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Amyloid fibril formation is associated with various amyloidoses, including neurodegenerative diseases such as Alzheimer's and Parkinson's diseases. Despite the numerous studies on the inhibition of amyloid formation, the prevention and treatment of a majority of amyloid-related disorders are still challenging. In this study, we investigated the effects of various plant extracts on amyloid formation of α-synuclein. We found that the extracts from Eucalyptus gunnii are able to inhibit amyloid formation, and to disaggregate preformed fibrils, in vitro. The extract itself did not lead cell damage. In the extract, miquelianin, which is a glycosylated form of quercetin and has been detected in the plasma and the brain, was identified and assessed to have a moderate inhibitory activity, compared to the effects of ellagic acid and quercetin, which are strong inhibitors for amyloid formation. The properties of miquelianin provide insights into the mechanisms controlling the assembly of α-synuclein in the brain.

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The Cosmic Gems arc is among the brightest and highly magnified galaxies observed at redshift z ≈ 10.2 (ref. 1). However, it is an intrinsically ultraviolet faint galaxy, in the range of those now thought to drive the reionization of the Universe2-4. Hitherto the smallest features resolved in a galaxy at a comparable redshift are between a few hundreds and a few tens of parsecs (pc)5,6. Here we report JWST observations of the Cosmic Gems. The light of the galaxy is resolved into five star clusters located in a region smaller than 70 pc. They exhibit minimal dust attenuation and low metallicity, ages younger than 50 Myr and intrinsic masses of about 106M⊙. Their lensing-corrected sizes are approximately 1 pc, resulting in stellar surface densities near 105M⊙ pc-2, three orders of magnitude higher than typical young star clusters in the local Universe7. Despite the uncertainties inherent to the lensing model, they are consistent with being gravitationally bound stellar systems, that is, proto-globular clusters. We conclude that star cluster formation and feedback likely contributed to shaping the properties of galaxies during the epoch of reionization.

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Upper-limb rehabilitation training for hemiplegic patients has been primarily conducted by human therapists, and, hence, their use of training methods and conditions strongly depends on their expertise. The force control and motion sensing functions of rehabilitation robots are expected to be used for the qualitative training/assessment in the next-generation computerized rehabilitation. In this study, we developed a desktop rehabilitation robot for upper limbs (D-SEMUL). In addition, we also assessed the usability of its user interface and the affinity (acceptance) of the training program with a questionnaire for elderly hemiplegic/non-hemiplegic participants (nine hemiplegic, five males and four females and seven non-hemiplegic, two males and five females). The results indicated that the touchscreen is acceptable for the user interface, and the background music used significantly affects the affinity of the program.

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A fundamental quest of modern astronomy is to locate the earliest galaxies and study how they influenced the intergalactic medium a few hundred million years after the Big Bang1-3. The abundance of star-forming galaxies is known to decline4,5 from redshifts of about 6 to 10, but a key question is the extent of star formation at even earlier times, corresponding to the period when the first galaxies might have emerged. Here we report spectroscopic observations of MACS1149-JD1 6 , a gravitationally lensed galaxy observed when the Universe was less than four per cent of its present age. We detect an emission line of doubly ionized oxygen at a redshift of 9.1096 ± 0.0006, with an uncertainty of one standard deviation. This precisely determined redshift indicates that the red rest-frame optical colour arises from a dominant stellar component that formed about 250 million years after the Big Bang, corresponding to a redshift of about 15. Our results indicate that it may be possible to detect such early episodes of star formation in similar galaxies with future telescopes.

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Upper limb rehabilitation training for Hemiplegie patients has been conducted mainly by human therapists. Training methods and conditions depend strongly on their experience because of the wide range of individual differences between patients. The force control and sensing functions of rehabilitation robots are expected to be used for the qualitative assessment of next-generation computational rehabilitation. In this study, we developed a simple exercise machine for upper limbs (SEMUL) using an electro-rheological fluid brake, as a safe brake-type robotic rehabilitation system. We also developed a new upper limb training/assessment program, called "WIPE," for the SEMUL. Furthermore, we conducted clinical tests on twelve subjects (six each for the SEMUL training and for general training). We adopted the ABA design methodology for the clinical research tests. The motor functions of upper limbs were assessed using five clinical scores: Fugl-Meyer Assessment (FMA), Brunnstrome recovery stage, Simple Test for Evaluating Hand Function (STEF), Stroke Impairment Assessment Set (SIAS), and Motor Activity Log. Improvements of the FMA, STEF, and SIAS in the SEMUL training groups were found to be higher than those in the general training groups.

