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PubMed2005

New and fast statistical-thermodynamic method for computation of protein-ligand binding entropy substantially improves docking accuracy.

We present a novel method to estimate the contributions of translational and rotational entropy to protein-ligand binding affinity. The method is based on estimates of the configurational integral through the sizes of clusters obtained from multiple docking positions. Cluster sizes are defined as the intervals of variation of center of ligand mass and Euler angles in the cluster. Then we suggest a method to consider the entropy of torsional motions. We validate the suggested methods on a set of 135 PDB protein-ligand complexes by comparing the averaged root-mean square deviations (RMSD) of the top-scored ligand docked positions, accounting and not accounting for entropy contributions, relative to the experimentally determined positions. We demonstrate that the method increases docking accuracy by 10-21% when used in conjunction with the AutoDock docking program, thus reducing the percent of incorrectly docked ligands by 1.4-fold to four-fold, so that in some cases the percent of ligands correctly docked to within an RMSD of 2 A is above 90%. We show that the suggested method to account for entropy of relative motions is identical to the method based on the Monte Carlo integration over intervals of variation of center of ligand mass and Euler angles in the cluster.

Algorithms↗
PubMed2003

Nuclear import of zinc binuclear cluster proteins proceeds through multiple, overlapping transport pathways.

In Aspergillus nidulans, the high transcriptional level of the ethanol utilization pathway genes (alc) is regulated by the specific activator AlcR. Here we have analyzed the mechanism of the nuclear import of AlcR, as well as that of other proteins belonging to the Zn(2)Cys(6) binuclear cluster family. The nuclear localization signal of AlcR maps within the N-terminal 75 amino acid residues and overlaps with its DNA-binding domain. It consists of five clusters rich in basic residues. Four of them are necessary and sufficient for nuclear targeting. The first two basic regions are crucial for both nuclear localization and recognition of AlcR-specific DNA targets. This nuclear localization signal (NLS) motif is recognized by the nuclear transport machinery of Saccharomyces cerevisiae and requires both Ran/Gsp1p activity and specific transport receptors. AlcR can be imported into nuclei via multiple transport pathways mediated by a distinct set of karyopherins composed of Kap104p, Sxm1p, and Nmd5p transport receptors. The two former karyopherins interact with the NLS of AlcR directly. Other Zn binuclear cluster proteins from S. cerevisiae, such as Gal4p and Pdr3p, also appear to be transported to the nuclei in a nonclassical, importin-alpha-independent manner and can share common importin beta receptors.

Active Transport, Cell Nucleus↗
PubMedDate not supplied

Responding to reported clusters of common diseases: the case of multiple sclerosis.

Reports of disease clustering are becoming ever more common, and there is increasing pressure on public health agencies to respond rapidly and appropriately to these reports. We investigated a cluster of five cases of MS occurring in a small multidisciplinary hospital department. Data were collected by a variety of methods, including measurement and description of the workplace, completion of survey instruments by department staff, and construction of case histories of persons with MS. The results indicated that the department comprised a high-risk population and that only one case of MS could have any possible etiologic significance. Investigators should consider a number of factors when evaluating disease clusters, including the accuracy of diagnosis, the induction period and cause of the disease, and possible biases in the population at risk. Additionally, boundaries should not encircle the cases that led to identification of the cluster and should reflect environmental significance.

Adult↗
PubMed2000

Multiple peptide synthetase gene clusters in Actinomycetes.

Two oligonucleotide probes derived from conserved motifs in peptide synthetases were hybridized with a cosmid library of Planobispora rosea genomic DNA. Detailed characterization of the physical organization of the positive cosmids indicated the existence of at least eight unlinked contigs containing multiple fragments that hybridized to both probes. Partial sequences of PCR products from the positive cosmids confirmed the existence of peptide synthetase genes. The combined results of hybridizations and physical mapping indicate that, in all likelihood, the isolated P. rosea contigs encode over 40 putative peptide synthetase modules. Similar results were obtained on screening a cosmid library of Actinoplanes teichomyceticus DNA. Furthermore, Southern hybridizations with several actinomycete strains, belonging to different genera, indicate that most strains contain multiple hybridizing bands well in excess of the number expected from the structure of the oligopeptides produced by these strains. Even strains not reported to produce oligopeptides gave clear positive signals when examined with the probes. These results strongly suggest that actinomycetes devote a notable fraction of their genomes to the non-ribosomal synthesis of peptides, and that most strains have the genetic potential to produce more oligopeptides than are currently described.

