxidase System-related Parameters and Gene Expressions Via α- and β-adrenergic Receptors in Litopenaeus Vannamei

The total (THC) and differential haemocyte counts (DHC), phenoloxidase (PO) activity, and prophenoloxidase (proPO) system-related genes were investigated in haemocytes of Litopenaeus vannamei that received saline, norepinephrine (NE), and NE co-treated with various adrenergic receptor (AR) antagonists both in vivo and in vitro. Results showed that semi-granular and granular cells of shrimp which received NE, NE + phentolamine (Phe), NE + prazosin (Pra), NE + propanolol (Pro) and NE + metoprolol (Met) significantly decreased, while the PO activity of the shrimp received NE + Phe in vivo was significant higher than all the other treatments. PO activities of haemocytes exposed to saline, Pra + NE, and Met + NE were significantly higher than those of haemocytes exposed to NE, Phe + NE, and Pro + NE in vitro. Similar phenomena in lipopolysaccharide- and β-1,3-glucan-binding protein (LGBP), proPO-I, proPO-II, serine proteinases (SP), and peroxinectin (PE) messenger (m)RNA expressions of haemocytes exposed to saline, NE, and NE co-treated with various AR antagonists were observed both in vivo and in vitro. No significant differences were observed for LGBP and proPO-II mRNA expressions between haemocytes treated with saline and Pra + NE, for proPO-I mRNA expression between haemocytes treated with saline and Met + NE; or for SP and PE mRNA expressions among haemocytes treated with saline, Pra + NE, and Met + NE. These results suggest that stress-induced NE may promote the migration of circulating granulocytes to the site of the injection and the existing proPO mRNA translation which had been stored in granulocytes. NE downregulated the LGBP, proPO-I, proPO-II, SP, and PE gene transcription by haemocytes via α1-, β1-, α1-, α1- and β1-, and α1- and β1-ARs, respectively, which subsequently decreased the PO activity by α1- and β1-ARs in haemocytes of L. vannamei.

Halofugine Prevents Cutaneous Graft Versus Host Disease by Suppression of Th17 Differentiation

Halofuginone, isolated from Dichroa febreifuga, is a potent inhibitor of skin collagen in chronic graft-versus-host disease (GVHD). To evaluate the effect of halofuginone on the development of cutaneous GVHD, we developed a murine model based on BALB/c (H-2d) as recipients with transplantation of C57BL/6(H-2b) bone marrow plus splenocytes. Halofuginone or its vehicle dimethyl sulfoxide (DMSO) was given introperitoneally at a dose of 5 ug/mouse daily from one day before transplantation until 20 days post-transplantation. Halofuginone-treated recipients showed only very mild appearance of cutaneous GVHD, whereas DMSO-treated recipients rapidly showed manifestation of severe cutaneous GVHD, indicating a protective effect of halofuginone in cutaneous GVHD. After injected with halofuginone, we observed a decrease in the number of CD4(+) interleukin (IL)-17(+) cells and a parallel increase in that of CD4(+) interferon (IFN)-gamma(+) cells in peripheral blood. This shift between CD4(+) IL-17(+) cells and CD4(+) IFN-gamma(+) cells developed through modulation of cytokine profile indicated by a marked increase in the levels of IFN-gamma, tumor necrosis factor (TNF)-alpha, and IL-6. The level of IL-10 was not changed obviously. Mechanistically, we demonstrate that severe tissue damage was associated with the production of IL-17 and expansion of CD4(+)IL-17(+) cells during this disorder. Specific inhibition of Th17 differentiation by halofuginone reduced disease severity. Our results indicate a significant role of halofuginone in suppressing cutaneous GVHD, apparently through effect on inhibition of Th17 cells differentiation.

Ultrasound-guided Peripheral Intravenous Placement with Standard-length Catheters and Long Catheters

Design and Performance of a Desktop Time-of-flight Mass Spectrometer for Analyzing Metal Ions

We have described a home-made desktop orthogonal-injection time-of-flight (O-ToF) mass spectrometer combining a collisional cooling system. This O-ToF consists of a simple electrospray ion source, an atmosphere-vacuum interface, an area of transmission, including a radio-frequency only quadrupole (RF- only quadrupole, RFQ) as a collisional cooling cell and an orthogonal ToF mass analyzer. In order to detect ions of small m/z value, such as small metal ions, the RFQ has been improved to weaken the mass discrimination effect against low mass ions. Metal salt solutions were used in the experiment. The system has shown a satisfactory resolving power in the spectra (m/Δm = 3500), a good mass stability, a limit of detection of 80 fg and a mass accuracy of 48 ppm. The dynamic range is found to be from 10(-8) mol L(-1) to 10(-5) mol L(-1), allowing the semi-quantitative analysis of metal ions.

Ultrasound of Metacarpophalangeal Joints is a Sensitive and Reliable Endpoint for Drug Therapies in Rheumatoid Arthritis: Results of a Randomized, Two-centre, Placebo-controlled Study

ABSTRACT: INTRODUCTION: We aimed to investigate the sensitivity and reliability of 2D ultrasonographic endpoints at the metacarpophalageal joints (MCPJs) and their potential to provide an early and objective indication of a therapeutic response to treatment intervention in rheumatoid arthritis (RA). METHODS: A randomized, double-blind, parallel-group, two-centre, placebo-controlled trial investigated the effect on ultrasonographic measures of synovitis of repeat dose oral prednisone; 15mg or 7.5mg, each compared to placebo, in consecutive 2-week studies; 18 subjects in a 1:1 ratio and 27 subjects in a 2:1 ratio respectively. All subjects met the 1987 American College of Rheumatology criteria for the diagnosis of RA, were [greater than or equal to]18 years-old with RA disease duration [greater than or equal to]6 months, and had a Disease Activity Score 28 based on C-reactive protein ( DAS28-CRP) [greater than or equal to]3.2. Subjects underwent high-frequency (gray-scale) and power Doppler ultrasonography at Days 1 (baseline), 2, 8 and 15 in the dorsal transverse and longitudinal planes of all 10 MCPJs to obtain summated scores of quantitative and semi-quantitative measures of synovial thickness as well as vascularity. The primary endpoint was the summated score of power Doppler area measured quantitatively in all 10 MCPJs in the transverse plane at Day 15. Clinical efficacy was assessed at the same time points by DAS28(CRP). RESULTS: All randomized subjects completed the trial. The comparison between daily 15 mg prednisone and placebo at Day 15 yielded a statistically significant treatment effect (effect size=1.02, P=0.019) in change from baseline in the primary endpoint, but borderline for prednisone 7.5 mg daily vs. placebo (effect size=0.61, P=0.071). A significant treatment effect for (DAS28-CRP) was only observed at Day 15 in the prednisone 15mg group (effect size=0.95, P=0.032). However, significant treatment effects at all time points for a variety of ultrasound endpoints were detected with both prednisone doses; the largest observed effect size=2.33. Combining ultrasound endpoints with (DAS28-CRP) improved the registration of significant treatment effects. The parallel scan inter-reader reliability of summated 10 MCPJ scores were good to excellent (ICC values >0.61) for the majority of ultrasound measures. CONCLUSIONS: Ultrasonography of MCPJs is an early, reliable indicator of therapeutic response in RA with potential to reduce patient numbers and length of trials designed to give preliminary indications of efficacy. Trial Registration: Clinicaltrials.gov identifier: NCT00746512.

Regulatory Effect of Hypoxia-Inducible Factor-1α on HCG-Stimulated Endothelin-2 Expression in Granulosa Cells from the PMSG-Treated Rat Ovary

Endothelin (ET)-2 plays a crucial role in ovarian ovulation in mammals. The present study was designed to test the hypothesis that hypoxia-inducible factor (HIF)-1α-mediated transcriptional activation contributes to the increased expression of ET-2 gene in response to hCG in rat ovarian granulosa cells (GCs) during gonadotropin-induced superovulation. By real-time RT-PCR analysis, ET-2 mRNA expression was found to significantly increase in cultured ovarian GCs after treatment with hCG, or even N-carbobenzoxyl-L-leucinyl-L-leucinyl-L-norvalinal (MG-132), while this increased ET-2 mRNA expression could also be blocked by ferrous ammonium sulfate (FAS) under human chorionic gonadotropin (hCG) treatment. Further analysis also found that these changes of ET-2 mRNA were consistent with HIF-1α expression or HIF-1 activity, and HIF-1α inhibitor echinomycin inhibited ovulation in rats. Taken together, these results indicate that ET-2 is transcriptionally activated by hCG through HIF-1α-mediated mechanism in GCs. This HIF-1α-induced transcriptional activation may be one of the important mechanisms mediating the increase of ET-2 expression in GCs during the gonadotropin-induced mammalian ovulatory process in vivo.

Development of InDel Markers for Brassica Rapa Based on Whole-genome Re-sequencing

Genome-wide detection of short insertion/deletion length polymorphisms (InDels, <5 bp) in Brassica rapa (named the A genome) was performed by comparing whole-genome re-sequencing data from two B. rapa accessions, L144 and Z16, to the reference genome sequence of Chiifu-401-42. In total, we identified 108,558 InDel polymorphisms between Chiifu-401-42 and L144, 26,795 InDels between Z16 and Chiifu-401-42, and 26,693 InDels between L144 and Z16. From these, 639 InDel polymorphisms of 3-5 bp in length between L144 and Z16 were selected for experimental validation; 491 (77 %) yielded single PCR fragments and showed polymorphisms, 7 (1 %) did not amplify a product, and 141 (22 %) showed no polymorphism. For further validation of these intra-specific InDel polymorphisms, 503 candidates, randomly selected from the 639 InDels, were screened across seven accessions representing different B. rapa cultivar groups. Of these assayed markers, 387 (77 %) were polymorphic, 111 (22 %) were not polymorphic and 5 (1 %) did not amplify a PCR product. Furthermore, we randomly selected 518 InDel markers to validate their polymorphism in B. napus (the AC genome) and B. juncea (the AB genome), of which more than 90 % amplified a PCR product; 132 (25 %) showed polymorphism between the two B. napus accessions and 41 (8 %) between the two B. juncea accessions. This set of novel PCR-based InDel markers will be a valuable resource for genetic studies and breeding programs in B. rapa.

Extensive Diversification of IgD-, IgY-, and Truncated IgY({Delta}Fc)-Encoding Genes in the Red-Eared Turtle (Trachemys Scripta Elegans)

IgY(ΔFc), containing only CH1 and CH2 domains, is expressed in the serum of some birds and reptiles, such as ducks and turtles. The duck IgY(ΔFc) is produced by the same υ gene that expresses the intact IgY form (CH1-4) using different transcriptional termination sites. In this study, we show that intact IgY and IgY(ΔFc) are encoded by distinct genes in the red-eared turtle (Trachemys scripta elegans). At least eight IgY and five IgY(ΔFc) transcripts were found in a single turtle. Together with Southern blotting, our data suggest that multiple genes encoding both IgY forms are present in the turtle genome. Both of the IgY forms were detected in the serum using rabbit polyclonal Abs. In addition, we show that multiple copies of the turtle δ gene are present in the genome and that alternative splicing is extensively involved in the generation of both the secretory and membrane-bound forms of the IgD H chain transcripts. Although a single μ gene was identified, the α gene was not identified in this species.

Exome Sequencing Identifies a COL14A1 Mutation in a Large Chinese Pedigree with Punctate Palmoplantar Keratoderma

Punctate palmoplantar keratoderma (PPPK) is a rare autosomal dominant skin disorder characterised by numerous hyperkeratotic papules irregularly distributed on the palms and soles. To date, no causal gene for this disease has been identified.

Coevolution in RNA Molecules Driven by Selective Constraints: Evidence from 5S RRNA

Understanding intra-molecular coevolution helps to elucidate various structural and functional constraints acting on molecules and might have practical applications in predicting molecular structure and interactions. In this study, we used 5S rRNA as a template to investigate how selective constraints have shaped the RNA evolution. We have observed the nonrandom occurrence of paired differences along the phylogenetic trees, the high rate of compensatory evolution, and the high TIR scores (the ratio of the numbers of terminal to intermediate states), all of which indicate that significant positive selection has driven the evolution of 5S rRNA. We found three mechanisms of compensatory evolution: Watson-Crick interaction (the primary one), complex interactions between multiple sites within a stem, and interplay of stems and loops. Coevolutionary interactions between sites were observed to be highly dependent on the structural and functional environment in which they occurred. Coevolution occurred mostly in those sites closest to loops or bulges within structurally or functionally important helices, which may be under weaker selective constraints than other stem positions. Breaking these pairs would directly increase the size of the adjoining loop or bulge, causing a partial or total structural rearrangement. In conclusion, our results indicate that sequence coevolution is a direct result of maintaining optimal structural and functional integrity.

Self-assembly of Filamentous Amelogenin Requires Calcium and Phosphate: From Dimers Via Nanoribbons to Fibrils

Enamel matrix self-assembly has long been suggested as the driving force behind aligned nanofibrous hydroxyapatite formation. We tested if amelogenin, the main enamel matrix protein, can self-assemble into ribbon-like structures in physiologic solutions. Ribbons 17nm wide were observed to grow several microns in length, requiring calcium, phosphate, and pH 4.0-6.0. The pH range suggests that the formation of ion bridges through protonated histidine residues is essential to self-assembly, supported by a statistical analysis of 212 phosphate-binding proteins predicting twelve phosphate-binding histidines. Thermophoretic analysis verified the importance of calcium and phosphate in self-assembly. X-ray scattering characterized amelogenin dimers with dimensions fitting the cross-section of the amelogenin ribbon, leading to the hypothesis that antiparallel dimers are the building blocks of the ribbons. Over 5-7 days, ribbons self-organized into bundles composed of aligned ribbons mimicking the structure of enamel crystallites in enamel rods. These observations confirm reports of filamentous organic components in developing enamel and provide a new model for matrix-templated enamel mineralization.

Factor Structure, Reliability, and Validity of the Chinese Version of the School Bullying Experience Questionnaire

The aims of this study were to examine the factor structure, internal consistency, 1-month test-retest reliability, and congruent validity of the Chinese version of the School Bullying Experience Questionnaire (C-SBEQ). Study 1, in which 5751 Taiwanese adolescents in Southern Taiwan participated, examined the adequacy of the original four-factor structure of the C-SBEQ using confirmatory factor analysis (CFA) and internal-consistency reliability using Cronbach α. Study 2, in which 108 adolescents in Southern Taiwan participated, examined the 1-month test-retest reliability using intraclass correlation coefficients (ICCs). We examined the congruent validity of the C-SBEQ by examining the consistency between self-reported and teacher- and classmate-nominated experiences of bullying involvement in Study 2. The results of CFA supported the four-factor structure of the C-SBEQ in Taiwanese adolescents. The test-retest and internal reliability values of all subscales of the C-SBEQ were at acceptable to satisfactory levels. Nominated adolescents had significantly higher self-reported scores on three C-SBEQ subscales than non-nominated ones, and the levels of agreement between self-reported and nominated victims were moderate. The results of this study indicate that the C-SBEQ is appropriate for assessing bullying experiences in Taiwanese adolescents.

Pectoralis Major Pyomyositis in an 88-year-old Man: Is Tooth Extraction Bacteremia the Source?