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The optimal distribution of the reinforcing fibers for stiffening hollow cylindrical composites is explored using the linear elasticity theory. The spatial distribution of the vascular bundles in wild bamboo, a nature-designed functionally graded material, is the basis for the design. Our results suggest that wild bamboos maximize their flexural rigidity by optimally regulating the radial gradation of their vascular bundle distribution. This fact provides us with a plant-mimetic design principle that enables the realization of high-stiffness and lightweight cylindrical composites.

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Fibrodysplasia ossificans progressiva (FOP) is an extremely rare genetic condition characterized by congenital malformation and progressive heterotopic ossification (HO) caused by a recurrent single nucleotide substitution at position 617 in the ACVR1 gene. As the condition progresses, HO leads to joint ankylosis, breathing difficulties, and mouth-opening restriction, and it can shorten the patient's lifespan. This report describes 3 cases of FOP confirmed by genetic testing in patients with restricted mouth opening. Each patient presented a different onset and degree of jaw movement restriction. The anatomic ossification site of the mandibular joint was examined in each patient using reconstructed computed tomographic (CT) images and 3-dimensional reconstructed CT (3D-CT) images. A 29-year-old woman complained of jaw movement restriction since 13 years of age. 3D-CT image of the mandibular joint showed an osseous bridge, formed by the mandibular depressors that open the mouth, between the hyoid bone and the mentum of the mandible. A 39-year-old man presented with jaw movement restriction that developed at 3 years of age after a mouth injury. 3D-CT image of the jaw showed ankylosis of the jaw from ossification of the mandibular depressors that was worse than in patient 1. CT images showed no HO findings of the masticatory muscles. To the authors' knowledge, these are the first 2 case descriptions of the anatomic site of ankylosis involving HO of the mandibular depressors in the jaw resulting from FOP. In contrast, a 62-year-old bedridden woman with an interincisal distance longer than 10 mm (onset, 39 years of age) had no HO of the mandibular depressors and slight HO of the medial pterygoid muscle on the right and left sides. These findings suggest that restricted mouth opening varies according to the presence or absence of HO of the mandibular depressors.

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The physical properties and elemental abundances of the interstellar medium in galaxies during cosmic reionization are important for understanding the role of galaxies in this process. We report the Atacama Large Millimeter/submillimeter Array detection of an oxygen emission line at a wavelength of 88 micrometers from a galaxy at an epoch about 700 million years after the Big Bang. The oxygen abundance of this galaxy is estimated at about one-tenth that of the Sun. The nondetection of far-infrared continuum emission indicates a deficiency of interstellar dust in the galaxy. A carbon emission line at a wavelength of 158 micrometers is also not detected, implying an unusually small amount of neutral gas. These properties might allow ionizing photons to escape into the intergalactic medium.

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Bamboo has a distinctive structure wherein a long cavity inside a cylindrical woody section is divided into many chambers by stiff diaphragms. The diaphragms are inserted at nodes and thought to serve as ring stiffeners for bamboo culms against the external load; if this is the case, the separation between adjacent nodes should be configured optimally in order to enhance the mechanical stability of the culms. Here, we reveal the hitherto unknown blueprint of the optimal node spacings used in the growth of wild bamboo. Measurement data analysis together with theoretical formulations suggest that wild bamboos effectively control their node spacings as well as other geometric parameters in accord with the lightweight and high-strength design concept.

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In kinesin X-ray crystal structures, the N-terminal region of the α-1 helix is adjacent to the adenine ring of the bound nucleotide, while the C-terminal region of the helix is near the neck-linker (NL). Here, we monitor the displacement of the α-1 helix within a kinesin monomer bound to microtubules (MTs) in the presence or absence of nucleotides using site-directed spin labeling EPR. Kinesin was doubly spin-labeled at the α-1 and α-2 helices, and the resulting EPR spectrum showed dipolar broadening. The inter-helix distance distribution showed that 20% of the spins have a peak characteristic of 1.4-1.7 nm separation, which is similar to what is predicted from the X-ray crystal structure, albeit 80% were beyond the sensitivity limit (>2.5 nm) of the method. Upon MT binding, the fraction of kinesin exhibiting an inter-helix distance of 1.4-1.7 nm in the presence of AMPPNP (a non-hydrolysable ATP analog) and ADP was 20% and 25%, respectively. In the absence of nucleotide, this fraction increased to 40-50%. These nucleotide-induced changes in the fraction of kinesin undergoing displacement of the α-1 helix were found to be related to the fraction in which the NL undocked from the motor core. It is therefore suggested that a shift in the α-1 helix conformational equilibrium occurs upon nucleotide binding and release, and this shift controls NL docking onto the motor core.

