Calmodulin Increases Ca-dependent Inhibition of the Na,K-ATPase in Human Red Blood Cells

Archives of Biochemistry and Biophysics. May, 1992  |  Pubmed ID: 1315506

Proteins in human red cell hemolysate were purified to determine which of them increase inhibition of the Na,K-ATPase in the presence of 2 microM free Ca. Samples purified 600,000-fold inhibited the Na,K-ATPase of human red cells in a Ca-dependent manner and stimulated the (Ca+Mg)-ATPase. These samples contained two proteins as analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE): calmodulin (18,000 Mr), which comprised most (greater than 90%) of the total protein, and an unidentified protein of approximately 13,000 Mr. Both proteins were a distinctive light yellow when stained with silver. Calmodulin from bovine testes also inhibited the Na,K-ATPase and stimulated the (Ca+Mg)-ATPase. This preparation also contained two proteins as analyzed by SDS-PAGE: calmodulin (95 to 99% of the total protein) and another protein of approximately 13,000 Mr (1 to 5% of the total protein). Both were light yellow when stained with silver. Since the amount of red cell protein was limited, the remainder of the study was carried out with the bovine testes preparation. Heating the testes preparation decreased, but did not abolish, inhibition of the Na,K-ATPase and reduced stimulation of the (Ca+Mg)-ATPase. When corrected for denatured calmodulin, both heated and unheated proteins increased inhibition of the Na,K-ATPase to the same extent. The Na,K-ATPase was inhibited at 2 microM free Ca in a dose-dependent manner over a range of 15 to 100 nM calmodulin. To establish if the inhibition was due to the calmodulin or the 13,000 Mr protein, both were electroeluted after SDS-PAGE. Electroeluted calmodulin stimulated the (Ca+Mg)-ATPase and increased Ca inhibition of the Na,K-ATPase. Electroeluted amounts of the smaller Mr protein slightly stimulated the (Ca+Mg)-ATPase, but had no effect on the Na,K-ATPase. This protein was digested with cyanogen bromide, partially sequenced, and thereby identified as a fragment of calmodulin. We conclude that intact calmodulin increases inhibition of the Na,K-ATPase at 2 microM free Ca. We suggest that calmodulin is part of a mechanism mediating the effects of physiological free Ca on the Na,K-ATPase.

Comparison of Self-assessment of Solvent Exposure with Measurement and Professional Assessment for Female Petrochemical Workers in China

American Journal of Industrial Medicine. Jun, 2002  |  Pubmed ID: 12173373

The primary objective of this paper is to examine the validity of self-assessment of solvent exposure by comparing it with professional assessment and actual measurements.

Asthma Symptoms in Hispanic Children and Daily Ambient Exposures to Toxic and Criteria Air Pollutants

Environmental Health Perspectives. Apr, 2003  |  Pubmed ID: 12676630

Although acute adverse effects on asthma have been frequently found for the U.S. Environmental Protection Agency's principal criteria air pollutants, there is little epidemiologic information on specific hydrocarbons from toxic emission sources. We conducted a panel study of 22 Hispanic children with asthma who were 10-16 years old and living in a Los Angeles community with high traffic density. Subjects filled out symptom diaries daily for up to 3 months (November 1999 through January 2000). Pollutants included ambient hourly values of ozone, nitrogen dioxide, sulfur dioxide, and carbon monoxide and 24-hr values of volatile organic compounds (VOCs), particulate matter with aerodynamic diameter < 10 microm (PM10, and elemental carbon (EC) and organic carbon (OC) PM10 fractions. Asthma symptom severity was regressed on pollutants using generalized estimating equations, and peak expiratory flow (PEF) was regressed on pollutants using mixed models. We found positive associations of symptoms with criteria air pollutants (O3, NO2, SO2, PM10), EC-OC, and VOCs (benzene, ethylbenzene, formaldehyde, acetaldehyde, acetone, 1,3-butadiene, tetrachloroethylene, toluene, m,p-xylene, and o-xylene). Selected adjusted odds ratios for bothersome or more severe asthma symptoms from interquartile range increases in pollutants were, for 1.4 ppb 8-hr NO2, 1.27 [95% confidence interval (CI), 1.05-1.54]; 1.00 ppb benzene, 1.23 (95% CI, 1.02-1.48); 3.16 ppb formaldehyde, 1.37 (95% CI, 1.04-1.80); 37 microg/m3 PM10, 1.45 (95% CI, 1.11-1.90); 2.91 microg/m3 EC, 1.85 (95% CI, 1.11-3.08); and 4.64 microg/m3 OC, 1.88 (95% CI, 1.12-3.17). Two-pollutant models of EC or OC with PM10 showed little change in odds ratios for EC (to 1.83) or OC (to 1.89), but PM10 decreased from 1.45 to 1.0. There were no significant associations with PEF. Findings support the view that air toxins in the pollutant mix from traffic and industrial sources may have adverse effects on asthma in children.

Respiratory Symptoms and Peak Expiratory Flow in Children with Asthma in Relation to Volatile Organic Compounds in Exhaled Breath and Ambient Air

Journal of Exposure Analysis and Environmental Epidemiology. Sep, 2003  |  Pubmed ID: 12973363

Indoor volatile organic compounds (VOCs) have been associated with asthma, but there is little epidemiologic work on ambient exposures, and no data on relationships between respiratory health and exhaled breath VOCs, which is a biomarker of VOC exposure. We recruited 26 Hispanic children with mild asthma in a Los Angeles community with high VOC levels near major freeways and trucking routes. Two dropped out, three had invalid peak expiratory flow (PEF) or breath VOC data, leaving 21. Children filled out symptom diaries and performed PEF maneuvers daily, November 1999-January 2000. We aimed to collect breath VOC samples on asthma episode and baseline symptom-free days, but six subjects only gave samples on symptom-free days. We analyzed 106 breath samples by GC-MS. Eight VOCs were quantifiable in >75% of breath samples (benzene, methylene chloride, styrene, tetrachloroethylene, toluene, m,p-xylene, o-xylene, and p-dichlorobenzene). Generalized estimating equation and mixed linear regression models for VOC exposure-response relationships controlled for temperature and respiratory infections. We found marginally positive associations between bothersome or more severe asthma symptoms and same day breath concentrations of benzene [odds ratio (OR) 2.03, 95% confidence interval (CI) 0.80, 5.11] but not other breath VOCs. Ambient petroleum-related VOCs measured on the same person-days as breath VOCs showed notably stronger associations with symptoms, including toluene, m,p-xylene, o-xylene, and benzene (OR 5.93, 95% CI 1.64, 21.4). On breath sample days, symptoms were also associated with 1-h ambient NO(2), OR 8.13 (1.52, 43.4), and SO(2), OR 2.36 (1.16, 4.81). Consistent inverse relationships were found between evening PEF and the same ambient VOCs, NO(2), and SO(2). There were no associations with O(3). Given the high traffic density of the region, stronger associations for ambient than for breath VOCs suggest that ambient VOC measurements were better markers for daily exposure to combustion-related compounds thought to be causally related to acute asthma. Alternatively, the low sample size of symptom responses (15-21 responses per 108 breath samples) may have led to the nonsignificant results for breath VOCs.