Frequency Specific Ultrasound Attenuation is Sensitive to Trabecular Bone Structure

This study investigated the efficacy of frequency modulated ultrasound attenuation in the assessment of the trabecular structural properties. Four frequency modulated signals were created to represent four frequency bands centered at 500 kHz, 900 kHz, 1.3 MHz and 1.7 MHz with the bandwidth of 400 kHz. Five 1-cm trabecular cubes were harvested from fresh bovine distal femur. The cubes underwent four steps of demineralization process to expand the sample size to 25 with the greater variations of the structural properties for the better correlation study. Pearson correlation study was performed between the ultrasound attenuation in four frequency bands and the trabecular structural properties. The results showed that correlations of frequency modulated ultrasound attenuation to the trabecular structural properties are dependent on frequency bands. The attenuation in proximal-distal orientation had the highest correlation to BV/TV (R(2) = 0.73, p < 0.001) and trabecular thickness (R(2) = 0.50, p < 0.001) at the frequency band centered at 1.7 MHz. It was equivalent in the four frequency bands in correlation to the trabecular number (average R(2) = 0.80, p < 0.001) and to the trabecular separation (average R(2) = 0.83, p < 0.001). The attenuation in anterio-posterial orientation had the highest correlation to BV/TV (R(2) = 0.80, p < 0.001) and trabecular thickness (R(2) = 0.71, p < 0.001) at the frequency band centered at 1.3 MHz. The attenuation in the first frequency band was the most sensitive to the trabecular number (R(2) = 0.71, p < 0.001) and trabecular separation (R(2) = 0.80, p < 0.001). No significant correlation was observed for the attenuation in medial-lateral orientation across the four frequency bands.

Ionic Liquids As Porogens in the Microwave-assisted Synthesis of Methacrylate Monoliths for Chromatographic Application

Several imidazolium-based ionic liquids (ILs) with varying cation alkyl chain length (C(4)-C(10)) and anion type (tetrafluoroborate ([BF(4)](-)), hexafluorophosphate ([PF(6)](-)) and bis(trifluoromethylsulfonyl)imide ([Tf(2)N](-))) were used as reaction media in the microwave polymerization of methacrylate-based stationary phases. Scanning electron micrographs and backpressures of poly(butyl methacrylate-ethylene dimethacrylate) (poly(BMA-EDMA)) monoliths synthesized in the presence of these ionic liquids demonstrated that porosity and permeability decreased when cation alkyl chain length and anion hydrophobicity were increased. Performance of these monoliths was assessed for their ability to separate parabens by capillary electrochromatography (CEC). Intra-batch precision (n=3 columns) for retention time and peak area ranged was 0.80-1.13% and 3.71-4.58%, respectively. In addition, a good repeatability of RSD(Retention time)=<0.30% and ∼1.0%, RSD(Peak area)=<1.30% and <4.3%, and RSD(Efficiency)=<0.6% and <11.5% for intra-day and inter-day, respectively exemplify monolith performance reliability for poly(BMA-EDMA) fabricated using 1-hexyl-3-methylimidazolium tetrafluoroborate ([C(6)mim][BF(4)]) porogen. This monolith was also tested for its potential in nanoLC to separate protein digests in gradient mode. ILs as porogens also fabricated different alkyl methacrylate (AMA) (C4-C18) monoliths. Furthermore, employing binary IL porogen mixture such as 1-butyl-3-methylimidazolium tetrafluoroborate ([C(4)mim][BF(4)]) and 1-butyl-3-methylimidazolium bis(trifluoromethylsulfonyl)imide ([C(4)mim][Tf(2)N]) successfully decreased the denseness of the monolith, than when using [C(4)mim][Tf(2)N] IL alone, enabling a chromatographic run to be performed with 1:1 ratio produced baseline separation for the analytes. The combination of ILs and microwave irradiation made polymer synthesis very fast (∼10min), entirely green (organic solvent-free) and energy saving process.

TGF-β-miR-34a-CCL22 Signaling-Induced Treg Cell Recruitment Promotes Venous Metastases of HBV-Positive Hepatocellular Carcinoma

Portal vein tumor thrombus (PVTT) is strongly correlated to a poor prognosis for patients with hepatocellular carcinoma (HCC). In this study, we uncovered a causative link between hepatitis B virus (HBV) infection and development of PVTT. Mechanistically, elevated TGF-β activity, associated with the persistent presence of HBV in the liver tissue, suppresses the expression of microRNA-34a, leading to enhanced production of chemokine CCL22, which recruits regulatory T (Treg) cells to facilitate immune escape. These findings strongly suggest that HBV infection and activity of the TGF-β-miR-34a-CCL22 axis serve as potent etiological factors to predispose HCC patients for the development of PVTT, possibly through the creation of an immune-subversive microenvironment to favor colonization of disseminated HCC cells in the portal venous system.

The Toxic Effects of Diethyl Phthalate on the Activity of Glutamine Synthetase in Greater Duckweed (Spirodela Polyrhiza L.)

The toxic effects of diethyl phthalate (DEP), a potent allelochemical, on the enzyme activity and polypeptide accumulation of glutamine synthetase (GS) in greater duckweed were investigated. In our previous studies, DEP induced oxidative responses at concentrations from 0.5 to 2mM in greater duckweed and the antioxidant enzymes played important roles in the defense strategy against DEP stress. In this study, DAB-H(2)O(2) and NBT stain for superoxide radicals (O(2)(.-)), lipid peroxidation, HSP70, and ammonia accumulation in DEP-treated duckweed tissues revealed adverse effect of DEP in plant growth. Biochemical analysis and physiological methods were combined to investigate GS activity and polypeptide accumulation under DEP-induced stress. The results showed that GS activity was reduced with the increasing concentration of DEP, indicative of enhanced toxic effect. Immunoblot analysis with chloroplast soluble fractions indicated that the chloroplastic GS (GS2) polypeptide from greater duckweed was degraded under DEP stress conditions. The response of GS2 to the DEP stress may be modulated by means of redox change in plant tissues, chloroplasts, and chloroplast lysates. The results suggest that DEP is toxic to the greater duckweed by inhibition of the GS isoenzymes in nitrogen assimilation and the GS2 plays important roles in the adaptation strategy against DEP toxicity.

Acupuncture Improves Cognitive Deficits and Increases Neuron Density of the Hippocampus in Middle-aged SAMP8 Mice

OBJECTIVES: To examine whether acupuncture could improve cognitive deficits and reduce the loss of neurons in mice models of ageing. METHODS: Male 7.5-month-old senescence-accelerated mouse prone 8 (SAMP8) and age-matched senescence-resistant inbred strains 1 (SAMR1) were divided into four groups (n=15 per group): SAMP8 acupuncture group (Pa), SAMP8 non-acupuncture point control group (Pn), SAMP8 control group (Pc) and SAMR1 normal control group (Rc). The behaviours were examined by the Morris water maze test and the neuron density in the hippocampus was estimated by the optical fractionator technique. RESULTS: The Morris water maze test demonstrated that the cognitive deficits of SAMP8 mice were improved by acupuncture treatment. Neuronal loss was found in hippocampal regions CA1 (-24%), CA3 (-18%) and DG (-28%) of Pc compared with Rc. The neuron number in hippocampal CA3 and DG of the Pa group was significantly increased by therapeutic acupuncture compared with the Pc group. CONCLUSIONS: Acupuncture improved the cognitive impairment of middle-aged SAMP8 mice which could be attributed to the reduced neuron loss in hippocampal regions CA3 and DG. These results suggest that reducing neuron loss in the hippocampus by acupuncture is a potential therapeutic approach for the treatment of Alzheimer's disease and cognitive impairment diseases.

Intercellular Adhesion Molecule-1 is a Regulator of Blood-testis Barrier Function

The mechanism underlying the movement of preleptotene/leptotene spermatocytes across the blood-testis barrier (BTB) during spermatogenesis is not well understood largely due to the fact that the BTB, unlike most other blood-tissue barriers, is comprised of several co-existing and co-functioning junction types. In this report, we show intercellular adhesion molecule-1 (ICAM-1, a Sertoli and germ cell adhesion protein having five immunoglobulin [Ig]-like domains, as well as transmembrane and cytoplasmic domains) to be a regulator of BTB integrity. Initial experiments showed ICAM-1 to co-immunoprecipitate and to co-localize with tight junction and basal ectoplasmic specialization proteins such as occludin and N-cadherin, which constitute BTB function. More importantly, over-expression (O-E) of ICAM-1 in Sertoli cells in vitro enhanced barrier function when monitored by transepithelial electrical resistance measurements, illustrating that ICAM-1-mediated adhesion can promote BTB integrity. On the other hand, O-E of a truncated form of ICAM-1 that only consisted of the five Ig-like domains (sICAM-1, this form of ICAM-1 is known to be secreted) elicited an opposable effect when Sertoli cell barrier function was found to be perturbed in vitro. Here, sICAM-1 O-E resulted in the down-regulation of several BTB constituent proteins, which was likely mediated by Pyk2/p-Pyk2-Y402 and c-Src/p-Src-Y530. These findings were expanded to the in vivo level when BTB function was found to be disrupted following sICAM-1 O-E. These data illustrate the existence of a unique mechanism in the mammalian testis where ICAM-1 can either positively or negatively regulate BTB function.

Puncture of Foramen Ovale Cranium in Computed Tomography Three-dimensional Reconstruction

ABSTRACT: The study aimed to provide the anatomic data for puncture of foramen ovale cranium in oral cavity. We scan 100 volunteers' skull on computed tomography who have no lesion of skull base, of which the images were for three-dimensional reconstruction. The following observations and measurements were carried out: the shape, size of foramen ovale cranium, and the angle and length of puncture line. The results we got are the following: foramen ovale cranium appears as oval, kidney shape, round, pear shape, and strip shape. Foramen ovale diameter is 8.20 ± 1.54 mm, and width is 4.08 ± 0.73 mm for men and 4.23 ± 0.79 mm for female. The distance from the center of foramen ovale to the maxillary second molar is 51.65 mm for male and 48.77 mm for female. The puncture line is from the center of foramen ovale to the maxillary second molar. The angle of the puncture line with the vertical plane, which is through the midpoint of supraorbital margin and the infraorbital margin, is 40.27 degrees for men and 37.31 degrees for women. The angle of the puncture line with the horizontal plane is 49.37 degrees for men and 52.26 degrees for women. The angle of the puncture line with the sagittal plane is 3.78 degrees. All data between the left and right sides have no statistically significant difference (P > 0.05), but the diameter, the length of the puncture, and the angle of puncture line with the horizontal and vertical have significant differences on sex (P < 0.01). The anatomic character of the foramen ovale cranium has important value on the accuracy of puncture for the treatment of trigeminal neuralgia.

Engineered Autologous Bone Marrow Mesenchymal Stem Cells: Alternative to Cleft Alveolar Bone Graft Surgery

ABSTRACT: Human recombinant bone morphogenetic protein 2 (rhBMP-2) accelerates bone regeneration but is associated with limited cementum and periodontal ligament regeneration, local root resorption, and ankylosis. This study assessed a new approach to the regeneration of the alveolar bone and periodontal attachment apparatus using a combination of ex vivo autologous bone marrow mesenchymal stem cells (MSCs) engineered by replication defective adenovirus to express the BMP-2 gene and pluronic F127 (PF127) in a large mammalian animal model. Bilateral maxillary periodontal defects were created over the premolar area in 9 mature male miniature swine. The 18 defects were randomly assigned to receive either BMP-2-expressing MSCs in the advBMP-2 group or MSCs alone in the MSC group. The regenerated periodontal attachment apparatus was evaluated histologically, and the total regenerated bone volume was calculated from three-dimensional computed tomography analysis. Three months after implantation, significant bone volume was regenerated in the advBMP-2 group. Periodontal apparatus regeneration was significantly better in the advBMP-2 group. New cementum and Sharpey fibers were observed on the denuded root surfaces in the advBMP-2 group, whereas incomplete healing with localized root surface resorption was noted in the control group. The use of ex vivo BMP-2-engineered autologous MSCs enhanced bone and periodontal apparatus regeneration in maxillary alveolar and periodontal defects in swine. This novel integrated approach might be suitable for clinical periodontal apparatus repair. This may be an alternative for cleft alveolar bone graft surgery.

Regio- and Enantioselective Cobalt-Catalyzed Reductive [3+2] Cycloaddition Reaction of Alkynes with Cyclic Enones: A Route to Bicyclic Tertiary Alcohols

Round and round: An unusual cobalt-catalyzed regio- and enantioselective reductive [3+2] cycloaddition of cyclic enones with alkynes affording bicyclic tertiary alcohols is described. A possible mechanism involving the formation of a cobaltacyclopentene intermediate is proposed.

Positive Selection at the ASPM Gene Coincides with Brain Size Enlargements in Cetaceans

The enlargement of cetacean brain size represents an enigmatic event in mammalian evolution, yet its genetic basis remains poorly explored. One candidate gene associated with brain size evolution is the abnormal spindle-like microcephaly associated (ASPM), as mutations in this gene cause severe reductions in the cortical size of humans. Here, we investigated the ASPM gene in representative cetacean lineages and previously published sequences from other mammals to test whether the expansion of the cetacean brain matched adaptive ASPM evolution patterns. Our analyses yielded significant evidence of positive selection on the ASPM gene during cetacean evolution, especially for the Odontoceti and Delphinoidea lineages. These molecular patterns were associated with two major events of relative brain size enlargement in odontocetes and delphinoids. It is of particular interest to find that positive selection was restricted to cetaceans and primates, two distant lineages both characterized by a massive expansion of brain size. This result is suggestive of convergent molecular evolution, although no site-specific convergence at the amino acid level was found.

Role of Nuclear Receptor Co-activator 3 (Ncoa3) in Pluripotency Maintenance

Nuclear receptors, including Esrrb, Dax1 and Nr5a2, have been shown to be involved in pluripotency maintenance. Yet, the role of their co-activators in mouse embryonic stem cells (ESCs) remains unexplored. Here, we demonstrated that the nuclear receptor co-activator 3 (Ncoa3) is essential for pluripotency maintenance. Knockdown of Ncoa3 not only compromises the expression of pluripotency markers, but also impairs in vitro and in vivo differentiation potential of mouse ESCs. Ncoa3 binds to the Nanog promoter, and recruits the histone acetyltransferase CBP and the histone arginine methyltransferase CARM1 to activate Nanog expression. Moreover, nuclear receptor co-activator 3 (GSK3) signaling down-regulates Ncoa3 protein level to suppress Nanog expression. Thus, Ncoa3 not only contributes to self-renewal by activating Nanog, but also facilitates ESC differentiation as a break point to disrupt the core transcriptional circuitry of pluripotency.

Paediatric Intra-axial Posterior Fossa Tumours: Pictorial Review

Paediatric brain tumours commonly arise in the posterior cranial fossa. Early diagnosis is often challenging due to initial non-specific clinical symptoms, especially in very young children. The typical MR features of tumours in this region including medulloblastoma, ependymoma, juvenile pilocytic subtype of cerebellar astrocytoma, brain stem glioma and atypical teratoid-rhabdoid tumour are illustrated. Diffusion-weighted imaging and apparent diffusion coefficient values combined with signal characteristics on conventional MR sequences can usually differentiate low-grade from high-grade tumours. Prompt diagnosis is crucial as total surgical resection, which is only possible in localised disease, improves prognosis. A practical MR flow chart is introduced for differentiating different types of posterior cranial fossa tumours, which might be useful in clinical practice.

