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The bHLH transcription factors that regulate early development of the central nervous system can generally be classified as either antineural or proneural. Initial expression of antineural factors prevents cell cycle exit and thereby expands the pool of neural progenitors. Subsequent (and typically transient) expression of proneural factors promotes cell cycle exit, subtype specification, and differentiation. Against this backdrop, the bHLH transcription factor Olig2 in the oligodendrocyte lineage is unorthodox, showing antineural functions in multipotent CNS progenitor cells but also sustained expression and proneural functions in the formation of oligodendrocytes. We show here that the proliferative function of Olig2 is controlled by developmentally regulated phosphorylation of a conserved triple serine motif within the amino-terminal domain. In the phosphorylated state, Olig2 maintains antineural (i.e., promitotic) functions that are reflected in human glioma cells and in a genetically defined murine model of primary glioma., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Continuing improvements in analytical technology along with an increased interest in performing comprehensive, quantitative metabolic profiling, is leading to increased interest pressures within the metabolomics community to develop centralized metabolite reference resources for certain clinically important biofluids, such as cerebrospinal fluid, urine and blood. As part of an ongoing effort to systematically characterize the human metabolome through the Human Metabolome Project, we have undertaken the task of characterizing the human serum metabolome. In doing so, we have combined targeted and non-targeted NMR, GC-MS and LC-MS methods with computer-aided literature mining to identify and quantify a comprehensive, if not absolutely complete, set of metabolites commonly detected and quantified (with today's technology) in the human serum metabolome. Our use of multiple metabolomics platforms and technologies allowed us to substantially enhance the level of metabolome coverage while critically assessing the relative strengths and weaknesses of these platforms or technologies. Tables containing the complete set of 4229 confirmed and highly probable human serum compounds, their concentrations, related literature references and links to their known disease associations are freely available at http://www.serummetabolome.ca.

Spinocerebellar ataxia type 3 (SCA3) is an autosomal dominant neurodegenerative disorder caused by polyglutamine-expanded ataxin-3. SCA3 neurodegeneration is found in the pontine nuclei and cerebellum. Polyglutamine-expanded ataxin-3-Q79 caused apoptotic death of cerebellar and pontine nuclei neurons by upregulating mRNA expression of pro-apoptotic Bax and activating mitochondria-mediated apoptotic cascade. Following various cellular stresses, transcription factor p53 promotes apoptotic neuronal death by enhancing the transcription of pro-apoptotic genes including Bax and PUMA. In the present study, cellular and animal models of SCA3 were used to test the hypothesis that mutant polyglutamine ataxin-3 upregulates Bax expression of cerebellar and pontine nuclei neurons by augmenting transcriptional activity of p53. Electrophoretic mobility shift assay (EMSA) indicated that p53 binding activity to Bax promoter sequence was significantly enhanced in cultured cerebellar neurons expressing mutant ataxin-3-Q79 and pontine nuclei and cerebellum of SCA3 transgenic mice expressing ataxin-3-Q79. The mRNA level of PUMA, a p53-inducible pro-apoptotic gene, was increased in the cerebellum and pontine nuclei of SCA3 transgenic mice and cultured cerebellar neurons expressing ataxin-3-Q79. Mutant polyglutamine ataxin-3 increased the protein level of active phospho-p53(Ser15) in cerebellar and pontine nuclei neurons without affecting mRNA or protein level of p53. Intraperitoneal administration of p53 inhibitor pifithrin-α significantly ameliorated neuronal death in the pontine nuclei of SCA3 transgenic mice. Our results suggest that polyglutamine-expanded ataxin-3 upregulates mRNA expression of Bax and PUMA and causes apoptotic death of affected neurons by enhancing phosphorylation and transcriptional activity of p53., (Copyright © 2010 Elsevier Ltd. All rights reserved.)

Inducible NO synthase (iNOS) and cyclooxygenase 2 (COX-2) have been suggested to play important roles in various inflammatory diseases. We explored the anti-inflammatory potential of a natural compound, denbinobin (5-hydroxy-3,7-dimethoxy-1,4-phenanthraquinone), by examining its effects on the expression and activity of iNOS and COX-2 in LPS-activated macrophages. Denbinobin markedly decreased the LPS (1 μg/mL)-induced increase in iNOS and COX-2 gene and protein expression, as well as levels of the downstream products NO and prostaglandin E2, in a concentration-dependent manner (0.3-3 μM). In clarifying the mechanisms involved, denbinobin was found not only to inhibit LPS-induced nuclear factor κB (NF-κB) activation, an effect highly correlated with its inhibitory effect on LPS-induced inhibitory κB kinase activation, inhibitory κB degradation, NF-κB phosphorylation, and binding of NF-κB to the κB motif of the iNOS and COX-2 promoters, but also suppressed phosphorylation of mitogen-activated protein kinases. Reporter gene assays and Western blotting revealed that denbinobin significantly suppressed NF-κB activation. Furthermore, denbinobin also downregulated the LPS-mediated CD14/toll-like receptor 4 complex level and TNF-α, IL-1β, and IL-10 mRNA expression. Our results demonstrate that denbinobin exerts potent anti-inflammatory activity, suggesting that it might provide a new therapeutic approach to inflammatory diseases.

Understanding molecular characteristics that distinguish inflammatory breast cancer (IBC) from non-IBC is crucial for elucidating breast cancer etiology and management. We included 3 sets of patients from Egypt (48 IBC and 64 non-IBC), Tunisia (24 IBC and 40 non-IBC), and Morocco (42 IBC and 41 non-IBC). Egyptian IBC patients had the highest combined erythema, edema, peau d'orange, and metastasis among the 3 IBC groups. Egyptian IBC tumors had the highest RhoC expression than Tunisians and Moroccan IBCs (87% vs. 50%, vs. 38.1, for the 3 countries, respectively). Tumor emboli were more frequent in Egyptian IBC than non-IBC (Mean ± SD: 14.1 ± 14.0 vs. 7.0 ± 12.9, respectively) (P < 0.001) and Tunisians (Mean ± SD: 3.4 ± 2.5 vs. 1.9 ± 2.0, respectively) (P < 0.01). There was no difference of emboli in Moroccan tumors (1.7 ± 1.2 vs. 1.8 ± 1.2 for IBC and non-IBC, respectively (P=0.66). This study illustrates that RhoC overexpression and tumor emboli are more frequent in IBC relative to non-IBC from Egypt and Tunisia. Tumors of Moroccans were significantly different from Egyptian and Tunisian tumors for RhoC expression and emboli. Future studies should focus on relating epidemiologic factors and clinical pictures to molecular features of IBC in these and other populations.

