Alteration of the nucleosomal DNA path in the crystal structure of a human nucleosome core particle

Gene expression in eukaryotes depends upon positioning, mobility and packaging of nucleosomes; thus, we need the detailed information of the human nucleosome core particle (NCP) structure, which could clarify chromatin properties. Here, we report the 2.5 Å crystal structure of a human NCP. The overall structure is similar to those of other NCPs reported previously. However, the DNA path of human NCP is remarkably different from that taken within other NCPs with an identical DNA sequence. A comparison of the structural parameters between human and Xenopus laevis DNA reveals that the DNA path of human NCP consecutively shifts by 1 bp in the regions of superhelix axis location −5.0 to −2.0 and 5.0 to 7.0. This alteration of the human DNA path is caused predominantly by tight DNA–DNA contacts within the crystal. It is also likely that the conformational change in the human H2B tail induces the local alteration of the DNA path. In human NCP, the region with the altered DNA path lacks Mn(2+) ions and the B-factors of the DNA phosphate groups are substantially high. Therefore, in contrast to the histone octamer, the nucleosomal DNA is sufficiently flexible and mobile and can undergo drastic conformational changes, depending upon the environment

Architectures of archaeal GINS complexes, essential DNA replication initiation factors

<p>Abstract</p> <p>Background</p> <p>In the early stage of eukaryotic DNA replication, the template DNA is unwound by the MCM helicase, which is activated by forming a complex with the Cdc45 and GINS proteins. The eukaryotic GINS forms a heterotetramer, comprising four types of subunits. On the other hand, the archaeal GINS appears to be either a tetramer formed by two types of subunits in a 2:2 ratio (α₂β₂) or a homotetramer of a single subunit (α₄). Due to the low sequence similarity between the archaeal and eukaryotic GINS subunits, the atomic structures of the archaeal GINS complexes are attracting interest for comparisons of their subunit architectures and organization.</p> <p>Results</p> <p>We determined the crystal structure of the α₂β₂GINS tetramer from <it>Thermococcus kodakaraensis </it>(<it>Tko</it>GINS), comprising Gins51 and Gins23, and compared it with the reported human GINS structures. The backbone structure of each subunit and the tetrameric assembly are similar to those of human GINS. However, the location of the C-terminal small domain of Gins51 is remarkably different between the archaeal and human GINS structures. In addition, <it>Tko</it>GINS exhibits different subunit contacts from those in human GINS, as a consequence of the different relative locations and orientations between the domains. Based on the GINS crystal structures, we built a homology model of the putative homotetrameric GINS from <it>Thermoplasma acidophilum </it>(<it>Tac</it>GINS). Importantly, we propose that a long insertion loop allows the differential positioning of the C-terminal domains and, as a consequence, exclusively leads to the formation of an asymmetric homotetramer rather than a symmetrical one.</p> <p>Conclusions</p> <p>The DNA metabolizing proteins from archaea are similar to those from eukaryotes, and the archaeal multi-subunit complexes are occasionally simplified versions of the eukaryotic ones. The overall similarity in the architectures between the archaeal and eukaryotic GINS complexes suggests that the GINS function, directed through interactions with other protein components, is basically conserved. On the other hand, the different subunit contacts, including the locations and contributions of the C-terminal domains to the tetramer formation, imply the possibility that the archaeal and eukaryotic GINS complexes contribute to DNA unwinding reactions by significantly different mechanisms in terms of the atomic details.</p

Adaptability and selectivity of human peroxisome proliferator-activated receptor (PPAR) pan agonists revealed from crystal structures

The structures of the ligand-binding domains (LBDs) of human peroxisome proliferator-activated receptors (PPARα, PPARγ and PPARδ) in complexes with a pan agonist, an α/δ dual agonist and a PPARδ-specific agonist were determined. The results explain how each ligand is recognized by the PPAR LBDs at an atomic level

Differences in the motion of typically developing children aged 4–6 years putting on trousers in a standing position