Cysteinyl Cathepsins: Multifunctional Enzymes in Cardiovascular Disease

Until recently, the role of lysosomal cysteine protease cathepsins in intracellular protein degradation was believed to be mainly restricted to scavenging. However, recent studies have revealed nontraditional roles for cysteine protease cathepsins in the extracellular space during the development and progression of cardiovascular disease. Although the precise mechanisms are unknown, data from animal studies suggest that members of the cathepsin family, like other extracellular proteases, contribute to extracellular matrix protein remodeling and interstitial matrix degradation, as well as to cell signaling and cell apoptosis in heart disease. Inflammatory cytokines and hormones regulate the expression and secretion of cathepsins in cultured cardiovascular cells and macrophages. Serum levels of cathepsins L, S, and K and their endogenous inhibitor cystatin C may be useful predictive biomarkers in patients with coronary artery disease and cardiac disease. Furthermore, in vivo pharmacological intervention with a synthetic cathepsin inhibitor and cardiovascular drugs (including statins and angiotensin II type 1 receptor antagonists) has the potential for pharmacologic targeting of cathepsins in cardiovascular disease. This review focuses on cathepsin biology (structure, synthesis, processing, activation, secretion, activity regulation, and function) and the involvement of cysteinyl cathepsins in the pathogenesis of several heart and vessel diseases, especially with respect to their potential application as diagnostic and prognostic markers and drug targets to prevent inappropriate proteolysis in cardiovascular disease.

Water-Gas-Shift Reaction on Metal Nanoclusters Encapsulated in Mesoporous Ceria Studied with Ambient Pressure X-ray Photoelectron Spectroscopy

Metal nanoclusters (Au, Pt, Pd, Cu) encapsulated in channels of mesoporous ceria (mp-CeO2) were synthesized. The activation energies of water gas shift reaction (WGS) performed at oxide-metal interfaces of metal nanoclusters encapsulated in mp-CeO2 (M@mp-CeO2) are lower than those of metal nanoclusters impregnated on ceria nanorods (M/rod-CeO2). In situ studies using ambient pressure XPS (AP-XPS) suggested that surface chemistry of the internal concave surface of CeO2 pores of M@mp-CeO2 is different from that of external surfaces of CeO2 of M/rod-CeO2 under reaction conditions. AP-XPS identified the metallic state of the metal nanoclusters of these WGS catalysts (M@mp-CeO2 and M/rod-CeO2) under a WGS reaction condition. The lower activation energy of M@mp-CeO2 in contrast to M/rod-CeO2 is related to the different surface chemistry of the two types of CeO2 under the same reaction condition.

Reversal of Ion Charge Selectivity Renders the Pentameric Ligand-gated Ion Channel GLIC Insensitive to Anesthetics

Pentameric ligand gated ion channels (pLGICs) are a family of structurally homologous cationic and anionic channels involved in neurotransmission. Cationic members of the pLGIC family are typically inhibited by general anesthetics, while anionic members are potentiated. GLIC is a prokaryotic cationic pLGIC and can be inhibited by clinical concentrations of general anesthetics. The introduction of three mutations, Y221A (Y-3'A), E222P (E-2'P) and N224R (N0'R), at the selectivity filter and one, A237T (A13'T), at the hydrophobic gate, converted GLIC to an anion channel. The mutated GLIC (GLIC4) became insensitive to the anesthetics propofol and etomidate as well as the channel blocker picrotoxin. Molecular dynamics (MD) simulations revealed changes in the structure and dynamics of GLIC4 in comparison to GLIC, particularly in the tilting angles of the pore-lining helix (TM2) that consequently resulted in different pore radius and hydration profiles. Propofol binding to an intra-subunit site of GLIC shifted the tilting angles of TM2 towards closure at the hydrophobic gate region, consistent with propofol inhibition of GLIC. In contrast, the pore of GLIC4 was much more resilient to perturbation from propofol binding. This study underscores the importance of pore dynamics and conformation to anesthetic effects on channel functions.

Sorafenib and Its Derivative SC-49 Sensitize Hepatocellular Carcinoma Cells to CS-1008, a Humanized Anti-DR5 Antibody

BACKGROUND & PURPOSE: Previously, we have shown that sorafenib sensitizes hepatocellular carcinoma (HCC) to TRAIL-induced apoptosis. Here, we report that sorafenib and SC-49 sensitize HCC cells to CS-1008, a novel anti-human death receptor 5 antibody. EXPERIMENTAL APPROACH: HCC cell lines (PLC5, Huh-7, and Hep3B) were treated with CS-1008 and/or sorafenib and analyzed in terms of apoptosis, signal transductions. KEY RESULTS: SC-49 is a sorafenib derivative which is devoid of kinase inhibition activity. Our data indicated that sorafenib as well as SC-49 down-regulated the phosphorylation of signal transducers and activators of transcription 3 (p-STAT3) at Tyr 705 and subsequently reduced the protein levels of STAT3-regulated proteins, Mcl-1, survivin and cylcin D1, in CS-1008-treated HCC cells. Knockdown of STAT3 by RNA-interference overcame apoptotic resistance to CS-1008 in HCC cells, and ectopic expression of STAT3 in HCC cells abolished the sensitizing effect of sorafenib or SC-49 on CS-1008-induced apoptosis, indicating that inhibition of STAT3 mediates the effects of the combination. Importantly, inhibition of SHP-1 by adding a specific SHP-1 inhibitor reduced the effects of SC-49 and CS-1008 on p-STAT3 and apoptosis, whereas co-treatment of CS-1008 and SC-49 increased the activity of SHP-1, suggesting that SHP-1 mediated the combinational effect of CS-1008 and SC-49 in HCC. Moreover, the combination of CS-1008 and SC-49 inhibited HCC xenograft tumor growth in vivo. CONCLUSIONS & IMPLICATIONS: Sorafenib and its derivative SC-49 sensitize HCC to CS-1008 through SHP-1-dependent STAT3 inactivation.

A Three-Channel Fluorescent Probe That Distinguishes Peroxynitrite from Hypochlorite

A novel fluorescent probe for peroxynitrite, PN(600), was rationally designed on the basis of a unique fluorophore assembly approach. PN(600) is a green-emitting coumarin derivative. Upon oxidation by peroxynitrite, PN(600) is transformed into a highly fluorescent red-emitting resorufin derivative via an orange-emitting intermediate. This three-channel signaling capability enables PN(600) to differentiate peroxynitrite from other reactive oxygen and nitrogen species, including hypochlorite and hydroxyl radical. Moreover, PN(600) is membrane-permeable and compatible with common TRITC filter sets and displays low cytotoxicity. Therefore, PN(600) is a promising candidate for in vitro peroxynitrite imaging.

Enantioselective Total Synthesis of (+)-Lithospermic Acid

An enantioselective synthesis of (+)-lithospermic acid, a potent anti-HIV agent, has been accomplished in a convergent manner in nine steps. The synthesis features an enantioselective intramolecular oxa-Michael addition catalyzed by a quinidine derivative, a hypervalent iodine-mediated rearrangement of chromanone to dihydrobenzofuran, an enantioselective α-oxyamination, and an intermolecular C-H olefination.

Detection of Single Influenza Viral RNA in Cells Using a Polymeric Sequence Probe

A polynucleotide probe, call a polymeric sequence probe (PSP), was used to detect influenza A (Influenza A/WSN/33) NA (Neuraminidase) viral RNA in Madin-Darby Canine Kidney (MDCK) cells. The PSP is a single-stranded DNA molecule with ~2,000 tandem repeat fluorescence binding sites and target binding sites that can bind with multiple fluorescence complementary oligos and target viral RNA using a fluorescence in situ hybridization (FISH) process. A single viral RNA labeled by PSP can be directly observed in MDCK cells. The simple FISH protocol enables the observation and quantitative analysis of the infectious process and drug effects with ultra-high sensitivity and spatial resolution.

E-selectin Deficiency Attenuates Brain Ischemia in Mice

AIMS: To determine whether E-selectin deficiency can attenuate brain ischemia in a mouse model of focal cerebral ischemia. METHODS: E-selectin was determined in spontaneously hypertensive rats (SHRs) and stroke-prone spontaneously hypertensive rats (SHR-SPs). E-selectin knockout (Es(-/-) ) mice and wild-type control (WT) mice underwent permanent distal middle cerebral artery occlusion (MCAO). Behavioral analyses were performed followed by the measurement of infarct areas. Myeloperoxidase (MPO) protein was determined by Western blot. IL-6, IL-1β, and TNF-α were detected by ELISA. In situ detection of apoptotic cells was performed by TUNEL staining. RESULTS: The brain and serum E-selectin levels were higher in SHR-SPs than in SHRs (P < 0.05) after salt intake. E-selectin deficiency improved neurological function and reduced infarct area in cerebral ischemic mice. MPO and IL-1β were lower in Es(-/-) mice than in WT mice. In addition, the number of apoptotic cells in Es(-/-) mice was significantly less than in WT mice after MCAO. CONCLUSIONS: E-selectin deficiency presents protective effect on cerebral ischemia. This protective effect is likely achieved by the inhibition of inflammation and apoptosis.

Noise Suppression of a Dipole Source by Tensioned Membrane with Side-branch Cavities

Reducing the ducted-fan noise at the low frequency range remains a big technical challenge. This study presents a passive approach to directly suppress the dipole sound radiation from an axial-flow fan housed by a tensioned membrane with cavity backing. The method aims at achieving control of low frequency noise with an appreciable bandwidth. The use of the membrane not only eliminates the aerodynamic loss of flow, but also provides flexibility in controlling the range of the stopband with high insertion loss by varying its tension and mass. A three-dimensional model is presented which allows the performance of the proposed device to be explored analytically. With the proper design, this device can achieve a noise reduction of 5 dB higher than the empty expansion cavity recently proposed by Huang et al. [J. Acoust. Soc. Am. 128, 152-163 (2010)]. Through the detailed modal analysis, even in vacuo modes of the membrane vibration are found to play an important role in the suppression of sound radiation from the dipole source. Experimental validation is conducted with a loudspeaker as the dipole source and good agreement between the predicted and measured insertion loss is achieved.

Micro-perforated Elements in Complex Vibro-acoustic Environment: Modelling and Applications

Micro-perforated structures/panels (MPP) are widely used in various architectural, industrial and environmental applications for providing efficient sound absorptions. More recently, they found their use in compact mechanical systems, in which the property of the MPP is shown to be strongly influenced by the surrounding vibro-acoustic environment, which is drastically different from the one dimensional Kundt tube configuration, usually used in existing works. Unfortunately, very little has been done in this regard, due to the fact that modeling such a vibro-coustic system with MPPs as integrative elements is a very challenging task, not even to mention the optimization. Recently, a vibro-acoustic formulation based on the Patch Transfer Function (PTF) approach was proposed to model micro-perforated structures in a complex vibro-acoustic environment. As a sub-structuring approach, PTF allows assembling different vibro-acoustic subsystems, including micro-perforations and the flexibility of a MPP, through coupled surfaces. The proposed formulation provides explicit representation of the coupling among subsystems, with enhanced capability of handling system complexities and facilitating system optimization. In this talk, the overall approach will be reviewed and applied to a number of typical examples. The versatility and efficiency of the method as well as the underlying physics are demonstrated.

Hybrid Silencer by Using Micro-perforated Plate with Side-branch Cavities

A plate silencer consists of an expansion chamber with two side-branch cavities covered by light but extremely stiff plates. It works effectively with wide stopband from low-to-medium frequencies only if the plate is extremely stiff, to ensure a strong reflection of acoustic wave to the upstream in the duct. However, a plate with slightly weak bending stiffness will result in non-uniform transmission loss (TL) spectra with narrowed stopband. In this study, a hybrid silencer is proposed by introducing micro-perforations into the plate to elicit the sound absorption in order to compensate for the deficiency in the passband caused by the insufficient sound reflection in certain frequency range due to plate with weaker stiffness. A theoretical model, capable of dealing with the strong coupling between the vibrating micro-perforated plate and sound fields inside the cavity and the duct, is developed. Through a proper balancing between the sound absorption and reflection, the proposed hybrid plate silencer with moderately stiff plates is shown to outperform the typical plate silencer with very stiff plate. Whilst releasing the harsh requirement on the bending stiffness of the plate, the proposed hybrid silencer provides a more flattened and uniform TL and a widened stopband by about 30%.

Viscous Boundary Layer Correction on a Pressure-field Acoustic Model

Fluid viscosity plays an important role in many acoustics and structural acoustics problems. For example, using an inviscid approximation to the flow of fluid-loaded micro-electro-mechanical systems and micro-scale biological structures results in large errors in the predicted response. Using a linearized Navier--Stokes solution, however, increases the number of unknowns by at least a factor of three compared to an inviscid approximation where pressure is the only degree of freedom. In this work, an approximate boundary condition is developed to include fluid viscosity for coupled fluid-structure systems. The viscous effect is included as a correction term to the inviscid boundary condition, written in terms of second order in-plane derivatives of pressure. This is the key step enabling the development of a variational formulation that is directly amenable for approximation in a finite element method (FEM) code as only a minor modification to existing structural acoustic code. Hence, this approach retains the great computational advantage over the conventional viscous FEM formulation. We show results demonstrating the accuracy of the approximate boundary condition as compared to the full three dimensional Navier-Stokes solution.

Imaging-based Quantitative Characterization of Fatigue Crack for Structural Integrity Monitoring Using Nonlinear Acousto-ultrasonics and Active Sensor Networks

The majority of today's damage detection techniques rely substantially on linear macroscopic changes in either global vibration signatures or local wave scattering phenomena. However, damage in real-world structures often initiates from fatigue cracks at microscopic levels, presenting highly nonlinear characteristics which may not be well evidenced in these linear macroscopic changes. It is of great significance but also a great challenge to quantitatively characterize micro-fatigue cracks without terminating the normal operation of an engineering structure. This is a critical step towards automatic and online structural integrity monitoring (SIM). By exploring the nonlinearities of higher-order acousto-ultrasonic (AU) waves upon interaction with fatigue cracks, a damage characterization approach, in conjunction with use of an active piezoelectric sensor network, was established, with the particular capacity of evaluating multiple fatigue cracks at a quantitative level (including the co-presence of multiple cracks, and their individual locations and severities). Identification results were presented in pixelated images using an imaging algorithm, enabling visualization of fatigue cracks and depiction of overall structural integrity in a quantitative, rapid and automatic manner. The effectiveness of the proposed technique was demonstrated by experimentally characterizing multiple fatigue cracks near rivet holes in aluminium plates.

Genetic Diversity and Demographical History of Coilia Ectenes (Clupeiformes: Engraulidae) Inferred from the Complete Control Region Sequences of Mitochondrial DNA

Coilia ectenes is a commercially important fishery species. In this study, genetic diversity and population structure of C. ectenes were examined by using mitochondrial DNA control region sequences in 246 individuals sampled from 10 localities in China. One hundred and ninety-five polymorphic sites defined 184 distinct haplotypes, revealing a moderately high haplotype diversity (Hd) and a relatively low nucleotide diversity (π) in the 10 localities. An excess of unique haplotypes at most sample locations were detected, which might influence the genetic structure of the C. ectenes populations. Hd ranged from 0.939 to 1.000 and π ranged from 0.26% to 1.15%. The Dongting fish population had the highest π level. The genetic distances ranged from 0.26% to 1.03% within populations and from 0.56% to 4.90% between populations. The distances between the Fuzhou (FZ) population and other populations were mostly >4.8%. Neighbor-joining tree indicated distinct patterns of phylogeographic structure among haplotypes from FZ population and those from other populations. Analyses of molecular variance and F(st) statistics suggested that the divergence existed among populations from 10 localities, indicating that gene flow might be restricted among those regions, despite the wide dispersal. In addition, neutral tests and analysis of mismatch distribution suggested that C. ectenes might have undergone a population expansion. Our study revealed the extant population genetic diversity and structure of the C. ectenes, and was in favor of the related fishery management issues including fishery stock identification and conservation.

