A user-defined data type for the storage of time series data allowing efficient similarity screening

The volume of the experimentally measured time series data is rapidly growing, while storage solutions offering better data types than simple arrays of numbers or opaque blobs for keeping series data are sorely lacking. A number of indexing methods have been proposed to provide efficient access to time series data, but none has so far been integrated into a tried-and-proven database system. To explore the possibility of such integration, we have developed a data type for time series storage in PostgreSQL, an object-relational database system, and equipped it with an access method based on SAX (Symbolic Aggregate approXimation). This new data type has been successfully tested in a database supporting a large-scale plant gene expression experiment, and it was additionally tested on a very large set of simulated time series data.     

Cysteine derivatives as inhibitors for carboxypeptidase A: synthesis and structure-activity relationships

A series of cysteine (Cys) derivatives having an alkyl or arylalkyl moiety on the alpha-amino group of the amino acid have been synthesized as a novel type of inhibitor for carboxypeptidase A. These compounds are readily prepared starting with Cys in an optically active form. The structure-activity relationship study revealed that the inhibitors prepared from D-Cys are much more potent than the corresponding inhibitors obtained from L-Cys, and the most potent inhibitor in the series, (S)-1j with a K(i) value of 55 +/- 4 nM, is obtained by introducing a phenethyl moiety on the amino group of D-Cys. In comparison, the most active inhibitor in the series of 2-substituted 3-mercaptopropanoic acid is found to be 20, in which the phenyl ring is linked to the mercaptocarboxylic acid at the alpha-position with a methylene unit. A proposal that accounts for the different structural requirement for the maximum activity between the two series of inhibitors is provided.     

A time series investigation of three nicotine regulation models.

Time series data were collected twice daily for 62 days from 10 individuals on three variables related to smoking habit strength: number of cigarettes smoked, salivary cotinine, and carbon monoxide. The two purposes of this study were: (a) to evaluate which time series model(s) best fits each of the measures; and (b) to determine which model of nicotine regulation is consistent with the data. Three models of nicotine regulation were considered: (a) nicotine fixed effect; (b) nicotine regulation; and (c) multiple regulation. These models provide different predictions about the size and direction of the lag-one autocorrelation. Each measure was described in terms of one of a family of time series models represented mathematically as ARIMA (p, d, q). Models varied by individual, but a single model described the majority of subjects for all three variables. The clearest model identification was for the number of cigarettes smoked where an ARIMA (1, 0, 0) model with a moderate to strong negative dependency fit the majority of the subjects. This provided strong support for the multiple regulation model. An appendix provides a brief review of time series methodology.     

A novel dipeptide-based HIV protease inhibitor containing allophenylnorstatine

Dipeptide analogues incorporating allophenylnorstatine [Apns; (2S,3S)-3amino-2-hydroxy-4-phenylbutyric acid] as a transition state mimic at the scissile bond were designed and synthesized in the hope of obtaining a novel KNI series of HIV protease inhibitors. The precursors, N-P2'-3-(2S,3S)-3-(tert-butyloxy-carbonyl)amino-2-hydroxy-4-phenylbutanoyl)-5,5-dimethylthiazolidine-4-carboxamide (N-Boc-Apns-Dmt-P2') 4a-p were prepared by deprotection of the synthones N-P2'-(tert-butyloxycarbonyl)-5,5-dimethylthiazolidine-4-carboxamide (Boc-Dmt-P2') 2a-p, then coupling with (2S,3S)3-(tert-butyloxycarbonyl)amino-2-hydroxy-4-phenylbutanoic acid (N-Boc-Apns-OH) 3. The deprotected intermediates 4 were coupled with the activated carboxyl groups of the P2 ligands to afford the target dipeptides. In this work, we fixed at the P2 site either a 2,6-dimethylphenoxyacetyl or a 3-hydroxy-2-methylbenzoyl group. Substitutes at the P2' site were varied to afford the members of the series 7 and 8. Improved activity of most of the members of series 8 relative to their analogues of series 7 can be partially attributed to the differences in the structures of the P2 moieties. Positional isomerism in the P2' moieties significantly affected the activity and polarity of the target.     

2-Amino-N-pyrimidin-4-ylacetamides as A2A receptor antagonists: 2. Reduction of hERG activity, observed species selectivity, and structure-activity relationships

Previously we have described a series of novel A 2A receptor antagonists with excellent water solubility. As described in the accompanying paper, the antagonists were first optimized to remove an unsubstituted furyl moiety, with the aim of avoiding the potential metabolic liabilities that can arise from the presence of an unsubstituted furan. This effort identified a series of potent and selective methylfuryl derivatives. Herein, we describe the further optimization of this series to increase potency, maintain selectivity for the human A 2A vs the human A 1 receptor, and minimize activity against the hERG channel. In addition, the observed structure-activity relationships against both the human and the rat A 2A receptor are reported.     

A message from the Co-Editor-in-Chief

This special APSB issue marks the beginning of a series of celebratory events for the 10-year anniversary of the journal.It was June 2011,when the first issue o...     