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We have identified 15 residues from the surface of sarcoplasmic reticulum Ca(2+)-pump ATPase, by mass spectrometry using diethylpyrocarbonate modification. The reactivity of 9 residues remained high under all the conditions. The reactivity of Lys-515 at the nucleotide site was severely inhibited by ATP, whereas that of Lys-158 in the A-domain decreased by one-half and increased by five-fold in the presence of Ca(2+) and MgF(4), respectively. These are well explained by solvent accessibility, pK(a) and nearby hydrophobicity of the reactive atom on the basis of the atomic structure. However, the reactivity of 4 residues near the interface among A-, N- and P-domain suggested larger conformational changes of these domains in membrane upon binding of Ca(2+) (Lys-436), ATP (Lys-158) and MgF(4) (His-5, -190, Lys-436).

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Skeletal muscles are classified into fast and slow muscles, which are characterized by the expression of fast-type myosin heavy chains (fMyHCs) or slow-type myosin heavy chains (sMyHCs), respectively. However, the mechanism of subtype determination during muscle fiber regeneration is unclear. We have analyzed whether the type of muscle is determined in the myoblast cells or is controlled by the environment in which the muscle fibers are formed from myoblast cells. When myoblast cells from 7-day-old chick embryo were cultured and formed into muscle fibers, more than half of the fibers produced only fMyHCs, and the remaining fibers produced both fMyHCs and sMyHCs. However, when myoblast cells were cultured in medium supplemented with a small amount of slow muscle extract, the expression of sMyHCs in muscle fibers increased, whereas the expression of fMyHCs increased in the group supplemented with fast muscle extract compared with the control group. The same results were obtained when cloned mouse myoblast cells (C2C12 cells) were cultured and formed into muscle fibers. The data presented here thus show that the subtype differentiation of muscle fiber is controlled by the environment in which the muscle fiber forms.

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Phthalates are used industrially as plasticizers and are known to contaminate natural environments, mostly as di-ester or mono-ester complexes. Because they are structurally similar to natural estrogens, they could act as endocrine disruptors. Here, we used a DNA microarray containing estrogen responsive genes (EstrArray) to examine gene expression profiles in MCF-7 cells treated with 10 microM butylbenzyl phthalate (BBP), dibutyl phthalate (DBP), diethyl phthalate (DEP), and diisopropyl phthalate (DIP) along with the natural estrogen 17beta-estradiol ([E(2)], 10 nM). The profiles for phthalate esters and E(2) were examined by correlation analysis using correlation coefficients (r-values) and cluster analysis. We found that BBP showed the highest correlation with E(2) (r = 0.85), and DEP and DIP showed moderate r-values (r = 0.52 and r = 0.49, respectively). Dibutyl phthalate exhibited the lowest (but still significant) correlation with E(2) (r = 0.36). Furthermore, among the pairs of chemicals, DEP-DIP and DIP-DBP showed very high correlations (r = 0.90 and r = 0.80, respectively), and the other pairs showed moderate relationships, which reflected how structurally close they are to each other. The analysis of six functional groups of genes (enzymes, signaling, proliferation, transcription, transport, and others) indicated that the genes belonging to the enzyme, transcription, and other functional groups showed common responses to phthalate esters and E(2). Although the effect of BBP was similar to that of E(2), the other phthalate esters showed different types of effects. These results indicate that the structure of estrogenic chemicals is strongly related to their estrogenic activity and can be evaluated by appropriate grouping of the responsive genes by focused microarray analysis.