Nuclear Factor Kappa B is Central to Marek's Disease Herpesvirus Induced Neoplastic Transformation of CD30 Expressing Lymphocytes In-vivo

ABSTRACT: BACKGROUND: Marek's Disease (MD) is a hyperproliferative, lymphomatous, neoplastic disease of chickens caused by the oncogenic Gallid herpesvirus type 2 (GaHV-2; MDV). Like several human lymphomas the neoplastic MD lymphoma cells overexpress the CD30 antigen (CD30hi) and are in minority, while the non-neoplastic cells (CD30lo) form the majority of population. MD is a unique natural in-vivo model of human CD30hi lymphomas with both natural CD30hi lymphomagenesis and spontaneous regression. The exact mechanism of neoplastic transformation from CD30lo expressing phenotype to CD30hi expressing neoplastic phenotype is unknown. Here, using microarray, proteomics and Systems Biology modeling; we compare the global gene expression of CD30lo and CD30hi cells to identify key pathways of neoplastic transformation. We propose and test a specific mechanism of neoplastic transformation, and genetic resistance, involving the MDV oncogene Meq, host gene products of the Nuclear Factor Kappa B (NF-kappaB) family and CD30; we also identify a novel Meq protein interactome. RESULTS: Our results show that a) CD30lo lymphocytes are pre-neoplastic precursors and not merely reactive lymphocytes; b) multiple transformation mechanisms exist and are potentially controlled by Meq; c) Meq can drive a feed-forward cycle that induces CD30 transcription, increases CD30 signaling which activates NF-kappaB, and, in turn, increases Meq transcription; d) Meq transcriptional repression or activation of the CD30 promoter generally correlates with polymorphisms in the CD30 promoter distinguishing MD-lymphoma resistant and susceptible chicken genotypes e) MDV oncoprotein Meq interacts with proteins involved in physiological processes central to lymphomagenesis. CONCLUSIONS: In the context of the MD lymphoma microenvironment (and potentially in other CD30hi lymphomas as well), our results show that the neoplastic transformation is a continuum and the non-neoplastic cells are actually pre-neoplastic precursor cells and not merely immune bystanders. We also show that NF-kappaB is a central player in MDV induced neoplastic transformation of CD30-expressing lymphocytes in vivo. Our results provide insights into molecular mechanisms of neoplastic transformation in MD specifically and also herpesvirus induced lymphoma in general.

Breast Cancer Therapies and Cardiomyopathy

The prevalence of chemotherapy-related cardiac disease is increasing and management demands a multidisciplinary approach from cardiologists and oncologists. Pretreatment identification of predisposing risk factors and assessment of cardiac function before and at intervals during and after therapy with cardiotoxic agents are necessary. In clinical practice, surveillance is largely performed using transthoracic echocardiography or multi-gated radionuclide angiography. Imaging strategies that detect cardiac injury before overt left ventricular systolic dysfunction provide an opportunity for early intervention and improved cardiac outcomes.

Enlarging Facial Plaques in a 76-year-old Woman

Impact of Chlorhexidine-impregnated Washcloths on Reducing Incidence of Vancomycin-resistant Enterococci Colonization in Hematology-oncology Patients

BACKGROUND: Daily skin cleansing with washcloths impregnated with chlorhexidine gluconate (CHG) of patients in intensive care unit is associated with reduction in incidence of vancomycin-resistant Enterococci (VRE) acquisition. This study describes the impact on incidence of VRE colonization after the implementation of daily skin cleansing with 2% CHG-impregnated washcloths in hematology-oncology patients. METHODS: In this before-and-after study, we compared the incidence rate of VRE colonization during the baseline period (where routine soap-and-water bathing was used) with the intervention period where patients were cleansed with 2% CHG-impregnated washcloths. RESULTS: Acquisition of VRE decreased from 7.8% in the baseline to 3.8% in the intervention period (relative risk, 0.48, 95% confidence interval [CI], 0.21-1.09; P = .07). The crude relative rate of acquisition during the intervention period compared with the baseline period was 0.53 (95% CI, 0.23-1.23; P = .13). Patients who had been a roommate of a patient subsequently found to have VRE were at a significantly increased risk for acquiring VRE (hazard ratio, 18.8, 95% CI, 5.37-66.15; P < .001). However, patients admitted to the same bed number of previously known VRE-colonized patient were not at increased risk of VRE acquisition (hazard ratio, 0.37, 95% CI, 0.11-1.22; P = .10). CONCLUSION: We did not observe a statistically significant reduction in the rate of VRE colonization in association with the use of 2% CHG-impregnated washcloths among hematology-oncology patients.

In Vivo and in Vitro Antidiabetic Effects of Aqueous Cinnamon Extract and Cinnamon Polyphenol-enhanced Food Matrix

Cinnamon has a long history of medicinal use and continues to be valued for its therapeutic potential for improving metabolic disorders such as type 2 diabetes. In this study, a phytochemically-enhanced functional food ingredient that captures water soluble polyphenols from aqueous cinnamon extract (CE) onto a protein rich matrix was developed. CE and cinnamon polyphenol-enriched defatted soy flour (CDSF) were effective in acutely lowering fasting blood glucose levels in diet induced obese hyperglycemic mice at 300 and 600mg/kg, respectively. To determine mechanisms of action, rat hepatoma cells were treated with CE and eluates of CDSF at a range of 1-25μg/ml. CE and eluates of CDSF demonstrated dose-dependent inhibition of hepatic glucose production with significant levels of inhibition at 25μg/ml. Furthermore, CE decreased the gene expression of two major regulators of hepatic gluconeogenesis, phosphoenolpyruvate carboxykinase and glucose-6-phosphatase. The hypoglycemic and insulin-like effects of CE and CDSF may help to ameliorate type 2 diabetes conditions.

Single-Cell Expression Analyses During Cellular Reprogramming Reveal an Early Stochastic and a Late Hierarchic Phase

During cellular reprogramming, only a small fraction of cells become induced pluripotent stem cells (iPSCs). Previous analyses of gene expression during reprogramming were based on populations of cells, impeding single-cell level identification of reprogramming events. We utilized two gene expression technologies to profile 48 genes in single cells at various stages during the reprogramming process. Analysis of early stages revealed considerable variation in gene expression between cells in contrast to late stages. Expression of Esrrb, Utf1, Lin28, and Dppa2 is a better predictor for cells to progress into iPSCs than expression of the previously suggested reprogramming markers Fbxo15, Fgf4, and Oct4. Stochastic gene expression early in reprogramming is followed by a late hierarchical phase with Sox2 being the upstream factor in a gene expression hierarchy. Finally, downstream factors derived from the late phase, which do not include Oct4, Sox2, Klf4, c-Myc, and Nanog, can activate the pluripotency circuitry.

Design, Synthesis and Pharmacological Evaluation of Novel Tacrine-caffeic Acid Hybrids As Multi-targeted Compounds Against Alzheimer's Disease

A novel series of tacrine-caffeic acid hybrids (5a-f) were designed and synthesized by combining caffeic acid (CA) with tacrine. The antioxidant study revealed that all the hybrids have much more antioxidant capacities compared to CA. Among these compounds, 5e showed the highest selectivity in inhibiting acetylcholinesterase (AChE) over butyrylcholinesterase (BuChE). Enzyme kinetic study had suggested that 5e binds to both catalytic (CAS) and peripheral anionic sites (PAS) of AChE. Moreover, compound 5e also inhibited self- or AChE-induced β-amyloid(1-40) aggregation, as well as had potent neuroprotective effects against H(2)O(2)- and glutamate- induced cell death with low toxicity in HT22 cells.

Statins Use and Coronary Artery Plaque Composition: Results from the International Multicenter CONFIRM Registry

OBJECTIVE: The effect of statins on coronary artery plaque features beyond stenosis severity is not known. Coronary CT angiography (CCTA) is a novel non-invasive method that permits direct visualization of coronary atherosclerotic features, including plaque composition. We evaluated the association of statin use to coronary plaque composition type in patients without known coronary artery disease (CAD) undergoing CCTA. METHODS: From consecutive individuals, we identified 6673 individuals (2413 on statin therapy and 4260 not on statin therapy) with no known CAD and available statin use status. We studied the relationship between statin use and the presence and extent of specific plaque composition types, which was graded as non-calcified (NCP), mixed (MP), or calcified (CP) plaque. RESULTS: The mean age was 59 ± 11 (55% male). Compared to the individuals not taking statins, those taking statins had higher prevalence of risk factors and obstructive CAD. In multivariable analyses, statin use was associated with increased the presence of MP [odds ratio (OR) 1.46, 95% confidence interval (CI) 1.27-1.68), p < 0.001] and CP (OR 1.54, 95% CI 1.36-1.74, p < 0.001), but not NCP (OR 1.11, 95% CI 0.96-1.29, p = 0.1). Further, in multivariable analyses, statin use was associated with increasing numbers of coronary segments possessing MP (OR 1.52, 95% CI 1.34-1.73, p < 0.001) and CP (OR 1.52, 95% CI 1.36-1.70, p < 0.001), but not coronary segments with NCP (OR 1.09, 95% CI 0.94-1.25, p = 0.2). CONCLUSION: Statin use is associated with an increased prevalence and extent of coronary plaques possessing calcium. The longitudinal effect of statins on coronary plaque composition warrants further investigation.

Mismatch Responses to Lexical Tone, Initial Consonant, and Vowel in Mandarin-speaking Preschoolers

The present study investigates how age, phonological saliency, and deviance size affect the presence of mismatch negativity (MMN) and positive mismatch response (P-MMR). This work measured the auditory mismatch responses to Mandarin lexical tones, initial consonants, and vowels in 4- to 6-year-old preschoolers using the multiple-deviant oddball paradigm. The data showed the coexistence of MMN and P-MMR in the same age group when responding to the three types of syllabic features in Mandarin. The transition from a predominantly positive response to a predominantly negative response supported the multiple MMN mechanisms. Congruent with the phonological saliency hypothesis and the phonetic acquisition order of Mandarin in behavioral studies, for the compulsory elements of Mandarin syllables, lexical tones, and vowels, the larger deviants elicited adult-like MMNs, whereas the smaller deviants elicited P-MMRs. The optional elements of the Mandarin syllables, the initial consonant, only elicited P-MMR in preschoolers. These findings suggest that MMN and P-MMR index different functional characteristics and may provide information on when and how children's speech perception becomes automatic at different developmental stages.

ICUD-EAU International Consultation on Bladder Cancer 2012: Non-Muscle-Invasive Urothelial Carcinoma of the Bladder

CONTEXT: Our aim was to present a summary of the Second International Consultation on Bladder Cancer recommendations on the diagnosis and treatment options for non-muscle-invasive urothelial cancer of the bladder (NMIBC) using an evidence-based approach. OBJECTIVE: To critically review the recent data on the management of NMIBC to arrive at a general consensus. EVIDENCE ACQUISITION: A detailed Medline analysis was performed for original articles addressing the treatment of NMIBC with regard to diagnosis, surgery, intravesical chemotherapy, and follow-up. Proceedings from the last 5 yr of major conferences were also searched. EVIDENCE SYNTHESIS: The major findings are presented in an evidence-based fashion. We analyzed large retrospective and prospective studies. CONCLUSIONS: Urothelial cancer of the bladder staged Ta, T1, and carcinoma in situ (CIS), also indicated as NMIBC, poses greatly varying but uniformly demanding challenges to urologic care. On the one hand, the high recurrence rate and low progression rate with Ta low-grade demand risk-adapted treatment and surveillance to provide thorough care while minimizing treatment-related burden. On the other hand, the propensity of Ta high-grade, T1, and CIS to progress demands intense care and timely consideration of radical cystectomy.

Histological Examination of Ulcer Margin for Diagnosing Helicobacter Pylori Infection in Patients with Gastric Ulcers

Biopsy of ulcer margin is routinely performed to exclude malignancy in patients with gastric ulcers, but its utility in diagnosing Helicobacter pylori infection has not yet been fully studied. A cohort of 50 patients with gastric ulcer was prospectively examined. Three tests including histology, rapid urease test, and urea breath test were performed in all patients for diagnosing H pylori infection. Six biopsied specimens from the margin of the gastric ulcer and 1 each specimen from antrum and body of non-ulcer part were obtained for histology using hematoxylin-eosin (H&E) stain. The criterion used for defining H pylori infection was a positive result in at least 2 of the 3 tests. H pylori infection was diagnosed in 27 (54%) of the patients. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of the histological examination of the ulcer margin were 92.6%, 95.7%, 96.2%, 91.7%, and 94%, respectively. The addition of 1 specimen from the antrum or body or a combination of the 2 specimens did not increase the diagnostic yields of those for histological examination of ulcer margin alone. The diagnostic sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for the rapid urease test were 96.3%, 100%, 100%, 95.8%, and 98%, respectively, and the corresponding values for the urea breath test were 88.9%, 87%, 88.9%, 87%, and 88%. We performed Giemsa stain for the 3 patients with false-negative and false-positive results of histological examination of ulcer margin using H&E stain, and all were positive for H pylori infection. In conclusion, histological examination of the ulcer margin using hematoxylin-eosin stain was quite accurate and useful for diagnosing H pylori infection in patients with gastric ulcers. A special stain is required when the diagnosis of H pylori infection is questionable on routine H&E staining.

TAK1 Ubiquitination Regulates Doxorubicin-induced NF-κB Activation

Chemotherapeutic agents- and radiation therapy-induced NF-κB activation in cancer cells contributes to aggressive tumor growth and resistance to chemotherapy and ionizing radiation during cancer treatment. TAK1 has been shown to be required for genotoxic stress-induced NF-κB activation. However, whether TAK1 ubiquitination is involved in genotoxic stress-induced NF-κB activation remains unknown. Herein, we demonstrate that TAK1 ubiquitination plays an important role in the positive and negative regulation of doxorubicin (Dox)-induced NF-κB activation. We found that TAK1 was required for Dox-induced NF-κB activation. At the early stage of Dox treatment, Dox induced Lys63-linked TAK1 polyubiquitination at lysine 158 residue. USP4 inhibited Dox-induced TAK1 Lys63-linked polyubiquitination and knockdown of USP4 enhanced Dox-induced NF-κB activation. At the late stage of Dox treatment, Dox induced Lys48-linked TAK1 polyubiquitination to promote TAK1 degradation. ITCH inhibited Dox-induced NF-κB activation by promoting Lys48-linked TAK1 polyubiquitination and its subsequent degradation. Our study indicates that TAK1 ubiquitination plays critical roles in the regulation of Dox-induced NF-κB activation. Thus, intervention of TAK1 kinase activity or TAK1 Lys63-linked polyubiquitination pathways might greatly enhance the therapeutic efficacy of Dox.

