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PubMed1995

The human HIV/peripheral blood lymphocyte (PBL)-SCID mouse. A modified human PBL-SCID model for the study of HIV pathogenesis and therapy.

PBL from HIV-infected patients were engrafted into CB-17 SCID mice to develop a novel small animal model for the study of HIV pathogenesis and therapy. Engraftment was achieved in 84% of mice, with human Ig (hu-Ig) levels and total human mononuclear cell recovery by peritoneal wash similar to those in control hu-PBL-SCID mice engrafted with uninfected donor cells. The hu-Ig produced by hu-HIV/PBL-SCID mice had broad reactivity against HIV. Virus could be detected in 98% of mice by polymerase chain reaction and/or viral coculture. Viremia was first detected by quantitative polymerase chain reaction on day 7 (approximately 10,000 copies of viral RNA/ml of plasma) and persisted through day 17. Quasispecies analysis of amplified, cloned, proviral DNA of the V3 region of the env gene showed that nucleotide sequences from hu-HIV/PBL-SCID mouse peritoneal wash cells on day 17 were not significantly changed from those derived from donor PBL at the time of injection. Relative to human CD4+ T cell recovery by peritoneal wash in control hu-PBL-SCID mice (CD4 = 19 +/- 2%; n = 40), severe CD4+ lymphocyte depletion (CD4 = 5 +/- 0.5%; n = 59; p < 0.001) was observed in untreated hu-HIV/PBL-SCID mice 18 to 25 days after engraftment. Treatment with 2'-beta-fluoro-2',3'-dideoxyadenosine, a nucleoside analogue, significantly reduced CD4+ T cell depletion (CD4 = 13 +/- 1; n = 59; p < 0.001) and the frequency of virus isolation (70%; p = 0.015) in the hu-HIV/PBL-SCID model. Boosting hu-Ig levels in the mice by injection of purified donor Ig with neutralizing activity did not affect the frequency of CD4+ lymphocyte recovery or virus isolation. The administration of a mAb to TNF had minimal effects. These studies demonstrate that PBL from HIV-infected donors can engraft SCID mice; that HIV can be detected in the spleen, peritoneal wash cells, and blood of these mice; that HIV infection within the model results in rapid CD4+ T cell depletion; and that anti-retroviral therapy is effective in improving CD4+ T cell recovery and reducing the frequency of virus isolation. The hu-HIV/PBL-SCID mouse model thus represents a potentially useful model in which to study HIV pathogenesis and therapy.

Amino Acid Sequence↗
PubMed2005

Defective rev response element (RRE) and rev gene in HAART treated AIDS patients with discordance between viral load and CD4+ T-cell counts.

BACKGROUND: Highly Active Antiretroviral Therapy (HAART) has emerged as one the most effective method for treating AIDS patients. However, after variable period of treatment, many AIDS patients on HAART show elevated PCR viral load without a corresponding decline in CD4+ T-cells. Our earlier studies have revealed that the viruses present in the plasma of such patients are not infectious. OBJECTIVE: The aim of this study is to characterize the changes in the regulatory genes of HIV-1, namely tat, rev and rev response element (RRE) isolated from the plasma of such AIDS patients and to assess their role in role in affecting viral infectivity, hence its contribution, in the 'contradictory phenomenon' of high viral load and high CD4+ T-cell counts. STUDY DESIGN: The viral RNA was isolated from the plasma of HAART patients when they exhibited high plasma viral load and high CD4+ T-cell counts. The target regulatory genes were amplified by RT-PCR and sequenced. Sequences were also obtained from the proviral DNA from the peripheral blood mononuclear cells (PBMCs) of the study subjects. The sequences were compared with the wild type viral sequence to look for the changes induced in them due to HAART regime. RESULTS AND CONCLUSION: Our data revealed that RRE was missing in the viral particles isolated from the plasma of all study subjects. In two patients, the second exon of the rev gene was missing thereby leading to defective Rev protein. In another patients, Rev synthesis was prematurely stopped due to G135T substitution in the amino terminal domain. No such changes were observed in the corresponding proviral DNA. These changes are likely to result in the assembly of non-infectious virus due to lack of envelope proteins. Absence of RRE and Rev protein also leads to transport and packaging of multiply spliced transcripts into the virions instead of complete genomic RNA.

Amino Acid Sequence↗
PubMed1995

A role for the orphan steroid receptor Nur77 in apoptosis accompanying antigen-induced negative selection.