　This study was designed to assess differences in the motion of putting on trousers in a standing position in typically developing children aged 4–6 years, and to find a relation between it and single-leg standing.　Participants in this study were 50 typically developing children (28 boys and 22 girls; 4.5±0.4 years, 5.5±0.3 years, 6.6±0.3 years). They performed two tasks: 10 s single-leg standing and putting on trousers in a standing position.　Based on the motion characteristics, the motions of putting on trousers were classified three types. Compared to types 1 and 2, type 3 showed that participants flexed their trunk, grasped the waistline of the trousers near the support leg knee, and fixed the trousers and extended swing leg to fit the trousers. These motion characteristics decreased the total time, path length, and anterior-posterior（AP）maximum displacement while putting on trousers. Moreover, the age increased as the type changing from 1 to 3. When standing on a single leg, the single-leg standing time increased, as did the path velocity, the AP and medial-lateral direction velocity and maximum displacement decreased as the type changing from 1 to 3.　These results suggested that the three types motion of putting on trousers in a standing position matured by age for typically developing children aged 4–6 years. The types were related with the ability to stand on a single leg

Herbal Medicine Containing Licorice May Be Contraindicated for a Patient with an HSD11B2 Mutation

Licorice ingestion, as well as mutations in the HSD11B2 gene, inhibits 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) enzyme activity, causing the syndrome of apparent mineral corticoid excess (AME). However, the combined effect of licorice ingestion and an HSD11B2 mutation has never been reported, until now. In this study, we demonstrated that licorice ingestion can produce overt hypertension in an individual without medical history of hypertension who is heterozygous for wild-type and mutant HSD11B2 genes. Our patient was a 51-year-old female with serious hypertension who had been taking herbal medicine containing licorice for more than one year. She was clinically diagnosed as having licorice intoxication, because she did not present with hypertension after ceasing the herbal medicine. Molecular analysis showed that she carried a missense mutation, c.40C>T, in HSD11B2. In conclusion, licorice ingestion is an environmental risk factor for hypertension or AME state in patients with a mutation in HSD11B2. Carrying a mutation in HSD11B2 is, conversely, a genetic risk factor for licorice-induced hypertension or AME state. Herbal medicine containing licorice may, therefore, be contraindicated in patients with an HSD11B2 mutation

ハーブで染色したウール織物とその抗菌性

Six herbal plants having various pharmacodynamic effects were dyed as a plant dye on the pre-mordanted wool fabrics. The dyed wool fabrics displayed attractive appearance in color and their color depth was in high levels from medium to deep shade. However their color range was limitted from yellowish brown to brown. Their color fastness was found to be acceptable level for apparel end-uses. Antibacterial activity of the wool fabrics dyed with herbal plant dyes against Staphylococcus aureus(S. aureus)IFO12732 and Escherichia coli. (E. coli.) K12 W3110 were measured by JIS L-1902 Test Method. The antibacterial activity of dyed wool fabrics differed remarkably for every herbal plants. For examples, sage dyed on the aluminium-mordanted fabrics showed bactericidel activities against both S. aureus and E. coli.. However, lavender, thyme and chamomile could not restrain the increase of viable cells. The antibacterial activity of these dyed wool fabrics was not in the acceptable levels as an antibacterial substance

Initial experience with contrast-enhanced ultrasonography in follow up assessment of small breast cancer treated by cryoablation