Disposable Diaper to Collect Urine Samples from Young Children for Pyrethroid Pesticide Studies

Journal of Exposure Analysis and Environmental Epidemiology. Sep, 2004  |  Pubmed ID: 15361896

Disposable diapers are widely used in the US and many other areas in the world; therefore, they are ideal media for urine collection for measurement of young children's exposure to pesticides. However, disposable diapers normally contain polyacrylate polymers that make the extraction and analysis of urine very difficult. The objectives of this paper were to evaluate whether disposable diapers that contain polyacrylate granules can be extracted using salt solutions, and whether they can be used for the collection and quantitative measurements of selected urinary pyrethroid pesticide metabolites and creatinine. The storage stability of the metabolites and creatinine in a wet diaper at body temperature and at refrigeration temperature was also evaluated. Salt solutions including calcium chloride dihydrate, magnesium sulfate, ammonium acetate, and sodium chloride solutions were tested for efficiency of polymer shrinkage. Pyrethroid metabolites 3-(2,2-dichlorovinyl)-2,2-dimethyl-(1-cyclopropane) carboxylic acid (DCCA), 3-(2,2-dibromovinyl)-2,2,dimethyl-(1-cyclopropane) carboxylic acid (DBCA) and 3-phenoxybenzoic acid (3-PBA) were analyzed using LC/MS/MS and evaluated for recoveries in the urine released from the diapers. The study found calcium chloride dihydate to be satisfactory in releasing urine and metabolites from the polymers. The percent recoveries for the three tested pyrethroid metabolites were mostly in the range of 65-130. The percent recoveries for creatinine were in the range of 71-133. The detection limit for each of the three metabolites was 0.1 microg/l. The pyrethroid metabolites and creatinine were stable on the diaper for at least 72 h. We concluded from this study that calcium chloride dihydrate can successfully release urine and metabolites from polyacrylate-containing diapers, and the method is promising for studies of pyrethroid metabolites.

Use of Pharmacokinetic Modeling to Design Studies for Pathway-specific Exposure Model Evaluation

Environmental Health Perspectives. Dec, 2004  |  Pubmed ID: 15579416

Validating an exposure pathway model is difficult because the biomarker, which is often used to evaluate the model prediction, is an integrated measure for exposures from all the exposure routes and pathways. The purpose of this article is to demonstrate a method to use pharmacokinetic (PK) modeling and computer simulation to guide the design of field studies to validate pathway models. The children's dietary intake model is discussed in detail as an example. Three important aspects are identified for a successful design to evaluate the children's dietary intake model: a) longitudinally designed study with significant changes in the exposure for the route/pathway of interest, b) short biologic half-life of the selected chemical, and c) surface loading of the selected chemical at sufficient levels. Using PK modeling to guide a study design allowed a path-specific exposure model to be evaluated using urinary metabolite biomarkers.

[Expression, Antibody Production and Bioactivity Detection of Cellular Repressor of E1A-stimulated Gene]

Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi = Chinese Journal of Cellular and Molecular Immunology. Sep, 2005  |  Pubmed ID: 16143059

To obtain the human cellular repressor of E1A-stimulated gene (hCREG) protein and the polyclonal antibody against the hCREG, and to further observe the expression and localization of hCREG protein in human internal thoracic artery cells (HITASY).

Determination of Mercury in an Assortment of Dietary Supplements Using an Inexpensive Combustion Atomic Absorption Spectrometry Technique

Journal of Automated Methods & Management in Chemistry. 2005  |  Pubmed ID: 18924735

The concentrations of mercury in forty, commercially available dietary supplements, were determined using a new, inexpensive analysis technique. The method involves thermal decomposition, amalgamation, and detection of mercury by atomic absorption spectrometry with an analysis time of approximately six minutes per sample. The primary cost savings from this approach is that labor-intensive sample digestion is not required prior to analysis, further automating the analytical procedure. As a result, manufacturers and regulatory agencies concerned with monitoring lot-to-lot product quality may find this approach an attractive alternative to the more classical acid-decomposition, cold vapor atomic absorption methodology. Dietary supplement samples analyzed included astragalus, calcium, chromium picolinate, echinacea, ephedra, fish oil, ginger, ginkgo biloba, ginseng, goldenseal, guggul, senna, St John's wort, and yohimbe products. Quality control samples analyzed with the dietary supplements indicated a high level of method accuracy and precision. Ten replicate preparations of a standard reference material (NIST 1573a, tomato leaves) were analyzed, and the average mercury recovery was 109% (2.0% RSD). The method quantitation limit was 0.3 ng, which corresponded to 1.5 ng/g sample. The highest found mercury concentration (123 ng/g) was measured in a concentrated salmon oil sample. When taken as directed by an adult, this product would result in an approximate mercury ingestion of 7 mug per week.

[The Beneficial Effect of Gingko Biloba Extract on Myocardial Impairment in Diabetic Rats]

Zhongguo Ying Yong Sheng Li Xue Za Zhi = Zhongguo Yingyong Shenglixue Zazhi = Chinese Journal of Applied Physiology. May, 2005  |  Pubmed ID: 21171336

To study the protective effect of Gingko biloba extract (EGb) against myocardial impairment in diabetic rats.

A Unique Role of the DNA Fragmentation Factor in Maintaining Genomic Stability

Proceedings of the National Academy of Sciences of the United States of America. Jan, 2006  |  Pubmed ID: 16432220

DNA fragmentation is a hallmark of apoptosis (programmed cell death). However, the biological function of apoptotic DNA fragmentation remains unclear. Here, we show that DNA fragmentation factor plays an important role for maintaining genomic stability. Inhibition or loss of the DNA fragmentation factor (DFF)/caspase-activated DNase (CAD), whose nuclease activity is responsible for digesting genomic DNA during apoptosis, led to significant increases in spontaneous or induced gene mutations, gene amplifications, and chromosomal instability in primary mouse cells and transformed human cell lines. The mechanism underlying genetic instability in DFF/CAD-deficient cells, at least in part, involves a small but significant elevation in the survival of cells exposed to ionizing radiation, suggesting that apoptotic DNA fragmentation factor contributes to genomic stability by ensuring the removal of cells that have suffered DNA damage. In support of this hypothesis are the observations of increased cellular transformation of mouse embryonic cells from the DFF/CAD-null mice and significantly enhanced susceptibility to radiation-induced carcinogenesis in these mice. These data, in combination with published reports on the existence of tumor-specific gene mutations/deletions in the DFF/CAD genes in human cancer samples, suggest that apoptotic DNA fragmentation factor is required for the maintenance of genetic stability and may play a role in tumor suppression.

[COX-2 Mediates U50488H-induced Delayed Cardioprotection in Isolated Rat Heart]

Zhejiang Da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences. Mar, 2006  |  Pubmed ID: 16610083

To determine whether U50488H, a selective agonist of kappa-opioid receptor, could induce biphasic (early and late) cardioprotection against myocardial ischemia/reperfusion injury and to explore the underlying mechanisms.