DrugBank (http://www.drugbank.ca) is a richly annotated database of drug and drug target information. It contains extensive data on the nomenclature, ontology, chemistry, structure, function, action, pharmacology, pharmacokinetics, metabolism and pharmaceutical properties of both small molecule and large molecule (biotech) drugs. It also contains comprehensive information on the target diseases, proteins, genes and organisms on which these drugs act. First released in 2006, DrugBank has become widely used by pharmacists, medicinal chemists, pharmaceutical researchers, clinicians, educators and the general public. Since its last update in 2008, DrugBank has been greatly expanded through the addition of new drugs, new targets and the inclusion of more than 40 new data fields per drug entry (a 40% increase in data 'depth'). These data field additions include illustrated drug-action pathways, drug transporter data, drug metabolite data, pharmacogenomic data, adverse drug response data, ADMET data, pharmacokinetic data, computed property data and chemical classification data. DrugBank 3.0 also offers expanded database links, improved search tools for drug-drug and food-drug interaction, new resources for querying and viewing drug pathways and hundreds of new drug entries with detailed patent, pricing and manufacturer data. These additions have been complemented by enhancements to the quality and quantity of existing data, particularly with regard to drug target, drug description and drug action data. DrugBank 3.0 represents the result of 2 years of manual annotation work aimed at making the database much more useful for a wide range of 'omics' (i.e. pharmacogenomic, pharmacoproteomic, pharmacometabolomic and even pharmacoeconomic) applications.

The 5-year survival rate for oral cavity cancer is poorer than for breast, colon or prostate cancer, and has improved only slightly in the last three decades. Hence, new therapeutic strategies are urgently needed. Here we demonstrate by tissue micro array analysis for the first time that RNA-binding protein La is significantly overexpressed in oral squamous cell carcinoma (SCC). Within this study we therefore addressed the question whether siRNA-mediated depletion of the La protein may interfere with known tumor-promoting characteristics of head and neck SCC cells. Our studies demonstrate that the La protein promotes cell proliferation, migration and invasion of lymph node-metastasized hypopharyngeal SCC cells. We also reveal that La is required for the expression of β-catenin as well as matrix metalloproteinase type 2 (MMP-2) within these cells. Taken together these data suggest a so far unknown function of the RNA-binding protein La in promoting tumor progression of head and neck SCC.

Modeling the chain-length distributions (CLDs, the molecular weight distributions of individual branches) in a polymer system can be exploited to obtain information on the underlying (bio)synthesis mechanisms. Such a model is developed for starch (a highly branched glucose polymer), taking into account multiple isoforms of the three types of enzymatic mechanisms contributing directly to the CLD: propagation, branching, and debranching. The resulting CLD is given by two parameters and can thus be represented by a point in a two-dimensional phase diagram. The model implies that all native-starch amylopectin CLDs are confined to a line in this phase diagram, an inference supported by fitting data for a wide range of plants. This gives new ways to classify mutants and suggests useful directions for plant engineering (e.g., which isoforms could be targeted to give long branches, which are nutritionally desirable).

Angiogenesis is a process that involves endothelial cell proliferation, migration, invasion, and tube formation, and the inhibition of these processes has implications for angiogenesis-mediated disorders. The purpose of this study was to examine the antiangiogenic efficacy of YD-3 [1-benzyl-3(ethoxycarbonylphenyl)-indazole], a selective thrombin inhibitor, on thrombin-induced endothelial cell proliferation and neoangiogenesis in a murine Matrigel model. First, the effect of YD-3 on angiogenesis was evaluated in vivo using the mouse Matrigel implant model. Plugs treated with 1 and 10 μM of YD-3 inhibited neovascularization induced by thrombin, protease-activated receptor (PAR) 1, and PAR-4, but not by vascular endothelial growth factor, in a concentration-dependent manner over 7 days. These results indicate that YD-3 has specific antiangiogenic activity on thrombin. YD-3 also inhibited (in a concentration-dependent manner) the ability of thrombin, PAR-1, and PAR-4, but not PAR-2, to induce the proliferation of human umbilical vascular endothelial cells, using a [³H]thymidine incorporation assay. YD-3 predominantly inhibited thrombin-induced vascular endothelial growth factor receptor 2 (Flk-1) expression, but not extracellular signal-regulated kinase 1/2 phosphorylation, using Western blot analysis. YD-3 may have benefit in elucidating pathophysiology induced by thrombin-induced angiogenesis.

Careful examination of the oral cavity may reveal findings indicative of an underlying systemic condition, and allow for early diagnosis and treatment. Examination should include evaluation for mucosal changes, periodontal inflammation and bleeding, and general condition of the teeth. Oral findings of anemia may include mucosal pallor, atrophic glossitis, and candidiasis. Oral ulceration may be found in patients with lupus erythematosus, pemphigus vulgaris, or Crohn disease. Additional oral manifestations of lupus erythematosus may include honeycomb plaques (silvery white, scarred plaques); raised keratotic plaques (verrucous lupus erythematosus); and nonspecific erythema, purpura, petechiae, and cheilitis. Additional oral findings in patients with Crohn disease may include diffuse mucosal swelling, cobblestone mucosa, and localized mucogingivitis. Diffuse melanin pigmentation may be an early manifestation of Addison disease. Severe periodontal inflammation or bleeding should prompt investigation of conditions such as diabetes mellitus, human immunodeficiency virus infection, thrombocytopenia, and leukemia. In patients with gastroesophageal reflux disease, bulimia, or anorexia, exposure of tooth enamel to acidic gastric contents may cause irreversible dental erosion. Severe erosion may require dental restorative treatment. In patients with pemphigus vulgaris, thrombocytopenia, or Crohn disease, oral changes may be the first sign of disease.

It has been documented that cannabidiol (CBD) induced apoptosis in a variety of transformed cells, including lymphocytic and monocytic leukemias. In contrast, a differential sensitivity between normal lymphocytes and monocytes to CBD-mediated apoptosis has been reported. The present study investigated the pro-apoptotic effect of CBD on human peripheral monocytes that were either freshly isolated or precultured for 72h. CBD markedly enhanced apoptosis of freshly isolated monocytes in a time- and concentration-dependent manner, whereas precultured monocytes were insensitive. By comparison, both cells were sensitive to doxorubicin-induced apoptosis. CBD significantly diminished the cellular thiols and glutathione in freshly isolated monocytes. The apoptosis induced by CBD was abrogated in the presence of N-acetyl-L-cysteine, a precursor of glutathione. In addition, precultured monocytes contained a significantly greater level of glutathione and heme oxygenase-1 (HO-1) compared to the freshly isolated cells. The HO-1 competitive inhibitor zinc protoporphyrin partially but significantly restored the sensitivity of precultured monocytes to CBD-mediated apoptosis. Collectively, our results demonstrated a contrasting pro-apoptotic effect of CBD between precultured and freshly isolated monocytes, which was closely associated with the cellular level of glutathione and the antioxidative capability of the cells., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Spinocerebellar ataxia type 7 (SCA7) is an autosomal dominant neurodegenerative disease caused by polyglutamine-expanded ataxin-7. Prominent SCA7 neurodegeneration is found in the cerebellum and inferior olivary nucleus. Mutant polyglutamine ataxin-7 activated mitochondrial apoptotic pathway and induced apoptotic death of cerebellar and inferior olivary neurons by upregulating mRNA expression of proapoptotic Bax. In response to various cellular stresses, transcription factor p53 promotes neuronal apoptosis by enhancing the transcription of proapoptotic genes including Bax and Puma. Cellular and animal models of SCA7 were used to test the hypothesis that polyglutamine-expanded ataxin-7-Q52 upregulates Bax expression of cerebellar and inferior olivary neurons by enhancing transcriptional activity of p53. Electrophoretic mobility shift assay (EMSA) indicated that binding activity of p53 to Bax promoter sequence was significantly enhanced in cultured cerebellar neurons expressing mutant ataxin-7-Q52 and inferior olivary nucleus of transgenic mice expressing ataxin-7-Q52. The mRNA expression of Puma, a p53-inducible proapoptotic gene, was upregulated in cerebellar and inferior olivary neurons expressing ataxin-7-Q52. In the absence of significantly altered mRNA or protein expression of p53, mutant ataxin-7-Q52 increased the protein level of active phospho-p53(Ser15) in cerebellar and inferior olivary neurons. Our study provides the evidence that polyglutamine-expanded ataxin-7 upregulates the expression of Bax and Puma and causes apoptotic neuronal death by enhancing phosphorylation and transcriptional activity of p53., ((c) 2010 Elsevier Inc. All rights reserved.)

