Search PubMed⌕ Search

Biomedical subjects

J Otsuka

Publications and source records attributed to J Otsuka.

At least 19 recordsLinked to original sources
PubMed2005

Association of MBL gene polymorphisms with major bacterial infection in patients treated with high-dose chemotherapy and autologous PBSCT.

A growing body of evidence indicates that genetic factors are involved in an increased risk of infection. We investigated whether mannose-binding lectin (MBL) gene polymorphisms that cause low levels of MBL are associated with the occurrence of major infections in patients, mainly bearing hematological malignancies, after high-dose chemotherapy (HDT) rescued by autologous peripheral blood stem cell transplantation (auto-PBSCT). A retrospective evaluation of 113 patients treated with HDT and auto-PBSCT revealed that the low-producing genotypes, B/B and B/LXA, were associated with major bacterial infection (P=0.0016, OR 7.9). We next performed a nation-wide large-scale study to assess the allele frequency of the MBL coding mutation in a total of 2623 healthy individuals in Japan. The frequency of allele B was estimated to be approximately 0.2, almost the same in seven different areas of Japan. This common occurrence suggests that MBL deficiency may play an important role in the clinical settings of immunosuppression.

Alleles↗
PubMed2004

Raised serum APRIL levels in patients with systemic lupus erythematosus.

OBJECTIVE: To determine whether serum levels of a proliferation-inducing ligand (APRIL) are raised in patients with systemic lupus erythematosus (SLE) and correlate with autoantibody titres or disease activity, or both. METHODS: Serum samples from 48 patients with SLE, 41 normal healthy subjects, and 21 patients with rheumatoid arthritis (RA) were assayed for APRIL by enzyme linked immunosorbent assay. Medical charts were retrospectively reviewed for autoantibody titres and immunoglobulin levels. Disease activity was assessed using the British Isles Lupus Assessment Group (BILAG) index. RESULTS: The APRIL levels in the serum samples from patients with SLE were significantly higher than in those from healthy controls and those from patients with RA. Serum APRIL levels did not correlate with serum IgG and IgM levels, but had a tendency to correlate with anti-double stranded DNA antibody titres. Moreover, serum APRIL levels correlated significantly with musculoskeletal manifestations among patients with SLE when assessed by the BILAG index. CONCLUSION: APRIL may be an important factor in raised autoantibody titres and musculoskeletal disease in patients with SLE. Patients with raised serum APRIL levels may be ideal candidates for therapeutic targeting of APRIL.

Adult↗
PubMed2004

Malignant transformation of endometriosis and genetic alterations of K-ras and microsatellite instability.

OBJECTIVES: To clarify the role of specific genetic alterations in the multi-step process of malignant transformation of endometriosis. METHODS: In cases of ovarian endometrioid carcinoma, we separated regions of normal endometriosis, atypical endometriosis and ovarian endometrioid carcinoma by laser microdissection, and examined K-ras mutation and microsatellite instability in each separated tissue sample. RESULTS: We detected K-ras mutation and microsatellite instability in endometrioid carcinoma tissue, but not in normal or atypical endometriosis bordering the cancerous region. CONCLUSIONS: The present findings suggest that K-ras mutation and microsatellite instability are associated with malignant transformation from atypical endometriosis to ovarian endometrioid carcinoma.

Adult↗
PubMed2003

Aberrant HS1 molecule in a patient with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the activation of autoreactive B lymphocytes, which are supposed to carry aberrant signal transduction after the stimulation of B-cell receptor (BCR). To investigate abnormalities in BCR-mediated signaling pathway in lupus B lymphocytes, we analyzed HS1, a molecule downstream of BCR, in 80 Japanese SLE patients. We identified 37 amino acid deletion of HS1 in a 25-year-old female patient, and the aberrant HS1 lacked a part of a functional motif. Analysis of genomic DNA revealed that the aberrant HS1 was caused by exon skipping. Family study showed that the patient as well as her father and sister are heterozygous for the abnormality. WEHI-231 cell, a mouse B cell line, transfected with the aberrant HS1 displayed a significantly increased cell death upon cross-linking of BCR. Additionally, peripheral B lymphocytes from the patient exerted increased apoptosis after BCR stimulation compared to those from control SLE patients. These data suggest that the aberrant HS1 molecule may transmit an accelerated signal after BCR stimulation and may play a role in the activation of autoreactive B lymphocytes.