[Over-expression of the Cellular Repressor of E1A-stimulated Genes Inhibits the Apoptosis of Human Vascular Smooth Muscle Cells in Vitro.]

Sheng Li Xue Bao : [Acta Physiologica Sinica]. Aug, 2006  |  Pubmed ID: 16906332

To investigate the effects and molecular mechanisms of the cellular repressor of E1A-stimulated genes (CREG) on the apoptosis of vascular smooth muscle cells (VSMCs), the human internal thoracic artery-Shenyang (HITASY) cells were infected with sense-CREG [pLNCX(2)(+)/CREG] and antisense-CREG [pLXSN(-)/CREG] retrovirus respectively. The stably infected cells were obtained by screening the G418-resistant clones. DAPI nuclei staining and Annexin V/PI FASC assay indicated that over-expression of CREG in HITASY cells infected with pLNCX(2) (+)/CREG inhibited VSMC apoptosis induced by serum deprivation, accompanied with decreased expression of caspase-9 mRNA detected by RT-PCR. Furthermore, Western blot analysis showed that p38 mitogen activated protein kinase (p38 MAPK) expression and activation were significantly enhanced in HITASY cells infected with pLNCX(2) (+)/CREG. The inhibition of CREG protein expression in cells infected with pLXSN(-)/CREG promoted the VSMC spontaneous apoptosis, as well as down-regulated p38 MAPK expression and activation, when cells were cultured with 10% fetal bovine serum (FBS) mediums. These results implicate that the CREG protein has the ability to regulate VSMC apoptosis in which the activation of p38 MAPK is possibly involved. To further identify the role of p38 MAPK in VSMC apoptosis, SB203580, a specific inhibitor of p38 MAPK, was used to inhibit p38 MAPK activity. When p38 MAPK signaling pathway was blocked, the effects that over-expression of CREG protein inhibited VSMC apoptosis disappeared. Taken together, the present work indicates that over-expression of CREG protein inhibits VSMC apoptosis, and this inhibitory effect is partly mediated by p38 MAPK signaling pathway.

[Revelation and Phylogenetic Analysis of the Predominant Bacterial Community Associated with Sponges in the South China Sea Based on PCR- DGGE Fingerprints]

Wei Sheng Wu Xue Bao = Acta Microbiologica Sinica. Jun, 2006  |  Pubmed ID: 16933628

The predominant bacterial community structure of Dysidea avara and Craniella australiensis in the South China Sea were revealed by PCR- DGGE fingerprinting in the present study. With further cloning, sequencing and phylogenetic analysis, it was found that Proteobacteria predominated in these two sponges. Alphaproteobacteria, Betaproteobacteria and Gammaproteobacteria were found in Dysidea avara and only Gammaproteobacteria found in Craniella australiensis. Although Bacteroidetes were found in both sponges, they differed in the species. These bacteria were found in sponges firstly. The bacteria in Craniella australiensis show more complex diversity than that in Dysidea avara. Because compared with Dysidea avara, Craniella australiensis include Actinobacteria, Firmicutes, etc. The bacterial community diversity in these two sponges indicates that the sponge-associated bacteria are host-specific even if the hosts are from the same marine location. DGGE fingerprint-based analysis should integrate with band cloning and sequencing, phylogenetic analysis, etc., molecular techniques to get precise results for the microbial community and diversity revelation. The research of studying sponge microbe by DGGE technique is initial work, that will accelerate the development of sponge microorganisms item.

[Reconstruction of Leptospira Interrogans LipL21 Gene and Characteristics of Its Expression Product]

Zhejiang Da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences. Sep, 2007  |  Pubmed ID: 17924464

To reconstruct the nucleotide sequence of Leptospira interrogans lipL21 gene for increasing the output of prokaryotic expression and to understand the changes on immunogenicity of the expression products before and after reconstruction, and to determine the position of envelope lipoprotein LipL21 on the surface of leptospiral body.

[Study on the Location of Membrane and Detection of Antibody in the Sera of Genus-specific Antigen LipL41s in Patients with Leptospira Interrogans]

Zhonghua Liu Xing Bing Xue Za Zhi = Zhonghua Liuxingbingxue Zazhi. Aug, 2007  |  Pubmed ID: 18080565

To determine the location on outer envelope and natural antibody response and types of genus-specific lipoprotein antigen LipL41s in patients with Leptospira interrogans.

Evaluation of an Electron Monte Carlo Dose Calculation Algorithm for Electron Beam

Journal of Applied Clinical Medical Physics / American College of Medical Physics. 2008  |  Pubmed ID: 18716583

The electron Monte Carlo (eMC) dose calculation algorithm of the Eclipse treatment planning system is based heavily upon Monte Carlo simulation of the linac head and modeling of the linac beam characteristics with minimal measurement of beam data. Commissioning of the eMC algorithm on multiple identical linacs provided a unique opportunity to systematically evaluate the algorithm with actual measurements of clinically relevant beam and dose parameters. In this study, measured and eMC calculated dose distributions were compared both along and perpendicular to electron beam direction for electron energy/applicator/depth combination using measurement data from four Varian 21EX CLINAC linear accelerator (Varian Medical System, Palo Alto, CA). Cutout factors for sizes down to 3 x 3 cm were also compared. Comparisons between the measurement and the eMC calculated values show that the R90, R80, R50, and R10 values mostly agree within 3 mm. Measure and Calculated bremsstrahlung dose Dx correlates well statistically although eMC calculated Dx values are consistently smaller than the measured, with maximum discrepancy of 1% for the 20 MeV electron beams. Surface dose agrees mostly within 2%. Field width and penumbra agree mostly within 3mm. Calculation grid size is found to have a significant effect on the dose calculation. A grid size of 5 mm can produce erroneous dose distributions. Using a grid size of 2.5 mm and a 3% accuracy specified for the eMC to stop calculation iteration, the absolute output agrees with measurements within 3% for field sizes of 5 x 5 cm or larger. For cutout of 3 x 3 cm, however, the output disagreement can reach 8%. Our result indicate that eMC algorithm in Eclipse provides acceptable agreement with measurement data for most clinical situations. Calculation grid size of 2.5 mm or smaller is recommended.

RelACCS-FP: a Structural Minimalist Approach to Fingerprint Design

Chemical Biology & Drug Design. Nov, 2008  |  Pubmed ID: 19012570

The design and evaluation of structural key-type fingerprints is reported that consist of only 10-30 substructures isolated from randomly generated fragment populations of different classes of active compounds. To identify minimal sets of fragments that carry substantial compound class-specific information, fragment frequency calculations are applied to guide fingerprint generation. These compound class-directed and extremely small structural fingerprints push the design of so-called mini-fingerprints to the limit and are the shortest bit string fingerprints reported to date. For the application of relative frequency-based activity class characteristic substructure fingerprints, a bit density-dependent similarity metric is introduced that makes it possible to adjust similarity coefficients for individual compound classes and balance the recall of active compounds with database selection size. In similarity search trials, these small compound class-directed fingerprints enrich active compounds in relatively small database selection sets and approach or exceed the performance of widely used structural fingerprints of much larger size and higher complexity.