Loss of TIMP-3 Promotes Tumor Invasion Via Elevated IL-6 Production and Predicts Poor Survival and Relapse in HPV-Infected Non-Small Cell Lung Cancer

Human papillomavirus (HPV) 16/18 E6 oncoprotein is expressed in lung tumors and is associated with p53 inactivation. The tissue inhibitor of metalloproteinase 3 (TIMP-3) is essential for limiting inflammation; therefore, we expected that TIMP-3 loss might induce chronic inflammation, thereby promoting tumor malignancy as well as poor survival and relapse in patients with HPV-infected non-small cell lung cancer. In this study, the loss of TIMP-3 by loss of heterozygosity and/or promoter hypermethylation was more frequent in HPV16/18 E6-positive tumors than in E6-negative tumors. To explore the possible underlying mechanism, E6-negative TL4 and CL1-0 cells were transfected with an E6 cDNA plasmid. A marked decrease in TIMP-3 expression was caused by promoter hypermethylation via increased DNMT1 expression. Mechanistic studies indicated that TIMP-3 loss promoted interleukin-6 (IL-6) production, which led to cell invasion and anchorage-independent growth on soft agar plates. Kaplan-Meier and Cox regression models showed that patients with low-TIMP-3/high-IL-6 tumors had shorter overall survival and relapse-free survival periods when compared with patients with high-TIMP-3/low-IL-6 tumors. In summary, loss of TIMP-3 may increase IL-6 production via the tumor necrosis factor α/nuclear factor κB axis, thereby promoting tumor malignancy and subsequent relapse and poor survival in patients with HPV-infected non-small cell lung cancer.

A Relatively Low Level of Ribosome Depurination by Mutant Forms of Ricin Toxin A Chain Can Trigger Protein Synthesis Inhibition, Cell Signaling and Apoptosis in Mammalian Cells

The A chain of the plant toxin ricin (RTA) is an N-glycosidase that inhibits protein synthesis by removing a specific adenine from the 28S rRNA. RTA also induces ribotoxic stress, which activates stress-induced cell signaling cascades and apoptosis. However, the mechanistic relationship between depurination, protein synthesis inhibition and apoptosis remains an open question. We previously identified two RTA mutants that suggested partial independence of these processes in a yeast model. The goals of this study were to establish an endogenous RTA expression system in mammalian cells and utilize RTA mutants to examine the relationship between depurination, protein synthesis inhibition, cell signaling and apoptosis in mammalian cells. The non-transformed epithelial cell line MAC-T was transiently transfected with plasmid vectors encoding precursor (pre) or mature forms of wild-type (WT) RTA or mutants. PreRTA was glycosylated indicating that the native signal peptide targeted RTA to the ER in mammalian cells. Mature RTA was not glycosylated and thus served as a control to detect changes in catalytic activity. Both pre- and mature WT RTA induced ribosome depurination, protein synthesis inhibition, activation of cell signaling and apoptosis. Analysis of RTA mutants showed for the first time that depurination can be reduced by 40% in mammalian cells with minimal effects on inhibition of protein synthesis, activation of cell signaling and apoptosis. We further show that protein synthesis inhibition by RTA correlates more linearly with apoptosis than ribosome depurination.

Protection Against Cardiac Injury by Small Ca(2+)-sensitive K(+) Channels Identified in Guinea Pig Cardiac Inner Mitochondrial Membrane

We tested if small conductance, Ca(2+)-sensitive K(+) channels (SK(Ca)) precondition hearts against ischemia reperfusion (IR) injury by improving mitochondrial (m) bioenergetics, if O(2)-derived free radicals are required to initiate protection via SK(Ca) channels, and, importantly, if SK(Ca) channels are present in cardiac cell inner mitochondrial membrane (IMM). NADH and FAD, superoxide (O(2)(-)), and m[Ca(2+)] were measured in guinea pig isolated hearts by fluorescence spectrophotometry. SK(Ca) and IK(Ca) channel opener DCEBIO (DCEB) was given for 10min and ended 20min before IR. Either TBAP, a dismutator of O(2)()(-), NS8593, an antagonist of SK(Ca) isoforms, or other K(Ca) and K(ATP) channel antagonists, were given before DCEB and before ischemia. DCEB treatment resulted in a 2-fold increase in LV pressure on reperfusion and a 2.5 fold decrease in infarct size vs. non-treated hearts associated with reduced O(2)(-) and m[Ca(2+)], and more normalized NADH and FAD during IR. Only NS8593 and TBAP antagonized protection by DCEB. Localization of SK(Ca) channels to mitochondria and IMM was evidenced by a) identification of purified mSK(Ca) protein by Western blotting, immuno-histochemical staining, confocal microscopy, and immuno-gold electron microscopy, b) 2-D gel electrophoresis and mass spectroscopy of IMM protein, c) [Ca(2+)]-dependence of mSK(Ca) channels in planar lipid bilayers, and d) matrix K(+) influx induced by DCEB and blocked by SK(Ca) antagonist UCL1684. This study shows that 1) SK(Ca) channels are located and functional in IMM, 2) mSK(Ca) channel opening by DCEB leads to protection that is O(2)(-) dependent, and 3) protection by DCEB is evident beginning during ischemia.

Fibroblast Growth Factor 2 Enhances the Kinetics of Mesenchymal Stem Cell Chondrogenesis

Treatment of mesenchymal stem cells (MSCs) with fibroblast growth factor 2 (FGF-2) during monolayer expansion leads to increased expression of cartilage-related molecules during subsequent pellet chondrogenesis. This may be due to faster differentiation and/or a durable change in phenotype. In order to evaluate changes over time, we assessed chondrogenesis of human MSCs at early and late time points during pellet culture using real-time PCR, measurement of glycosaminoglycan accumulation, and histology. Marked enhancement of chondrogenesis was seen early compared to controls. However, the differences from controls in gene expression dramatically diminished over time. Depending on conditions, increases in glycosaminoglycan accumulation were maintained. These results suggest that FGF-2 can enhance the kinetics of MSC chondrogenesis, leading to early differentiation, possibly by a priming mechanism.

Two Novel Short C-type Lectin from Chinese Mitten Crab, Eriocheir Sinensis, Are Induced in Response to LPS Challenged

The basic mechanism of host fighting against pathogens is pattern recognition receptors recognized pathogen-associated molecular patterns. However, the specificity of recognition within the innate immune molecular of invertebrates remains largely unknown. For this reason, we investigated the immune functionality of two pattern recognition receptors, C-type lectin EsLecA and EsLecG, post lipopolysaccharides (LPS) challenge in Chinese mitten crab (Eriocheir sinensis), which is a commercially important and disease vulnerable aquaculture species. The cloning of full-length EsLecA and EsLecG cDNA were based on the initial expressed sequence tags (EST) isolated from a hepatopancreatic cDNA library via PCR. The EsLecA cDNA contained a 480-bp open reading frame that encoded a putative 159-amino-acid protein, while EsLecG cDNA contained a 465-bp open reading frame that encoded a putative 154-amino-acid protein. Comparison, with other reported invertebrate and vertebrate sequences, revealed the presence of carbohydrate recognition domains that were common among C-type lectin superfamilies. EsLecA and EsLecG mRNA expression in E. sinensis were (a) both detected in all tissues, including the hepatopancreas, gills, hemocytes, testis, accessory gland, ovary, muscle, stomach, intestine, heart, thoracic ganglia and brain, and (b) responsive in hepatopancreas, gill, hemocytes post-LPS immuno-challenge all appeared dramatically variation. Collectively, the data presented here demonstrate the successful isolation of two novel C-type lectins from the Chinese mitten crab, and their role in the innate immune system of an invertebrate.

Isolation of a New Meroterpene and Inhibitors of Nitric Oxide Production from Psoralea Corylifolia Fruits Guided by TLC Bioautography

A new meroterpene, psoracorylifol F (1), was isolated from Psoralea corylifolia fruits, along with two known meroterpenes (2 and 3), guided by TLC bioautography against O(2)(-) radicals. The structure of 1 was elucidated by means of NMR, HRESIMS, and X-ray crystallographic analysis. All the three metroterpenes possessed potential inhibitory activity against LPS-induced NO production in RAW 264.7 cells with IC(50) values ranging from 7.71 to 27.63μM.

Expression in Pichia Pastoris and Characterization of Echistatin, an RGD-containing Short Disintegrin

Echistatin (Ech) is a potent inhibitor of integrins and was isolated from snake Echis carinatus. To facilitate the study on the molecular determinants of integrin-ligand interactions, we expressed recombinant Ech and its mutants in the Pichia pastoris (P. pastoris) expression system and purified them to homogeneity with the yields of 2-7 mg/L. Ech produced in P. pastoris inhibited platelet aggregation with the IC(50) value of 210.5 nM. The sequential assignment and structure analysis of recombinant Ech were obtained by 2D and 3D (15)N-edited NMR spectra. These data suggests that Ech produced in P. pastoris retained its function and native fold. The results presented here provide the evidences that four disulfide-bonded peptide inhibitor of integrin, Ech, can be expressed in P. pastoris with correct fold and high yield. Platelet aggregation analysis of Ech mutants showed that the length of C-terminus and the K45 residue of Ech are important for interacting with integrin αIIbβ3. We also found that recombinant Ech can inhibit the migration of human A375 melanoma cell. These findings may serve as the basis for understanding the activities of Ech.

Vascular Peroxidase 1 Catalyzes the Formation of Hypohalous Acids: Characterization of Its Substrate Specificity and Enzymatic Properties

The heme-containing peroxidase family comprises eight members in humans. The physiological and pathophysiological roles of heme-containing peroxidases are not well understood. Phagocyte-derived myeloperoxidase (MPO) utilizes chloride and bromide, in the presence of hydrogen peroxide (H(2)O(2)), to generate hypochlorous acid and hypobromous acid, potent oxidizing species that are known to kill invading pathogens. Vascular peroxidase 1 (VPO1) is a new member of the heme-containing peroxidase family; VPO1 is highly expressed in the cardiovascular system, lung, liver, pancreas and spleen. However, functional roles of VPO1 have not been defined. In this report, we demonstrate the capacity for VPO1 to catalyze formation of hypohalous acids, and characterize its enzymatic properties. VPO1, like MPO but unlike lactoperoxidase, is able to generate hypochlorous acid, hypobromous acid and hypothiocyanous acid in the presence of H(2)O(2). Under physiological pH and concentrations of halides (100µM KBr, 100µM KSCN and 100mM NaCl), VPO1 utilizes approximately 45% of hydrogen peroxide for the generation of hypobromous acid, 35% for hypothiocyanous acid, and 18% for hypochlorous acid. The specific activity of VPO1 is ~10 to 70-fold lower than that of MPO, depending on the specific substrate. These studies demonstrate that the enzymatic properties and substrate specificity of VPO1 is similar to MPO; however, significantly lower catalytic rate constants of VPO1 relative to MPO suggest the possibility of other physiologic roles for this novel heme-containing peroxidase.

Neuromagnetic Index of Hemispheric Asymmetry Predicting Long-term Outcome in Sudden Hearing Loss

The neuromagnetic index of hemispheric asymmetry in terms of ipsilateral/contralateral ratio at acute stage was previously revealed to prognosticate the 1-month hearing outcome of acute unilateral idiopathic sudden sensorineural hearing loss (ISSNHL), showing a dynamic relationship between top- and down-levels of auditory pathway. However, the prognostic effect of reorganization pattern for the long-term results remained elusive. This study aimed to probe the prognosticating relevance of hemispheric asymmetry to the hearing at chronic stage of ISSNHL. Using magnetoencephalography (MEG), inter-hemispheric differences in peak dipole of N100m responses to monaural tones were evaluated in 21 controls and 21 ISSNHL patients at initial and final (12months later) stages. Predictive value of hemispheric asymmetry was assessed by correlating hearing level and ipsilateral/contralateral ratio (I/C) of N100m latency and amplitude. Healthy-side dominance of N100m was observed in ISSNHL initially, and remained in three final prognostic subgroups (complete, partial, and no recovery) of ISSNHL. The initial I/C(amplitude) on affected-ear stimulation strongly correlated with the hearing level of final stage in ISSNHL. However, there was no prognostic effect of hemispheric asymmetry pattern for the 12-month hearing improvement. The heterogeneity between neuromagnetic index and hearing levels possibly echoed different pathogeneses of ISSNHL. Since a restored hearing status did not necessarily lead toward a normal functional organization, the dynamics of hemispheric asymmetry could actually index a central resilient reorganization in the brain for sound processing in ISSNHL. Our finding showed not only a clinically relevant measure to predict final hearing of ISSNHL, but also a linkage between central plasticity and cochlear lesion. This finding suggests a new perspective, and perhaps new interventions, to diagnose and treat unilateral ISSNHL.

Enhanced Phosphoserine Insertion During Escherichia Coli Protein Synthesis Via Partial UAG Codon Reassignment and Release Factor 1 Deletion

Genetically encoded phosphoserine incorporation programmed by the UAG codon was achieved by addition of engineered elongation factor and an archaeal aminoacyl-tRNA synthetase to the normal Escherichia coli translation machinery (Park et al., 2011) Science 333, 1151) [2]. However, protein yield suffers from expression of the orthogonal phosphoserine translation system and competition with release factor 1 (RF-1). In a strain lacking RF-1, phosphoserine phosphatase, and where seven UAG codons residing in essential genes were converted to UAA, phosphoserine incorporation into GFP and WNK4 was significantly elevated, but with an accompanying loss in cellular fitness and viability.

Multilocular Cystic Renal Cell Carcinoma: Similarities and Differences in Immunoprofile Compared With Clear Cell Renal Cell Carcinoma

Multilocular cystic renal cell carcinoma (RCC) is an uncommon renal neoplasm composed of thin fibrous septa lining multiple cystic spaces and associated with an excellent prognosis. Clear cells with generally low-grade nuclear features line the cystic spaces and may be present within the fibrous septa, although solid mass-forming areas are by definition absent. Despite the excellent prognosis, molecular-genetic alterations are similar to those of clear cell RCC. Immunohistochemical staining characteristics, however, have not been well elucidated. We studied 24 cases of multilocular cystic RCC, classified according to the 2004 World Health Organization System. Immunohistochemical analysis was performed using an automated immunostainer for CD10, cytokeratin 7 (CK7), α-methylacyl-CoA-racemase, epithelial membrane antigen (EMA), cytokeratin CAM 5.2, carbonic anhydrase IX (CA-IX), estrogen/progesterone receptors, smooth muscle actin, PAX-2, and vimentin. Twenty-four cases of grade 1 to 2 clear cell RCC were stained for comparison. Multilocular cystic RCC and control cases of clear cell RCC showed the following results, respectively: CD10 (63%, 96%), CK7 (92%, 38%), α-methylacyl-CoA-racemase (21%, 67%), vimentin (58%, 33%), estrogen receptor (8%, 8%), CAM 5.2 (100%, 96%), EMA, CA-IX, PAX-2 (all 100%), and progesterone receptor (0%). Smooth muscle actin highlighted myofibroblastic cells within the septa of multilocular cystic RCC and the fine capillary vascular network of clear cell RCC. In summary, multilocular cystic RCC showed expression of common clear cell RCC markers CA-IX, EMA, and PAX-2, supporting the hypothesis that multilocular cystic RCC is a subtype of clear cell RCC. In contrast to clear cell RCC, tumors less frequently expressed CD10 (63% and often focal vs. 96% and diffuse) and more frequently expressed CK7 (92%), often diffusely (63%). Coexpression of CA-IX and CK7 represents a point of overlap with the recently described clear cell papillary RCC, which also may show a prominent cystic architecture. However, the latter lacks mutation of the VHL gene and deletion of chromosome 3p by molecular methodologies.