Adaptor Proteins, Signal Transducing↗
PubMed2001

The influence of selection on the evolutionary distance estimated from the base changes observed between homologous nucleotide sequences.

In most studies of molecular evolution, the nucleotide base at a site is assumed to change with the apparent rate under functional constraint, and the comparison of base changes between homologous genes is thought to yield the evolutionary distance corresponding to the site-average change rate multiplied by the divergence time. However, this view is not sufficiently successful in estimating the divergence time of species, but mostly results in the construction of tree topology without a time-scale. In the present paper, this problem is investigated theoretically by considering that observed base changes are the results of comparing the survivals through selection of mutated bases. In the case of weak selection, the time course of base changes due to mutation and selection can be obtained analytically, leading to a theoretical equation showing how the selection has influence on the evolutionary distance estimated from the enumeration of base changes. This result provides a new method for estimating the divergence time more accurately from the observed base changes by evaluating both the strength of selection and the mutation rate. The validity of this method is verified by analysing the base changes observed at the third codon positions of amino acid residues with four-fold codon degeneracy in the protein genes of mammalian mitochondria; i.e. the ratios of estimated divergence times are fairly well consistent with a series of fossil records of mammals. Throughout this analysis, it is also suggested that the mutation rates in mitochondrial genomes are almost the same in different lineages of mammals and that the lineage-specific base-change rates indicated previously are due to the selection probably arising from the preference of transfer RNAs to codons.

Animals↗
PubMed2000

Development of colonic necrosis following severe acute pancreatitis.

We herein describe a 70-year-old male patient who developed colonic necrosis following severe acute pancreatitis. He was referred to our hospital with a diagnosis of acute pancreatitis. In the course of the disease, he developed sudden and massive hematochezia and died. The autopsy findings revealed large bowel ischemia with transmural infarction. The possible pathogenic mechanisms of colonic ischemia are also discussed.

Acute Disease↗
PubMed1999

Similarity relations of DNA and RNA polymerases investigated by the principal component analysis of amino acid sequences.

The principal component analysis based on the physicochemical properties of amino acid residues is applied to DNA and RNA polymerases to assign the sequence motifs for the polymerization activities of these proteins. After the reconfirmation of the sequence motifs of families A and B of DNA polymerases indicated previously, it elucidates the sequence motifs for the polymerization activity of DNA polymerase III (family C) by the similarity to the polymerization center of multimeric DNA dependent RNA polymerases. This identification proceeds to clarify the sequence motifs for polymerization activities of primases; eukaryotic and archaebacterial primases carry motifs similar to those of family C, while the motifs of eubacterial primase fall into the category of the motifs in family B DNA polymerases such as alpha, delta, epsilon and II. This finding means that DNA dependent RNA polymerases are also divided into groups corresponding to three families, A, B and C, because the monomeric DNA dependent RNA polymerases in phages are reconfirmed to carry sequence motifs similar to those of family A DNA polymerases. Furthermore, the three families of polymerization motifs are found to fall within the variation range of polymerization motifs displayed by many RNA dependent RNA polymerases, suggesting a close evolutionary relation between them. The sequence motifs for polymerization activities of reverse transcriptase and telomerase seem to be the intermediate between family A DNA polymerase and some RNA dependent RNA polymerases, e.g., from Leviviridae. On the contrary, the sequence fragments similar to the nucleotidyltransferase superfamily including DNA polymerase beta are not found in any RNA dependent RNA polymerase, suggesting their other lineage of polymerization motifs.

Amino Acid Sequence↗
PubMed1999

Phylogeny of organisms investigated by the base-pair changes in the stem regions of small and large ribosomal subunit RNAs.

In order to obtain the evolutionary distance data that are as purely additive as possible, we have developed a novel method for evaluating the evolutionary distances from the base-pair changes in stem regions of ribosomal RNAs (rRNAs). The application of this method to small-subunit (SSU) and large-subunit (LSU) rRNAs provides the distance data, with which both the unweighted pair group method of analysis and the neighbor-joining method give almost the same tree topology of most organisms except for some Protoctista, thermophilic bacteria, parasitic organisms, and endosymbionts. Although the evolutionary distances calculated with LSU rRNAs are somewhat longer than those with SSU rRNAs, the difference, probably due to a slight difference in functional constraint, is substantially decreased when the distances are converted into the divergence times of organisms by the measure of the time scale estimated in each type of rRNAs. The divergence times of main branches agree fairly well with the geological record of organisms, at least after the appearance of oxygen-releasing photosynthesis, although the divergence times of Eukaryota, Archaebacteria, and Eubacteria are somewhat overestimated in comparison with the geological record of Earth formation. This result is explained by considering that the mutation rate is determined by the accumulation of misrepairs for DNA damage caused by radiation and that the effect of radiation had been stronger before the oxygen molecules became abundant in the atmosphere of the Earth.