Actinomycetales↗
PubMed2006

Modeling adolescent drug-use patterns in cluster-unit trials with multiple sources of correlation using robust latent class regressions.

PURPOSE: The purpose of the study is to examine variation in adolescent drug-use patterns by using latent class regression analysis and evaluate the properties of an estimating-equations approach under different cluster-unit trial designs. METHODS: A set of second-order estimating equations for latent class models under the cluster-unit trial design are proposed. This approach models the correlation within subclusters (drug-use behaviors), but ignores the correlation within clusters (communities). A robust covariance estimator is proposed that accounts for within-cluster correlation. Performance of this approach is addressed through a Monte Carlo simulation study, and practical implications are illustrated by using data from the National Evaluation of the Enforcing Underage Drinking Laws Randomized Community Trial. RESULTS: The example shows that the proposed method provides useful information about the heterogeneous nature of drug use by identifying two subtypes of adolescent problem drinkers. A Monte Carlo simulation study supports the proposed estimation method by suggesting that the latent class model parameters were unbiased for 30 or more clusters. Consistent with other studies of generalized estimating equation (GEE) estimators, the robust covariance estimator tended to underestimate the true variance of regression parameters, but the degree of inflation in the test size was relatively small for 70 clusters and only slightly inflated for 30 clusters. CONCLUSIONS: The proposed model for studying adolescent drug use provides an alternative to standard diagnostic criteria, focusing on the nature of the drug-use profile, rather than relying on univariate symptom counts. The second-order GEE-type estimation procedure provided a computationally feasible approach that performed well for a moderate number of clusters and was consistent with prior studies of GEE under the generalized linear model framework.

Adolescent↗
PubMedDate not supplied

Centrosome multiplication accompanies a transient clustering of polyploid cells during tissue repair.

Cells from different human wounds were analyzed concerning their degree of ploidy. The experiments showed an increased tetraploidization rate in well-healing wounds especially during inflammation and proliferation. Recent data described a polyploidization in different tissues, which is accompanied and maybe caused by the multiplication of the centrosome. We show here for the first time that cells from nonmalignant tissue, namely human wound cells, are characterized by an extensive centrosome multiplication. In an effort to identify a certain mechanism, by which the centrosome may act as a modulator of the cells' ploidy, we focused our interest on p53, whose interaction with the centrosome was recently described. Applying a wound model onto p53-wildtype (wt) and p53-knockout (ko) mice, we could show that polyploidization was not reversible in p53-ko mice during wound healing. The lack of p53, the centrosome multiplication, and the polyploidization therefore may contribute to the physiological process of tissue repair in physiologically "normal" tissue.

Animals↗
PubMed2006

Prenatal and birth complications in autism.

OBJECTIVES: Prenatal and birth history as potential sources of risk factors in relation to the onset of autism were examined. METHODS: A cohort of 164 families of autistic children referred to The Autism Center at New Jersey Medical School-UMDNJ, Newark, New Jersey, over a two-year period was studied. Intake prenatal and birth history information was obtained from each family and reviewed by a clinician. RESULTS: Prevalence rates in this cohort for vaginal bleeding, prolonged labor and prematurity were higher than comparable rates reported nationally and in New Jersey. Clustering of multiple prenatal risk factors was observed. This clustering was associated with the age of the mother, but uncorrelated with birth order. CONCLUSIONS: These findings support the general hypothesis that systemic problems at the prenatal stage may form a distinct dimension of risk associated with autism.

Adolescent↗
PubMed2004

Multiple primary cancers as clues to environmental and heritable causes of cancer and mechanisms of carcinogenesis.