[Upregulation of FasL/Fas Expression and FasL/Fas-associated Apoptosis in J774A.1 Cells Induced by Leptospira Interrogans]

Zhejiang Da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences. Nov, 2008  |  Pubmed ID: 19084951

To determine the involvement of FasL/Fas pathway in apoptosis of J774A.1 cells induced by Leptospira interrogans.

Characterization of the OmpL1 Gene of Pathogenic Leptospira Species in China and Cross-immunogenicity of the OmpL1 Protein

BMC Microbiology. 2008  |  Pubmed ID: 19087358

The usefulness of available vaccine and serological tests for leptospirosis is limited by the low cross-reactivity of antigens from numerous serovars of pathogenic Leptospira spp. Identification of genus-specific protein antigens (GP-Ag) of Leptospira would be important for development of universal vaccines and serodiagnostic methods. OmpL1, a transmembrane porin of pathogenic leptospires, was identified as a possible GP-Ag, but its sequence diversity and immune cross-reactivity among different serovars of pathogenic leptospires remains largely unknown.

[Effects of Montelukast and BCG-PSN on the Expression of STAT5b MRNA and IL-4 MRNA in Blood Mononuclearcells of Rats with Asthma]

Zhongguo Dang Dai Er Ke Za Zhi = Chinese Journal of Contemporary Pediatrics. Feb, 2009  |  Pubmed ID: 19222952

To study the expression of signal transducer and activator of transcription 5b (STAT5b) mRNA and interleukin-4 (IL-4) mRNA in blood mononuclearcells in a rat model of asthma and the effect of montelukast (MK) and BCG-polysaccharide and nucleic acid injection (BCG-PSN) on STAT5b mRNA and IL-4 mRNA expression.

Improving the Search Performance of Extended Connectivity Fingerprints Through Activity-oriented Feature Filtering and Application of a Bit-density-dependent Similarity Function

ChemMedChem. Apr, 2009  |  Pubmed ID: 19263458

The Pipeline Pilot extended connectivity fingerprints (ECFPs) are currently among the most popular similarity search tools in drug discovery settings. ECFPs do not have a fixed bit string format but generate variable numbers of structural features for individual test molecules. This variable string design makes ECFP representations amenable to compound-class-directed modification. We have devised an intuitive feature-filtering technique that focuses ECFP search calculations on feature string ensembles of given compound activity classes. In combination with a simple bit-density-dependent similarity function, feature filtering consistently improved the search performance of ECFP calculations based on Tanimoto similarity and state-of-the-art data fusion techniques on a diverse array of activity classes. Feature filtering and the bit density similarity metric are easily implemented in the Pipeline Pilot environment. The approach provides a viable alternative to conventional similarity searching and should be of general interest to further improve the success rate of practical ECFP applications.

[Changes of Prostaglandin D2 Receptor on T Cells in Peripheral Blood of Children with Asthma]

Zhongguo Dang Dai Er Ke Za Zhi = Chinese Journal of Contemporary Pediatrics. Mar, 2009  |  Pubmed ID: 19292959

Chronic airway inflammation is associated with the polarization of TH2 cells in asthma. Prostaglandin D2 (PGD2) plays an important role in the polarization of TH2 cells. This study aimed to investigate the changes of PGD2 receptors (DP1/CRTH2) on T lymphocytes and their significance in asthma.

Relevance of Feature Combinations for Similarity Searching Using General or Activity Class-directed Molecular Fingerprints

Journal of Chemical Information and Modeling. Mar, 2009  |  Pubmed ID: 19434896

We introduce a methodology for the systematic identification of feature combinations derived from fingerprints of bioactive compounds. Structural features were organized in co-occurrence networks from which reference set-based feature cliques were extracted. A similarity search strategy is presented that is based on frequency ranking of cliques. Three types of fingerprints have been compared that are either general in their design or incorporate, to a different degree, compound class information. Taking control calculations into account, search performance was overall best for a molecule-specific extended connectivity fingerprint. For compound class-directed fingerprints, reference set-derived feature cliques occurring with low frequency in a screening database were found to consistently enrich active compounds in database selection sets, even if the features are not highly conserved among reference compounds. Thus, in contrast to general fingerprints, feature combinations play a crucial role in similarity searching using activity-class-directed fingerprints.

Filtering and Counting of Extended Connectivity Fingerprint Features Maximizes Compound Recall and the Structural Diversity of Hits

Chemical Biology & Drug Design. Jul, 2009  |  Pubmed ID: 19519749

Extended connectivity fingerprints produce variable numbers of structural features for molecules and quantitative comparison of feature ensembles is typically carried out as a measure of molecular similarity. As an alternative way to utilize the information content of extended connectivity fingerprint features, we have introduced a compound class-directed feature filtering technique. In combination with a simple feature counting protocol, feature filtering significantly improves the performance of extended connectivity fingerprint similarity searching compared with state-of-the-art fingerprint search methods. Subsets of extended connectivity fingerprint features that are unique to active compounds are found to be responsible for high compound recall. Moreover, feature filtering and counting is shown to result in significantly higher scaffold hopping potential than data fusion or fingerprint averaging methods. Extended connectivity fingerprint feature filtering and counting represents one of the simplest similarity search methods introduced to date, yet it produces top compound recall and maximizes the scaffold diversity of hits, which is a longstanding goal of similarity searching.

Sensitive and Specific ELISA Coated by TpN15-TpN17-TpN47 Fusion Protein for Detection of Antibodies to Treponema Pallidum

Clinical Chemistry and Laboratory Medicine : CCLM / FESCC. 2009  |  Pubmed ID: 19676144

We constructed an artificial fusion gene tpN15-17-47 and then used the prokaryotic expression fusion protein rTpN15-17-47 as the coated antigen to establish a new enzyme-linked immunosorbent assay (ELISA) for serological diagnosis of syphilis.

From Structure-activity to Structure-selectivity Relationships: Quantitative Assessment, Selectivity Cliffs, and Key Compounds

ChemMedChem. Nov, 2009  |  Pubmed ID: 19750525

The exploration of structure-activity relationships (SARs) in chemical lead optimization is mostly focused on activity against single targets. Because many active compounds have the potential to act against multiple targets, achieving a sufficient degree of target selectivity often becomes a major issue during optimization. Herein we report a data analysis approach to explore compound selectivity in a systematic and quantitative manner. Sets of compounds that are active against multiple targets provide a basis for exploring structure-selectivity relationships (SSRs). Compound similarity and selectivity data are analyzed with the aid of network-like similarity graphs (NSGs), which organize molecular networks on the basis of similarity relationships and SAR index (SARI) values. For this purpose, the SARI framework has been adapted to quantify SSRs. Using sets of compounds with differential activity against four cathepsin thiol proteases, we show that SSRs can be quantitatively described and categorized. Furthermore, local SSR environments are identified, the analysis of which provides insight into compound selectivity determinants at the molecular level. These environments often contain "selectivity cliffs" formed by pairs or groups of similar compounds with significantly different selectivity. Moreover, key compounds are identified that determine characteristic features of single-target SARs and dual-target SSRs. The comparison of compounds involved in the formation of selectivity cliffs often reveals chemical modifications that render compounds target selective.

