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Biomedical subjects

Hiroyuki Sasaki

Publications and source records attributed to Hiroyuki Sasaki.

At least 55 records · Page 3Linked to original sources

Cross-bridge number, position, and angle in target zones of cryofixed isometrically active insect flight muscle.

Electron micrographic tomograms of isometrically active insect flight muscle, freeze substituted after rapid freezing, show binding of single myosin heads at varying angles that is largely restricted to actin target zones every 38.7 nm. To quantify the parameters that govern this pattern, we measured the number and position of attached myosin heads by tracing cross-bridges through the three-dimensional tomogram from their origins on 14.5-nm-spaced shelves along the thick filament to their thin filament attachments in the target zones. The relationship between the probability of cross-bridge formation and axial offset between the shelf and target zone center was well fitted by a Gaussian distribution. One head of each myosin whose origin is close to an actin target zone forms a cross-bridge most of the time. The probability of cross-bridge formation remains high for myosin heads originating within 8 nm axially of the target zone center and is low outside 12 nm. We infer that most target zone cross-bridges are nearly perpendicular to the filaments (60% within 11 degrees ). The results suggest that in isometric contraction, most cross-bridges maintain tension near the beginning of their working stroke at angles near perpendicular to the filament axis. Moreover, in the absence of filament sliding, cross-bridges cannot change tilt angle while attached nor reach other target zones while detached, so may cycle repeatedly on and off the same actin target monomer.

Actins↗

De novo DNA methylation is dispensable for the initiation and propagation of X chromosome inactivation.

Xist (X-inactive specific transcript) plays a crucial role in X-inactivation. This non-coding RNA becomes upregulated on the X chromosome that is to be inactivated upon differentiation. Previous studies have revealed that although maintenance-type DNA methylation is not essential for X-inactivation to occur, it is required for the stable repression of Xist in differentiated cells. However, it is unknown whether differential de novo methylation at the Xist promoter, which is mediated by Dnmt3a and/or Dnmt3b, is a cause or a consequence of monoallelic expression of Xist. We show that Xist expression is appropriately regulated in the absence of Dnmt3a and Dnmt3b and that a single X chromosome undergoes proper inactivation in mutant females. Our results indicate that a mechanism(s) other than DNA methylation plays a principal role in initiating X-inactivation. We also demonstrate that delayed upregulation of Xist does not induce X-inactivation, consistent with a crucial developmental window for the chromosomal silencing.

Animals↗

Claudins in Caenorhabditis elegans: their distribution and barrier function in the epithelium.

Claudins ( approximately 23 kDa) with four transmembrane domains are major cell adhesion molecules working at tight junctions in vertebrates, where the intercellular space is tightly sealed (reviewed in ). We examined here the possible occurrence of claudin-like proteins in invertebrates, which do not bear typical tight junctions. Close blast searching of the C. elegans genome database identified four claudin-related, approximately 20-kDa integral membrane proteins (CLC-1 to -4), which showed sequence similarity to the vertebrate claudins. The expression and distribution of CLC-1 was then examined in detail by GFP technology as well as by immunofluorescence microscopy. CLC-1 was mainly expressed in the epithelial cells in the pharyngeal region of digestive tubes and colocalized with AJM-1 at their intercellular junctions. Then, to examine the possible involvement of CLC-1 in the barrier function, we performed RNA interference in combination with a tracer experiment: in CLC-1-deficient worms, the barrier function of the pharyngeal portion of the digestive tubes appeared to be severely affected. CLC-2 was expressed in seam cells in the hypodermis, and it also appeared to be involved in the hypodermis barrier. These findings indicated that multiple species of the claudin homologs, which are involved in the barrier function of the epithelium, exist in C. elegans.

Amino Acid Sequence↗

Genomic organization and promoter analysis of the Dnmt3b gene.

The Dnmt3b gene encodes a de novo DNA methyltransferase that is essential for normal mouse development. It is highly expressed in early embryos and embryonic stem (ES) cells but downregulated in most adult somatic tissues. To gain insight into the regulation of Dnmt3b, we have isolated a mouse genomic bacterial artificial chromosome clone that contains the Dnmt3b gene. Complete sequence analysis of the clone demonstrated that Dnmt3b consists of at least 24 exons and spans 38 kilobases. S1 nuclease analysis identified two adjacent transcriptional start sites located downstream of a unique TATA-like element in a CpG island. There was an unknown gene which we named mU(3) 17 kb upstream of the Dnmt3b locus, and it was transcribed ubiquitously and in the opposite direction of Dnmt3b. Transfection analysis revealed that the minimal promoter region containing an Sp1 site was active even in somatic cells, and that there were several repressor elements within 7.9 kb upstream of Dnmt3b downregulated this gene specifically in somatic cells but not in ES cells. These findings provide a basis for future detailed studies of the mechanisms controlling Dnmt3b expression.