Algorithms↗
PubMed1998

Self-reproducing system can behave as Maxwell's demon: theoretical illustration under prebiotic conditions.

The recent discovery of polymerase activity in a ribosomal RNA intervening sequence as well as other studies of RNA-replicating systems suggest that the first living molecules were RNAs called replicases. According to this suggestion from biochemical studies, the replicase system is chosen as the simplest case of self-reproducing systems, and the fundamental problem of "what is life" is theoretically investigated by analysing the behavior of a replicase system with a supply of organic materials under prebiotic conditions. In this analysis, it is essential to consider (i) self-reproduction on the basis of its own information, (ii) maintenance and improvement of the information by selection and (iii) environmental event of non-biologically generating organic materials from inorganic matter by photochemical reactions, probably occurring in prebiotic conditions on the Earth. The replicases can retain and further elevate their self-reproducibility through competition among their descendant mutants for acquiring a limited quantity of materials, if the initial ability of self-reproduction and the concentration of replicases are above some critical values. By this selection, the replicase molecules retain a narrowed range of nucleotide sequences, or a state of lower entropy, against the natural tendency of sequence divergence, but this entropy reduction is sufficiently compensated by the entropy production in the environmental event of energy conversion from photons to heat. Once the stability of a self-reproducing system is established in the above sense, the self-reproducing system can operate as Maxwell's demon to regulate the outside flow of matter by its catalytic function without any contradiction to the second law of thermodynamics.

Animals↗
PubMed1998

A method for comparing circular genomes from gene locations: application to mitochondrial genomes.

MOTIVATION: Data on the entire structures of organelle and bacterial genomes, most of which are known to be circular, have accumulated at a rapid pace. This information enables us to utilize the locations of homologous gene pairs for measuring the dissimilarity between complete genomic structures. RESULTS: A macroscopic distance is presented for comparing circular genomes from their overall structures, on the basis of the locations of two pairs of homologous genes on the compared genomes. The novel aspect of our method is that the comparison between the genomes automatically reveals a relationship based on the information on all gene locations, by incorporating the mobility of each gene, which includes not only the gene order, but also the relative location between gene pairs. The plausibility of the newly defined distances is evaluated by means of 44 mitochondrial genomes. The genome distance shows high performance for quantitatively describing the differences between the gene organizations of the genomes. AVAILABILITY: Since the programs implementing these calculations require well-arranged gene organization data, they have not been released yet. However, one of the authors will analyze circular genomes upon request. Data on the gene organizations may be submitted electronically to the address below.

Animals↗
PubMed1997

A theoretical study on the nucleotide changes under a definite functional constraint of forming stable base-pairs in the stem regions of ribosomal RNAs; its application to the phylogeny of eukaryotes.

Homologous alignment of 5 S rRNAs shows the characteristic features that (i) nucleotide changes are more remarkably seen in the stem region than in the loop region and (ii) most of the changes in the former region occur under a definite functional constraint of maintaining the stable base pairs G:C, C:G, A:U and U:A. In order to obtain a better evolutionary measure, we derived a theoretical equation for expressing the changes between the stable base-pairs in the stem region from an elementary process, in which the nucleotides in a pair mutate individually and the mis-matched pairs thus generated are eliminated by selection or return to the stable pairs by successive mutations. This equation leads us to a simple method of estimating the base-pair change rate by formally enumerating the base-pair changes observed in the pairwise comparison of homologous sequences from different species, just like the estimation of the change rate of individual nucleotides. The application of this method to 5 S rRNAs of eukaryotes reveals a new feature, in which the evolutionary distance of yeasts (Saccharomyces, Pichia and Hansenula) from higher plants and animals is much more expanded than that obtained previously by the enumeration of individual nucleotide changes observed in a whole region of 5 S rRNA and many other fungi, protozoans and algae are allocated to the middle positions between the yeasts and higher plants. The base-pair change rate is estimated to be about 2 x 10(-10) year-1, which is less than the mutation rate by one order of magnitude, and is suitable for resolving the phylogeny of species which diverged a few billion years ago. The selective term for eliminating the mis-matched pairs is also evaluated to be stronger than the mutation rate by about one order of magnitude even for the outstanding mis-matched pair of G:U and U:G.