BackgroundCryoablation (CA) is a nonsurgical focal therapy for small tumours. To detect residual or relapsed tumour after CA of renal cancer, contrast-enhanced imaging is generally used to identify tumour blood flow, but no definitive criteria are established for such follow-up after CA of breast cancer.AimsThe aim of this study was to compare the usefulness of contrast-enhanced ultrasonography (CEUS) and magnetic resonance (MR) imaging for assessing residual tumours and local relapse following CA of small breast cancers.Methods We enrolled 4 patients treated by CA at our institution between January 2015 and December 2016 for luminal A breast cancer with maximum tumour size of 1.5cm and neither distant metastasis nor metastatic findings in sentinel lymph node biopsy, who underwent CEUS and MR imaging before CA. In addition to our standard postoperative follow-up for breast cancer, these patients underwent CEUS every 3 months and MR imaging every 6 months after CA.Results Six months after CA, no patient showed enhancement at the lesion site on MR imaging, but there were two with continued enhancement on CEUS. They underwent vacuum-assisted breast biopsy under US guidance followed by histopathological examination of tissue that identified no malignancy.ConclusionOur findings of focal enhancement within ablated breast tissue in CEUS after CA is likely attributable to the much higher sensitivity of CEUS to that of other modalities to even slight vascularization. Further investigation in more patients is needed to clarify the utility of CEUS to detect residual or relapsed tumour after CA of small breast cancer

Correlation between musculoskeletal structure of the hand and primate locomotion: Morphometric and mechanical analysis in prehension using the cross- and triple-ratios

Biometric ratios of the relative length of the rays in the hand have been analyzed between primate species in the light of their hand function or phylogeny. However, how relative lengths among phalanges are mechanically linked to the grasping function of primates with different locomotor behaviors remains unclear. To clarify this, we calculated cross and triple-ratios, which are related to the torque distribution, and the torque generation mode at different joint angles using the lengths of the phalanges and metacarpal bones in 52 primates belonging to 25 species. The torque exerted on the finger joint and traction force of the flexor tendons necessary for a cylindrical grip and a suspensory hand posture were calculated using the moment arm of flexor tendons measured on magnetic resonance images, and were compared among\ua0Hylobates\ua0spp.,\ua0Ateles\ua0sp., and\ua0Papio hamadryas. Finally, the torques calculated from the model were validated by a mechanical study detecting the force exerted on the phalanx by pulling the digital flexor muscles during suspension in these three species. Canonical discriminant analysis of cross and triple-ratios classified primates almost in accordance with their current classification based on locomotor behavior. The traction force was markedly reduced with flexion of the MCP joint parallel to the torque in brachiating primates; this was notably lower in the terrestrial quadrupedal primates than in the arboreal primates at mild flexion. Our mechanical study supported these features in the torque and traction force generation efficiencies. Our results suggest that suspensory or terrestrial quadrupedal primates have hand structures that can exert more torque at a suspensory posture, or palmigrade and digitigrade locomotion, respectively. Furthermore, our study suggests availability of the cross and triple-ratios as one of the indicators to estimate the hand function from the skeletal structure

Difficult Stones in the Common Bile Duct Successfully Treated by Electrohydraulic Lithotripsy using a Double Lumen Balloon Catheter and Rotating Hemostatic Valve under 180 Degree Revolving X-ray System.

The effectiveness of electrohydraulic lithotripsy (EHL) for stones in the common bile duct (CBD) is well established. It is recommended that the procedure is performed under cholangioscopic control for correct positioning of the probe onto the surface of the stones and prevention of complications arising from contact between the tip of the probe and biliary mucosa. However problems are encountered if insertion of the babyscope into the bile duct is not successful particularly in the presence of duct stenosis or technical difficulties, or when the mother-baby system can not be prepared. For the latter reason, large difficult stones in the CBD were treated by EHL using a double lumen balloon catheter and rotating hemostatic valve (EHLB) under 180 degree revolving X-ray system. The tip of the EHL probe was placed at 2-3 mm out of the balloon catheter, which was used to avoid contact between the tip of the probe and mucosa of the CBD under fluoroscopic control. Rotating hemostatic valve was used to allow examination of the effect of EHL without changing the catheter or pulling out the probe during operation. After endoscopic sphincterotomy, the device was delivered close to the surface of the stone under fluoroscopic guidance. After inflation of the balloon, we confirmed that the tip of the device was set at almost the center of the CBD by 180 degree revolving X-ray system. Partial fragmentation and complete removal of the stones was achieved by combined treatment including EHLB, basket or balloon catheter for stone extraction. There were no serious procedure-related complications