Attacking angiogenesis is considered an effective strategy for controls the expansion and metastasis of tumors and other related-diseases. The aim of this study was to assess the effects of moscatilin, a bibenzyl derivative, on VEGF and bFGF-induced angiogenesis in cultured human umbilical vein endothelial cells (HUVECs) in vitro and in vivo. Moscatilin significantly inhibited growth of lung cancer cell line A549 (NSCLC) and suppressed growth factor-induced neovascularization. In addition, VEGF- and bFGF-induced cell proliferation, migration, and tube formation of HUVECs was markedly inhibited by moscatilin. Western blotting analysis of cell signaling molecules indicated that moscatilin inhibited ERK1/2, Akt, and eNOS signaling pathways in HUVECs. These results suggest that inhibition of angiogenesis by moscatilin may be a major mechanism in cancer therapy., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Purpose: Lifestyle factors and environmental exposures might help explain the risk of colorectal carcinoma in countries where the incidence is low, but unique patterns of young onset and a high proportion of rectal cancer exist., Methods: We obtained detailed lifestyle information from 421 patients with colorectal cancer and 439 hospital-controls in Egypt. Logistic regression models were computed to evaluate the risk factors of colorectal carcinoma., Results: A history of pesticide exposure and more frequently eating food directly from farms were significantly associated with a higher risk of colorectal carcinoma (odds ratio = 2.6; 95% CI = 1.1-5.9, and odds ratio = 4.6; 95% CI = 1.5-14.6, respectively). Parous women who reported 7 or more live births or breastfed for 19 months or longer per live birth had a significantly lower risk for colorectal carcinoma (odds ratio = 0.3; 95% CI = 0.2-0.7, and odds ratio = 0.2; 95% CI = 0.1-0.4, respectively). Compared with patients aged 40 years or older, industrial exposures were more common in younger patients (P = .05)., Conclusions: Agricultural and industrial exposures were associated with increased risk of colorectal carcinoma, whereas prolonged lactation and increased parity were inversely associated with colorectal carcinoma in women. Further research to elucidate the biological role of intense environmental and industrial exposures and reproductive factors including lactation may further clarify the etiology of colorectal cancer.

Orthotopic liver transplantation (OLT) recipients without hepatitis B virus (HBV) infection who receive liver grafts from antibody to hepatitis B core antigen-positive [HBcAb(+)], hepatitis B surface antigen-negative [HBsAg(-)] donors have an increased risk of developing de novo hepatitis B infection. We compared the 2 most commonly employed prophylactic regimens-lamivudine (LAM) monotherapy and hepatitis B immunoglobulin (HBIG)+LAM combination therapy-to determine the relative efficacies of these 2 protocols in preventing de novo hepatitis B infection. A comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to June 2009), and bibliographies of retrieved trials was conducted. Eligible studies included OLT recipients who received HBcAb(+) liver grafts and were treated prophylactically with either LAM monotherapy or HBIG+LAM combination therapy. 13 studies were identified as meeting the eligibility criteria. The rates of de novo hepatitis B infection, mortality, and mortality due to de novo hepatitis B infection were assessed. The incidence of de novo hepatitis B infection was 2.7% (n = 73) in patients receiving LAM-only prophylaxis versus 3.6% (n = 110) in patients receiving HBIG+LAM combination therapy. In the HBIG+LAM group, the dose and duration of HBIG therapy were highly variable. The median follow-up time for the LAM monotherapy group was 25.4 months with a range of 14.78 to 27.6 months, whereas the median follow-up time for the LAM+HBIG group was 31.1 months with a range of 15.3 to 38.5 months. The risk of developing de novo hepatitis B infection based on the pretransplant recipient HBV serology in each treatment group could not be calculated because of incomplete data and the limited number of de novo hepatitis B infection cases in the series reviewed. In conclusion, on the basis of these findings, we conclude that published studies have not shown HBIG+LAM combination therapy to be more effective than LAM-only treatment. Nucleoside analogue monotherapy should therefore be considered when one is treating HBV(-) patients who have received liver allografts from HBcAb(+) donors.

CHM-1 (2'-fluoro-6,7-methylenedioxy-2-phenyl-4-quinolone) has been identified as a potent antitumor agent in human hepatocellular carcinoma; however, its role in tumor angiogenesis is unclear. This study investigated the effects of CHM-1 and the mechanisms by which it exerts its antiangiogenic and vascular disrupting properties. Using a xenograft model antitumor assay, we found that CHM-1 significantly inhibits tumor growth and microvessel formation. Flow cytometry, immunofluorescence microscopy, and cell death enzyme-linked immunosorbent assay kit revealed that CHM-1 inhibits growth of human umbilical vein endothelial cells (HUVEC) by induction of apoptotic cell death in a concentration-dependent manner. CHM-1 also suppresses HUVEC migration and capillary-like tube formation. We were able to correlate CHM-1-induced apoptosis in HUVEC with the cleavage of procaspase-3, -7, and -8, as well as with the cleavage of poly(ADP-ribose) polymerase by Western blotting assay. Such sensitization was achieved through up-regulation of death receptor 5 (DR5) but not DR4 or Fas. CHM-1 was also capable of increasing the expression level of p53, and most importantly, the induction of DR5 by CHM-1 was abolished by p53 small interfering RNA. Taken together, the results of this study indicate that CHM-1 exhibits vascular targeting activity associated with the induction of DR5-mediated endothelial cell apoptosis through p53 up-regulation, which suggests its potential as an antivascular and antitumor therapeutic agent.