The transcription factor Nur77, an orphan member of the nuclear hormone receptor superfamily, is highly expressed during T cell receptor-signaled apoptosis, suggesting a possible role for Nur77 in negative selection. We examined this by generating two sets of transgenic mice. In one set of mice, a dominant-negative Nur77 mutant is constitutively expressed and the other in which wild-type Nur77 protein is constitutively expressed in developing thymocytes. We report that inhibition of endogenous Nur77 by the dominant-negative mutant perturbed T cell development and inhibited antigen-induced negative selection in F5T cell receptor transgenic mice. Constitutive expression of wild-type Nur77 protein induced apoptosis in developing thymocytes, resulting in a decreased number of thymocytes and mature T cells. Together, these data support a role for Nur77 in the downstream signaling events in antigen-induced negative selection.

Animals↗
PubMedDate not supplied

Safety and immunogenicity of REMUNE in HIV-infected Thai subjects.

The safety and immunogenicity of REMUNE, an HIV-specific immune based therapy for HIV infection, was evaluated in a cohort of 30 HIV infected subjects in Thailand. This therapy utilizes a gp120 depleted inactivated virus (HZ321), which exhibits a high degree of conservation with the core antigens of both type B' and E strains of HIV, the predominant Thailand isolates. The treatment was well tolerated, with no serious adverse events reported over the course of the 4-month trial. Treatment in which four doses were administered with REMUNE appeared to boost HIV-specific immune responses, with approximately 75% of the treated subjects demonstrating an increase in either the repertoire or the intensity of the serological response to HIV as measured by Western blot. CD4%, viral load, and weight remained stable over the course of the 4-month study relative to baseline values. Viral subtyping of this cohort revealed a predominance of type 'E'. These data suggest that REMUNE is safe and immunogenic in seropositive Thai subjects and supports further study of the therapeutic potential of REMUNE to treat HIV-1 infection.

AIDS Vaccines↗
PubMed1995

Osteosarcoma hybrids can preferentially target alkaline phosphatase activity to matrix vesicles: evidence for independent membrane biogenesis.

Alkaline phosphatase is the marker enzyme for matrix vesicles, extracellular organelles that play a major role in primary bone formation and calcification. Recently, we developed osteosarcoma x fibrosarcoma hybrids in which alkaline phosphatase expression was greatly reduced, a phenomenon known as extinction. In the present study, we used to cell hybrids, LTA-1 and LTA-5, constructed from a human osteoblast-like osteosarcoma. TE85, and a mouse fibrosarcoma, La-t-, to examine the differential distribution of alkaline phosphatase between matrix vesicles and the plasma membrane, postulated to be the parent membrane from which matrix vesicles are derived. While alkaline phosphatase in plasma membranes was extinguished, enzyme activity in matrix vesicles from LTA-1 hybrid cells was 34.2% of that present in matrix vesicles from the TE85 parent cells and 200 times that found in La-t- matrix vesicles. Matrix vesicles from LTA-5 had alkaline phosphatase levels similar to La-t-. When other membrane enzymes (phospholipase A2, 5'-nucleotidase, and Na+/K+ ATPase) were examined, hybrid matrix vesicle and plasma membrane levels were similar to those of TE85 and significantly higher than in La-t- membrane fractions. Northern analysis detected mRNA for alkaline phosphatase in TE85 cells, but not in the hybrids or La-t- cells. In contrast, reverse transcription-polymerase chain reaction (RT-PCR) revealed alkaline phosphatase mRNA in the hybrid cells, but at very low levels. Taken together, the data indicate that regulation of plasma membrane and matrix vesicle alkaline phosphatase is independent and suggest that matrix vesicle biogenesis is independent and distinct from that of plasma membrane biogenesis. Analysis of 1B- and 1L-type alkaline phosphatase mRNA by RT-PCR showed that alternate promoter usage of the alkaline phosphatase gene was not responsible for the differential localization of this enzyme in matrix vesicle. Thus, it is likely that matrix vesicle and plasma membrane alkaline phosphatase are regulated differently at a post-transcriptional level.

5'-Nucleotidase↗
PubMed2000

Diet influences the colonisation of Campylobacter jejuni and distribution of mucin carbohydrates in the chick intestinal tract.