[The Effect of Budesonide on the Eosinophil Infiltration in Airway of Asthmatic Rats]

Zhongguo Ying Yong Sheng Li Xue Za Zhi = Zhongguo Yingyong Shenglixue Zazhi = Chinese Journal of Applied Physiology. Aug, 2009  |  Pubmed ID: 21155237

Nanotexture Optimization by Oxygen Plasma of Mesoporous Silica Thin Film for Enrichment of Low Molecular Weight Peptides Captured from Human Serum

Science China. Chemistry. Nov, 2010  |  Pubmed ID: 21179395

This study investigated the optimization of mesoporous silica thin films by nanotexturing using oxygen plasma versus thermal oxidation. Calcination in oxygen plasma provides superior control over pore formation with regard to the pore surface and higher fidelity to the structure of the polymer template. The resulting porous film offers an ideal substrate for the selective partitioning of peptides from complex mixtures. The improved chemico-physical characteristics of porous thin films (pore size distribution, nanostructure, surface properties and pore connectivity) were systematically characterized with XRD, Ellipsometry, FTIR, TEM and N(2) adsorption/desorption. The enrichment of low molecular weight proteins captured from human serum on mesoporous silica thin films fabricated by both methodologies were investigated by comparison of their MALDI-TOF MS profiles. This novel on-chip fractionation technology offers advantages in recovering the low molecular weight peptides from human serum, which has been recognized as an informative resource for early diagnosis of cancer and other diseases.

Systematic Analysis of Public Domain Compound Potency Data Identifies Selective Molecular Scaffolds Across Druggable Target Families

Journal of Medicinal Chemistry. Jan, 2010  |  Pubmed ID: 20000355

Molecular scaffolds that yield target family-selective compounds are of high interest in pharmaceutical research. There continues to be considerable debate in the field as to whether chemotypes with a priori selectivity for given target families and/or targets exist and how they might be identified. What do currently available data tell us? We present a systematic and comprehensive selectivity-centric analysis of public domain target-ligand interactions. More than 200 molecular scaffolds are identified in currently available active compounds that are selective for established target families. A subset of these scaffolds is found to produce compounds with high selectivity for individual targets among closely related ones. These scaffolds are currently underrepresented in approved drugs.

Mesoporous Silica Chips for Selective Enrichment and Stabilization of Low Molecular Weight Proteome

Proteomics. Feb, 2010  |  Pubmed ID: 20013801

The advanced properties of mesoporous silica have been demonstrated in applications, which include chemical sensing, filtration, catalysis, drug delivery and selective biomolecular uptake. These properties depend on the architectural, physical and chemical properties of the material, which in turn are determined by the processing parameters in evaporation-induced self-assembly. In this study, we introduce a combinatorial approach for the removal of the high molecular weight proteins and for the specific isolation and enrichment of low molecular weight species. This approach is based on mesoporous silica chips able to fractionate, selectively harvest and protect from enzymatic degradation, peptides and proteins present in complex human biological fluids. We present the characterization of the harvesting properties of a wide range of mesoporous chips using a library of peptides and proteins standard and their selectivity on the recovery of serum peptidome. Using MALDI-TOF-MS, we established the correlation between the harvesting specificity and the physicochemical properties of mesoporous silica surfaces. The introduction of this mesoporous material with fine controlled properties will provide a powerful platform for proteomics application offering a rapid and efficient methodology for low molecular weight biomarker discovery.

Scaffold Distributions in Bioactive Molecules, Clinical Trials Compounds, and Drugs

ChemMedChem. Feb, 2010  |  Pubmed ID: 20014088

Tailoring of the Nanotexture of Mesoporous Silica Films and Their Functionalized Derivatives for Selectively Harvesting Low Molecular Weight Protein

ACS Nano. Jan, 2010  |  Pubmed ID: 20014864

We present a fast, efficient, and reliable system based on mesoporous silica chips to specifically fractionate and enrich the low molecular weight proteome. Mesoporous silica thin films with tunable features at the nanoscale were fabricated using the triblock copolymer template pathway. Using different templates and concentrations in the precursor solution, various pore size distributions, pore structures, and connectivity were obtained and applied for selective recovery of low mass proteins. In combination with mass spectrometry and statistic analysis, we demonstrated the correlation between the nanophase characteristics of the mesoporous silica thin films and the specificity and efficacy of low mass proteome harvesting. In addition, to overcome the limitations of the prefunctionalization method in polymer selection, plasma ashing was used for the first time for the treatment of the mesoporous silica surface prior to chemical modification. Surface charge modifications by different functional groups resulted in a selective capture of the low molecular weight proteins from serum sample. In conclusion, our study demonstrates that the ability to tune the physicochemical properties of mesoporous silica surfaces, for a selective enrichment of the low molecular weight proteome from complex biological fluids, has the potential to promote proteomic biomarker discovery.

[CRTH2 Antagonist Ameliorates Airway Inflammation in Rats with Asthma]

Zhejiang Da Xue Xue Bao. Yi Xue Ban = Journal of Zhejiang University. Medical Sciences. Jan, 2010  |  Pubmed ID: 20175238

To investigate the effect of prostaglandin D2 receptor antagonists on the airway inflammation in rats with asthma.

Molecular Scaffolds with High Propensity to Form Multi-target Activity Cliffs

Journal of Chemical Information and Modeling. Apr, 2010  |  Pubmed ID: 20361784

In target-dependent activity landscapes of compound series, cliffs are formed by pairs of molecules that are structurally analogous but display significant differences in potency. The detection and analysis of such activity cliffs is a major task in structure-activity relationship analysis and compound optimization. In analogy to activity cliffs, selectivity cliffs can be defined that are formed by structural analogs having significantly different potencies against two targets. The formation of activity cliffs by analogs is generally a consequence of different R-group patterns; e.g., a specific substitution of a given scaffold might increase and another substitution decrease potency. Therefore, activity (or selectivity) cliffs are typically analyzed for a given scaffold representing an analog series, and it has thus far not been explored whether certain scaffolds might display a general tendency to yield compounds forming activity cliffs against different targets. We have exhaustively analyzed scaffolds and associated compound activity data in the ChemblDB and BindingDB databases in order to compare the availability of target-selective scaffolds in these databases and determine whether multi-target activity and multi-target selectivity cliff scaffolds exist. Perhaps unexpectedly, we have identified 143 scaffolds that are represented by multiple compounds and form activity or selectivity cliffs against different targets. These scaffolds have varying chemical complexities and are in part promiscuous binders (i.e., compounds containing these scaffolds bind to distantly related or unrelated targets). However, analogs derived from these scaffolds form steep activity cliffs against different targets. A catalog of scaffolds with high propensity to form activity or selectivity cliffs against multiple targets is provided to help identify potentially promiscuous candidate scaffolds during compound optimization efforts.

[Effect of Ginkgo Biloba Extract on Glucose Uptake of Diaphragm in Diabetic Rats]

Zhongguo Zhong Yao Za Zhi = Zhongguo Zhongyao Zazhi = China Journal of Chinese Materia Medica. Feb, 2010  |  Pubmed ID: 20423005

To investigate the effects of Ginkgo biloba extract (GbE) on the glucose uptake rate and gene expression of glucose transporter 4 (GLUT4) in diaphragm of diabetic rats.

