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PubMed2005

Genome-wide assembly and analysis of alternative transcripts in mouse.

To build a mouse gene index with the most comprehensive coverage of alternative transcription/splicing (ATS), we developed an algorithm and a fully automated computational pipeline for transcript assembly from expressed sequences aligned to the genome. We identified 191,946 genomic loci, which included 27,497 protein-coding genes and 11,906 additional gene candidates (e.g., nonprotein-coding, but multiexon). Comparison of the resulting gene index with TIGR, UniGene, DoTS, and ESTGenes databases revealed that it had a greater number of transcripts, a greater average number of exons and introns with proper splicing sites per gene, and longer ORFs. The 27,497 protein-coding genes had 77,138 transcripts, i.e., 2.8 transcripts per gene on average. Close examination of transcripts led to a combinatorial table of 23 types of ATS units, only nine of which were previously described, i.e., 14 types of alternative splicing, seven types of alternative starts, and two types of alternative termination. The 47%, 18%, and 14% of 20,323 multiexon protein-coding genes with proper splice sites had alternative splicings, alternative starts, and alternative terminations, respectively. The gene index with the comprehensive ATS will provide a useful platform for analyzing the nature and mechanism of ATS, as well as for designing the accurate exon-based DNA microarrays. The sequence data from this study have been submitted to GenBank under accession numbers: CK329321-CK334090; CF891695-CF906652; CF906741-CF916750; CK334091-CK347104; CK387035-CK393993; CN660032-CN690720; CN690721-CN725493.

Algorithms↗
PubMed2000

A phylogenetic tree of the Wnt genes based on all available full-length sequences, including five from the cephalochordate amphioxus.

The WNT: gene family is large, and new members are still being discovered. We constructed a parsimony tree for the WNT: family based on all 82 of the full-length sequences currently available. The inclusion of sequences from the cephalochordate amphioxus is especially useful in comprehensive gene trees, because the amphioxus genes in each subfamily often mark the base of the vertebrate diversification. We thus isolated full-length cDNAs of five amphioxus WNT: genes (AmphiWnt1, AmphiWnt4, AmphiWnt7, AmphiWnt8, and AmphiWnt11) for addition to the overall WNT: family tree. The analysis combined amino acid and nucleotide sequences (excluding third codon positions), taking into account 97% of the available data for each sequence. This combinatorial method had the advantage of generating a single most-parsimonious tree that was trichotomy-free. The reliability of the nodes was assessed by both jackknifing and Bremer support (decay index). A regression analysis revealed that branch length was strongly correlated with branch support, and possible reasons for this pattern are discussed. The tree topology suggested that in amphioxus, at least an AmphiWnt5 and an AmphiWnt10 have yet to be discovered.

Animals↗
PubMed2002

In Silico and Ex silico ADME approaches for drug discovery.

The high attrition rate of drug candidates during clinical trials for poor pharmacokinetic and metabolic properties has created a need to do these studies as early as it is possible during the drug discovery process. In addition the most successful drug is often not the most potent one but the one that has the suitable level of potency, safety, and pharmacokinetics. Science and technology development during the last few years and the generation of last databases and information has created the basis for doing early experimental PK and ADME studies in addition to eADME. Similarly, testing safety features as early as possible is key to affordable drug discovery and development. Throughput and cost are crucial for early application. In silico methods have by far the highest throughput, followed by the in vitro and in vivo approaches. On the other hand, with regard to relevance and reliability of data the ranking is the opposite. The great challenge for in silico methods is generation of models that correlate more closely with in vivo systems. For the in vitro assays increasing the throughput is an absolute must. Ex silico methods that combine in silico predictions with experimental methods are new additions to the scientific repertoire (e.g. Chromatographic Hydrophobicity Index that is deduced from the reverse phase HPLC data can be used for calculation of lipophilicity). The emerging new approaches have clear impact on the design of early stage screening and combinatorial libraries. In addition to the Lipinski's rules descriptors such as number of rotatable bonds, number of aromatic rings, branching behavior and polar surface area (PSA) are commonly used is the drug design process.

Absorption↗
PubMed2026

A combinatorial construct library enables an expanded expression range of secreted therapeutic proteins by probiotic yeast.