Alpha-momorcharin, a RIP Produced by Bitter Melon, Enhances Defense Response in Tobacco Plants Against Diverse Plant Viruses and Shows Antifungal Activity in Vitro

Alpha-momorcharin (α-MMC) is type-1 ribosome inactivating proteins (RIPs) with molecular weight of 29 kDa and has lots of biological activity. Our recent study indicated that the α-MMC purified from seeds of Momordica charantia exhibited distinct antiviral and antifungal activity. Tobacco plants pre-treated with 0.5 mg/mL α-MMC 3 days before inoculation with various viruses showed less-severe symptom and less reactive oxygen species (ROS) accumulation compared to that inoculated with viruses only. Quantitative real-time PCR analysis revealed that the replication levels of viruses were lower in the plants treated with the α-MMC than control plants at 15 days post inoculation. Moreover, the coat protein expression of viruses was almost completely inhibited in plants which were treated with the α-MMC compared with control plants. Furthermore, the SA-responsive defense-related genes including non-expressor of pathogenesis-related genes 1 (NPR1), PR1, PR2 were up-regulated and activities of some antioxidant enzymes including superoxide dismutase (SOD), catalase (CAT), peroxidase (POD) were increased after the α-MMC treatment. In addition, the α-MMC (500 μg/mL) revealed remarkable antifungal effect against phytopathogenic fungi, in the growth inhibition range 50.35-67.21 %, along with their MIC values ranging from 100 to 500 μg/mL. The α-MMC had also a strong detrimental effect on spore germination of all the tested plant pathogens along with concentration as well as time-dependent kinetic inhibition of Sclerotinia sclerotiorum. The α-MMC showed a remarkable antiviral and antifungal effect and hence could possibly be exploited in crop protection for controlling certain important plant diseases.

Oxidative Aliphatic C-H Fluorination with Fluoride Ion Catalyzed by a Manganese Porphyrin

Despite the growing importance of fluorinated organic compounds in drug development, there are no direct protocols for the fluorination of aliphatic C-H bonds using conveniently handled fluoride salts. We have discovered that a manganese porphyrin complex catalyzes alkyl fluorination by fluoride ion under mild conditions in conjunction with stoichiometric oxidation by iodosylbenzene. Simple alkanes, terpenoids, and even steroids were selectively fluorinated at otherwise inaccessible sites in 50 to 60% yield. Decalin was fluorinated predominantly at the C2 and C3 methylene positions. Bornyl acetate was converted to exo-5-fluoro-bornyl acetate, and 5α-androstan-17-one was fluorinated selectively in the A ring. Mechanistic analysis suggests that the regioselectivity for C-H bond cleavage is directed by an oxomanganese(V) catalytic intermediate followed by F delivery via an unusual manganese(IV) fluoride that has been isolated and structurally characterized.

A Killer-protector System Regulates Both Hybrid Sterility and Segregation Distortion in Rice

Hybrid sterility is a major form of postzygotic reproductive isolation that restricts gene flow between populations. Cultivated rice (Oryza sativa L.) consists of two subspecies, indica and japonica; inter-subspecific hybrids are usually sterile. We show that a killer-protector system at the S5 locus encoded by three tightly linked genes [Open Reading Frame 3 (ORF3) to ORF5] regulates fertility in indica-japonica hybrids. During female sporogenesis, the action of ORF5+ (killer) and ORF4+ (partner) causes endoplasmic reticulum (ER) stress. ORF3+ (protector) prevents ER stress and produces normal gametes, but ORF3- cannot prevent ER stress, resulting in premature programmed cell death and leads to embryo-sac abortion. Preferential transmission of ORF3+ gametes results in segregation distortion in the progeny. These results add to our understanding of differences between indica and japonica rice and may aid in rice genetic improvement.

Correction: Investigation of Indazole Unbinding Pathways in CYP2E1 by Molecular Dynamics Simulations

[This corrects the article on p. e33500 in vol. 7.].

Integrating Various Resources for Gene Name Normalization

The recognition and normalization of gene mentions in biomedical literature are crucial steps in biomedical text mining. We present a system for extracting gene names from biomedical literature and normalizing them to gene identifiers in databases. The system consists of four major components: gene name recognition, entity mapping, disambiguation and filtering. The first component is a gene name recognizer based on dictionary matching and semi-supervised learning, which utilizes the co-occurrence information of a large amount of unlabeled MEDLINE abstracts to enhance feature representation of gene named entities. In the stage of entity mapping, we combine the strategies of exact match and approximate match to establish linkage between gene names in the context and the EntrezGene database. For the gene names that map to more than one database identifiers, we develop a disambiguation method based on semantic similarity derived from the Gene Ontology and MEDLINE abstracts. To remove the noise produced in the previous steps, we design a filtering method based on the confidence scores in the dictionary used for NER. The system is able to adjust the trade-off between precision and recall based on the result of filtering. It achieves an F-measure of 83% (precision: 82.5% recall: 83.5%) on BioCreative II Gene Normalization (GN) dataset, which is comparable to the current state-of-the-art.

The Metabolic Responses to Aerial Diffusion of Essential Oils

Anxiety disorders are the most prevalent psychiatric disorders and affect a great number of people worldwide. Essential oils, take effects through inhalation or topical application, are believed to enhance physical, emotional, and spiritual well-being. Although clinical studies suggest that the use of essential oils may have therapeutic potential, evidence for the efficacy of essential oils in treating medical conditions remains poor, with a particular lack of studies employing rigorous analytical methods that capture its identifiable impact on human biology. Here, we report a comprehensive gas chromatography time-of-flight mass spectrometry (GC-TOFMS) based metabonomics study that reveals the aromas-induced metabolic changes and the anxiolytic effect of aromas in elevated plus maze (EPM) induced anxiety model rats. The significant alteration of metabolites in the EPM group was attenuated by aromas treatment, concurrent with the behavioral improvement with significantly increased open arms time and open arms entries. Brain tissue and urinary metabonomic analysis identified a number of altered metabolites in response to aromas intervention. These metabolic changes included the increased carbohydrates and lowered levels of neurotransmitters (tryptophan, serine, glycine, aspartate, tyrosine, cysteine, phenylalanine, hypotaurine, histidine, and asparagine), amino acids, and fatty acids in the brain. Elevated aspartate, carbohydrates (sucrose, maltose, fructose, and glucose), nucleosides and organic acids such as lactate and pyruvate were also observed in the urine. The EPM induced metabolic differences observed in urine or brain tissue was significantly reduced after 10 days of aroma inhalation, as noted with the loss of statistical significance on many of the metabolites in the aroma-EPM group. This study demonstrates, for the first time, that the metabonomics approach can capture the subtle metabolic changes resulting from exposure to essential oils and provide the basis for pinpointing affected pathways in anxiety-related behavior, which will lead to an improved mechanistic understanding of anxiolytic effect of essential oils.

Evolution of CT Imaging Features of Carotid Atherosclerotic Plaques in a 1-Year Prospective Cohort Study

PURPOSE: The purpose of this study was to identify imaging markers and clinical risk factors that significantly predict the evolution of computed tomography (CT) imaging features of carotid artery atherosclerotic disease over a 1-year period. METHODS: Our prospective study involved 120 consecutive patients undergoing emergent CT evaluation for symptoms of acute stroke. These patients were asked to consent to a follow-up CT exam in 1 year. To evaluate for atherosclerotic plaque, both at baseline and on follow-up, we employed a comprehensive computed tomography angiography (CTA) protocol that captured the carotid, vertebral, aortic, and coronary arteries. To further evaluate carotid artery plaque components, we used an automated classifier computer algorithm that distinguishes among the histological components of the carotid artery wall (lipids, calcium, fibrous tissue) based on appropriate thresholds of CT density. Baseline values of carotid imaging features and clinical variables were assessed for their ability to significantly predict changes in these imaging features over 1 year. RESULTS: Of these 120 consecutive patients, 17 received both a baseline and a follow-up CTA exam. Wall volume increased more when the largest lipid cluster was located close to the lumen (coefficient -7.61, -13.83 to -1.40, P= .016). The volume of lipid increased with age (coefficient .36, .21 to .50, P= .000), in smokers (coefficient 8.89, 6.82 to 10.95, P= .000) and when fewer lipid clusters were present at baseline (coefficient -0.11, -0.17 to -.04, P= .001). The volume of calcium increased with greater volume of lipid at baseline (coefficient .35, .02 to .68, P= .035) and in patients on statins (coefficient 4.79, 1.73 to 7.86, P= .002). CONCLUSIONS: There are a number of imaging markers and risk factors that significantly predict the evolution of CT imaging features of carotid artery atherosclerotic disease over a 1-year period.

Selection, Synthesis, and Anti-inflammatory Evaluation of the Arylidene Malonate Derivatives As TLR4 Signaling Inhibitors

Inhibition of TLR4 signaling is an important therapeutic strategy for intervention in the etiology of several pro-inflammatory diseases. There has been intensive research in recent years aiming to explore this strategy, and identify small molecule inhibitors of the TLR4 pathway. However, the recent failure of a number of advanced drug candidates targeting TLR4 signaling (e.g., TAK242 and Eritoran) prompted us to continue the search for novel chemical scaffolds to inhibit this critical inflammatory response pathway. Here we report the identification of a group of new TLR4 signaling inhibitors through a cell-based screening. A series of arylidene malonate analogs were synthesized and assayed in murine macrophages for their inhibitory activity against LPS-induced nitric oxide (NO) production. The lead compound 1 (NCI126224) was found to suppress LPS-induced production of nuclear factor-kappaB (NF-κB), tumor necrosis factor (TNF-α), interleukin-1β (IL-1β), and nitric oxide (NO) in the nanomolar-low micromolar range. Taken together, this study demonstrates that 1 is a promising potential therapeutic candidate for various inflammatory diseases.

Pulmonary Well-differentiated Fetal Adenocarcinoma with Platelet-derived Growth Factor Receptor (PDGFR)α Expression

Well-differentiated fetal adenocarcinoma (WDFA) is a rare pulmonary malignancy. Biomarkers of tumor biology has rarely been studied in WDFA. Here, we report two WDFA patients. Both patients had blood-streaked sputum or mild hemoptysis at presentation. They underwent lobectomy and systematic mediastinal lymphadenectomy. Expression of PDGFRα on the plasma membrane was demonstrated by immunohistochemistry (IHC) in the resected tumor specimens. Further IHC examination showed intense immunostaining of β-catenin in both patients but negative staining for TP53, CEA, CD56, EGFR, CK5/6, HER2, S-100, ER, PR, BCL2, and NSE. Both patients had no recurrence to date after more than 3 years of follow up. Herein, we reviewed this rare disease with special emphasis on the clinico-pathological features, treatment and potential role of PDGFRα.

Single-breath Vital Capacity High Concentration Sevoflurane Induction in Children: with or Without Nitrous Oxide?

BACKGROUND: /st>Single-breath vital capacity inhalation induction with high concentration sevoflurane (SBVC-HC) is a rapid and 'needleless' technique, preferred and well tolerated in the cooperative child. The addition of nitrous oxide may speed up induction by its second gas effects. Previous studies done in children looking at the effect of N(2)O on this technique lacked power and showed conflicting results. This study aims to investigate the effect of N(2)O on induction time for SBVC-HC sevoflurane induction in children. METHODS: /st>Eighty unpremedicated, ASA I and II children, aged 5-15 yr having elective surgical procedures under general anaesthesia, were recruited and randomized to: Group A: 8% sevoflurane in O(2) 6 litre min(-1), and Group B: 8% sevoflurane in N(2)O 4 litre min(-1) and O(2) 2 litre min(-1). The primary outcome was the time to 'loss of eyelash reflex'. The time to return of 'regular respiration' and 'conjugate gaze' were also noted. RESULTS: /st>The difference in the 'time to loss of eyelash reflex' was small but statistically significant. Group B: mean duration 53.6 s, standard deviation (sd) 16.1, compared with Group A: 63.5 s, sd 16.1 (mean difference 9.9, 95% confidence interval 2.5-17.3, P=0.01). Differences in the time to return of 'regular breathing' and 'conjugate gaze' were not statistically significant. Patients receiving N(2)O had less excitatory movements (P=0.007), but incidence of other adverse events was low and did not differ significantly between both groups. More than 94% of children would choose this method of induction again in both groups. CONCLUSIONS: /st>We conclude that for SBVC-HC sevoflurane induction in children, the addition of N(2)O resulted in faster loss of consciousness and reduced excitatory movements.

Notch1 Signaling Contributes to the Oncogenic Effect of HBx on Human Hepatic Cells

Hepatocellular carcinoma (HCC) is a malignant tumor and hepatitis B virus X protein (HBx) plays a crucial role in its pathogenesis. The Notch1 signaling pathway is involved in various malignant tumors including liver cancers and down-regulation of Notch-1 may exert anti-tumor effects. Here, we demonstrate that inhibition of Notch1 by plasmid-based shRNA suppresses growth of human hepatic cells transfected with HBx through G0/G1 cell cycle arrest and apoptosis inhibition, possibly linked to the promoted expression of cyclin-dependent kinase inhibitor, P16, and decreased expression of apoptosis inhibitor, Bcl-2. The anti-proliferative and pro-apoptotic effects of Notch1 shRNA in HBx-transformed L02 cell may be partly mediated by down-regulation of nuclear factor-kappaB (NF-κB) binding activities, demonstrating possible cross-talk between Notch-1 and NF-κB signaling pathways. The oncogene HBx may therefore induce malignant transformation of human hepatic cells via Notch1 pathway, indicating that Notch1 plays a crucial role in HBx-related liver cancer and could be an effective therapeutic target for HCC.

SIRT1 Pathway Dysregulation in the Smoke-exposed Airway Epithelium and Lung Tumor Tissue

Cigarette smoke produces a molecular "field of injury" in epithelial cells lining the respiratory tract. However, the specific signaling pathways that are altered in the airway of smokers and the signaling processes responsible for the transition from smoking-induced airway damage to lung cancer remain unknown. In this study, we use a genomic approach to study the signaling processes associated with tobacco smoke exposure and lung cancer. First, we developed and validated pathway-specific gene expression signatures in bronchial airway epithelium that reflect activation of signaling pathways relevant to tobacco-exposure including ATM, BCL2, GPX1, NOS2, IKBKB, and SIRT1. Using these profiles and four independent gene expression datasets, we found that SIRT1 activity is significantly up-regulated in cytologically normal airway epithelial cells from active smokers compared to non-smokers. In contrast, this activity is strikingly down-regulated in non-small cell lung cancer. This pattern of signaling modulation was unique to SIRT1, and down-regulation of SIRT1 activity is confined to tumors from smokers. Decreased activity of SIRT1 was validated using genomic analyses of mouse models of lung cancer and biochemical testing of SIRT1 activity in patient lung tumors. Together, our findings indicate a role of SIRT1 in response to smoke and a potential role in repressing lung cancer. Further, our findings suggest that the airway gene-expression signatures derived in this study can provide novel insights into signaling pathways altered in the "field of inury" induced by tobacco smoke and thus may impact strategies for prevention of tobacco-related lung cancer.

Prevalence of Adjacent Segment Degeneration After Spine Surgery: A Systematic Review and Meta-analysis

Study Design. Systematic review of published prevalence of adjacent segment degeneration (ASD) after spine surgery.Objective. The aim of this systematic review was to evaluate the prevalence of ASD in patients after cervical and lumbar spine surgery.Summary of Background Data. ASD is a common complication after spine surgery in long-term follow up. A large body of literature emerged, but no meta-analysis of the epidemiological data on ASD has been publishedMethods. We searched the MEDLINE until Match 2012 published in English that reported the prevalence of ASD after spine surgery. We calculated the ASD rates by calculating proportions and 95% CI for each study, and then pooled the data to derive a pooled proportion and 95% confidence interval (CI).Results. A total of 94 studies with 34,716 patients from 19 countries were included. The occurrence of radiograph ASD ranged from 4.8% to 92.2%, and the pooled prevalence was 29.3% (95% CI 22.7-35.8%) by the random effects model. The occurrence of symptoms ASD ranged from 0.0% to 30.3%, and the pooled prevalence was 7.4% (95% CI 6.4-8.5%). In cervical position, the occurrence of radiograph ASD and symptoms ASD was 32.8% (95% CI 17.8-47.9%) and 6.3% (95% CI 4.8-7.8%); in lumbar position, the occurrence of radiograph ASD and symptoms ASD was 26.6% (95% CI 21.3-31.9%) and 8.5% (95% CI 6.4-10.7%).In the 0.5-≤2 year, >2-≤5 year and >5-≤20 year diagnosis time, the radiograph ASD prevalence was 21.8% (16.0%-27.6%), 33.6% (21.8%-45.4%), and 37.4% (10.7%-64.1%), respectively; and the symptoms ASD prevalence was 6.5% (4.8%-8.1%), 12.1% (8.2%-16.0%), and 3.2% (2.5%-4.0%) respectively.Conclusion. Spine surgery is associated with significant risk of adjacent segment degeneration. These figures may be useful in the estimation of the burden of the adjacent segment degeneration after spine surgery.