Pleural Aspergillosis Complicated by Recurrent Pneumothorax: a Case Report

Journal of Medical Case Reports. 2010  |  Pubmed ID: 20565739

Pneumothorax as the first symptom of pleural aspergillosis is rare.

Determination of Glucosinolates in 19 Chinese Medicinal Plants with Spectrophotometry and High-pressure Liquid Chromatography

Natural Product Research. Aug, 2010  |  Pubmed ID: 20645206

Glucosinolates were evaluated in 19 traditional Chinese medicinal plants involved in seven different families: Brassicaceae, Capparaceae, Euphorbiaceae, Phytolaccaceae, Tropaeolaceae, Caricaceae and Rubiaceae. The total glucosinolate contents were determined by spectrophotometry. Results showed that the high contents of total glucosinolates were found in some herbs of Brassicaceae, Capparaceae and Euphorbiaceae families, while low total glucosinolate contents were observed in two Rubiaceae herbs. In addition, eight glucosinolates (glucoraphanin, glucoraphenin, sinalbin, sinigrin, progoitrin, 4-hydroglucobrassicin, glucoiberin and glucoibervirin) in these herbs were measured using HPLC, and the data showed that individual glucosinolates and their contents varied at different degrees among the distinct species. The highest contents of cancer-protective compounds were found in the seeds of Raphanus sativus L. (glucoraphenin), Sinapis alba (sinalbin) and Phyllanthus emblica L. (sinigrin).

[Effects of Ginkgo Biloba Extraction on Contraction Capacity of Diaphragm from Type 2 Diabetic Rats]

Zhongguo Ying Yong Sheng Li Xue Za Zhi = Zhongguo Yingyong Shenglixue Zazhi = Chinese Journal of Applied Physiology. May, 2010  |  Pubmed ID: 20684294

To investigate the effects of Ginkgo biloba extract (GbE) on the activities of energy metabolism enzymes and contraction capacity of diaphragm from type 2 diabetic rats.

Structural and Potency Relationships Between Scaffolds of Compounds Active Against Human Targets

ChemMedChem. Oct, 2010  |  Pubmed ID: 20721999

Enhanced Microcontact Printing of Proteins on Nanoporous Silica Surface

Nanotechnology. Oct, 2010  |  Pubmed ID: 20834118

We demonstrate porous silica surface modification, combined with microcontact printing, as an effective method for enhanced protein patterning and adsorption on arbitrary surfaces. Compared to conventional chemical treatments, this approach offers scalability and long-term device stability without requiring complex chemical activation. Two chemical surface treatments using functionalization with the commonly used 3-aminopropyltriethoxysilane (APTES) and glutaraldehyde (GA) were compared with the nanoporous silica surface on the basis of protein adsorption. The deposited thickness and uniformity of porous silica films were evaluated for fluorescein isothiocyanate (FITC)-labeled rabbit immunoglobulin G (R-IgG) protein printed onto the substrates via patterned polydimethlysiloxane (PDMS) stamps. A more complete transfer of proteins was observed on porous silica substrates compared to chemically functionalized substrates. A comparison of different pore sizes (4-6 nm) and porous silica thicknesses (96-200 nm) indicates that porous silica with 4 nm diameter, 57% porosity and a thickness of 96 nm provided a suitable environment for complete transfer of R-IgG proteins. Both fluorescence microscopy and atomic force microscopy (AFM) were used for protein layer characterizations. A porous silica layer is biocompatible, providing a favorable transfer medium with minimal damage to the proteins. A patterned immunoassay microchip was developed to demonstrate the retained protein function after printing on nanoporous surfaces, which enables printable and robust immunoassay detection for point-of-care applications.

Polypharmacology Directed Compound Data Mining: Identification of Promiscuous Chemotypes with Different Activity Profiles and Comparison to Approved Drugs

Journal of Chemical Information and Modeling. Dec, 2010  |  Pubmed ID: 21070069

Increasing evidence that many pharmaceutically relevant compounds elicit their effects through binding to multiple targets, so-called polypharmacology, is beginning to change conventional drug discovery and design strategies. In light of this paradigm shift, we have mined publicly available compound and bioactivity data for promiscuous chemotypes. For this purpose, a hierarchy of active compounds, atomic property based scaffolds, and unique molecular topologies were generated, and activity annotations were analyzed using this framework. Starting from ∼35 000 compounds active against human targets with at least 1 μM potency, 33 chemotypes with distinct topology were identified that represented molecules active against at least 3 different target families. Network representations were utilized to study scaffold-target family relationships and activity profiles of scaffolds corresponding to promiscuous chemotypes. A subset of promiscuous chemotypes displayed a significant enrichment in drugs over bioactive compounds. A total of 190 drugs were identified that had on average only 2 known target annotations but belonged to the 7 most promiscuous chemotypes that were active against 8-15 target families. These drugs should be attractive candidates for polypharmacological profiling.

Direct Evidence for Catalase and Peroxidase Activities of Ferritin-platinum Nanoparticles

Biomaterials. Feb, 2011  |  Pubmed ID: 21112084

Using apoferritin (apoFt) as a nucleation substrate, we have successfully synthesized 1-2 nm platinum nanoparticles (Pt-Ft) which are highly stable. By directly measuring the products of Pt-Ft-catalyzed reactions, we showed, with no doubt, Pt-Ft possesses both catalase and peroxidase activities. With hydrogen peroxide as substrate, we observed oxygen gas bubbles were generated from hydrogen peroxide decomposed by Pt-Ft; the generation of oxygen gas strongly supports Pt-Ft reacts as catalase, other than peroxidase. While with organic dyes and hydrogen peroxide as substrates, distinctive color products were formed catalyzed by Pt-Ft, which indicates a peroxidase-like activity. Interestingly, these biomimetic properties showed differential response to pH and temperature for different reaction substrates. Pt-Ft showed a significant increase in catalase activity with increasing pH and temperature. The HRP-like activity of Pt-Ft was optimal at physiological temperature and slightly acidic conditions. Our current study demonstrates that Pt-Ft possesses both catalase and peroxidase activities for different substrates under different conditions.

Surface Engineering on Mesoporous Silica Chips for Enriching Low Molecular Weight Phosphorylated Proteins

Nanoscale. Feb, 2011  |  Pubmed ID: 21135976

Phosphorylated peptides and proteins play an important role in normal cellular activities, e.g., gene expression, mitosis, differentiation, proliferation, and apoptosis, as well as tumor initiation, progression and metastasis. However, technical hurdles hinder the use of common fractionation methods to capture phosphopeptides from complex biological fluids such as human sera. Herein, we present the development of a dual strategy material that offers enhanced capture of low molecular weight phosphoproteins: mesoporous silica thin films with precisely engineered pore sizes that sterically select for molecular size combined with chemically selective surface modifications (i.e. Ga3+, Ti4+ and Zr4+) that target phosphoroproteins. These materials provide high reproducibility (CV=18%) and increase the stability of the captured proteins by excluding degrading enzymes, such as trypsin. The chemical and physical properties of the composite mesoporous thin films were characterized by X-ray diffraction, transmission electron microscopy, X-ray photoelectron spectroscopy, energy dispersive X-ray spectroscopy and ellipsometry. Using mass spectroscopy and biostatistics analysis, the enrichment efficiency of different metal ions immobilized on mesoporous silica chips was investigated. The novel technology reported provides a platform capable of efficiently profiling the serum proteome for biomarker discovery, forensic sampling, and routine diagnostic applications.