Orally administered engineered probiotics, including Saccharomyces cerevisiae var. boulardii (Sb), are of emerging interest as protein therapeutic delivery platforms to treat gastrointestinal diseases. Tools to readily optimize protein output are required to optimize the therapeutic index of Sb-produced therapies. In this study, a 125-plex Sb secretion construct library was developed consisting of all possible combinations of five promoters, five secretion signals, and five terminators, which enabled a greater than 1800-fold range in Sb expression of a Gaussia luciferase (GLuc) reporter. Secretion signal and promoter identities had significant effects on secretion output. This library further enabled a 28-fold improvement of binding activity of Sb-secreted haPD-1, an established anti-tumor immunotherapeutic, and improved haPD-1 detection in mouse stool samples following oral gavage of Sb_haPD-1. Sb secretion trends of both GLuc and haPD-1 in vitro mirrored payload expression in vivo. This protein secretion library toolkit will serve as a valuable resource to rapidly optimize protein therapeutic output from engineered Sb.

Saccharomyces boulardii↗
PubMed2004

Deficits in thematic integration processes in Broca's and Wernicke's aphasia.

This study investigated how normal subjects and Broca's and Wernicke's aphasics integrate thematic information incrementally using syntax, lexical-semantics, and pragmatics in a simple active declarative sentence. Three priming experiments were conducted using an auditory lexical decision task in which subjects made a lexical decision on a 'target' (the last word of each sentence) preceded by a 'prime' (a subject noun phrase and verb). The presence and magnitude of priming was compared to a baseline condition in which non-words systematically replaced real word primes. Normal subjects showed evidence for combinatorial thematics by exhibiting significant and larger amounts of thematic priming in the condition where two real words were present in the prime than in the conditions in which only one real word was present in the prime. Additionally, normal subjects showed sensitivity to both syntactic structures and pragmatics. In contrast, Broca's patients did not show significant priming for any condition nor did they show a difference in the magnitude of priming among the conditions. Nonetheless, they showed sensitivity to pragmatics. Wernicke's patients showed significant priming for all conditions, but did not show differences in the magnitude of priming among the conditions. However, they showed sensitivity to sentence grammaticality and pragmatics. The distinct patterns of performance of Broca's and Wernicke's aphasics are discussed in terms of the nature of their impairments in the processes of combinatorial thematics.

Adult↗
PubMedDate not supplied

Explicit Diversity Index (EDI): a novel measure for assessing the diversity of compound databases.

A novel diversity assessment method, the Explicit Diversity Index (EDI), is introduced for druglike molecules. EDI combines structural and synthesis-related dissimilarity values and expresses them as a single number. As an easily interpretable measure, it facilitates the decision making in the design of combinatorial libraries, and it might assist in the comparison of compound sets provided by different manufacturers. Because of its rapid calculation algorithm, EDI enables the diversity assessment of in-house or commercial compound collections.

Algorithms↗
PubMed2001

Alcohol biomarkers: clinical significance and biochemical basis.

This article represents the proceedings of a symposium at the 2000 ISBRA Meeting in Yokohama, Japan. The chairs were Raj Lakshman and Mikihiro Tsutsumi. The presentations were (1) Sialic acid index of apolipoprotein J: A new marker for chronic alcohol consumption, by P. Ghosh and M. R. Lakshman; (2) Microheterogeneity of serum glycoproteins in alcoholics, by M. Tsutsumi and S. Takase; (3) Probing protein-ethanol adducts with combinatorial peptide libraries displayed by filamentous phage, by H. Anni, O. Nikolaeva, and Y. Israel Y; (4) Carbohydrate-deficient transferrin as a marker for heavy alcohol use: What have we learned; Where do we go from here, by R. F. Anton; (5) Sensitivity and specificity of carbohydrate-deficient transferrin in drinking experiments and different patient groups, by O. M. Lesch; (6), Transferrin variants interfere with the measurement of carbohydrate-deficient transferrin, by A. Helender, G. Eriksson, and J-O. Jeppson; and (7) Chronic ethanol on protein trafficking in liver, by P. Marmillot, M. N. Rao, and M. R. Lakshman.

Alcoholism↗
PubMed2001

Evidence for an antigen-driven humoral immune response in medullary ductal breast cancer.