The objectives of this study were to evaluate the effect of diet on the colonisation by Campylobacter jejuni of the chick caeca, and to determine whether the viscosity of the intestinal contents and mucin carbohydrates were altered by the diet. The diets investigated were maize based, wheat-based or wheat-based supplemented with xylanase. The xylanase-supplemented diet reduced the viscosity and lowered the numbers of Camp. jejuni. Feeding the enzyme-supplemented diet increased the amount of neutral and sulphated mucins in the goblet cells of the small and large intestines and caecum. An abundance of sulphated and carboxylated mucins was seen in the surface goblet cells of the large intestine with the maize- and wheat-based diets. Both the diet supplemented with xylanase and the maize diets increased crypt-surface glycosylation of the sialic acid residues. The analysed data from the combined sites showed significant differences in the amount of neutral and acidic mucins when comparing the wheat and the wheat plus xylanase diets. However, no changes were shown in the staining intensity of sulphated mucins between the three diets. Significant differences in the glycosylation of sialic acid and in the N-acetylglucosamine residues were shown between dietary groups. These results provide evidence that the wheat diet supplemented with xylanase leads to greater changes in the mucin composition and carbohydrate expression of goblet cell glycoconjugates, which are associated with a reduction in intestinal viscosity and decreased numbers of Camp. jejuni.

Animals↗
PubMed2025

CountASAP: a lightweight, easy to use python package for processing ASAPseq data.

BACKGROUND: Declining sequencing costs coupled with the increasing availability of easy-to-use kits for the isolation of DNA and RNA transcripts from single cells have driven a rapid proliferation of studies centered around genomic and transcriptomic data. Simultaneously, a wealth of new techniques have been developed that utilize single cell technologies to interrogate a broad range of cell-biological processes. One recently developed technique, transposase-accessible chromatin with sequencing (ATAC) with select antigen profiling by sequencing (ASAPseq), provides a combination of chromatin accessibility assessments with measurements of cell-surface marker expression levels. While software exists for the characterization of these datasets, there currently exists no tool explicitly designed to reformat ASAP surface marker FASTQ data into a count matrix which can then be used for these downstream analyses. RESULTS: To address this lack of a dedicated tool for ASAPseq data processing, we created CountASAP, an easy-to-use Python package purposefully designed to transform FASTQ files from ASAP experiments into count matrices compatible with commonly-used downstream bioinformatic analysis packages. CountASAP takes advantage of the independence of the relevant data structures to perform fully parallelized matches of each sequenced read to user-supplied input ASAP oligos and unique cell-identifier sequences. We directly compare the performance and user-friendliness of CountASAP to existing tools using similarly-structured data from a more common sequencing experiment: cellular indexing of transcriptomes and epitopes by sequencing (CITEseq). Further benchmarking against existing tools helps to identify proper defaults for CountASAP and assess the agreement of outputs from all tested software. A final test using a novel ASAPseq dataset provides evidence that CountASAP can generate biologically meaningful results that correlate well with paired chromatin accessibility data. CONCLUSIONS: CountASAP shows good agreement with existing, well-tested data processing tools in the analysis of similarly-structured benchmarking data. CountASAP runs efficiently on a standard laptop, has user-friendly documentation, a one-step installation, and represents the first and only tool designed specifically for the processing of ASAPseq data.

Software↗
PubMed1999

Phylogenetic affiliation and quantification of psychrophilic sulfate-reducing isolates in marine Arctic sediments.

Thirteen psychrophilic sulfate-reducing isolates from two permanently cold fjords of the Arctic island Spitsbergen (Hornsund and Storfjord) were phylogenetically analyzed. They all belonged to the delta subclass of Proteobacteria and were widely distributed within this group, indicating that psychrophily is a polyphyletic property. A new 16S rRNA-directed oligonucleotide probe was designed against the largest coherent cluster of these isolates. The new probe, as well as a set of available probes, was applied in rRNA slot blot hybridization to investigate the composition of the sulfate-reducing bacterial community in the sediments. rRNA related to the new cluster of incompletely oxidizing, psychrophilic isolates made up 1.4 to 20.9% of eubacterial rRNA at Storfjord and 0.6 to 3. 5% of eubacterial rRNA at Hornsund. This group was the second-most-abundant group of sulfate reducers at these sites. Denaturing gradient gel electrophoresis and hybridization analysis showed bands identical to those produced by our isolates. The data indicate that the psychrophilic isolates are quantitatively important in Svalbard sediments.

Arctic Regions↗
PubMed1997

Presence of cyclophilin A in synovial fluids of patients with rheumatoid arthritis.