Nanodevices in Diagnostics

Wiley Interdisciplinary Reviews. Nanomedicine and Nanobiotechnology. Jan-Feb, 2011  |  Pubmed ID: 20229595

The real-time, personalized and highly sensitive early-stage diagnosis of disease remains an important challenge in modern medicine. With the ability to interact with matter at the nanoscale, the development of nanotechnology architectures and materials could potentially extend subcellular and molecular detection beyond the limits of conventional diagnostic modalities. At the very least, nanotechnology should be able to dramatically accelerate biomarker discovery, as well as facilitate disease monitoring, especially of maladies presenting a high degree of molecular and compositional heterogeneity. This article gives an overview of several of the most promising nanodevices and nanomaterials along with their applications in clinical practice. Significant work to adapt nanoscale materials and devices to clinical applications involving large interdisciplinary collaborations is already underway with the potential for nanotechnology to become an important enabling diagnostic technology.

Combining Horizontal and Vertical Substructure Relationships in Scaffold Hierarchies for Activity Prediction

Journal of Chemical Information and Modeling. Feb, 2011  |  Pubmed ID: 21271729

For a systematic exploration of structural relationships between molecular scaffolds, ∼24,000 unique scaffolds were extracted from 458 different target sets. Substructure relationships between these scaffolds were systematically determined. The scaffold tree data structure was utilized to study structural relationships between original scaffolds and derivative scaffolds obtained by rule-based decomposition. Leaf-to-root substructure relationships that resulted from rule-based decomposition were compared to leaf-to-leaf relationships between original scaffolds most of which were not part of the scaffold tree hierarchy. Decomposed scaffolds not contained in active target set compounds were prioritized on the basis of hierarchical scaffold patterns and additional substructure relationships. For high-priority virtual scaffolds, activity predictions were carried out, and these scaffolds were often found in external test compounds having the predicted activity. Taken together, our results suggest that leaf-to-root substructure relationships in scaffold trees should best be complemented with additional substructure relationships to determine high-priority virtual scaffolds for activity prediction.

SAR Monitoring of Evolving Compound Data Sets Using Activity Landscapes

Journal of Chemical Information and Modeling. Mar, 2011  |  Pubmed ID: 21322535

In pharmaceutical research, collections of active compounds directed against specific therapeutic targets usually evolve over time. Small molecule discovery is an iterative process. New compounds are discovered, alternative compound series explored, some series discontinued, and others prioritized. The design of new compounds usually takes into consideration prior chemical and structure-activity relationship (SAR) knowledge. Hence, historically grown compound collections represent a viable source of chemical and SAR information that might be utilized to retrospectively analyze roadblocks in compound optimization and further guide discovery projects. However, SAR analysis of large and heterogeneous sets of active compounds is also principally complicated. We have subjected evolving compound data sets to SAR monitoring using activity landscape models in order to evaluate how composition and SAR characteristics might change over time. Chemotype and potency distributions in evolving data sets directed against different therapeutic targets were analyzed and alternative activity landscape representations generated at different points in time to monitor the progression of global and local SAR features. Our results show that the evolving data sets studied here have predominantly grown around seed clusters of active compounds that often emerged early on, while other SAR islands remained largely unexplored. Moreover, increasing scaffold diversity in evolving data sets did not necessarily yield new SAR patterns, indicating a rather significant influence of "me-too-ism" (i.e., introducing new chemotypes that are similar to already known ones) on the composition and SAR information content of the data sets.

Noninvasive Monitoring of Pirenoxine Sodium Concentration in Aqueous Humor Based on Dual-wavelength Iris Imaging Technique

Biomedical Optics Express. 2011  |  Pubmed ID: 21339869

We present a noninvasive method of detecting substance concentration in the aqueous humor based on dual-wavelength iris imaging technology. Two light sources, one centered within (392 nm) and the other centered outside (850 nm) of an absorption band of Pirenoxine Sodium, a common type of drugs in eye disease treatment, were used for dual-wavelength iris imaging measurement. After passing through the aqueous humor twice, the back-scattering light was detected by a charge-coupled device (CCD). The detected images were then used to calculate the concentration of Pirenoxine Sodium. In eye model experiment, a resolution of 0.6525 ppm was achieved. Meanwhile, at least 4 ppm can be distinguished in in vivo experiment. These results demonstrated that our method can measure Pirenoxine Sodium concentration in the aqueous humor and its potential ability to monitor other materials' concentration in the aqueous humor.

Microfluidic Enrichment of Small Proteins from Complex Biological Mixture on Nanoporous Silica Chip

Biomicrofluidics. 2011  |  Pubmed ID: 21522500

The growing field of miniaturized diagnostics is hindered by a lack of pre-analysis treatments that are capable of processing small sample volumes for the detection of low concentration analytes in a high-throughput manner. This letter presents a novel, highly efficient method for the extraction of low-molecular weight (LMW) proteins from biological fluids, represented by a mixture of standard proteins, using integrated microfluidic systems. We bound a polydimethylsiloxane layer patterned with a microfluidic channel onto a well-defined nanoporous silica substrate. Using rapid, pressure-driven fractionation steps, this system utilizes the size-exclusion properties of the silica nanopores to remove high molecular weight proteins while simultaneously isolating and enriching LMW proteins present in the biological sample. The introduction of the microfluidic component offers important advantages such as high reproducibility, a simple user interface, controlled environment, the ability to process small sample volumes, and precise quantification. This solution streamlines high-throughput proteomics research on many fronts and may find broad acceptance and application in clinical diagnostics and point of care detection.

Mesoporous Silica As a Membrane for Ultra-thin Implantable Direct Glucose Fuel Cells

Lab on a Chip. Jul, 2011  |  Pubmed ID: 21637881

The design, fabrication and characterization of an inorganic catalyst based direct glucose fuel cell using mesoporous silica coating as a functional membrane is reported. The desired use of mesoporous silica based direct glucose fuel cell is for a blood vessel implantable device. Blood vessel implantable direct glucose fuel cells have access to higher continuous glucose concentrations. However, reduction in the implant thickness is required for application in the venous system as part of a stent. We report development of an implantable device with a platinum thin-film (thickness: 25 nm) deposited on silicon substrate (500 μm) to serve as the anode, and graphene pressed on a stainless steel mesh (175 μm) to serve as the cathode. Control experiments involved the use of a surfactant-coated polypropylene membrane (50 μm) with activated carbon (198 μm) electrodes. We demonstrate that a mesoporous silica thin film (270 nm) is capable of replacing the conventional polymer based membranes with an improvement in the power generated over conventional direct glucose fuel cells.