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Glycyrrhiza glabra root is one of the common traditional Chinese medicines and used as flavoring and sweetening agents for tobaccos, chewing gums, candies, toothpaste and beverages. While glycyrrhizin is one of the main components in the extract of G. glabra root and has been characterized, the other components have not been well characterized. The mechanism of growth activation of breast cancer MCF-7 cells, including the activation of Erk1/2 and Akt, and the transcriptional regulation of estrogen-responsive genes, was examined by means of sulforhodamine B, luciferase reporter gene, real-time RT-PCR and Western blotting assays after the induction of the cells with the extract of G. glabra root. The extract has similar activity to that induced by 17beta-estradiol (E(2)), although glycyrrhizin did not show such an activity. Moreover, the estrogen receptor alpha-dependent neurite outgrowth induced by the extract was similar to that by E(2), whereas glycyrrhizin had no effect. Furthermore, the expression profile examined by cDNA microarray assay using a set of 120 estrogen-responsive genes, which were related to proliferation, transcription, transport, enzymes and signaling, showed a statistically significant correlation (R=0.47, P<0.0001) between the profiles for E(2) and the extract. However, the expression profile for glycyrrhizin was different from that of the extract and E(2). The results indicate that rapid signaling pathways, including Erk1/2 and Akt, and the subsequent transcriptional regulation are involved in the proliferation of MCF-7 cells induced by the extract of G. glabra root. Furthermore, the extract had estrogenic activity and a distinguishable profile of gene expression, suggesting the presence of potentially useful components other than glycyrrhizin in G. glabra root for hormone and anti-cancer therapies.

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Early growth responsive gene 3 (EGR3) is a zinc-finger transcription factor and plays important roles in cellular growth and differentiation. We recently demonstrated estrogen-mediated induction of EGR3 in breast carcinoma cells. However, EGR3 has not yet been examined in breast carcinoma tissues and its significance remains unknown. Therefore, in this study, we examined biological functions of EGR3 in the breast carcinoma by immunohistochemistry, in vitro study, and nude mouse xenograft model. EGR3 immunoreactivity was detected in carcinoma cells in 99 (52%) out of 190 breast carcinoma tissues and was associated with the mRNA level. EGR3 immunoreactivity was positively associated with lymph node status, distant metastasis into other organs, estrogen receptor alpha, or EGR3 immunoreactivity in asynchronous recurrent lesions in the same patients, and was negatively correlated with tubule formation. EGR3 immunoreactivity was significantly associated with an increased risk of recurrence and adverse clinical outcome by both uni- and multivariate analyses. Egr3-expressing transformant cell lines derived from MCF-7 Tet-Off cells (Eg-10 and Eg-11) significantly enhanced the migration and invasion properties according to the treatment of doxycyclin, but did not significantly change the cell proliferation. Moreover, Eg-11 cells injected into athymic mice irregularly invaded into the adjacent peritumoral tissues, although Clt-7, which was stably transfected with empty vector as a control, demonstrated a well-circumscribed tumor. Eg-11 cells were significantly associated with invasive components and less tubule formation in the xenograft model. These results suggest that EGR3 plays an important role in estrogen-meditated invasion and is an independent prognostic factor in breast carcinoma.

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It is important to know the difference as well as the similarity in estrogen responsiveness among cell lines for understanding the effects of estrogenic chemicals. Here, using 120 estrogen responsive genes, we examined comparative expression profiles between the profile in breast cancer MCF-7 cells treated with 17beta-estradiol and the profiles in other cell lines derived from breast (T-47D and HBC-4 cells), endometrium (Ishikawa cells) and kidney (RXF-631L cells) treated with estrogenic chemicals. First, comparative profiling between MCF-7 and T-47D cells showed similar (correlation coefficient or R value=0.49-0.87) profiles for all chemicals examined: 17beta-estradiol, estrone, estriol, diethylstilbestrol, bisphenol A, nonylphenol and genistein. The analysis using other cell lines indicated that significant correlations to the profile in MCF-7 cells treated with 17beta-estradiol were observed for the profiles in Ishikawa cells treated with 17beta-estradiol, diethylstilbestrol and bisphenol A, and HBC-4 cells treated with 17beta-estradiol. The profiles for diethylstilbestrol and bisphenol A in HBC-4 cells and all three chemicals in RXF-631L cells did not show significant correlation with those in MCF-7 cells. Hierarchical cluster analysis revealed that there are cell-specific responses to estrogenic chemicals (T-47D and HBC-4 cells for example). Correlation analysis using six (proliferation, transcription, transport, enzymes, signaling and others) functionally-categorized gene groups indicated that the genes related to enzymes showed greater correlations for all chemicals tested in T-47D cells and some chemicals in Ishikawa and HBC-4 cells while those related to transcription contributed to variations.