In an effort to capture meaningful biological, chemical and mechanistic information about clinically relevant, commonly encountered or important toxins, we have developed the Toxin and Toxin-Target Database (T3DB). The T3DB is a unique bioinformatics resource that compiles comprehensive information about common or ubiquitous toxins and their toxin-targets into a single electronic repository. The database currently contains over 2900 small molecule and peptide toxins, 1300 toxin-targets and more than 33,000 toxin-target associations. Each T3DB record (ToxCard) contains over 80 data fields providing detailed information on chemical properties and descriptors, toxicity values, protein and gene sequences (for both targets and toxins), molecular and cellular interaction data, toxicological data, mechanistic information and references. This information has been manually extracted and manually verified from numerous sources, including other electronic databases, government documents, textbooks and scientific journals. A key focus of the T3DB is on providing 'depth' over 'breadth' with detailed descriptions, mechanisms of action, and information on toxins and toxin-targets. T3DB is fully searchable and supports extensive text, sequence, chemical structure and relational query searches, similar to those found in the Human Metabolome Database (HMDB) and DrugBank. Potential applications of the T3DB include clinical metabolomics, toxin target prediction, toxicity prediction and toxicology education. The T3DB is available online at http://www.t3db.org.

The Small Molecule Pathway Database (SMPDB) is an interactive, visual database containing more than 350 small-molecule pathways found in humans. More than 2/3 of these pathways (>280) are not found in any other pathway database. SMPDB is designed specifically to support pathway elucidation and pathway discovery in clinical metabolomics, transcriptomics, proteomics and systems biology. SMPDB provides exquisitely detailed, hyperlinked diagrams of human metabolic pathways, metabolic disease pathways, metabolite signaling pathways and drug-action pathways. All SMPDB pathways include information on the relevant organs, organelles, subcellular compartments, protein cofactors, protein locations, metabolite locations, chemical structures and protein quaternary structures. Each small molecule is hyperlinked to detailed descriptions contained in the Human Metabolome Database (HMDB) or DrugBank and each protein or enzyme complex is hyperlinked to UniProt. All SMPDB pathways are accompanied with detailed descriptions, providing an overview of the pathway, condition or processes depicted in each diagram. The database is easily browsed and supports full text searching. Users may query SMPDB with lists of metabolite names, drug names, genes/protein names, SwissProt IDs, GenBank IDs, Affymetrix IDs or Agilent microarray IDs. These queries will produce lists of matching pathways and highlight the matching molecules on each of the pathway diagrams. Gene, metabolite and protein concentration data can also be visualized through SMPDB's mapping interface. All of SMPDB's images, image maps, descriptions and tables are downloadable. SMPDB is available at: http://www.smpdb.ca.

Mitochondrial volume regulation depends on K+ movement across the inner membrane and a mitochondrial Ca2+-dependent K+ channel (mitoK(Ca)) reportedly contributes to mitochondrial K+ uniporter activity. Here we utilize a novel K(Ca) channel activator, NS11021, to examine the role of mitoK(Ca) in regulating mitochondrial function by measuring K+ flux, membrane potential (DeltaPsi(m)), light scattering, and respiration in guinea pig heart mitochondria. K+ uptake and the influence of anions were assessed in mitochondria loaded with the K+ sensor PBFI by adding either the chloride (KCl), acetate (KAc), or phosphate (KH2PO4) salts of K+ to energized mitochondria in a sucrose-based medium. K+ fluxes saturated at approximately 10 mM for each salt, attaining maximal rates of 172+/-17, 54+/-2.4, and 33+/-3.8 nmol K+/min/mg in KCl, KAc, or KH2PO4, respectively. NS11021 (50 nM) increased the maximal K+ uptake rate by 2.5-fold in the presence of KH2PO4 or KAc and increased mitochondrial volume, with little effect on DeltaPsi(m). In KCl, NS11021 increased K+ uptake by only 30% and did not increase volume. The effects of NS11021 on K+ uptake were inhibited by the K(Ca) toxins charybdotoxin (200 nM) or paxilline (1 microM). Fifty nanomolar of NS11021 increased the mitochondrial respiratory control ratio (RCR) in KH2PO4, but not in KCl; however, above 1 microM, NS11021 decreased RCR and depolarized DeltaPsi(m). A control compound lacking K(Ca) activator properties did not increase K+ uptake or volume but had similar nonspecific (toxin-insensitive) effects at high concentrations. The results indicate that activating K+ flux through mitoK(Ca) mediates a beneficial effect on energetics that depends on mitochondrial swelling with maintained DeltaPsi(m).

A novel hybrid surface-enhanced Raman scattering (SERS) substrate based on Au nanoparticles decorated inverse opal (IO) photonic crystal (PhC) is presented. In addition to the enhancement contributed from Au nanoparticles, a desired Raman signal can be selectively further enhanced by appropriately overlapping the center of photonic bandgap of the IO PhC with the wavelength of the Raman signal. Furthermore, the lattice structure of the IO PhC provides excellent control of the distribution of Au nanoparticles to produce SERS spectra with high uniformity. The new design of SERS substrate provides extra maneuverability for ultra-high sensitivity sensor applications.

Unlabelled: Polyaromatic hydrocarbons, including benzo[a]pyrene (BP), are major tobacco carcinogens. Their carcinogenic effects require metabolic activation by cytochrome p450 (CYP) enzymes. Relative CYP isoform expression is related to tissue-specific tobacco-related squamous cell carcinoma (SCC) susceptibility. There have been conflicting reports regarding relative CYP1A1 and CYP1B1 oral expression, and information regarding CYP1B1 expression in oral tissues is limited. To quantify BP- and tobacco-induced CYP1A1 and CYP1B1 expression in oral SCC cells and oral mucosa., Study Design: Real-time qPCR was performed to measure (1) BP-induced CYP1A1 and CYP1B1 mRNA expression in seven oral/other head and neck SCC cell lines (2) CYP1A1 and CYP1B1 mRNA expression in gingiva from 22 smokers and 24 nonsmokers. SCC lines exhibited either similar induction of both isoforms or preferential CYP1A1 induction (CYP1A1-to-CYP1B1 ratios 0.8-4.3). In contrast, gingival tissues from smokers exhibited preferential CYP1B1 induction. Marked interindividual variation in CYP1A1 and CYP1B1 expression was observed among smokers. In vitro conditions may not account for factors that modulate expression in vivo. Interindividual variation in inducible CYP1A1 and CYP1B1 expression may account in part for variation in tobacco-related oral SCC risk.

IkappaB kinase beta (IKKbeta) is involved in tumor development and progression through activation of the nuclear factor (NF)-kappaB pathway. However, the molecular mechanism that regulates IKKbeta degradation remains largely unknown. Here, we show that a Cullin 3 (CUL3)-based ubiquitin ligase, Kelch-like ECH-associated protein 1 (KEAP1), is responsible for IKKbeta ubiquitination. Depletion of KEAP1 led to the accumulation and stabilization of IKKbeta and to upregulation of NF-kappaB-derived tumor angiogenic factors. A systematic analysis of the CUL3, KEAP1, and RBX1 genomic loci revealed a high percentage of genome loss and missense mutations in human cancers that failed to facilitate IKKbeta degradation. Our results suggest that the dysregulation of KEAP1-mediated IKKbeta ubiquitination may contribute to tumorigenesis.