Antiparkinsonian effects of novel adenosine A(2A) receptor antagonists

The present work describes the synthesis of a pyrazinopurinedione derivative which was together with a series of pyrimidopurinedione derivatives tested for potential antiparkinsonian activity in two tests: the "oxotremorine" and the "reserpine" test. For the studies compounds which had shown affinity for the adenosine A(2A) receptor were chosen. One compound, a pyrazinopurinedione derivative, without affinity for A(2A) receptors, but showing adenosine A(1) receptor affinity was also investigated. The performed preliminary tests indicated that, contrary to the pyrazinopurinedione all pyrimidopurinediones demonstrated antiparkinsonian effects. As a result of present studies it may be concluded that antiparkinsonian effects of the examined compounds are correlated with the antagonistic activity toward adenosine A(2A) receptors in this class of compounds. However a direct correlation of the potency of both effects was not observed possibly due to different pharmacokinetic properties of the compounds. The most active derivatives of the present series were aryl-substituted pyrimidopurinediones.     

A new pyridazine series of GABAA alpha5 ligands

Screening of the Merck compound collection identified 6 as an unusually simple, low molecular weight hit with moderate affinity for GABAA receptors. The structural novelty of 6, compared to our advanced series of GABAA alpha5 inverse agonists, made it an attractive molecule for further exploration. This paper will describe the evolution of 6 into a new series of ligands with nanomolar affinity and functional selectivity for GABAA alpha5 receptor subtypes.     

A novel series of 4-piperidinopyridine and 4-piperidinopyrimidine inhibitors of 2,3-oxidosqualene cyclase-lanosterol synthase

A novel series of 4-piperidinopyridines and 4-piperidinopyrimidines showed potent and selective inhibition of rat 2,3-oxidosqualene cyclase-lanosterol synthase (OSC) (e.g. 26 IC(50) rat = 398 +/- 25 nM, human = 112 +/- 25 nM) and gave selective oral inhibition of rat cholesterol biosynthesis (26 ED(80) = 1.2 +/- 0.3 mg/kg, n = 5; HMGCoA reductase inhibitor simvastatin ED(80) = 1.2 +/- 0.3 mg/kg, n = 5). The piperidinopyrimidine OSC inhibitors have a significantly lower pK(a) than the corresponding pyridine or the previously reported quinuclidine OSC inhibitor series. This indicates that other novel OSC inhibitors may be found in analogues of this series across a broader pK(a) range (6.0-9.0). These series may yield novel hypocholesterolemic agents for the treatment of cardiovascular disease.     

Identification of novel, water-soluble, 2-amino-N-pyrimidin-4-yl acetamides as A2A receptor antagonists with in vivo efficacy

Potent adenosine hA2A receptor antagonists are often accompanied by poor aqueous solubility, which presents issues for drug development. Herein we describe the early exploration of the structure-activity relationships of a lead pyrimidin-4-yl acetamide series to provide potent and selective 2-amino-N-pyrimidin-4-yl acetamides as hA2A receptor antagonists with excellent aqueous solubility. In addition, this series of compounds has demonstrated good bioavailability and in vivo efficacy in a rodent model of Parkinson's disease, despite having reduced potency for the rat A2A receptor versus the human A2A receptor.     

Comparative molecular field analysis (CoMFA) of a series of selective adenosine receptor A2A antagonists

Selective and potent antagonists for the A_2A adenosine receptors have been described recently. The most potent compounds have a triazolo‐pyrimidine structure, whereas 8‐styryl‐xanthines usually possess lower affinity at the A_2A receptor. We have examined the quantitative structure activity relationships of 34 triazolo‐pyrimidines using the Comparative Molecular Field Analysis (CoMFA). The model developed accounts in a satisfactory manner for the structure‐activity relationships within this series of A_2A receptor antagonists (q² = 0.840, r² = 0.970) and, consequently, it can be used as a guide in the design of novel analogs with optimized antagonistic activity. The overall predictivity of this model was tested on the published data of a set of external molecules giving acceptable results. The validity of the CoMFA approach as an effective tool for studying the 3D‐QSAR of series of biologically active compounds is confirmed, even if additional efforts clearly are needed for trying to extend the models to structurally more varied series of derivatives. Drug Dev. Res. 46:126–133, 1999. © 1999 Wiley‐Liss, Inc.     

3-O-Desacyl monophosphoryl lipid A derivatives: synthesis and immunostimulant activities

The synthesis of a series of novel analogues of lipid A, the active principle of lipopolysaccharide, is reported. In these compounds, the 1-O-phosphono and (R)-3-hydroxytetradecanoyl moieties of native Salmonella minnesota R595 lipid A have been replaced with hydrogen and the length of the normal fatty acyl residues has been systematically varied. Normal fatty acid chain length in the 3-O-desacyl monophosphoryl lipid A (MLA) series is shown to be a critical determinant of iNOS gene expression in activated mouse macrophages and the induction of proinflammatory cytokines in human peripheral monocytes. Examination of pyrogenicity in rabbits and lethal toxicity in D-galactosamine-treated mice shows that toxic effects in the MLA series can be ameliorated by modifying fatty acid chain length. When used as an adjuvant for tetanus toxoid vaccines, certain MLA derivatives enhance the production of tetanus toxoid-specific antibodies in mice.     