3T3 Cells↗

Size-selective loosening of the blood-brain barrier in claudin-5-deficient mice.

Tight junctions are well-developed between adjacent endothelial cells of blood vessels in the central nervous system, and play a central role in establishing the blood-brain barrier (BBB). Claudin-5 is a major cell adhesion molecule of tight junctions in brain endothelial cells. To examine its possible involvement in the BBB, claudin-5-deficient mice were generated. In the brains of these mice, the development and morphology of blood vessels were not altered, showing no bleeding or edema. However, tracer experiments and magnetic resonance imaging revealed that in these mice, the BBB against small molecules (<800 D), but not larger molecules, was selectively affected. This unexpected finding (i.e., the size-selective loosening of the BBB) not only provides new insight into the basic molecular physiology of BBB but also opens a new way to deliver potential drugs across the BBB into the central nervous system.

Animals↗

Tocolytic effects of formoterol are associated with local change in the progesterone/estradiol ratio.

OBJECTIVE: The aim of the study was to determine whether a beta(2)-adrenoceptor agonist, formoterol, inhibits premature delivery in connection with change in estradiol and progesterone concentrations in the amniotic fluid in ovariectomized rats. STUDY DESIGN: Pregnant rats at the 15th day of gestation were bilaterally ovariectomized and given injection of 17beta-estradiol immediately after the operation and every 24 h. An osmotic pump filled with a solution of formoterol or saline was also implanted subcutaneously into the back of each. The animals were killed by decapitation under light ether anesthesia 18, 36, 54 or 72 h after ovariectomy, and the numbers of undelivered fetuses and newborn were counted. Amniotic fluid was collected 16, 36, and 54 h after ovariectomy. RESULTS: Formoterol (0.15 mg/(kg h)) reversed the decline in premature delivered fetuses due to 17beta-estradiol 54 and 72 h after ovariectomy. Although no influence was evident regarding the progesterone and estradiol concentrations in amniotic fluid in ovariectomized rats supplemented with 17beta-estradiol, formoterol significantly inhibited the increment in the estradiol/progesterone ratio as well as the elevation in prostaglandin F2alpha concentration. CONCLUSION: These findings indicate that tocolytic effects of formoterol may be associated with suppression of uterine activity due to modulation of hormone secretion.

Adrenergic beta-Agonists↗

Dynamic behavior of paired claudin strands within apposing plasma membranes.

The tight junction (TJ) strand is a linear proteinaceous polymer spanning plasma membranes, and each TJ strand associates laterally with another TJ strand in the apposing membranes of adjacent cells to form "paired" TJ strands. Claudins have been identified as the major constituents of TJ strands, and when exogenously expressed in L fibroblasts, they polymerize into paired strands, which are morphologically similar to paired TJ strands in epithelia. Here, we show that a fusion protein of GFP with claudin-1 can also form similar paired strands in L fibroblasts, allowing us to directly observe individual paired claudin strands in live cells in real time. These paired strands showed more dynamic behavior than expected; they were occasionally broken and annealed, and dynamically associated with each other in both an end-to-side and side-to-side manner. Through this behavior of individual paired claudin strands, the network of strands was reorganized dynamically. Furthermore, fluorescence recovery after photobleaching analyses revealed that claudin molecules were not mobile within paired strands. Although these observations are not necessarily representative of TJ strands per se in epithelial cells, they provide important information on the structural and kinetic properties of TJ strands in situ with significant implications for barrier function of TJs.

Animals↗

Expression of claudin-5 in dermal vascular endothelia.

Claudins and occludin are integral membrane proteins at tight junctions (TJs). We examined subcellular localization of claudin-5 and occludin in dermal vascular endothelia. Immunofluorescence staining showed that claudin-5 was expressed at the cell-cell border of dermal vascular endothelia in mouse skin. However, in some dermal vessels, claudin-5 expression was markedly decreased or absent in amount by double-immunofluorescence stainings with PECAM-1 and PAL-E. In contrast, occludin was not detected in dermal vessels. Freeze-fracture and immunoreplica electron microscopy on primary-cultured human dermal endothelial cells showed that claudin-5 was localized at tight junctions. These findings confirmed that TJs in dermal vascular endothelial cells are composed of claudin-5.

Animals↗

Appropriate cut-off value of 13C-urea breath test after eradication of Helicobacter pylori infection in Japan.