Phylogenetic Diversity of Bacterial Endophytes of Panax Notoginseng with Antagonistic Characteristics Towards Pathogens of Root-rot Disease Complex

Endophytes play an important role in protection of host plants from infection by phytopathogens. Endophytic bacteria were isolated from five different parts (root, stem, petiole, leaf and seed) of Panax notoginseng and evaluated for antagonistic activity against Fusarium oxysporum, Ralstonia sp. and Meloidogyne hapla, three major pathogens associated with root-rot disease complex of P. notoginseng. From 1000 endophytic bacterial strains evaluated in vitro, 104 strains exhibited antagonistic properties against at least one of these three pathogens. Phylogenetic analyses of their 16S rRNA gene sequences showed that these 104 antagonistic bacteria belong to four clusters: Firmicutes, Proteobacteria, Actinobacteria and Bacteroidetes/Chlorobi. Members of the Firmicutes, in particular the Bacillus spp., were predominant in all analyzed tissues. The root was the main reservoir for antagonistic bacteria. Of the 104 antagonists, 51 strains showed antagonistic activities to one pathogen only, while 43 and 10 displayed the activities towards two and all three pathogens, respectively. The most dominant species in all tissues were Bacillus amyloliquefaciens subsp. plantarum and Bacillus methylotrophicus, which were represented by eight strains with broad antagonistic spectrum to the all three test pathogens of root-rot disease complex of P. notoginseng.

Peripapillary Atrophy Detection by Sparse Biologically Inspired Feature Manifold

Peripapillary atrophy (PPA) is an atrophy of preexisting retina tissue. Because of its association with eye diseases such as myopia and glaucoma, PPA is an important indicator for diagnosis of these diseases. Experienced ophthalmologists are able to determine the presence of PPA using visual information from the retinal images. However, it is tedious, time consuming and subjective to examine all images especially in a screening program. This paper presents biologically inspired feature (BIF) for the automatic detection of PPA. BIF mimics the process of cortex for visual perception. In the proposed method, a focal region is segmented from the retinal image and the BIF is extracted. As BIF is an intrinsically low dimensional feature embedded in a high dimensional space, it is not suitable to measure the similarity between two BIFs directly based on the Euclidean distance. Therefore, it is necessary to obtain a suitable mapping to reduce the dimensionality. In this paper, we explore sparse transfer learning to transfer the label information from ophthalmologists to the sample distribution knowledge contained in all samples. Selective pair-wise discriminant analysis is used to define two strategies of sparse transfer learning: negative and positive sparse transfer learning. Experimental results show that negative sparse transfer learning is superior to the positive one for this task. The proposed BIF based approach achieves an accuracy of more than 90% in detecting PPA, much better than previous methods. It can be used to save the workload of ophthalmologists and thus reduce the diagnosis costs.

Combining MR Elastography and Diffusion Tensor Imaging for the Assessment of Anisotropic Mechanical Properties: A Phantom Study

PURPOSE: To investigate the anisotropic elasticity of soft tissues using MR elastography (MRE) combined with diffusion tensor imaging (DTI). MATERIALS AND METHODS: The storage moduli parallel (μ(‖) ) and perpendicular (μ(⟂) ) to the local fiber orientation were calculated assuming a transversely isotropic model. The local fiber orientation was provided by DTI. The proposed technique was validated against rheometry using anisotropic viscoelastic phantoms with various fiber volume fractions (V(f) = 0%, 15%, and 35%) and bovine skeletal muscle samples. RESULTS: The anisotropic ratio (μ(‖) /μ(⟂) ) as measured by MRE correlated well with rheometry for all samples (R(2) = 0.809). The combined MRE/DTI technique was also able to differentiate different levels of mechanical anisotropy with the mechanical anisotropy (μ(‖) /μ(⟂) ) of the V(f) = 35% phantoms being significantly higher than the V(f) = 15% and the isotropic (V(f) = 0%) phantoms. The bovine muscle samples showed significantly higher mechanical anisotropy than all phantoms. CONCLUSION: This study has demonstrated the feasibility of the proposed imaging technique for characterizing mechanical anisotropy of anisotropic materials and biological tissues, and validated the mechanical anisotropy results. J. Magn. Reson. Imaging 2012. © 2012 Wiley Periodicals, Inc.

Inequality and Inequity in Access to Health Care and Treatment for Chronic Conditions in China: the Guangzhou Biobank Cohort Study

Non-communicable diseases (NCDs) are a large and rapidly-growing problem in China and other middle-income countries. Clinical treatment of NCDs is long-term and expensive, so it may present particular problems for equality and horizontal equity (equal treatment for equal need) in access to health care, although little is known about this at present in low- and middle-income countries. To address this gap, and inform policy for a substantial proportion of the global population, we examined inequality and inequity in general health care utilization (doctor consultations and hospital admissions) and in treatment of chronic conditions (hypertension, hyperglycaemia and dyslipidaemia), in 30 499 Chinese adults aged ≥50 years from one of China's richest provinces, using the Guangzhou Biobank Cohort Study (2003-2008). We used concentration indices to test for inequality and inequity in utilization by household income per head. Inequality was decomposed to show the contributions of income, indicators of 'need for health care' (age, sex, self-rated health, coronary heart disease risk and chronic obstructive pulmonary disease) and non-need factors (education, occupation, out-of-pocket health care payments and health insurance). We found inequality and inequity in treatment of chronic conditions but not in general health care utilization. Using more objective and specific measures of 'need for health care' increased estimates of inequity for treatment of chronic conditions. Income and non-need factors (especially health insurance, education and occupation) made the largest contributions to inequality. Further work is needed on why access to treatment for chronic conditions in China is restricted for those on low incomes and how these inequities can be mitigated.

Impaired Mitochondrial Respiration and Decreased Fatigue Resistance Followed by Severe Muscle Weakness in Skeletal Muscle of MtDNA Mutator Mice

Mitochondrial dysfunction can drastically impair muscle function with weakness and exercise intolerance as key symptoms. Here, we examine the time course of development of muscle dysfunction in a mouse model of premature ageing induced by defective proofreading function of mitochondrial DNA (mtDNA) polymerase (mtDNA mutator mouse). Isolated fast-twitch muscles and single muscle fibres from young (3-5 months) and end-stage (11 months) mtDNAmutator mice were compared to age-matched control mice. Force and free myoplasmic [Ca2+] ([Ca2+]i) were measured under resting conditions and during fatigue induced by repeated tetani. Muscles of young mtDNA mutator mice displayed no weakness in the rested state, but had lower force and [Ca2+]I than control mice during induction of fatigue. Muscles of young mtDNA mutator showed decreased activities of citrate synthase and β-hydroxyacyl-CoA dehydrogenase, reduced expression of cytochrome c oxidase; and decreased expression of triggers of mitochondrial biogenesis (PGC-1α, PPAR α, AMPK). Muscles from end-stage mtDNA mutator mice showed weakness under resting conditions with markedly decreased tetanic [Ca2+]i, force per cross-sectional area and protein expression of the sarcoplasmic reticulum Ca2+ pump (SERCA1). In conclusion, fast-twitch muscles of prematurely ageing mtDNA mutator mice display a sequence of deleterious mitochondrial-to-nucleus signalling with an initial decrease in oxidative capacity, which was not counteracted by activation of signalling to increase mitochondrial biogenesis. This was followed by severe muscle weakness in the end-stage. These results have implication for normal ageing and suggest that decreased mitochondrial oxidative capacity due to a sedentary life style may predispose for muscle weakness developing later in life.

Glycosyltransferase-specific Golgi Targeting Mechanisms

Glycosylation of secreted and membrane-bound mucins is carried out by glycosyl-transferases localized to specific Golgi compartments according to the step in which each enzyme participates. However, the Golgi targeting mechanisms of these enzymes are not clear. Herein, we investigate the Golgi targeting mechanisms of core 1 β3 galactosyltransferase (C1GalT1) and core 2 N-acetylglucosaminyltransferase 2/M (C2GnT-2/M), which participate in the early O-glycosylation steps. siRNAs, co-immuno-precipitation and confocal fluorescence microscopy were employed to identify the golgins involved in the Golgi docking of vesicular complexes (VCs) that carry these two enzymes. We have found that these VCs use different golgins for docking: C2GnT-M-VC utilizes Giantin while C1GalT1-VC employs GM130-GRASP65 complex. However, in the absence of GRASP65, C1GalT1-VC utilizes GM130-Giantin complex. Also, we have found that these VCs are 1.1-1.2 μm in diameter, specific for each enzyme, and independent of COPII and COPI. These two fluorescently-tagged enzymes exhibit different fluorescence recovery times in the Golgi after photobleaching. Thus, novel enzyme-specific Golgi targeting mechanisms are employed by glycosyltransferases, and multiple Golgi docking strategies are utilized by C1GalT1.

The Interaction of CDK12/CrkRS with CYCLIN K1 is Required for the Phosphorylation of the C-terminal Domain of RNA Pol II

CrkRS (Cdc2-related kinase, Arg/Ser), or CDK12 (Cyclin Dependent Kinase 12), is a serine/threonine kinase believed to coordinate transcription and RNA splicing. While CDK12/CrkRS complexes were known to phosphorylate the C-Terminal Domain (CTD) of RNA Pol II, the cyclin regulating this activity was not known. Using immunoprecipitation and mass spectrometry, we identified a 65 KDa isoform of CYCLIN K (K1) in endogenous CDK12/CrkRS protein complexes. We show that CYCLIN K1 complexes isolated from mammalian cells contain CDK12/CrkRS but do not contain CDK9, a presumed partner of CYCLIN K. Analysis of extensive RNA-seq data shows that the 65 KDa CYCLIN K1 isoform is the predominantly expressed form across numerous tissue types. We also demonstrate that CDK12/CrkRS is dependent on CYCLIN K1 for its kinase activity and siRNA knockdown of CDK12/CrkRS or CYCLIN K1 have similar affects on the expression of a luciferase reporter gene. Our data suggest that CYCLIN K1 is the primary cyclin partner for CDK12/CrkRS and CYCLIN K1 is required to activate CDK12/CrkRS to phosphorylate the CTD of RNA Pol II. These properties are consistent with a role of CDK12/CrkRS in regulating gene expression through phosphorylation of RNA Pol II.

Celiac Artery Compression Syndrome: an Experience in a Single Institution in Taiwan

Celiac artery compression syndrome (CACS) or median arcuate ligament (MAL) syndrome is a rare vascular disease. The clinical manifestations of CACS include the triad of postprandial pain, vomiting, and weight loss. The pathogenesis of CACS is the external compression of celiac artery by the MAL or celiac ganglion. Moreover, some authors also reported the compression with different etiologies, such as neoplasms of pancreatic head, adjacent duodenal carcinoma, vascular aneurysms, aortic dissection, or sarcoidosis. In the literature, most cases of CACS were reported from Western countries. In contrast, this disease was seldom reported in Oriental countries or regions, including Taiwan. Superior mesenteric artery syndrome (SMAS) is also a rare disease characterized by compression of the third portion of the duodenum by the SMA. The clinical features of SMAS are postprandial pain, vomiting, and weight loss. To date, there are no guidelines to ensure the proper treatment of patients with CACS because of its low incidence. Thus, tailored therapy for patients with CACS remains a challenge as well as the prediction of clinical response and prognosis. The aim of our present study was to investigate the clinical features, the association with SMAS, treatments, and outcomes of patients with CACS in a single institution in Taiwan.

Analysis of LRRK2 Accessory Repeat Domains: Prediction of Repeat Length, Number and Sites of Parkinson's Disease Mutations

Various investigators have identified the major domain organization of LRRK2 (leucine-rich repeat kinase 2), which includes a GTPase ROC (Ras of complex proteins) domain followed by a COR (C-terminal of ROC) domain and a protein kinase domain. In addition, there are four domains composed of structural repeat motifs likely to be involved in regulation and localization of this complex protein. In the present paper, we report our bioinformatic analyses of the human LRRK2 amino acid sequence to predict the repeat size, number and likely boundaries for the armadillo repeat, ankyrin repeat, the leucine-rich repeat and WD40 repeat regions of LRRK2. Homology modelling using known protein structures with similar domains was used to predict structures, exposed residues and location of mutations for these repeat regions. We predict that the armadillo repeats, ankyrin repeats and leucine-rich repeats together form an extended N-terminal flexible 'solenoid'-like structure composed of tandem repeat modules likely to be important in anchoring to the membrane and cytoskeletal structures as well as binding to other protein ligands. Near the C-terminus of LRRK2, the WD40 repeat region is predicted to form a closed propeller structure that is important for protein complex formation.

Primary and Secondary Metabolism in the Sun-exposed Peel and the Shaded Peel of Apple Fruit

The metabolism of carbohydrates, organic acids, amino acids, and phenolics was compared between the sun-exposed peel and the shaded peel of apple fruit. Contents of sorbitol and glucose were higher in the sun-exposed peel, whereas those of sucrose and fructose were almost the same in the two peel types. This was related to lower sorbitol dehydrogenase activity and higher activities of sorbitol oxidase, neutral invertase, and acid invertase in the sun-exposed peel. The lower starch content in the sun-exposed peel was related to lower sucrose synthase activity early in fruit development. Dark respiratory metabolism in the sun-exposed peel was enhanced by the high peel temperature due to high light exposure. Activities of most enzymes in respiratory metabolism were higher in the sun-exposed peel, but the concentrations of most organic acids were relatively stable, except pyruvate and oxaloacetate. Due to the different availability of carbon skeletons from dark respiration in the two peel types, amino acids with higher C/N ratios accumulated in the sun-exposed peel whereas those with lower C/N ratios accumulated in the shaded peel. Contents of anthocyanins and flavonols and activities of phenylalanine ammonia-lyase, UDP-galactose:flavonoid 3-O-glucosyltransferase, and several other enzymes were higher in the sun-exposed peel than in the shaded peel, indicating the entire phenylpropanoid pathway is up-regulated in the sun-exposed peel. Comprehensive analyses of the metabolites and activities of enzymes involved in primary metabolism and secondary metabolism have allowed us to gain a full picture of the metabolic network in the two peel types under natural light exposure.

Editorial Comment to Malignant Mixed Epithelial and Stromal Tumor of the Kidney: Report of the First Male Case

[Upper Gastrointestinal Bleeding and Hyperglycemia Induced by Acute Alcoholism in an Infant]

[Expression and Bioinformatic Analysis of Ornithine Aminotransferase 
in Non-small Cell Lung Cancer]

It has been proven that ornithine aminotransferase (OAT) might play an important role in the oncogenesis and progression of numerous malignant tumors. The aim of this study is to detect the mRNA and protein expression of OAT in non-small cell lung cancer (NSCLC), as well as to analyze the bioinformatic features and binary interactions.