Animals↗
PubMed1997

A theoretical method for evaluating the relative importance of positive selection and neutral drift from observed base changes.

To evaluate the relative importance of positive selection and neutral drift from the nucleotide base changes observed in the homologous alignment of genes, a theoretical equation of base changes is formulated by including both the influence of selection and the base substitutions due to mutations. Under the assumption that the average rate of base substitutions estimated from synonymous changes is the "true" mutation rate applicable at all positions, this method is applied to the vertebrate globin gene family, and evaluates the departures of base change rates from the "true" mutation rate at the first and second codon positions as a consequence of preferential selection for the conservation of important function. In addition to the strong effect of selection on the amino acid residues in the internal region mostly common to myoglobin and hemoglobin chains, the distinctive directions of selective parameter values are seen at sites on the globin surface, distinguishing the subunit contact residues of hemoglobins from the polar residues on the surface of myoglobins. Moreover, this effect of selection distinguishing between the myoglobin and hemoglobin chain genes becomes weaker in cold-blooded vertebrates, especially in fish, strongly suggesting the possibility that the clear distinction between these globins is a result of selection out of the changes regarded as neutral ones in an ancestor of vertebrates. Thus, the present method may also serve to investigate the homology of many other proteins from the aspect of molecular evolution, mainly focusing on the evolution of their biological functions.

Animals↗
PubMed1996

Evolution of the self-reproducing system to the biosynthesis of the membrane: an approach from the amino acid sequence similarity in proteins.

In order to study the problem of how the biomembrane synthesis started in the evolutionary process of the self-reproducing system, we carry out an extensive similarity search of the sequence data stored in databases, using the acetyl-CoA carboxylase, fatty acid synthase and the enzyme proteins leading to the combination of sn-glycerol 3-phosphate and fatty acid as the query sequences. With the use of the FASTA program (Pearson & Lipman, 1988), the proteins that carry an amino acid sequence showing similarity to any of the query sequences are picked up under the criterion of statistical significance of more than 6.0 for the homology, then classified according to the functional blocks where they operate. Finally they are filtered to the enzyme proteins in the metabolic pathways and to the DNA- or RNA-interacting proteins in the translation, transcription and replication apparatuses by eliminating proteins such as membrane proteins, lipase etc. which seem to have been generated after the appearance of the biomembrane. The distribution of the proteins thus selected shows a clear pattern that the amino acid sequences showing considerable similarity to the biomembrane synthetic proteins are concentrically found in the enzyme proteins in and around the section of glycolytic pathway from glyceraldehyde 3-phosphate to pyruvate while the DNA- or RNA-interacting proteins similar to the query sequences are distributed sparsely over the translation, transcription and replication systems. The assignment of similarity regions ascertains that considerable regions of most biomembrane synthetic proteins are covered by the enzyme proteins in and around the glycolytic pathway. Although acetyl-CoA carboxylase and fatty acid synthase are full of variety in the constitution of active domains depending on species, the above-mentioned pattern is also obtained by using either the monofunctional or the multifunctional type of proteins as the query sequences. Thus, the evolution towards biomembrane synthesis may be positioned as an event following the establishment of a section of glycolytic pathway from glyceraldehyde 3-phosphate to pyruvate. The causality of this evolution from the glycolytic pathway to the biomembrane synthesis is also discussed in connection with the absorption of protons released in the glycolytic process.

Amino Acid Sequence↗
PubMed1996

Evolution of transcriptional regulation system through promiscuous coupling of regulatory proteins with operons; suggestion from protein sequence similarities in Escherichia coli.

As an advanced molecular study of the problems of the evolution of organisms, the transcriptional regulation system is studied by investigating the amino acid sequence similarities between the proteins in the regulation system of Escherichia coli in which the data of sequenced proteins as well as of regulator-regulon relationships are accumulated. The similarities between the proteins are calculated by the FASTA algorithm and their homology is also evaluated in terms of statistical significance with the use of the RDF2 program. This investigation reveals that the similarity between the regulatory protein and the regulated protein is hardly found, but many similarities are found between regulatory proteins and between regulated proteins. These similarity relations are compared with the regulator-regulon relationships ascertained experimentally. From this comparison, it is found that similar regulatory proteins rarely regulate the transcription of similar protein genes. As most of the highly similar proteins are considered to have diverged from a common ancestral protein, this finding strongly suggests the possibility that descendant regulatory proteins have been promiscuously coupled with descendant operons, independently of their ancestral regulator-regulon relationship, and that some of the couplings have been fixed by selection to form the present system of transcriptional regulation. The compatibility of such promiscuous coupling with regulatory organization is illustrated in the carbohydrate transport systems and the succeeding metabolic pathways, whose organization is comprehensive in sending nutritious substances to the central path of glycolysis under different environmental conditions. The benefit of flexibility in regulator-regulon relationships in evolutionary processes is also discussed in connection with the punctuational divergence of species in macroevolution and the cell differentiation in multicellular organisms.