A novel carbapenem antibiotic, SM-7338 structure-activity relationships

A series of new carbapenem compounds, which have a pyrrolidin-3'-ylthio group substituted with various aminocarbonyl group at C-5' position as C-2 side chain, have been prepared. The antibacterial activity and the stability to renal dehydropeptidase-I of these compounds were investigated, and the structure-activity relationships were discussed. In this series, SM-7338; (1R,5S,6S)-2-[(3S,5S)-5-dimethylaminocarbonylpyrrolidin-3-ylthi o]-6-[(R)-1-hydroxyethyl]-1-methylcarbapen-2-em-3-carboxylic acid (5a) was the most interesting compound.     

A heteroskedasticity and autocorrelation robust F test using an orthonormal series variance estimator

Summary The paper develops a new heteroskedasticity and autocorrelation robust test in a time series setting. The test is based on a series long‐run variance matrix estimator that involves projecting the time series of interest onto a set of orthonormal bases and using the sample variance of the projection coefficients as the long‐run variance estimator. When the number of orthonormal bases K is fixed, a finite‐sample‐corrected Wald statistic converges to a standard F distribution. When K grows with the sample size, the usual uncorrected Wald statistic converges to a chi‐square distribution. We show that critical values from the F distribution are second‐order correct under the conventional increasing smoothing asymptotics. Simulations show that the F approximation is more accurate than the chi‐square approximation in finite samples.     

Synthesis and biological evaluation of 3,4-diaryloxazolones: A new class of orally active cyclooxygenase-2 inhibitors

A series of 3,4-diaryloxazolones were prepared and evaluated for their ability to inhibit cyclooxygenase-2 (COX-2). Extensive structure-activity relationship work was carried out within this series, and a number of potent and selective COX-2 inhibitors were identified. The replacement of the methyl sulfone group on the 4-phenyl ring by a sulfonamide moiety resulted in compounds with superior in vivo antiinflammatory properties. In the sulfonamide series, the introduction of a methyl group at the 5-position of the oxazolone ring gave rise to very COX-2-selective compounds but with decreased in vivo activity. Selected 3,4-diaryloxazolones exhibited excellent activities in experimental models of arthritis and hyperalgesia. The in vivo activity of these compounds was confirmed with the evaluation of their antipyretic effectiveness and their ability to inhibit migration of proinflammatory cells. As expected from their COX-2 selectivity, most of the active compounds lacked gastrointestinal toxicity in vivo in rats after a 4-day treatment of 100 mg/kg/day. Within this novel series, sulfonamides 9-11 have been selected for further preclinical evaluation.     

A new class of diamine-based human histamine H3 receptor antagonists: 4-(aminoalkoxy)benzylamines

4-(Aminoalkoxy)benzylamines were prepared and screened for in vitro activity at the human histamine H(3) receptor. Some members of this series exhibited subnanomolar binding affinities. Analogues in which one nitrogen atom was replaced with a methine group showed greatly reduced binding affinities. Six members of this series were found to be antagonists in a cell-based model of human histamine H(3) receptor activation. One member of this series, 1-[4-(3-piperidin-1-ylpropoxy)benzyl]piperidine (7b), was found to be a selective and potent human H(3) receptor antagonist.     

Using time series analysis to forecast the health-related quality of life of post-menopausal women with non-metastatic ER+ breast cancer: A tutorial and case study

BackgroundTime series models are widely used forecasting techniques in health care for long time series and are typically built in commercial statistical packages. However, for short time series data, such as health-related quality of life (HRQoL), guidance on how to select and use appropriate time series models is lacking. This tutorial provides a step-by-step guide adopting a time series analysis framework for HRQoL forecasting.ObjectiveWe walk through a case study examining the forecasting of the effects of adjuvant endocrine therapy on the HRQoL of post-menopausal women with non-metastatic ER + breast cancer using data from the HRQoL sub-protocol of the Tamoxifen arm of the Arimidex, tamoxifen, alone or in combination (ATAC) trial.MethodsThe forecasting of HRQoL consists of four steps: 1) data extraction and accuracy check, 2) forecasting horizon definition and identification of data pattern, 3) forecasting model identification and fitting using five forecasting approaches appropriate for short time series ((i) double exponential smoothing, (ii) double moving average, (iii) fuzzy forecasting, (iv) grey forecasting, and (v) Volterra series), 4) forecasting model selection. A user-friendly visual basic for applications (VBA) Excel add-in is made available to interested users to facilitate the application of the tutorial.ResultsThe Grey method and Volterra series appeared to be good candidates to forecast the effects of adjuvant endocrine therapy on the HRQoL of post-menopausal women with non-metastatic ER + breast cancer enrolled in the ATAC trial.ConclusionIt is feasible to forecast the effects of treatments on HRQOL even when the time series is short.     

Hydration Site Thermodynamics Explain SARs for Triazolylpurines Analogues Binding to the A2A Receptor

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