Cyclophilins have been suggested to act as leukocyte chemotactic factors produced in the course of inflammation. Therefore we looked for the presence of cyclophilins in the synovial fluids (SF) from patients with rheumatoid arthritis (RA). Peptidyl prolyl cis-trans isomerase activity (PPIase) was measured in SF from knee punctures of 26 patients with RA and five patients with knee osteoarthritis (OA). PPIase was detected in SF from RA patients, but not in samples from OA patients. Enzyme activity was sensitive to inhibition by cyclosporin A (IC50 = 28-50 nM). Estimated concentrations of the SF-derived cyclophilin based on the enzyme activity were in the range of 11 to 705 nM. The presence of cyclophilin in the SF showed disease correlation; its concentration correlated with the number of cells in the SF (r = 0.91, P < 0.0001) and with the percentage of neutrophils in the cellular infiltrate and was higher in more acute cases of joint swelling. In immunoblots of partially purified preparations of SF from RA patients, an approximately 18-kD protein band reacted with polyclonal antibodies that recognize cyclophilin A and B, but not with antibodies specific for cyclophilin B. Sequencing of this protein revealed identity of the NH2-terminal amino acids with those of human cyclophilin A. The finding is unexpected since cyclophilin B rather than A is generally regarded as the secreted isoform, the presence of cyclophilin A being confined to the cytoplasm. Our data support the hypothesis that cyclophilins may contribute to the pathogenesis of inflammatory diseases, possibly by acting as cytokines. This may offer a possible explanation of the effectiveness of cyclosporin A in RA, in addition to the known immunosuppressive effects of the drug.

Adult↗
PubMed1974

Nucleotide sequence relationships of avian RNA tumor viruses: measurement of the deletion in a transformation-defective mutant of Rous sarcoma virus.

Stocks of cloned helper-independent Rous sarcoma virus (RSV) spontaneously segregate transformation-defective (td) mutants that appear to have an RNA genome composed of smaller subunits than those of the patent virus. Differential hybridization and competitive hybridization techniques involving reactions between viral RNA and proviral sequences in host cell DNA (under conditions of initial DNA excess) were used to measure the extent of the deletion in a td mutant of Prague strain (Pr) of RSV (Pr RSV-C). Viral 60 to 70S RNA sequences labeled to 1 to 5 x 10(7) counts per min per mug with (125)I were characterized with respect to their properties in hybridization reactions and used to reinforce data obtained with [(3)H]RNA of lower specific activity. By these techniques, about 13% +/- 3% of the sequences Pr RSV-C that formed hybrids with DNA from virus-induced sarcomas appeared to be deleted from the genome of td Pr RSV-C. Studies comparing hybridization of RNA from Pr RSV-C and td Pr RSV-C with RSV-related sequences in normal cells, and competition experiments with RNA from the endogenous chicken oncornavirus Rous-associated virus type 0 (RAV-0) provided evidence that the majority, if not all, of the RNA sequences of Pr RSV-C deleted from its transformation-defective mutant are not represented in normal chicken DNA. Competition studies with a leukosis virus, RAV-7, indicated this virus also lacks a genome segment of about the same size as the deletion in the td mutant. Finally, the genome of all three "exogenous" viruses was found to lack a small segment (about 12%) of sequences present in the endogenous provirus of RAV-O.

Animals↗
PubMed1994

Comparison of quantitative whole-body autoradiographic and tissue dissection techniques in the evaluation of the tissue distribution of [14C]daptomycin in rats.

Quantitative whole-body autoradiography (QWBA) was evaluated and compared to tissue dissection/liquid scintillation counting (TD/LSC) techniques by determining the tissue distribution of radiocarbon in rats following iv administration of the antibiotic [14C]daptomycin (LY146032). QWBA, using computer-assisted video-image analysis, was initially evaluated by characterizing and calibrating commercial standards to blood and brain, kidney, liver, and lung homogenates. Frozen (carboxymethyl)cellulose blocks containing tissue homogenates spiked with [14C]glucose (370-37,000 Bq/g or 10-1000 nCi/g) were sectioned and optical densities (OD) measured. Characterization of QWBA included repeated measures data analysis to determine the significance of tissue type and intra- and inter-section and block variability. Regression models relating OD to radiocarbon concentration were also used to calibrate commercial standards for use in QWBA analyses. Results indicated that there were no substantial differences between OD readings from different tissues; however, the greatest source of variation in OD reading was section thickness. Because quantitative variations were largely attributed to section thickness, an internal standard (IS), consisting of liver homogenates spiked with [14C]glucose, was evaluated as a correction factor. Tissue concentrations of radiocarbon in male Fischer 344 rats were evaluated by QWBA and TD/LSC techniques 0.25 h following a single iv 10 mg/kg dose of [14C]daptomycin. Results indicated that tissue concentrations of radiocarbon obtained by QWBA, normalized using an IS, were comparable to those obtained by TD/LSC.