A minority of breast cancers is characterized by lymphoplasmacytic infiltrates that have been correlated with improved patient survivals. The association of improved prognosis with plasmacytic infiltrates has been classically linked with the rare medullary carcinoma subtype but is also evident in the smaller infiltrated fraction of the more abundant nonmedullary (not otherwise specified) tumors. It is our hypothesis that these plasma cell (PC) infiltrates represent a host humoral response driven by one or more tumor-derived neoantigens. As the index study group, two primary medullary carcinoma tumors were examined. Immunophenotyping confirmed a large number of IgG PCs in contradistinction to normal breast, which typically contains a lesser number of mainly IgA isotypes. IgG heavy and light chains were expressed as combinatorial phage Fab libraries. VH and VL sequences showed a preponderance of clonal groups in both patients, as identified by germ-line gene usage and junctional mutation patterns. Panning of phage Fab libraries against purified antigens excluded Her2/neu and p53 as the eliciting antigen, and failure of clonal enrichment by cell panning suggested that the neoantigen was not membrane expressed or was expressed at low levels. Cognate, original VH+VL pairs were obtained by single cell PCR of tumor PCs, which showed overlap with the pooled IgG libraries. Tumor-derived IgG V genes exhibited mutational patterns that were consistent with antigenic selection and affinity maturation. Where examined, IgG1 was the predominant isotype, consistent with a T-dependent (i.e., protein) antigen. From these data, we infer that the breast tumor PC infiltrates of the medullary carcinoma subtype are compatible with an autogenic tumor neoantigen-driven humoral immune response.

Antibodies, Neoplasm↗
PubMed2001

Molecular interaction maps as information organizers and simulation guides.

A graphical method for mapping bioregulatory networks is presented that is suited for the representation of multimolecular complexes, protein modifications, as well as actions at cell membranes and between protein domains. The symbol conventions defined for these molecular interaction maps are designed to accommodate multiprotein assemblies and protein modifications that can generate combinatorially large numbers of molecular species. Diagrams can either be "heuristic," meaning that detailed knowledge of all possible reaction paths is not required, or "explicit," meaning that the diagrams are totally unambiguous and suitable for simulation. Interaction maps are linked to annotation lists and indexes that provide ready access to pertinent data and references, and that allow any molecular species to be easily located. Illustrative interaction maps are included on the domain interactions of Src, transcription control of E2F-regulated genes, and signaling from receptor tyrosine kinase through phosphoinositides to Akt/PKB. A simple method of going from an explicit interaction diagram to an input file for a simulation program is outlined, in which the differential equations need not be written out. The role of interaction maps in selecting and defining systems for modeling is discussed. (c) 2001 American Institute of Physics.

Journal Article↗
PubMed2001

Similarity searching in large combinatorial chemistry spaces.

We present a novel algorithm, called Ftrees-FS, for similarity searching in large chemistry spaces based on dynamic programming. Given a query compound, the algorithm generates sets of compounds from a given chemistry space that are similar to the query. The similarity search is based on the feature tree similarity measure representing molecules by tree structures. This descriptor allows handling combinatorial chemistry spaces as a whole instead of looking at subsets of enumerated compounds. Within few minutes of computing time, the algorithm is able to find the most similar compound in very large spaces as well as sets of compounds at an arbitrary similarity level. In addition, the diversity among the generated compounds can be controlled. A set of 17,000 fragments of known drugs, generated by the RECAP procedure from the World Drug Index, was used as the search chemistry space. These fragments can be combined to more than 10(18) compounds of reasonable size. For validation, known antagonists/inhibitors of several targets including dopamine D4, histamine H1, and COX2 are used as queries. Comparison of the compounds created by Ftrees-FS to other known actives demonstrates the ability of the method to jump between structurally unrelated molecule classes.

Algorithms↗
PubMed2006

Development and validation of a high-throughput screen for inhibitors of SARS CoV and its application in screening of a 100,000-compound library.