Successes in cancer therapy are leading to an increasing incidence of second cancers, which may be due to the same factors that cause first cancers or to the effect of therapy for the first cancer. There are also a number of specific methodological and sampling problems that have to be controlled before informative studies can be embarked upon. The risk of a second cancer is higher than that for the first one, which may be an indication of a particular exposure, an inherited set of genes, or both. We show clustering of multiple cancers caused by tobacco, alcohol and infections. We discuss familial aggregation of cancer as one of the causes of multiple primary cancers. However, multiple primary cancers may particularly be a manifestation of polygenic susceptibility, which cannot easily be recognized as familial clustering, and multiple cancers may offer a model for understanding the complex etiology of human cancer and for generating and testing hypotheses on mechanisms of carcinogenesis.

Animals↗
PubMed2005

Mammary ducts with and without focal myoepithelial cell layer disruptions show a different frequency of white blood cell infiltration and growth pattern: implications for tumor progression and invasion.

The authors' previous studies revealed that a subset of ductal carcinoma in situ (DCIS) contained focally disrupted myoepithelial (ME) cell layers and basement membrane (BM). As the disruption of these two structures is a prerequisite for tumor invasion, and white blood cells (WBCs) contain digestive enzymes capable of degrading both the BM and damaged host cells, this study was designed to assess the possible roles of WBC in ME cell layer disruptions and tumor invasion. A total of 23 DCIS containing ducts with focally disrupted ME cell layers were selected from 94 such cases identified in the authors' previous studies. Two consecutive sections from each case were double immunostained, one with leukocyte common antigen (LCA) plus smooth muscle actin (SMA) and the other with Ki-67 plus SMA. Ducts lined by at least 50 epithelial cells and distinct ME cell layers were examined. A total of 191 duct cross-sections were found to contain focal ME cell layer disruptions; of these, 186 (97.4%) were with and 5 (2.6%) were without WBC infiltration. Of 207 morphologically similar sections without ME disruptions, 46 (22.2%) were with and 161 (77.8%) were without WBC infiltration. Ki-67-positive cells in ducts with focally disrupted ME cell layers were generally subjacent to ME cell layers, and more than 30 clusters of multiple proliferating cells were seen directly overlying or near focally disrupted ME cell layers. In contrast, Ki-67-positive cells in ducts without ME disruptions were scattered over the entire epithelial compartment. The significantly different frequency of WBC infiltration and clusters of multiple proliferating cells in ducts with and without ME disruptions suggests that WBCs might play important roles in ME disruption and tumor invasion.

Basement Membrane↗
PubMed1995

Childhood cancers: space-time distribution in Britain.

STUDY OBJECTIVES: To examine a national data set of all childhood cancers for evidence of space-time interactions within three distinct sets of dates and places (at birth, at diagnosis, and at death), to show whether the patterns found for these events represent separate phenomena or statistically interdependent processes, and to see whether the childhood leukaemias and the childhood solid cancers have separate distinctive patterns in these respects. DESIGN: This was a space-time cluster analysis. The large number of cases enabled division of the data into two sets, one for hypothesis generation and the other for hypothesis testing. SETTING: England, Scotland, and Wales. SUBJECTS: A national collection of 22,360 children aged 0-15 years with fatal cancers and leukaemias in the period 1953 to 1980. MAIN RESULTS: There was significant clustering among the leukaemias and lymphomas on date and place of birth (particularly among cases born within 1 km and up to 5 months apart), and on date and place of diagnosis (particularly among cases diagnosed from 3 to 5 km apart and up to 9 months apart). There was no clustering among the solid cancers. These findings were confirmed in two separate analyses of two separate sets of data. CONCLUSIONS: The birth clustering was significant among pairs diagnosed at differing ages, and diagnosis clustering was significant among pairs born at different times, and it was concluded that the two types of clustering must be regarded as separate and statistically independent phenomena. Both the birth and the diagnosis clusters comprised many independent pairs of cases, with no large multiple case clusters. This suggests the involvement of multiple time-space localised exposures to hazards with short and constant latent intervals; probably an infectious agent or an environmental toxin. Given the separate nature of the two types of clustering, exposure to more than one hazard may be involved.

Adolescent↗
PubMed2001

Genetic and transcriptional analysis of absA, an antibiotic gene cluster-linked two-component system that regulates multiple antibiotics in Streptomyces coelicolor.