Ischemia-induced shortening of the cardiac action potential and its heterogeneous recovery upon reperfusion are thought to set the stage for reentrant arrhythmias and sudden cardiac death. We have recently reported that the collapse of mitochondrial membrane potential (DeltaPsi(m)) through a mechanism triggered by reactive oxygen species (ROS), coupled to the opening of sarcolemmal ATP-sensitive potassium (K(ATP)) channels, contributes to electrical dysfunction during ischemia-reperfusion. Here we present a computational model of excitation-contraction coupling linked to mitochondrial bioenergetics that incorporates mitochondrial ROS-induced ROS release with coupling between the mitochondrial energy state and electrical excitability mediated by the sarcolemmal K(ATP) current (I(K,ATP)). Whole-cell model simulations demonstrate that increasing the fraction of oxygen diverted from the respiratory chain to ROS production triggers limit-cycle oscillations of DeltaPsi(m), redox potential, and mitochondrial respiration through the activation of a ROS-sensitive inner membrane anion channel. The periods of transient mitochondrial uncoupling decrease the cytosolic ATP/ADP ratio and activate I(K,ATP), consequently shortening the cellular action potential duration and ultimately suppressing electrical excitability. The model simulates emergent behavior observed in cardiomyocytes subjected to metabolic stress and provides a new tool for examining how alterations in mitochondrial oxidative phosphorylation will impact the electrophysiological, contractile, and Ca(2+) handling properties of the cardiac cell. Moreover, the model is an important step toward building multiscale models that will permit investigation of the role of spatiotemporal heterogeneity of mitochondrial metabolism in the mechanisms of arrhythmogenesis and contractile dysfunction in cardiac muscle.

A hybrid inorganic-polymer nanocomposite using CdSe nanocrystals with high electron mobility has been successfully synthesized by atom transfer radical polymerization (ATRP). First the hydroxyl-coated CdSe nanoparticles (i.e., CdSe-OH) were prepared via a wet chemical route. A polymerization initiator was then prepared for ATRP of N-vinylcarbazole. FT-IR, (1) H NMR, and XRD analyses confirmed the successful synthesis of CdSe-poly(N-vinylcarbazole) (PVK) nanohybrid. UV-Vis spectra and photoluminescence data revealed that grafting of PVK onto the surface of CdSe nanocrystals would reduce the band gap of PVK and cause the red shift of emission peak. TEM and SEM micrographs exhibited CdSe nanoparticles that were well-coated with PVK polymer., (Copyright © 2009 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Purpose: Antiangiogenic therapy is considered as an effective strategy for controlling the growth and metastasis of tumors. Among a myriad of biological activities described for xanthone derivatives, the anticancer activity is quite remarkable, but the molecular mechanism is not clearly resolved. In the present study, we investigated the antiangiogenic mechanism of 3,6-di(2,3-epoxypropoxy)xanthone (EPOX), a novel Mcl-1 targeting drug., Experimental Design: To evaluate the antiangiogenic activity of EPOX, we did cell viability, cell cycle, tube formation assay in vitro, and Matrigel plug assay in vivo. To evaluate the effect of EPOX on the endothelial signaling pathway, we did immunoblotting, immunoprecipitation, and immunofluorescence analysis. Intracellular glutathione levels were determined with the use of monochlorobimane, a glutathione-specific probe., Results: EPOX induced endothelial cell apoptosis in association with proteasome-dependent Mcl-1 degradation. Down-regulation of Mcl-1 resulted in an increase in Mcl-1-free Bim, activation of Bax, and then signaling of mitochondria-mediated apoptosis. Additionally, glutathione depletion and extracellular signal-regulated kinase (ERK) inactivation was observed in EPOX-treated cells. Glutathione supplementation reversed the inhibitory effects of EPOX on ERK, which increases the phosphorylation of Mcl-1 at T(163.) Overexpression of mitogen-activated protein/ERK kinase (MEK) partially reversed the effect of EPOX on Mcl-1 dephosphorylation, ubiquitination, and degradation, further implicating ERK in the regulation of Mcl-1 stability., Conclusions: This study provides evidence that EPOX induces glutathione depletion, ERK inactivation, and Mcl-1 degradation on endothelial cells, which leads to inhibition of angiogenesis. Our results suggest that EPOX is a novel antiangiogenic agent, making it a promising lead compound for further development in the treatment of angiogenesis-related pathologies.

Cell fate decisions mediated by the Notch signalling pathway require direct cell-cell contact between adjacent cells. In Drosophila melanogaster, an external sensory organ (ESO) develops from a single sensory organ precursor (SOP) and its fate specification is governed by differential Notch activation. Here we show that mutations in actin-related protein-3 (Arp3) compromise Notch signalling, leading to a fate transformation of the ESO. Our data reveal that during ESO fate specification, most endocytosed vesicles containing the ligand Delta traffic to a prominent apical actin-rich structure (ARS) formed in the SOP daughter cells. Using immunohistochemistry and transmission electron microscopy (TEM) analyses, we show that the ARS contains numerous microvilli on the apical surface of SOP progeny. In Arp2/3 and WASp mutants, the surface area of the ARS is substantially reduced and there are significantly fewer microvilli. More importantly, trafficking of Delta-positive vesicles from the basal area to the apical portion of the ARS is severely compromised. Our data indicate that WASp-dependent Arp2/3 actin polymerization is crucial for apical presentation of Delta, providing a mechanistic link between actin polymerization and Notch signalling.

Bacterial wilt (BW), caused by Ralstonia solanacearum, is a devastating vascular disease of tomato worldwide. However, information on tomato's defense mechanism against infection by this soil-borne bacterium is limited. In this study, virus-induced gene silencing (VIGS) was employed to decipher signaling pathways involved in the resistance of tomato to this pathogen. Defined sequence fragments derived from a group of genes known or predicted to be involved in ethylene (ET) and salicylic acid (SA) signaling transduction pathways and mitogen-activated protein kinase (MAPK) cascades were subjected to VIGS in 'Hawaii 7996', a tomato cultivar with stable resistance to BW, and their effect on resistance was determined. The results indicated that silencing of ACO1/3, EIN2, ERF3, NPR1, TGA2.2, TGA1a, MKK2, MPK1/2 and MPK3 caused significant increase in bacterial proliferation in stembases and/or mid-stems. Partial wilting symptoms appeared on plants in which TGA2.2, TGA2.1a, MKK2 and MPK1/2 were silenced. These results suggested that ET-, SA- and MAPK-related defense signaling pathways are involved in the resistance of tomato to BW. This is the first report elucidating the multiple layers of defense governing the resistance of tomato to BW. The results are discussed to enlighten an important and complex interaction between tomato and a soil-borne vascular pathogen.

In the filamentous fungus Aspergillus nidulans, cytokinesis/septation is triggered by the septation initiation network (SIN), which first appears at the spindle pole body (SPB) during mitosis. The coiled-coil protein SNAD is associated with the SPB and is required for timely septation and conidiation. We have determined that SNAD acted as a scaffold protein that is required for the localization of the SIN proteins of SIDB and MOBA to the SPB. Another scaffold protein SEPK, whose localization at the SPB was dependent on SNAD, was also required for SIDB and MOBA localization to the SPB. In the absence of either SEPK or SNAD, SIDB/MOBA successfully localized to the septation site, indicating that their earlier localization at SPB was not essential for their later appearance at the division site. Unlike their functional counterparts in fission yeast, SEPK and SNAD were not required for vegetative growth but only for timely septation. Furthermore, down-regulation of negative regulators of the SIN suppressed the septation and conidiation phenotypes due to the loss of SNAD. Therefore, we conclude that SPB localization of SIN components is not essential for septation per se, but critical for septation to take place in a timely manner in A. nidulans.