Malignant Solitary Fibrous Tumor of the Urinary Bladder

A 67-year-old man was examined for persistent pain over his lower abdomen and was found to have a large pelvic tumor. During surgery, we detected a 16 × 9 × 9 cm(3) urinary bladder tumor with small intestinal adhesions, and performed partial cystectomy and segmental resection. Histological and immunohistochemical examinations established the diagnosis of malignant solitary fibrous tumor (SFT). Only 10 cases of urinary bladder SFT have been reported in the English literature; our patient is the second one with malignancy and had a longer follow-up period than the other case.

Acute Bilateral Hearing Loss As a "worsening Sign" in a Patient with Critical Basilar Artery Stenosis

We report a patient who presented with an acute-onset transient vertigo and unsteady gait with bilateral hearing loss. Brain MRI revealed a critical basilar artery (BA) stenosis at the lower pons and infarction in various areas on both sides in the territories of the posterior inferior cerebellar arteries (PICA). Further, we could not visualize the right anterior inferior cerebellar artery (AICA). The bilateral hearing loss may be ascribed to stroke due to the critical BA stenosis, causing hypoperfusion injury extending from the PICA to the AICA on both sides. Local intra-arterial thrombolytic therapy with the administration of 1×10(6) IU of urokinase aided partial recanalization of the BA, after which the right AICA reappeared. The neurological function of the patient recovered to normal, and no hemorrhagic complications were observed. Therefore, practitioners should be alert when treating patients with acute bilateral hearing loss, which may be related to an underlying catastrophic stroke.

The Role of the Basal Ganglia in Decision Making: a New FMRI Study

KRAS Testing in Clinical Laboratory: Optimizing Targeted Therapy

Background/Aim: Activating mutations in the KRAS gene are found in more than 30% of colorectal tumors, where they are associated with a poor response to anti-epidermal growth factor receptor therapies. Mutation testing techniques have therefore become an urgent concern. Several methods for KRAS mutation detection have been described in the literature. Most of these are laboratory developed tests and only a few commercial assays are currently available.

Tracheal Intubation Performed with GlideScope® Video Laryngoscope and Direct Laryngoscopy in Neonates and Infants

A Piece of My Mind. Food for Thought

Double-stranded RNA Induces Molecular and Inflammatory Signatures That Are Directly Relevant to COPD

Polyinosinic:polycytidylic acid (poly I:C) is a synthetic analogue of double-stranded (ds)RNA, a molecular pattern associated with viral infections, that is used to exacerbate inflammation in lung injury models. Despite its frequent use, there are no detailed studies of the responses elicited by a single topical administration of poly I:C to the lungs of mice. Our data provides the first demonstration that the molecular responses in the airways induced by poly I:C correlate to those observed in the lungs of chronic obstructive pulmonary disease (COPD) patients. These expression data also revealed three distinct phases of response to poly I:C, consistent with the changing inflammatory cell infiltrate in the airways. Poly I:C induced increased numbers of neutrophils and natural killer cells in the airways, which were blocked by CXCR2 and CCR5 antagonists, respectively. Using gene set variation analysis on representative clinical data sets, gene sets defined by poly I:C-induced differentially expressed genes were enriched in the molecular profiles of COPD but not idiopathic pulmonary fibrosis patients. Collectively, these data represent a new approach for validating the clinical relevance of preclinical animal models and demonstrate that a dual CXCR2/CCR5 antagonist may be an effective treatment for COPD patients.Mucosal Immunology advance online publication 19 September 2012; doi:10.1038/mi.2012.86.

A Randomized, Double-blind, Multiple-dose Escalation Study of a Chinese Herbal Medicine Preparation (Dang Gui Buxue Tang) for Moderate to Severe Menopausal Symptoms and Quality of Life in Postmenopausal Women

OBJECTIVE: This study is a phase II clinical trial that aims to investigate the dose-response relationship of a Chinese herbal medicine preparation, Dang Gui Buxue Tang (DBT), with short-term menopausal symptoms and quality of life in local postmenopausal women. METHODS: A randomized, double-blind, multiple-dose escalation trial was performed in 60 postmenopausal women experiencing severe hot flashes and night sweats. The participants were randomized to receive DBT preparations at 1.5, 3.0, or 6.0 g/day for 12 weeks. The primary outcomes were vasomotor symptoms, Greene Climacteric Scale (GCS) score, and Menopause-Specific Quality of Life (MENQOL) score. Secondary outcomes included serum hormones and lipids. RESULTS: There were between-group differences in psychological/psychosocial (P = 0.015, GCS; P = 0.013, MENQOL) and somatic/physical (P = 0.019, GCS; P = 0.037, MENQOL) domains, and improvement was significantly greatest (P < 0.05) in the 6.0 g/day dose group. The frequency and severity of hot flashes and night sweats were significantly reduced in the 3.0 g/day (14.5%-21.2%, P < 0.05, hot flashes; 28.6%-39.6%, P < 0.05, night sweats) and 6.0 g/day (34.9%-37.4.0%, P < 0.01, hot flashes; 10.1%-12.8%, P < 0.01, night sweats) dose groups. The female hormones follicle-stimulating hormone, luteinizing hormone, and 17β-estradiol, as well as the lipids total cholesterol, triglycerides, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol, were not significantly different within groups and between groups. CONCLUSIONS: DBT preparations at 6.0 g/day significantly improve physical and psychological scores and significantly reduce vasomotor symptoms from baseline. The treatment was well tolerated, with no serious adverse events noted during the 12-week intervention period. The changes do not affect hormones and lipid profiles.

[Comparative Study of Endoscopic Musoucal Resection with Transparent Cap and Endoscopic Multi-band Mucosectomy for Early Esophageal Cancer and Precancerous Lesion]

To evaluate the efficacy and safety of endoscopic musoucal resection with transparent cap(EMR-Cap) and endoscopic multi-band mucosectomy(MBM) in the treatment of early esophageal cancer and precancerous lesion.

Mechanically Strong, Optically Transparent, Giant Metal Superlattice Nanomembranes From Ultrathin Gold Nanowires

Metallic membranes of about 2.5 nm thick but with macroscopic lateral dimensions have been successfully fabricated from ultrathin gold nanowires. Such metallic nanomembranes are transparent, conductive and mechanically strong, with an optical transmittance of 90-97%, an electrical resistance of ∼1142 kΩ sq(-1) , and a breaking strength of ∼14 N m(-1) with a typical atomic force microscope probe.

Gamma-irradiation Reduces the Allogenicity of Donor Corneas

Purpose: To evaluate the utility and allogenicity of gamma-irradiated corneal allografts. Methods: Corneal buttons were harvested from C57BL/6 mice and decellularized with gamma-irradiation. Cell viability was assessed using TUNEL and viability/cytotoxicity assays. Orthotopic penetrating keratoplasty was performed using irradiated or non-irradiated (freshly excised) C57BL/6 donor grafts and BALB/c or C57BL/6 recipients. Graft opacity was assessed over an 8 week period and graft survival was evaluated using Kaplan-Meier survival curves. Mixed-lymphocyte reactions and delayed-type hypersensitivity assays were performed to evaluate T cell alloreactivity. Real-time polymerase chain reaction was employed to investigate the corneal expression of potentially pathogenic T helper 1, 2, and 17 cell-associated cytokines. Results: Corneal cells were devitalized by gamma-irradiation as evidenced by widespread cellular apoptosis and plasma membrane disruption. Non-irradiated allograft and isograft rates of survival were superior to irradiated allograft and isograft rates of survival (P < 0.001). Mixed lymphocyte reactions demonstrated that T cells from irradiated allograft recipients did not exhibit a secondary alloimmune response (P < 0.001). Delayed-type hypersensitivity assays demonstrated that irradiated allografts did not elicit an alloreactive delayed-type hypersensitivity response in graft recipients (P ≤ 0.01). The corneal expression of T helper 1, 2, and 17 cell-associated cytokines was significantly lower in failed irradiated allografts than rejected non-irradiated allografts (P ≤ 0.001). Conclusions: Gamma-irradiated corneas failed to remain optically clear following murine penetrating keratoplasty; however, gamma-irradiation reduced the allogenicity of these corneas, potentially supporting their use in procedures such as anterior lamellar keratoplasty or keratoprosthesis implantation.

Reporting of Incorrect Cause-of-death Causal Sequence on Death Certificates in the USA: Using Hypertension and Diabetes As an Educational Illustration

BACKGROUND: Little is known about the extent of reporting an incorrect cause-of-death (COD) causal sequence on death certificates. OBJECTIVE: To determine the frequency of incorrect reporting of hypertension as cause of diabetes on death certificates in the USA. METHODS: Multiple-cause mortality files were used to identify death certificates which mentioned both hypertension and diabetes in the USA from 1985 to 2005. The frequency of reporting hypertension on the line below diabetes in part I of the death certificate was calculated. RESULTS: The percentage of cases in which both hypertension and diabetes were included in part I of the death certificate, in which hypertension was reported on the line below diabetes on the death certificate-that is, suggesting that hypertension was a cause of diabetes-increased from 15.5% in 1985 to 36.1% in 2000 and 38.2% in 2005. CONCLUSIONS: The frequency of reporting of an incorrect COD causal sequence on death certificates in the USA has increased. Education, training and questioning the opinions of certifying physicians are needed to improve the quality of reporting of COD statements.

The Integration and Functional Evaluation of Rabbit Pacing Cells Transplanted into the Left Ventricular Free Wall

To evaluate the feasibility of cell transplantation to treat bradyarrhythmia, we analyzed the in vivo integration and pacing function after transplantation of mHCN4-modified rabbit bone marrow mesenchymal stem cells (MSCs) into the rabbit left ventricle free wall epicardium. In our investigation, we injected MSCs transduced with or without mHCN4 into the rabbit left ventricle free wall epicardium. Chemical ablation of the sinoatrial node was performed and bilateral vagus nerves were sequentially stimulated to observe premature left ventricular contraction or left ventricular rhythm. We found that the mHCN4-transduced MSC group had a significantly higher ventricular rate and a shorter QRS duration than that of the control and EGFP group. Furthermore, the mHCN4-transduced MSCs, but not the control cells, gradually adapted long-spindle morphology and became indistinguishable from adjacent ventricle myocytes. The modified MSCs showed pacing function approximately 1 week after transplantation and persisted at least 4 weeks after transplantation. In conclusion, a bradyarrhythmia model can be successfully established by chemical ablation of the sinoatrial node and sequential bilateral vagus nerve stimulation. The mHCN4-modified rabbit MSCs displayed evident dynamic morphology changes after being transplanted into rabbit left ventricle free wall epicardium. Our studies may provide a promising strategy of using modified stem cell transplantation to treat bradyarrhythmia.

Clinical Significance of ErbB Receptor Family in Urothelial Carcinoma of the Bladder: A Systematic Review and Meta-Analysis

The prognostic importance of examining ErbB receptor family expression in human bladder cancer remains uncertain. Using published evidence, we examined the clinical value and the updated results of clinical trials targeting ErbB receptor family members. Twenty-seven articles from 65 references related to ErbB receptor expression assessment in bladder cancer were reviewed. The estimates included the association significance, hazard ratios, and 95% confidence intervals (CIs) from actuarial curves and survival analyses. A meta-analysis was done on those reports using univariate log-rank tests or a Cox-regression model. The methods of analysis and study subjects chosen varied widely among studies. The overall risks of disease progression for patients with EGFR or ErbB2 overexpression were 4.5 (95% CI: 2.5-8.4) and 1.1 (95% CI: 0.6-1.9), and the risks of mortality were 3.0 (95% CI: 1.6-5.9) and 1.1 (95% CI: 1.0-1.2), respectively. However, the significance of coexpression patterns of the ErbB receptor family remains controversial. None of six clinical trials yielded convincing results for blockading ErbB receptor signaling in urothelial carcinoma. The results of this analysis suggest that assessing co-expression patterns of the ErbB family may provide better prognostic information for bladder cancer patients.

Development and Application of Specific Polymerase Chain Reaction Assay Targeting the GyrB Gene for Rapid Detection of Riemerella Anatipestifer

A pair of PCR primers was designed and synthesized to amplify a gyrB gene sequence from Riemerella anatipestifer (RA). A fragment of 194 bp was detected in RA-positive isolates, whereas other isolates were negative, which confirmed the high specificity of the primers and PCR conditions. As little as 1.6 × 10(4) cfu/mL of cultural liquid was required by this method. We compared a 16S rRNA sequence-based PCR method and a Biolog bacterial identification system used in the detection and identification of suspicious isolates of RA in clinical tests. The results showed that the gyrB-based PCR was consistent with the results of the Biolog identification system and was more specific. By applying the gyrB-PCR to detect RA strains in 56 duck livers, a positive rate of 46% (26/56) was observed, whereas the positive rate of 85 throat swabs from clinically healthy ducks was 11%. Thus, this method could be used for the epidemiological investigation and preliminary isolate identification of RA.

Molecular Cloning, Characterization, and Expression Analysis of the Muscovy Duck Toll-like Receptor 3 (MdTLR3) Gene

Toll-like receptor 3 (TLR3) is an important membrane-bound receptor for recognizing double-stranded RNA in innate immunity. In this study, we described the cloning and characterization of the Muscovy duck TLR3 (MdTLR3) gene. The full-length MdTLR3 cDNA (2,836 bp) encoded a polypeptide of 895 amino acids. The deduced amino acid sequence contained 4 main structural domains: a signal peptide, an extracellular leucine rich repeats domain, a transmembrane domain, and a Toll/IL-1 receptor domain. Quantitative real-time PCR analysis indicated that MdTLR3 mRNA was constitutively expressed in all sampled tissues of uninfected Muscovy duck except muscle. Expression of MdTLR3 in brain was significantly upregulated at 24 h (1.94-fold, P < 0.05), reached a peak at 48 h (4.64-fold, P < 0.05), and recovered to normal levels at 72 h postinfection with the H5N1 highly pathogenic avian influenza virus. In contrast, MdTLR3 expression was downregulated during the test period in spleen and lung. These results implicated MdTLR3 was a novel member of the TLR family, which is involved in the early stage of antiviral innate immunity.

New Therapeutic Approaches for Malignant Glioma: in Search of the Rosetta Stone

Malignant gliomas are heterogeneous, diffuse and highly infiltrating by nature. Despite wide surgical resection and improvements in radio- and chemotherapies, the prognosis of patients with glioblastoma multiforme remains extremely poor, with a median survival time of only 14.5 months from diagnosis to death. Particular challenges for glioblastoma multiforme therapy are posed by limitations in the extent of feasible surgical resections, distinct tumor heterogeneity, difficulties in drug delivery across the blood-brain barrier and low drug distribution within the tumor. Therefore, new paradigms permitting tumor-specific targeting and extensive intratumoral distribution must be developed to allow an efficient therapeutic delivery. This review highlights the latest advances in the treatment of glioblastoma multiforme and the recent developments that have resulted from the interchange between preclinical and clinical efforts. We also summarize and discuss novel therapies for malignant glioma, focusing on advances in the following main topics of glioblastoma multiforme therapy: immunotherapy, gene therapy, stem cell-based therapies and nanotechnology. We discuss strategies and outcomes of emerging therapeutic approaches in these fields, and the main challenges associated with the integration of discoveries that occur in the laboratory into clinical practice.

[Analysis of the Epidemiological Characteristics of Hepatitis E and Genotypes of Hepatitis E Virus Among Drug Users]

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