The authors have developed a high-throughput screen (HTS) that allows for the identification of potential inhibitors of the severe acute respiratory syndrome coronavirus (SARS CoV) from large compound libraries. The luminescent-based assay measures the inhibition of SARS CoV-induced cytopathic effect (CPE) in Vero E6 cells. The assay was validated in 96-well plates in a BSL3 containment facility. The assay is sensitive and robust, with Z values > 0.6, signal to background (S/B) > 16, and signal to noise (S/N) > 3. The assay was further validated with 2 different diversity sets of compounds against the SARS CoV. The "hit" rate for both libraries was approximately 0.01%. The validated HTS assay was then employed to screen a 100,000-compound library against SARS CoV. The hit rate for the library in a single-dose format was determined to be approximately 0.8%. Screening of the 3 libraries resulted in the identification of several novel compounds that effectively inhibited the CPE of SARS CoV in vitro-compounds which will serve as excellent lead candidates for further evaluation. At a 10-microM concentration, 3 compounds with selective indexes (SI50) of > 53 were discovered.

Animals↗
PubMed1998

"Cut and combine": an easy membrane-supported combinatorial synthesis technique.

A combinatorial synthesis process involving sequential cycles of cutting a membrane support into pieces and combining these into groups and subjecting the groups to simultaneous solid-phase chemical reactions is demonstrated by the rapid assembly of four hundred N-terminally biotinylated, soluble, octameric peptide pools. Index patterns printed onto the synthesis membrane allowed a direct identification of the compounds. These were used to study protein kinase substrate selection in a parallel microplate adapted 32P-phosphorylation assay with subsequent spotting on a biotin-capture membrane.

Amino Acid Sequence↗
PubMed2006

A multifunctional PEI-based cationic polyplex for enhanced systemic p53-mediated gene therapy.

We recently reported a novel coupling strategy involving salicylhydroxamic acid and phenyl(di)boronic acid molecules to attach the CNGRC peptide to PEI/DNA for CD13 targeting in tumors. Here, we doubly coupled Simian Virus (SV) 40 peptide-(nuclear localization signal)) and oligonucleotide-based (DNA nuclear targeting signal) nuclear signals to the same vector using peptide nucleic acid chemistry. This vector, CNGRC/PEG/PEI/DNA-betagal/NLS/DNTS, was predominantly localized in the cell nucleus, yielding about 200-fold higher betagal gene expression in vitro, more than 20-fold increase in tumor-specific gene delivery, and a robust betagal gene expression as demonstrated in stained tumor sections. For gene therapy purposes, we further engineered a similar targeting polyplex, CNGRC/PEG/PEI/DNA-p53/NLS/DNTS, with EBV-based episomal vector for sustained p53 gene expression. A distribution of vector DNA and apoptosis in p53-containing tumors was observed, yielding a significant tumor regression and 95% animal survival after 60 days. This multicomponent vector also co-targeted tumor and tumor-associated endothelial cells but not normal cells, and had more efficient therapeutic index than each vector administered as a single modality. The use of an efficient coupling strategy without compromising the vector's integrity for DNA condensation and endosomal escape; nuclear import; tumor-specific and persistent p53 gene expression clearly provides a basis for developing a single combinatorial approach for non-viral gene therapy.

Animals↗
PubMed1995

Subclinical thought disorder in first-degree relatives of schizophrenic patients. Results from a matched-pairs study with the Thought Disorder Index.

To assess the frequency and quality of formal thought disorder in schizophrenic patients and their first-degree relatives, a consecutive series of 36 unmedicated patients, 20 siblings of these patients and 37 normal control subjects were examined with Holzman's Thought Disorder Index (TDI). As a proof of the internal validity of this tool, the patients demonstrated significantly more thought disorder than the controls as measured by the TDI total score and various subscores, which proved the internal validity of this tool in a German-speaking sample. In addition, in a pairwise comparison with controls who were individually matched by age and sex the patients' siblings had a significantly higher total TDI score and nonsignificant elevations on several subscores (combinatory and flippant). As to the level of severity of the thought disorder, the siblings mostly took an intermediate position between patients and controls. In conjunction with previous reports from other authors, our findings lend further support to the notion of subclinical thought disorder as an indicator of familial vulnerability to schizophrenia.

Adult↗
PubMed1987

Comparative studies of thought disorders. II. Schizoaffective disorder.