Pseudomembranous disease (or ligneous inflammation) is a rare condition characterized by accumulations of fibrin-rich eosinophilic material. Recent investigations have linked the etiology of this condition to plasminogen deficiency (hypoplasminogenemia). Although much of the literature concerning this disease has focused upon the often clinically striking ocular manifestations, it is important to note that pathologic changes may develop in a variety of anatomic locations, including the oral cavity, upper and lower respiratory tract, female genital tract, kidneys, and gastrointestinal tract. Here, we report an unusual case of a 33-year-old woman who initially presented with gingival inflammation. In subsequent years, she developed additional signs and symptoms related to sinonasal and genital tract involvement. Despite numerous clinical evaluations, biopsies, and laboratory tests, the patient's diagnosis remained elusive for 7 years. Ultimately, it was the distinctive appearance of the gingiva that led to a diagnosis of plasminogen deficiency. Unfortunately, the complicated clinical course and elapsed time between initial presentation and diagnosis illustrated by the present case are not uncommon among patients with this condition. Greater familiarity with the clinical and histopathologic features of this condition among pathologists and treating clinicians is essential for timely diagnosis and management.

Objectives: Spontaneous bacterial peritonitis (SBP) is a serious complication of advanced liver disease resulting in high mortality rates. Although studies that assessed the use of oral antibiotics in advanced liver disease demonstrated a clear benefit in reducing the risk of recurrent peritonitis, it is unclear whether mortality rates are similarly affected by this practice. The goal of this study was to determine whether oral antibiotic therapy provides a survival benefit for patients with advanced cirrhosis and ascites. Through subgroup analysis, we also evaluated the effect of prophylactic oral antibiotic therapy on the prevention of SBP and the incidence of all infections (including SBP) when compared with non-treated or placebo controls., Methods: We conducted a comprehensive search of the Cochrane Database of Systematic Reviews, MEDLINE (1966 to May 2008), bibliographies of retrieved trials, and reports presented at major scientific meetings. Eligible studies included prospective, randomized controlled trials comparing high-risk cirrhotic patients receiving oral antibiotic prophylaxis for SBP with groups receiving placebo or no intervention. Dichotomous outcomes were reported as relative risk (RR) with 95% confidence intervals (CIs)., Results: Eight studies with a total of 647 patients were identified and included in this analysis. The combined analysis showed an overall mortality benefit (RR=0.65; 95% CI, 0.48-0.88) for treatment groups. The overall mortality rate was 16% (52/324) for treated patients and 25% (81/323) for the control group. Groups treated with prophylactic antibiotics also demonstrated a lower incidence of all infections (including SBP) of 6.2% as compared with the control groups with a rate of 22.2% (RR=0.32; P<0.00001; 95% CI, 0.20-0.51). Subgroup analysis showed a survival benefit at 3 months (RR=0.28; P=0.005; 95% CI, 0.12-0.68)., Conclusions: Antibiotic prophylaxis improved short-term survival in treated patients when compared with untreated control groups and reduced the overall risk of infections, including SBP, during follow-up. In summary, antibiotic prophylaxis should be considered for high-risk cirrhotic patients with ascites.

Cell-cell signaling mediated by the Notch receptor is iteratively involved in numerous developmental contexts, and its dysregulation has been associated with inherited genetic disorders and cancers. The core components of the signaling pathway have been identified for some time, but the study of the modulation of the pathway in different cellular contexts has revealed many layers of regulation. These include complex sugar modifications in the extracellular domain as well as transit of Notch through defined cellular compartments, including specific endosomes.

Understanding the molecular factors that distinguish inflammatory breast cancer (IBC) from non-IBC is important for IBC diagnosis. We reviewed the records of 48 IBC patients and 64 non-IBC patients from Egypt. We determined RhoC expression and tumor emboli and their relationship to demographic and reproductive characteristics. Compared with non-IBC patients, IBC patients had significantly lower parity (P=0.018) and fewer palpable tumors (P<0.0001). IBC tumors showed RhoC overexpression more frequently than non-IBC tumors (87% vs. 17%, respectively) (P<0.0001). Tumor emboli were significantly more frequent in IBC tumors than non-IBC tumors (Mean+/- SD: 14.1+/-14.0 vs. 7.0+/-12.9, respectively) (P<0.0001). This study illustrates that RhoC overexpression and tumor emboli are more frequent in tumors of IBC relative to non-IBC from Egypt. Future studies should focus on relating epidemiologic factors to molecular features of IBC in this population.

The Human Metabolome Database (HMDB, http://www.hmdb.ca) is a richly annotated resource that is designed to address the broad needs of biochemists, clinical chemists, physicians, medical geneticists, nutritionists and members of the metabolomics community. Since its first release in 2007, the HMDB has been used to facilitate the research for nearly 100 published studies in metabolomics, clinical biochemistry and systems biology. The most recent release of HMDB (version 2.0) has been significantly expanded and enhanced over the previous release (version 1.0). In particular, the number of fully annotated metabolite entries has grown from 2180 to more than 6800 (a 300% increase), while the number of metabolites with biofluid or tissue concentration data has grown by a factor of five (from 883 to 4413). Similarly, the number of purified compounds with reference to NMR, LC-MS and GC-MS spectra has more than doubled (from 380 to more than 790 compounds). In addition to this significant expansion in database size, many new database searching tools and new data content has been added or enhanced. These include better algorithms for spectral searching and matching, more powerful chemical substructure searches, faster text searching software, as well as dedicated pathway searching tools and customized, clickable metabolic maps. Changes to the user-interface have also been implemented to accommodate future expansion and to make database navigation much easier. These improvements should make the HMDB much more useful to a much wider community of users.

Breast cancer is the most common cancer among women in North Africa. Women in this region have unique reproductive profiles. It is essential to obtain reliable information on reproductive histories to help better understand the relationship between reductive health and breast cancer. We tested the reliability of a reproductive history-based questionnaire. We interviewed 25 breast cancer patients and 25 non-cancer controls from hospitals in Morocco and Egypt about their reproductive history in colloquial Arabic. The questions included pregnancy history, breastfeeding practices, menstruation, contraceptive use and knowledge of breast screening and re-interviewed the same women after 2 weeks. Two-way paired t-test was used to compare observed mean changes in response, and the Fishers Exact test was used for small-cell data. Pearson's correlation test was used to estimate the correlation of subjects' responses to continuous questions between the first and second interview. For categorical questions, percentage of agreement was calculated along with Cohen's Kappa Coefficient values. Moroccan subjects showed good to excellent agreement for responses to all demographic and reproductive questions (r = 0.87 to 0.99). Egyptian subjects had excellent agreement for these questions(r = 0.87 to 0.99), except for those regarding duration of oral contraceptive pill use and reported age at menarche (r = 0.72 and 0.59, respectively). We showed highly correlated responses to most reproductive questions. Duration of contraception use and age at first pregnancy elicited slightly less than reliable responses. In Egypt, responses relating to self-reported age at menarche were less reliable than those given by Moroccan subjects. Future epidemiological studies should take these differences into account when constructing reproductive history questionnaires.