In Streptomyces coelicolor, the AbsA1-AbsA2 two-component system regulates the expression of multiple antibiotic gene clusters. Here, we show that the response regulator encoded by the absA2 gene is a negative regulator of these antibiotic gene clusters. A genetic analysis shows that the phosphorylated form of the AbsA2 response regulator (phospho-AbsA2), generated by the cognate AbsA1 sensor histidine kinase, is required for normal growth phase regulation of antibiotic synthesis. In the absence of phospho-AbsA2, antibiotics are produced earlier and more abundantly. Overexpression of AbsA1 also deregulates antibiotic synthesis, apparently shifting the AbsA1 protein from a kinase-active to a phospho-AbsA2 phosphatase-active form. The absA1 and absA2 genes, which are adjacent, are located in one of the antibiotic gene clusters that they regulate, the cluster for the calcium-dependent antibiotic (CDA). The absA genes themselves are growth phase regulated, with phospho-AbsA2 responsible for growth phase-related positive autoregulation. We discuss the possible role and mechanism of AbsA-mediated regulation of antibiotic synthesis in the S. coelicolor life cycle.

Anthraquinones↗
PubMed2003

Identification of a gene cluster encoding meilingmycin biosynthesis among multiple polyketide synthase contigs isolated from Streptomyces nanchangensis NS3226.

A cluster encoding genes for the biosynthesis of meilingmycin, a macrolide antibiotic structurally similar to avermectin and milbemycin alpha11, was identified among seven uncharacterized polyketide synthase gene clusters isolated from Streptomyces nanchangensis NS3226 by hybridization with PCR products using primers derived from the sequences of aveE, aveF and a thioesterase domain of the avermectin biosynthetic gene cluster. Introduction of a 24.1-kb deletion by targeted gene replacement resulted in a loss of meilingmycin production, confirming that the gene cluster encodes biosynthesis of this important anthelminthic antibiotic compound. A sequenced 8.6-kb fragment had aveC and aveE homologues ( meiC and meiE) linked together, as in the avermectin gene cluster, but the arrangement of aveF ( meiF) and the thioesterase homologues differed. The results should pave the way to producing novel insecticidal compounds by generating hybrids between the two pathways.

Amino Acid Sequence↗
PubMed1996

patial pattern analysis of beta-amyloid (A beta) deposits in Alzheimer disease by linear regression.

The spatial patterns of discrete beta-amyloid (Abeta) deposits in brain tissue from patients with Alzheimer disease (AD) were studied using a statistical method based on linear regression, the results being compared with the more conventional variance/mean (V/M) method. Both methods suggested that Abeta deposits occurred in clusters (400 to <12,800 mu m in diameter) in all but 1 of the 42 tissues examined. In many tissues, a regular periodicity of the Abeta deposit clusters parallel to the tissue boundary was observed. In 23 of 42 (55%) tissues, the two methods revealed essentially the same spatial patterns of Abeta deposits; in 15 of 42 (36%), the regression method indicated the presence of clusters at a scale not revealed by the V/M method; and in 4 of 42 (9%), there was no agreement between the two methods. Perceived advantages of the regression method are that there is a greater probability of detecting clustering at multiple scales, the dimension of larger Abeta clusters can be estimated more accurately, and the spacing between the clusters may be estimated. However, both methods may be useful, with the regression method providing greater resolution and the V/M method providing greater simplicity and ease of interpretation. Estimates of the distance between regularly spaced Abeta clusters were in the range 2,200-11,800 mu m, depending on tissue and cluster size. The regular periodicity of Abeta deposit clusters in many tissues would be consistent with their development in relation to clusters of neurons that give rise to specific neuronal projections.

Aged↗
PubMed2003

AntiClustal: Multiple Sequence Alignment by antipole clustering and linear approximate 1-median computation.

In this paper we present a new Multiple Sequence Alignment (MSA) algorithm called AntiClusAl. The method makes use of the commonly use idea of aligning homologous sequences belonging to classes generated by some clustering algorithm, and then continue the alignment process ina bottom-up way along a suitable tree structure. The final result is then read at the root of the tree. Multiple sequence alignment in each cluster makes use of the progressive alignment with the 1-median (center) of the cluster. The 1-median of set S of sequences is the element of S which minimizes the average distance from any other sequence in S. Its exact computation requires quadratic time. The basic idea of our proposed algorithm is to make use of a simple and natural algorithmic technique based on randomized tournaments which has been successfully applied to large size search problems in general metric spaces. In particular a clustering algorithm called Antipole tree and an approximate linear 1-median computation are used. Our algorithm compared with Clustal W, a widely used tool to MSA, shows a better running time results with fully comparable alignment quality. A successful biological application showing high aminoacid conservation during evolution of Xenopus laevis SOD2 is also cited.