We examined thought disorder in 22 patients with schizoaffective disorder (12 schizoaffective-manic and ten schizoaffective-depressed) using Research Diagnostic Criteria. The Thought Disorder Index was used to tag 22 categories of thought disorder that ranged from mild to severe. Qualitative patterns in the thought disorder of schizoaffective patients were compared with those of 20 manic and 43 schizophrenic patients. Manic and schizoaffective-manic patients produced a high number of combinatory responses, but those produced by the schizoaffective-manic patients lacked the humor and playfulness of those of the manics. The schizoaffective-manic patients, like the schizophrenic patients, produced a high number of responses in the categories of idiosyncratic verbalizations, autistic thinking, and confusion. Unlike the manic patients, schizoaffective-depressed patients generally produced a few absurd and idiosyncratic responses in a setting of constricted output. The data strongly suggest that the thinking disorders of schizoaffective patients are like those of the schizophrenic patients.

Adult↗
PubMed1996

Multiple human taste receptor sites: a molecular modeling approach.

Numerous experimental data on the human peripheral taste system suggest the existence of multiple low-affinity and low-specificity receptor sites which are responsible for the detection and the complete discrimination of a very large number of organic molecules. According to this hypothesis, a given molecule interacts with numerous taste receptors and vice versa. Statistical analysis of taste intensities estimated by 58 human subjects for various molecules enables the calculation of taste intermolecular distances. For the present modeling study, we hypothesized that a short taste distance (i.e. taste similarity) between two distinct molecules indicates that they bind with similar distributions of affinities to the taste receptors, and hence display similar binding motifs. In order to find common molecular binding motifs among 14 selected organic tastants, hydrogen-bonding and hydrophobic interaction properties were mapped onto their molecular surfaces. The 14 surfaces were then cut in 240 fragments, most of which were made up of 2-4 potentially interacting zones. A correspondence index was defined to measure the analogy between two optimally superimposed fragments. The 75 most representative fragments were all matched pairwise. Twelve distinct clusters of fragments were isolated from the 2775 calculated comparisons. These 12 fragment types were used to calculate structural similarity distances. We then performed a combinatorial analysis to identify which fragment combination best reconciled structural and taste distances. We finally identified an optimal subset of seven fragment types out of the 12, which significantly and best accounted for the 91 pairwise taste distances between all 14 modeled tastants. These seven validated fragment types are therefore presented as good candidates to be recognized by the same number of distinct taste receptor sites. Potential applications of these identified binding motifs to tastant design are suggested.

Binding Sites↗
PubMed2004

Counting primes, groups, and manifolds.

Let Lambda=SL(2)(Z) be the modular group and let c(n)(Lambda) be the number of congruence subgroups of Lambda of index at most n. We prove that lim(n--> infinity )(log c(n)(Lambda)/((log n)(2)/log log n))=(3-2(sqrt)2)/4. The proof is based on the Bombieri-Vinogradov "Riemann hypothesis on the average" and on the solution of a new type of extremal problem in combinatorial number theory. Similar surprisingly sharp estimates are obtained for the subgroup growth of lattices in higher rank semisimple Lie groups. If G is such a Lie group and Gamma is an irreducible lattice of G it turns out that the subgroup growth of Gamma is independent of the lattice and depends only on the Lie type of the direct factors of G. It can be calculated easily from the root system. The most general case of this result relies on the Generalized Riemann Hypothesis, but many special cases are unconditional. The proofs use techniques from number theory, algebraic groups, finite group theory, and combinatorics.

Journal Article↗
PubMed2006

Fast-Find: a novel computational approach to analyzing combinatorial motifs.

BACKGROUND: Many vital biological processes, including transcription and splicing, require a combination of short, degenerate sequence patterns, or motifs, adjacent to defined sequence features. Although these motifs occur frequently by chance, they only have biological meaning within a specific context. Identifying transcripts that contain meaningful combinations of patterns is thus an important problem, which existing tools address poorly. RESULTS: Here we present a new approach, Fast-FIND (Fast-Fully Indexed Nucleotide Database), that uses a relational database to support rapid indexed searches for arbitrary combinations of patterns defined either by sequence or composition. Fast-FIND is easy to implement, takes less than a second to search the entire Drosophila genome sequence for arbitrary patterns adjacent to sites of alternative polyadenylation, and is sufficiently fast to allow sensitivity analysis on the patterns. We have applied this approach to identify transcripts that contain combinations of sequence motifs for RNA-binding proteins that may regulate alternative polyadenylation. CONCLUSION: Fast-FIND provides an efficient way to identify transcripts that are potentially regulated via alternative polyadenylation. We have used it to generate hypotheses about interactions between specific polyadenylation factors, which we will test experimentally.

Algorithms↗