Background: Very limited information has been published regarding cardiac apoptosis in menopausal women or in those after bilateral oophorectomy. The purpose of this study was to evaluate whether cardiac Fas-dependent (type I) and mitochondria-dependent (type II) apoptotic pathways are activated in ovariectomized rats., Methods: Thirty-two female Wistar rats at 6-7 months of age were randomly divided into sham-operated group (Sham) and bilateral ovariectomized group (OVX). Two months after the operation, the cardiac characteristics, myocardial architecture, and two major apoptotic pathways in the excised left ventricle from rats were measured by histopathological analysis, Western blotting and reverse transcription polymerase chain reaction (RT-PCR), and positive TUNEL assays., Results: The whole heart weight, the left ventricular weight, the ratios of whole heart weight to tibia length, and the ratios of left ventricle to tibia length were significantly increased in OVX relative to Sham. Abnormal myocardial architecture, enlarged interstitial spaces, more minor cardiac fibrosis, and more cardiac TUNEL-positive apoptotic cells were observed in OVX. The key components of Fas-dependent apoptosis (TNF-alpha, Fas ligand, Fas death receptors, Fas-associated death domain (FADD), activated caspase 8, and activated caspase 3) and key components of mitochondria-dependent apoptosis (Bad, Bax, Bax-to-Bcl2 ratio, cytosolic cytochrome c, activated caspase 9, and activated caspase 3) were significantly increased in OVX hearts., Conclusions: The absence of female ovaries will activate the cardiac Fas-dependent and mitochondria-dependent apoptotic pathways, which might provide one of possible mechanism for developing heart failure in post-menopause women.

Background: Inflammatory breast cancer (IBC) is a lethal form of breast cancer with unknown etiology. A higher frequency of IBC and a more aggressive IBC phenotype was reported in Egypt than in the United States. This difference in disease frequency and presentation might be related to molecular epidemiologic factors., Methods: We used tumor blocks and demographic, epidemiologic, and clinical data of 48 IBC patients from Egypt and 12 patients from the United States. We counted tumor emboli in tumors before and after immunohistochemical staining with lymphatic vessel endothelial receptor-1 (LYVE-1), and measured the expression of RhoC GTPase protein in the two groups., Results: Erythema, edema, and peau d'orange were found in 77% of the Egyptian patients as compared with 29% found in the US patients (P=0.02). The number of tumor emboli was significantly higher in tumors from Egypt (mean+/-SD, 14.1+/-14.0) than in the tumors from the United States (5.0+/-4.0, P=0.01). The number of tumor emboli in LYVE-1 positive vessels was higher in tumors from Egypt (3.5+/-2.8) than tumors from the United States (1.6+/-0.5, P=0.15). We detected a high level of RhoC in 87% of the tumors from Egypt and 14% of the tumors from the United States (P=0.0003)., Conclusion: Patients from Egypt have a more aggressive form of IBC than those in the United States. Our analysis of IBC patients shows that distinct molecular phenotypes can be found when these two study populations are compared. Future studies should explore the epidemiologic and environmental exposures and the genetic factors that might lead to the different clinical and molecular features of IBC in patients from these two countries.

Salmonella enterica serotype Dublin harbors an approximately 80-kb virulence plasmid (pSDV), which mediates systemic infection in cattle. There are two types of pSDV: one is pSDVu (pOU1113) in strain OU7025 and the other pSDVr (pOU1115) in OU7409 (SD Lane) and many clinical isolates. Sequence analysis showed that pSDVr was a recombinant plasmid (co-integrate) of pSDVu and a plasmid similar to a 35-kb indigenous plasmid (pOU1114) of S. Dublin. Most of the F-transfer region in pSDVu was replaced by a DNA segment from the pOU1114-like plasmid containing an extra replicon and a pilX operon encoding for a type IV secretion system to form pSDVr. We reconstructed the particular evolutionary history of the seven virulence plasmids of Salmonella by comparative sequence analysis. The whole evolutionary process might begin with two different F-like plasmids (IncFI and IncFII), which then incorporated the spv operon and fimbriae operon from the chromosome to form the primitive virulence plasmids. Subsequently, these plasmids descended by deletion from a relatively large plasmid to smaller ones, with some recombination events occurring over time. Our results suggest that the phylogeny of virulence plasmids as a result of frequent recombination provides the opportunity for rapid evolution of Salmonella in response to the environmental cues.

Notch-mediated cell-cell communication regulates numerous developmental processes and cell fate decisions. Through a mosaic genetic screen in Drosophila melanogaster, we identified a role in Notch signaling for a conserved thiol oxidase, endoplasmic reticulum (ER) oxidoreductin 1-like (Ero1L). Although Ero1L is reported to play a widespread role in protein folding in yeast, in flies Ero1L mutant clones show specific defects in lateral inhibition and inductive signaling, two characteristic processes regulated by Notch signaling. Ero1L mutant cells accumulate high levels of Notch protein in the ER and induce the unfolded protein response, suggesting that Notch is misfolded and fails to be exported from the ER. Biochemical assays demonstrate that Ero1L is required for formation of disulfide bonds of three Lin12-Notch repeats (LNRs) present in the extracellular domain of Notch. These LNRs are unique to the Notch family of proteins. Therefore, we have uncovered an unexpected requirement for Ero1L in the maturation of the Notch receptor.

Neurogenesis requires precise control of cell specification and division. In Drosophila, the timing of cell division of the sensory organ precursor (SOP) is under strict temporal control. But how the timing of mitotic entry is determined remains poorly understood. Here, we present evidence that the timing of the G2-M transition is determined by when proneural proteins are degraded from SOPs. This process requires the E3 ubiquitin ligase complex, including the RING protein Sina and the adaptor Phyl. In phyl mutants, proneural proteins accumulate, causing delay or arrest in the G2-M transition. The G2-M defect in phyl mutants is rescued by reducing the ac and sc gene doses. Misexpression of phyl downregulates proneural protein levels in a sina-dependent manner. Phyl directly associates with proneural proteins to act as a bridge between proneural proteins and Sina. As phyl is a direct transcriptional target of Ac and Sc, our data suggest that, in addition to mediating cell cycle arrest, proneural protein initiates a negative-feedback regulation to time the mitotic entry of neural precursors.

Real-time and specific detection of single bacterium remains a fundamental challenge and draws very much attention. Using test patterns composed of interdigitated Au-electrode arrays modified with antibody, the specific and quantitative detection of the electrical conductivity of a single Escherichia coli (E. coli, JM109) has been carried out in this work. The key is to ensure low background current of the antibody-modified test patterns before bacteria detection (<0.7pA in this case) and minimize the residual moisture or hydration after E. coli immobilization, such as via the use of 1-min bake at 50 degrees C prior to electrical measurement. This method holds great potential for future application in the real-time, specific, and quantitative bacterium detection down to a single bacterium cell.