Algorithms↗
PubMed2006

An investigation of polymorphisms in the 17q11.2-12 CC chemokine gene cluster for association with multiple sclerosis in Australians.

BACKGROUND: Multiple sclerosis (MS) is a disorder of the central nervous system (CNS) characterised by inflammation and neuronal degeneration. It is believed to result from the complex interaction of a number of genes, each with modest effect. Chemokines are vital to the migration of cells to sites of inflammation, including the CNS, and many are implicated in MS pathogenesis. Most of the CC chemokine genes are encoded in a cluster on chromosome 17q11.2-12, which has been identified in a number of genome wide screens as being potentially associated with MS. METHODS: We conducted a two-stage analysis to investigate the chemokine gene cluster for association with MS. After sequencing the chemokine genes in several DNA pools to identify common polymorphisms, 12 candidate single-nucleotide polymorphisms (SNPs) were genotyped in a cohort of Australian MS trio families. RESULTS: Marginally significant (uncorrected) transmission distortion was identified for four of the SNPs after stratification for several factors. We also identified marginally significant (uncorrected) transmission distortion for haplotypes encompassing the CCL2 and CCL11 genes, using two independent cohorts, which was consistent with recent reports from another group. CONCLUSION: Our results implicate several chemokines as possibly being associated with MS susceptibility, and given that chemokines and their receptors are suitable targets for therapeutic agents, further investigation is warranted in this region.

Australia↗
PubMed1990

Market segmentation for multiple option healthcare delivery systems--an application of cluster analysis.

Healthcare providers of multiple option plans may be confronted with special market segmentation problems. This study demonstrates how cluster analysis may be used for discovering distinct patterns of preference for multiple option plans. The availability of metric, as opposed to categorical or ordinal, data provides the ability to use sophisticated analysis techniques which may be superior to frequency distributions and cross-tabulations in revealing preference patterns.

Cluster Analysis↗
PubMed2000

Efficacy of potential chemopreventive agents on rat colon aberrant crypt formation and progression.

We assessed the effects of 78 potential chemopreventive agents in the F344 rat using two assays in which the inhibition of carcinogen-induced aberrant crypt foci (ACF) in the colon was the measure of efficacy. In both assays ACF were induced by the carcinogen azoxymethane (AOM) in F344 rats by two sequential weekly injections at a dose of 15 mg/kg. Two weeks after the last AOM injection, animals were evaluated for the number of aberrant crypts detected in methylene blue stained whole mounts of rat colon. In the initiation phase protocol agents were given during the period of AOM administration, whereas in the post-initiation assay the chemopreventive agent was introduced during the last 4 weeks of an 8 week assay, a time when ACF had progressed to multiple crypt clusters. The agents were derived from a priority listing based on reports of chemopreventive activity in the literature and/or efficacy data from in vitro models of carcinogenesis. During the initiation phase carboxyl amidoimidazole, p-chlorphenylacetate, chlorpheniramine maleate, D609, diclofenac, etoperidone, eicosatetraynoic acid, farnesol, ferulic acid, lycopene, meclizine, methionine, phenylhexylisothiocyanate, phenylbutyrate, piroxicam, 9-cis-retinoic acid, S-allylcysteine, taurine, tetracycline and verapamil were strong inhibitors of ACF. During the post-initiation phase aspirin, calcium glucarate, ketoprofen, piroxicam, 9-cis-retinoic acid, retinol and rutin inhibited the outgrowth of ACF into multiple crypt clusters. Based on these data, certain phytochemicals, antihistamines, non-steroidal anti-inflammatory drugs and retinoids show unique preclinical promise for chemoprevention of colon cancer, with the latter two drug classes particularly effective in the post-initiation phase of carcinogenesis.

Animals↗