BACKGROUND AND AIM: A cut-off value of 2.5 per thousand for the 13C-urea breath test (UBT) is recommended in Japanese persons, based on the result of a multicenter trial in patients prior to treatment for eradication of Helicobacter pylori. The cut-off value of 2.5 per thousand has also been used in the assessment of eradication after treatment. The 6-8-week evaluation after treatment is recommended in the guidelines of the Japanese Society of Gastroenterology. The present study aimed to prospectively re-assess the cut-off value of the 13C-UBT at 6 weeks after treatment by using the results obtained at 6 months as an indication of true positive or true negative H. pylori infection status. METHODS: One hundred and ninety patients who were positive for H. pylori underwent eradication treatment, and 177 patients of these patients who were assessed as having true positive or true negative H. pylori status at 6 months after treatment were evaluated in this study. Eradication was assessed by 13C-UBT, culture, and histology at 6 weeks and at 6 months after treatment, and the cut-off value of 13C-UBT at 6 weeks was re-assessed. RESULTS: A cut-off value of 3.5 per thousand. at 6 weeks after treatment showed 97.2% diagnostic accuracy, while a cut-off value of 2.5 per thousand at 6 weeks showed 96.0% diagnostic accuracy. For a 3.5 per thousand cut-off value, only five patients were positive by 13C-UBT and were negative by culture and histology at 6 weeks, and three patients were true positive and two were false positive by the 13C-UBT at 6 months. CONCLUSION: A cut-off value of 3.5 per thousand for the 13C-UBT is recommended at 6 weeks after eradication treatment in Japanese persons.

Adult↗

The origin and genetic relationships of the Baikal seal, Phoca sibirica, by restriction analysis of mitochondrial DNA.

The origin and genetic relationships of the Baikal seal, Phoca sibirica, were studied by restriction fragment length polymorphism analysis of mitochondrial DNA (mtDNA). Using 17 different six-base recognition restriction endonucleases, we examined 98 Baikal seals, and two other related species, the ringed seal, P. hispida, (n=87), and the Caspian seal, P. caspica, (n=94). Analysis revealed the existence of 87 mtDNA haplotypes in the total of 279 specimens. The haplotypes of each species were divided into different clusters on a dendrogram obtained by UPGMA based on haplotype frequency and mtDNA base substitution. No common haplotypes were found among the species examined. The Baikal seal is much more closely related to the ringed seal than the Caspian seal. The amount of divergence suggested that an ancestor of the Baikal seal came down to the lake approximately 0.4 million years ago as was previously indicated by paleontological studies. The seals examined here showed lower variabilities.

Analysis of Variance↗

Three novel DNMT3B mutations in Japanese patients with ICF syndrome.

ICF syndrome is a rare autosomal recessive disorder characterized by immunodeficiency, centromeric instability, and facial anomalies. It is caused by mutations in a de novo DNA methyltransferase gene, DNMT3B. We here report the first three Japanese cases of ICF syndrome from two unrelated families. All patients had typical facial dysmorphism and immunoglobulin A (IgA) deficiency, but none of them had apparent mental retardation. Cytogenetic analysis of peripheral blood lymphocytes showed chromosomal abnormalities, including multiradial configurations and a stretching of the pericentromeric heterochromatin of chromosomes 1 and 16. Hypomethylation of classical satellite 2 DNA was also observed. Mutation analyses of DNMT3B revealed three novel mutations: patient 1 from the first family was a compound heterozygote for a nonsense mutation (Q42Term) and a missense mutation (R832Q); patients 2 and 3 from the second family were both homozygous for a missense mutation (S282P). The R832Q mutation occurred within the conserved methyltransferase domain, and thus may affect the enzyme activity directly. The S282P mutation, on the other hand, occurred close to the PWWP domain, which is presumably involved in protein-protein interaction. This is the first missense mutation mapped to the N-terminal half of the protein, suggesting that the region plays an important role in the regulation of the DNMT3B enzyme.

Adult↗

Paternal UPD14 is responsible for a distinctive malformation complex.

We present a boy and two girls with paternal uniparental disomy of chromosome 14q (patUPD14). One girl had a Robertsonian translocation, whereas two a normal karyotype. Based on the manifestations of these patients and four previously reported patients who all had translocated chromosome 14, The patUPD14 was thought to constitute a distinctive syndrome. The hallmarks included abdominal muscular defects, skeletal anomalies, and characteristic facies. The phenotype of patUPD14 was consistent with that of a previously reported mouse model, i.e., mouse embryos with paternal uniparental disomy of chromosome 12 that has a region orthologous to that of human chromosome 14. Dose effects of newly recognized imprinted genes on human chromosome 14q32, DLK1 and GTL2, could play an important role in the pathogenic mechanism of the distinctive malformation complex.

Abnormalities, Multiple↗

An evolutionarily conserved putative insulator element near the 3' boundary of the imprinted Igf2/H19 domain.