The mechanism of DNA transfer from Escherichia coli ( E. coli) Hfr donor strain AT2453 to recipient strain AB1157 during the conjugation process has been investigated by liquid atomic force microscopy (AFM). With the success of immobilizing both E. coli strains on gelatin-treated glass under aqueous solution, the F-pilus between an E. coli mating pair could be clearly imaged and dissected by an AFM probe. Another AFM probe functionalized with an anti-single-stranded DNA (ssDNA) antibody was then applied to detect transferring ssDNA. According to the AFM force spectrum, the transferring ssDNA could be detected only in the dissected area with a binding force of 109 +/- 5 pN measured. Our results provide direct evidence indicating that the DNA was transferred through the F-pilus channel between an E. coli mating pair during their conjugation.

Background: Several recent reports suggest an increasing incidence of oral squamous cell carcinoma (OSCC) among young persons in many regions of the world--a trend which is particularly concerning given the overall stabilization or even decline in incidence rates for head and neck cancer in general. The aim of this study is to determine whether there has been an increase in the number of cases of OSCC diagnosed in patients < 40 years old by our biopsy service from 1971 to 2006., Methods: A retrospective review of all OSCC cases diagnosed from 1971 to 2006 by the Emory University Hospital Oral Pathology biopsy service was performed. A comparison of demographic information, frequency, location and histologic grade was made between these cases as a whole and those occurring in a subset of patients < 40 years old. Statistical procedures included chi-square analyses., Results: From 1971-2006, 1,919 cases of OSCC were diagnosed, and 95 (5.0%) occurred in patients < 40 years old. A total of 8 cases were diagnosed from 1971 to 1980, compared to 36 cases during the period 1981-1990, 31 during the period 1991-2000 and 21 cases from 2001 to 2006. The increase in OSCC incidence from the 1970s when compared to 1981-2000 was statistically significant (P < 0.002). A 1.7:1 male:female ratio was seen in all decades. The mobile (oral) tongue was the most common location in all decades (62.1%) in young patients. In contrast, tongue cancers accounted for 27.4% in patients > or = 40. This difference between the two groups was statistically significant (P < 0.0001). Of great surprise, however, was the significant increase in tongue cancer during the study period in patients > or = 40 which accounted for 37.1% of all OSCC diagnoses from 2001 to 2006, compared to 20.5% of OSCC cases from 1971 to 1980 (P < 0.0001)., Conclusions: We demonstrated a greater than fourfold increase in the incidence of oral squamous cell carcinoma (OSCC) in young patients < 40 years old beginning in 1974 and peaking in the late 1980s, then remaining stable. The mobile tongue is the most common location for cancer in this age group accounting for 62.1% of cancers. However, the mobile tongue increasingly appears to be the most common site for oral cancer in all age groups.

The protein property prediction and testing database (PPT-DB) is a database housing nearly 30 carefully curated databases, each of which contains commonly predicted protein property information. These properties include both structural (i.e. secondary structure, contact order, disulfide pairing) and dynamic (i.e. order parameters, B-factors, folding rates) features that have been measured, derived or tabulated from a variety of sources. PPT-DB is designed to serve two purposes. First it is intended to serve as a centralized, up-to-date, freely downloadable and easily queried repository of predictable or 'derived' protein property data. In this role, PPT-DB can serve as a one-stop, fully standardized repository for developers to obtain the required training, testing and validation data needed for almost any kind of protein property prediction program they may wish to create. The second role that PPT-DB can play is as a tool for homology-based protein property prediction. Users may query PPT-DB with a sequence of interest and have a specific property predicted using a sequence similarity search against PPT-DB's extensive collection of proteins with known properties. PPT-DB exploits the well-known fact that protein structure and dynamic properties are highly conserved between homologous proteins. Predictions derived from PPT-DB's similarity searches are typically 85-95% correct (for categorical predictions, such as secondary structure) or exhibit correlations of >0.80 (for numeric predictions, such as accessible surface area). This performance is 10-20% better than what is typically obtained from standard 'ab initio' predictions. PPT-DB, its prediction utilities and all of its contents are available at http://www.pptdb.ca.

DrugBank is a richly annotated resource that combines detailed drug data with comprehensive drug target and drug action information. Since its first release in 2006, DrugBank has been widely used to facilitate in silico drug target discovery, drug design, drug docking or screening, drug metabolism prediction, drug interaction prediction and general pharmaceutical education. The latest version of DrugBank (release 2.0) has been expanded significantly over the previous release. With approximately 4900 drug entries, it now contains 60% more FDA-approved small molecule and biotech drugs including 10% more 'experimental' drugs. Significantly, more protein target data has also been added to the database, with the latest version of DrugBank containing three times as many non-redundant protein or drug target sequences as before (1565 versus 524). Each DrugCard entry now contains more than 100 data fields with half of the information being devoted to drug/chemical data and the other half devoted to pharmacological, pharmacogenomic and molecular biological data. A number of new data fields, including food-drug interactions, drug-drug interactions and experimental ADME data have been added in response to numerous user requests. DrugBank has also significantly improved the power and simplicity of its structure query and text query searches. DrugBank is available at http://www.drugbank.ca.

Posttranslational modification through palmitoylation regulates protein localization and function. In this study, we identify a role for the Drosophila melanogaster palmitoyl transferase Huntingtin-interacting protein 14 (HIP14) in neurotransmitter release. hip14 mutants show exocytic defects at low frequency stimulation and a nearly complete loss of synaptic transmission at higher temperature. Interestingly, two exocytic components known to be palmitoylated, cysteine string protein (CSP) and SNAP25, are severely mislocalized at hip14 mutant synapses. Complementary DNA rescue and localization experiments indicate that HIP14 is required solely in the nervous system and is essential for presynaptic function. Biochemical studies indicate that HIP14 palmitoylates CSP and that CSP is not palmitoylated in hip14 mutants. Furthermore, the hip14 exocytic defects can be suppressed by targeting CSP to synaptic vesicles using a chimeric protein approach. Our data indicate that HIP14 controls neurotransmitter release by regulating the trafficking of CSP to synapses.

The purpose of this paper was to determine the criteria that reflect the quality of care provided by long-term care institutions. Research was conducted using a two-step procedure that first utilized the SERVQUAL model with Fuzzy Delphi Method to establish the proper criteria by which service quality could be measured. A total of 200 questionnaires were mailed to expert respondents, of which 89 were returned and 77 deemed valid for use in this study. We then applied the Multi-Criteria Decision Making Process to determine the degree of importance of each criterion to long-term care institution service quality planning work. Secondly, 200 questionnaires were distributed and 74 valid responses were returned. Based on the 5 SERVQUAL model constructs, this study found 17 of the 28 criteria, to be pertinent to nursing care quality, with those in the Responsiveness and Empathy domains being the ones most critical.