Amino Acid Sequence↗
PubMed2004

Automatic classification of interference patterns in driven event series: application to single sympathetic neuron discharge forced by mechanical ventilation.

This study proposes a method for the automatic classification of nonlinear interactions between a strictly periodical event series modelling the activity of an exogenous oscillator working at a fixed and well-known rate and an event series modelling the activity of a self-sustained oscillator forced by the exogenous one. The method is based on a combination of several well-known tools (probability density function of the cyclic relative phase, probability density function of the count of forced events per forcing cycle, conditional entropy of the cyclic relative phase sequence and a surrogate data approach). Classification is reached via a sequence of easily applicable decision rules, thus rendering classification virtually user-independent and fully reproducible. The method classifies four types of dynamics: full uncoupling, quasiperiodicity, phase locking and aperiodicity. In the case of phase locking, the coupling ratio (i.e. n: m) and the strength of the coupling are calculated. The method, validated on simulations of simple and complex phase-locking dynamics corrupted by different levels of noise, is applied to data derived from one anesthetized and artificially ventilated rat to classify the nonlinear interactions between mechanical ventilation and: (1) the discharges of two (contemporaneously recorded) single postganglionic sympathetic neurons innervating the caudal ventral artery in the tail and (2) arterial blood pressure. Under central apnea, the activity of the underlying sympathetic oscillators is perturbed by means of five different lung inflation rates (0.58, 0.64, 0.76, 0.95, 1.99 Hz). While ventilation and arterial pressure are fully uncoupled, ventilation is capable of phase locking sympathetic discharges, thus producing 40% of phase-locked patterns (one case of 2:5, 1:1, 3:2 and 2:2) and 40% of aperiodic dynamics. In the case of phase-locked patterns, the coupling strength is low, thus demonstrating that this pattern is sliding. Non-stationary interactions are observed in 20% of cases. The two discharges behave differently, suggesting the presence of a population of sympathetic oscillators working at different frequencies.

Adrenergic Fibers↗
PubMed1995

Lymphopenia in interleukin (IL)-7 gene-deleted mice identifies IL-7 as a nonredundant cytokine.

Interleukin (IL)-7 is a potent stimulus for immature T and B cells and, to a lesser extent, mature T cells. We have inactivated the IL-7 gene in the mouse germline by using gene-targeting techniques to further understand the biology of IL-7. Mutant mice were highly lymphopenic in the peripheral blood and lymphoid organs. Bone marrow B lymphopoiesis was blocked at the transition from pro-B to pre-B cells. Thymic cellularity was reduced 20-fold, but retained normal distribution of CD4 and CD8. Splenic T cellularity was reduced 10-fold. Splenic B cells, also reduced in number, showed an abnormal population of immature B cells in adult animals. The remaining splenic populations of lymphocytes showed normal responsiveness to mitogenic stimuli. These data show that proper T and B cell development is dependent on IL-7. The IL-7-deficient mice are the first example of single cytokine-deficient mice that exhibit severe lymphoid abnormalities.

Animals↗
PubMed2006

Immuno-electron microscopic quantification of the fucoxanthin chlorophyll a/c binding polypeptides Fcp2, Fcp4, and Fcp6 of Cyclotella cryptica grown under low- and high-light intensities.