Amino Acid Sequence↗
PubMed1995

A comprehensive representation of extensive similarity linkage between large numbers of proteins.

A method is described for the representation of a bird's-eye view of similarity relationships between large numbers of proteins. With the aid of single-linkage clustering, proteins are clustered into groups on the basis of various types of similarity such as sequence similarity estimated between all the protein pairs. Proteins in a group are directly or indirectly connected to all proteins in the same group by similarities higher than a given threshold and show no similarity higher than the threshold to any proteins outside the group. Thus, all the proteins directly or indirectly related to a protein can be selected out of a large number of proteins by the clustering. Recursion of this clustering of proteins in each group leads to further classification of the proteins. The similarity relationships in each group are visually represented by a similarity matrix. This representation has the advantage of easy detection of the existence of multidomain proteins and diverged families as well as closely related proteins. Such as exhaustive approach to similarity relationships of proteins will be useful for revealing functional/structural/evolutionary units in proteins.

Algorithms↗
PubMed1994

Evolution of genetic information flow from the viewpoint of protein sequence similarity.

As a course of inquiry into the evolution of genetic information flow, similarity relations of amino acid sequences between the proteins involved in translation, transcription and replication are investigated. The sequence data of these proteins are mostly accumulated from Escherichia coli, and the present investigation is carried out mainly on this organism by the FASTP program. This result reveals an interesting similarity linkage extending from ribosomal proteins to the proteins participating in translational elongation process and to the proteins in transcription and replication. Although the ribosomal proteins are of relatively short polypeptide chains, our systematic comparison between these proteins finds many similarity relations, being more than 100 in terms of "overlap", reducing them to about 14 elementary ribosomal proteins from which other ribosomal proteins would have diverged. Moreover, the proteins involved in translation, transcription and replication contain the regions similar to the elementary ribosomal proteins. In particular, some initiation and elongation factors in translation process are assigned to be similar to the elementary ribosomal proteins almost over the whole regions. To such an elongation factor Tu, the alpha and sigma 70 subunits of RNA polymerase and primase also show similarity in the wider regions than the individual ribosomal proteins, and they are shown to be fundamental for the similarity linkage extending to the other polypeptide chains involved in transcription and replication processes, although the latter polypeptide chains contain regions not similar to any ribosomal protein. This divergence pattern of similarity relations strongly suggests that the proteins involved in the contemporary genetic information flow DNA-->RNA-->protein have evolved from some elementary ribosomal proteins, first by gene fusion, in a primitive organism of the RNA-protein world, and then by the addition of the mechanism of domain shuffling from other genes in the DNA-RNA-protein world.

Amino Acid Sequence↗
PubMed1994

A simple procedure for assigning a sequence motif with an obscure pattern: application to the basic/helix-loop-helix motif.

We have developed a simple method to assign a sequence motif with an obscure pattern. Given a multiple sequence alignment for a region of protein that is known or strongly believed to have the same secondary and tertiary structures, the quantification method by principal component analysis is designed to find the regions most likely to have the same structure in a protein outside of the original set. The potential of this newly developed method was evaluated with reference to the known basic/helix-loop-helix (bHLH) motifs, and its characteristics were discussed with four obscure but well-defined motifs and compared with the other methods for searching sequence motifs. The method was also applied to assign the bHLH motif in Epstein-Barr virus nuclear antigen 1 (EBNA-1). This application revealed one candidate for the basic/helix 1 region and two candidates for the helix 2 region in the bHLH motif, within the region from amino acid residues 460 to 600, which is in good agreement with our previous experimental studies on the DNA binding region of EBNA-1. The basic/helix-loop-helix-loop-helix structure thus assigned suggests a function of EBNA-1 which is associated with both replication and transcription.

Amino Acid Sequence↗