Lessons Learned from Molecular Scaffold Analysis

Journal of Chemical Information and Modeling. Aug, 2011  |  Pubmed ID: 21755989

Activity Profile Sequences: a Concept to Account for the Progression of Compound Activity in Target Space and to Extract SAR Information from Analogue Series with Multiple Target Annotations

ChemMedChem. Dec, 2011  |  Pubmed ID: 22052747

Target Family-directed Exploration of Scaffolds with Different SAR Profiles

Journal of Chemical Information and Modeling. Dec, 2011  |  Pubmed ID: 22091691

The scaffold concept is widely applied in chemoinformatics and medicinal chemistry to organize bioactive compounds according to common core structures or associate compound classes with specific biological activities. A variety of scaffold analyses have been carried out to derive statistics for scaffold distributions, generate structural organization schemes, or identify scaffolds that preferentially occur in given compound activity classes. Herein we further extend scaffold analysis by identifying scaffolds that display defined SAR profiles consisting of multiple properties. A structural relationship-based scaffold network has been designed as the basic data structure underlying our analysis. From network representations of scaffolds extracted from compounds active against 32 different target families, scaffolds with different SAR profiles have been extracted on the basis of decision trees that capture structural and functional characteristics of scaffolds in different ways. More than 600 scaffolds and 100 scaffold clusters were assigned to 10 SAR profiles. These scaffold sets represent different activity and target selectivity profiles and are provided for further SAR investigations including, for example, the exploration of alternative analog series for a given target of target family or the design of novel compounds on the basis of scaffold(s) with desired SAR profiles.

Self-assembled Zinc/copper Hydroxide Carbonates with Tunable Hierarchical Nanostructure

Journal of Nanoscience and Nanotechnology. Aug, 2011  |  Pubmed ID: 22103119

Here, we report a synthetic, polymer-mediated method for the self-assembly of zinc/copper hydroxide carbonate superstructures including 3D hierarchical sunflower-like, urchin-like, alga-like, and rotiform-like zinc hydroxide carbonate (ZHC) microstructures, and hierarchical copper hydroxide carbonate (CHC) microspheres with radiating nanoplates and nanorods. As a capping agent, poly(vinylpyrrolidone) (PVP) was found to play an important role in directing the growth and self-assembly of such unique structures. The crystal structure of the products and the resulting hierarchical superstructure morphology, as controlled by the molecular weight and concentration of PVP, were systematically investigated. A possible growth mechanism for the formation of hierarchical superstructures with different morphologies is also proposed.

Exploration of 3D Activity Cliffs on the Basis of Compound Binding Modes and Comparison of 2D and 3D Cliffs

Journal of Chemical Information and Modeling. Mar, 2012  |  Pubmed ID: 22394306

Activity cliffs are formed by pairs or groups of structurally similar compounds having large differences in potency and are focal points of structure-activity relationship (SAR) analysis. The choice of molecular representations is a critically important aspect of activity cliffs analysis. Thus far, activity cliffs have predominantly been defined on the basis of molecular graph or fingerprint representations. Herein we introduce 3D activity cliffs derived from comparisons of experimentally determined compound binding modes. The analysis of 3D activity cliffs is generally applicable to target proteins for which structures of multiple ligand complexes are available. For two popular targets, β-secretase 1 (BACE1) and factor Xa (FXa), public domain X-ray structures with bound inhibitors were collected. Crystallographic binding modes of inhibitors were systematically compared using a 3D similarity method taking conformational, positional, and atomic property differences into account. In addition, standard 2D similarity relationships were also determined. SAR information associated with individual compounds substantially changed when either bioactive conformations or 2D molecular graphs were used for similarity evaluation. 3D activity cliffs were identified for BACE1 and FXa inhibitor sets and systematically compared to 2D cliffs. It was found that less than 40% of 3D activity cliffs were conserved when 2D similarity was applied. The limited conservation of 3D and 2D cliffs provides further evidence for the strong molecule representation dependence of activity cliffs. Moreover, 3D cliffs represent a new class of activity cliffs that convey SAR information in ways that differ from graph-based similarity measures. In cases where sufficient structural information is available, the comparison of 3D and 2D cliffs is expected to aid in SAR analysis and mapping of critical binding determinants.

A Novel Model Might Predict the Risk of Chronic Atrophic Gastritis: a Multicenter Prospective Study in China

Scandinavian Journal of Gastroenterology. May, 2012  |  Pubmed ID: 22404449

Abstract Objective. To find a new way to predict the risk of chronic atrophic gastritis (CAG). Material and methods. All the participants received endoscopy and histological examination as well as a standard questionnaire. Multivariate analysis was performed by logistic regression to build the CAG risk model. The accuracy was evaluated by 1418 subjects recruited from six medical centers. 63 subjects received another endoscopy after 1-year follow-up and divided into three groups according to the comparison of the histological results (improved, no change and worse). Results. The model showed relatively good discrimination, with an AUROC of 0.888 (95% CI 0.852-0.925). A final probability cut-off score of 0.73 was used to predict the presence (>0.73) or absence of CAG (≤0.73). Sensitivity, specificity, PPV and NPV were 82.8%, 74.7%, 91.8% and 56%, respectively. The predicted results of 1418 subjects compared with the histological results were quite similar. There was a significant difference of the scores between three groups who were followed-up for 1 year (F = 3.248, p = 0.046). In multiple comparisons, a significant difference existed between Group A (the histological results had improved after 1-year follow-up) and Group C (the results were worse) (p = 0.019). Conclusions. This is the first demonstration of the use of a mathematical model for CAG risk screening. Endoscopy should be recommended to those who are positive according to the model, to detect CAG early and conserve medical resources. In those who have a high-risk score, closer follow-up is needed.

MMP-Cliffs: Systematic Identification of Activity Cliffs on the Basis of Matched Molecular Pairs

Journal of Chemical Information and Modeling. Apr, 2012  |  Pubmed ID: 22489665

Activity cliffs are generally defined as pairs of structurally similar compounds having large differences in potency. The analysis of activity cliffs is of general interest because structure-activity relationship (SAR) determinants can often be deduced from them. Critical questions for the study of activity cliffs include how similar compounds should be to qualify as cliff partners, how similarity should be assessed, and how large potency differences should be. Thus far, activity cliffs have mostly been defined on the basis of calculated Tanimoto similarity values using structural descriptors, especially 2D fingerprints. As any theoretical assessment of molecular similarity, this approach has its limitations. For example, calculated Tanimoto similarities might often be difficult to reconcile and interpret from a chemical perspective; a point of critique frequently raised in medicinal chemistry. Herein, we have explored activity cliffs by considering well-defined substructure replacements instead of calculated similarity values. For this purpose, the matched molecular pair (MMP) formalism has been applied. MMPs were systematically derived from public domain compounds and activity cliffs were extracted from them, termed MMP-cliffs. The frequency of cliff formation was determined for compounds active against different targets, MMP-cliffs were analyzed in detail, an re-evaluated on the basis of Tanimoto similarity. In many instances, chemically intuitive activity cliffs were only detected on the basis of MMPs, but not Tanimoto similarity.