The diatom Cyclotella cryptica was grown under low- and high-intensity white light of 50 and 500 micromol photons m-2 s-1, respectively. Western immunoblotting showed that the diatom adapted its light-harvesting apparatus, giving rise to different amounts of distinct fucoxanthin chlorophyll a/c binding polypeptides (Fcp). The amount of Fcp2 was approximately two-fold higher under low-light than under high-light conditions, whereas the amount of Fcp6 increased four- to five-fold under high-light conditions. For Fcp4, no significant differences were detected in response to either light regime. Cells of Cyclotella grown under high- and low-light intensity were subjected to immunoelectron microscopy. Quantification of the gold label, expressed as gold particles per microm2, confirmed the results obtained by Western immunoblotting. Exposure to low light resulted in the detection of approximately six times more Fcp2-bound gold particles per microm2 in thylakoid membranes, whereas in cells grown under high light the number of Fcp6-bound gold particles increased ten-fold. For Fcp4, similar amounts of gold particles per microm2 were counted under the two light regimes. These immunocytochemical results confirmed molecular data derived from phylogenetic analyses of the sequences of genes encoding fucoxanthin chlorophyll a/c binding polypeptides (fcp genes) and from measurements of steady-state fcp mRNA concentrations. The results show that Fcp2 and Fcp6 accumulate under low- and high-light intensity, respectively, whereas Fcp4 seems to be constitutively synthesized.

Algal Proteins↗
PubMed2004

Bacterial population dynamics and community structure in a pharmaceutical manufacturing water supply system determined by real-time PCR and PCR-denaturing gradient gel electrophoresis.

AIMS: To control bacteria in the pharmaceutical water supply system. METHODS AND RESULTS: Bacteria were enumerated by conventional culture method and fluorescent vital staining. Activated carbon treatment and storage in a tank provided favourable environments for bacterial growth. The bacterial population of the water in both the post-activated carbon treatment and the tank was analysed by denaturing gradient gel electrophoresis (DGGE) with PCR-amplified 16S rDNA fragments including V6, -7, and -8 regions. The bacterial community structure in activated carbon treated water was stable throughout the year. Several kinds of bacteria such as genus Aquaspirillum and Methylobacterium were found in the water after activated carbon treatment. The bacterial community structure was changed and other bacteria such as mycobacteria were detected after storage. Mycobacteria were quantified in water samples using real-time PCR targeting the 16S rDNA gene. Mycobacteria were also detected in tap water and their number was increased 10(3)-10(4)-fold higher after storage. CONCLUSION: These data suggest the importance of culture-independent methods for quality control of water used in pharmaceutical manufacturing. SIGNIFICANCE AND IMPACT OF THE STUDY: Critical steps and specified bacteria that should be controlled in the water supply system were recognized by culture-independent methods. These data will enable effective control of water used in the pharmaceutical industry.

Bacteria↗
PubMed2003

Microbial community dynamics during start-up operation of flowerpot-using fed-batch reactors for composting of household biowaste.

Microbial community changes during start-up operation of flowerpot-using fed-batch reactors for composting of household biowaste were studied by quinone profiling, rRNA-targeted fluorescence in situ hybridization (FISH) and cultivation methods. Total and plate counts of bacteria and quinone contents in the reactors increased sharply with time during the start-up period. These increase patterns had two phases; the first increase occurred during 3-4 weeks from the start of waste loading and the second increase was found during the subsequent 4 weeks. The microbial biomass was temporally reduced between the two succession phases. Ubiquinones predominated at the beginning of operation but decreased sharply with time, whereas partially saturated menaquinones became predominant at the fully acclimated stage. These data indicated that the major constituents of microbial populations changed from ubiquinone-containing Proteobacteria to Actinobacteria during the period of operation. Neighbour-joining dendrograms constructed based on the quinone profile data suggested that at least one month is required to establish a stable community structure with the Actinobacteria predominating. The characteristic population shift in the start-up process was also demonstrated by FISH probing and 16S rDNA sequence comparisons of bacterial strains isolated.

Actinobacteria↗
PubMed2006

Predicting transcription factor affinities to DNA from a biophysical model.

MOTIVATION: Theoretical efforts to understand the regulation of gene expression are traditionally centered around the identification of transcription factor binding sites at specific DNA positions. More recently these efforts have been supplemented by experimental data for relative binding affinities of proteins to longer intergenic sequences. The question arises to what extent these two approaches converge. In this paper, we adopt a physical binding model to predict the relative binding affinity of a transcription factor for a given sequence. RESULTS: We find that a significant fraction of genome-wide binding data in yeast can be accounted for by simple count matrices and a physical model with only two parameters. We demonstrate that our approach is both conceptually and practically more powerful than traditional methods, which require selection of a cutoff. Our analysis yields biologically meaningful parameters, suitable for predicting relative binding affinities in the absence of experimental binding data. AVAILABILITY: The C source code for our TRAP program is freely available for non-commercial use at http://www.molgen.mpg.de/~manke/papers/TFaffinities/

Algorithms↗