Igf2 and H19 are closely linked imprinted genes lying at the centromeric end of a 1 Mb imprinted domain on mouse chromosome 7. L23mrp and other genes located 3' (more centromeric) to H19 are not imprinted and do not interact with the enhancers shared by Igf2 and H19. It is therefore suggested that the intergenic region between H19 and L23mrp contains a boundary or an insulator element. We have identified a binding site for CTCF, a nuclear factor that mediates insulator activity in vertebrates, in the intergenic region. This site is conserved between human and mouse, associated with a major DNase I-hypersensitive site, and bound by CTCF in vivo. Functional assays using reporter constructs demonstrated that this element functions as an insulator in transfected cells. The findings suggest that this CTCF site contributes to the 3' boundary of this imprinted domain. Together with the findings on the differentially methylated CTCF sites 5' to H19, CTCF-dependent insulators may not only regulate but also delimit the imprinted domain.

3' Flanking Region↗

Unregulated expression of the imprinted genes H19 and Igf2r in mouse uniparental fetuses.

The present study shows that the H19 and Igf2r genes, which are imprinted and expressed solely from maternal alleles, are expressed in an unregulatable manner in mouse uniparental, androgenetic, and parthenogenetic fetuses at day 9.5 of gestation. In the androgenetic fetuses, the H19 and Igf2r genes were respectively expressed at 12 and 40% of the levels in biparental fetuses. In addition, the expression of both genes was excessive (1259 and 482%, respectively) in the parthenotes. These expressions of the imprinted genes were not regulated by methylation in the regulatory regions. Moreover, the expression of the antisense Igf2r RNA (Air) was also excessive and was not correlated with Igf2r gene expression in the uniparental fetuses. Taken together, these results indicate that the parental specific expression of imprinted genes is not maintained in particular genes in uniparental embryos, which in turn suggests that both parental genomes are required to establish maternal specific expression of the H19 and Igf2r genes by trans-acting mechanisms.

Alleles↗

Molecular architecture of tight junctions of periderm differs from that of the maculae occludentes of epidermis.

Occludin and claudins are tetraspan-transmembrane proteins in tight junctions. Maculae occludentes, which are less-developed tight junctions, occur in the granular cell layer of the epidermis. The periderm, which overlies the developing epidermis and functions as a protective layer for the embryo, carries developed tight junctions as observed in simple epithelia. In both periderm and epidermis, occludin is expressed at the cell-cell border. To determine the difference between tight junctions of periderm and epidermis, claudin-6 expression was examined in periderm and epidermis. Immunofluorescence staining showed claudin-6 expression at the cell-cell border of the periderm, but not in the epidermis. Reverse transcription-polymerase chain reaction confirmed that claudin-6 was not expressed in mouse adult skin, whereas immunoelectron microscopy revealed that claudin-6 was localized at tight junctions of the periderm. Furthermore, L fibroblasts with stable expression of exogenous claudin-6 formed developed tight junctions at cell-cell borders. These findings indicate that molecular architecture of tight junctions of the periderm is different from that of the maculae occludentes of the epidermis, and that claudin-6 is important in the formation of tight junctions of the periderm.

Animals↗

Selective attention to stimulus features modulates interocular suppression.

Psychological and neurophysiological studies have shown that attention modulates various sorts of perceptual processing. Here, we report that attention affects the perceptual dominance of binocular rivalry. Experiments using a dichoptic masking paradigm revealed that when an observer was attending to one of the two orientations of the elements of a monocular texture, a texture briefly presented to the opposite eye suppressed the perception of the elements with the attended orientation, while the elements with the orientation which was ignored sustained their dominance. Moreover, subsequent experiments indicated that the suppression depended on the orientation of the texture elements constituting the mask, but was independent of their locations. These results suggest that attention to specific features modulates interocular suppression in a mode which is different from that found in a previous study [Ooi and He, 1999 Perception 28 551 -574].

Attention↗

Disruption of mesodermal enhancers for Igf2 in the minute mutant.

The radiation-induced mutation minute (Mnt) in the mouse leads to intrauterine growth retardation with paternal transmission and has been linked to the distal chromosome 7 cluster of imprinted genes. We show that the mutation is an inversion, whose breakpoint distal to H19 disrupts and thus identifies an enhancer for Igf2 expression in skeletal muscle and tongue, and separates the gene from other mesodermal and extra-embryonic enhancers. Paternal transmission of Mnt leads to drastic downregulation of Igf2 transcripts in all mesodermal tissues and the placenta. Maternal transmission leads to methylation of the H19 differentially methylated region (DMR) and silencing of H19, showing that elements 3' of H19 can modify the maternal imprint. Methylation of the maternal DMR leads to biallelic expression of Igf2 in endodermal tissues and foetal overgrowth, demonstrating that methylation in vivo can open the chromatin boundary upstream of H19. Our work shows that most known enhancers for Igf2 are located 3' of H19 and establishes an important genetic paradigm for the inheritance of complex regulatory mutations in imprinted gene clusters.

Animals↗