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Cardiomyocytes are generated from the precardiac mesoderm and the size of the heart increases dramatically during embryogenesis. However, it is unclear how differentiation and proliferation correlate in the cardiac cell line during development. Here, we show that cardiomyocytes re-entered into a proliferative state after differentiation with a concomitant cell cycle arrest in chick embryo. The cells in the course of differentiation from Isl1-positive cardiac precursors to cardiomyocytes did not proliferate, but differentiated cardiomyocytes proliferated even after the acquisition of contractile function. After differentiation, cardiomyocytes developed a proliferative potential to contribute to the increase in cell numbers during heart development. Almost all differentiated cardiomyocytes (82.8%) incorporated bromodeoxyuridine (BrdU) in vitro, indicating the ability of DNA replication. Furthermore, mitotic chromosomes were observed in the cardiomyocytes in which a sarcomeric structure was sustained in the cytoplasm. We conclude that the sequential events of the differentiation to contractile myocytes and the re-entry into the cell cycle are strictly regulated during cardiac cell maturation. These results provide an insight into the maturation mechanism of the cardiac cell line.

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As inhibitors of bone resorption, bisphosphonates and vitamin D derivatives have been extensively used for the treatment of osteoporosis in various parts of the world, but the clinical effects of these two groups of agents have rarely been compared in detail. A multicenter, prospective, double-blind controlled study was started comparing the effects of etidronate and alfacalcidol (1-alpha-hydroxycholecalciferol) in 414 patients with established osteoporosis from 36 centers. Among these patients, 135 were given 400 mg etidronate daily at bedtime for 2 weeks followed by 10 weeks off treatment, and this cycle was repeated four times along with a placebo indistinguishable from the alfacalcidol capsule daily throughout the 48 weeks of study (Group A, High Dose Etidronate Group). In 133 patients, 200 mg etidronate was used instead of 400 mg (Group B, Low Dose Etidronate Group). In 138 patients, 1 microg alfacalcidol was given daily throughout the 48-week study period along with a placebo indistinguishable from the etidronate tablet in four separate periods of 2 weeks (Group C, Control Group). Dual-energy X-ray absorptiometry of the lumbar spine (L2-L4) was performed before the beginning of the study and every 12 weeks thereafter. Changes in spinal deformity were also assessed based on the lateral thoracic and lumbar spine X-ray films taken before and after the study. The lumbar spine bone mineral density (BMD) changes were +3.4% +/- 0.6% (mean +/- SEM) in Group A, +2.4% +/- 0.5% in Group B, and -0.5% +/- 0.4% in Group C, the former two being significantly higher than the last. New occurrence of spinal compression fracture was also significantly reduced in Group A compared to Group C. In patients without previous fracture at entry, incident fracture was 10.2% in Group C, but 0% in Groups A and B. In patients with prevalent fracture at entry, corresponding figures were 21.5% (Group C), 12.0% (Group A), and 13.2% (Group B), respectively. Alfacalcidol maintained lumbar spine BMD, preventing a decrease for 48 weeks, and etidronate significantly increased it further, demonstrating its usefulness in the treatment of established osteoporosis.

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Little is known about the influence of simple limbectomy on the growth of the acetabulum. An experimental study was carried out in ten monkeys divided into two groups: limbectomy only (Group A) and limbectomy with concomitant cartilage resection (Group B). After three years and four months postoperatively, monkeys were sacrificed. Excised joints were examined macro-and microscopically. Degenerative changes in the cartilage and hypertrophy in the joint capsule were noted in all five monkeys of Group B, and in none of Group A. The diameter of the acetabulum was significantly enlarged in Group B (longitudinal diameter: p<0.05, transverse diameter: p<0.01, Mann-Whitney's U test), compared with Group A and the contralateral hips as controls. There was no other significant difference in other soft tissue or osseous components, between two groups. Histologically, the injured limbus was healed with irregular and sparse fibrous tissue in both groups. Fibrillation in the superficial layer of the cartilage and cluster formation was frequently noted in group B, while normal appearance was noted in Group A. This study demonstrated that simple limbectomy dose not affect the growth of the acetabulum, but may cause degenerative changes if the adjacent acetabular cartilage was simultaneously injured.

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We examined expression profiles of estrogen-responsive genes after treatment with alkylphenols (p-cresol (pC), 4-n-ethylphenol (4EP), 4-n-heptylphenol (4HP), 4-t-octylphenol (4OP) and nonylphenol (NP)), chlorinated phenols (4-chlorophenol (4CP), 4-chloro-3,5-dimethylphenol (CDP), 2,4-dichlorophenol (DCP) and pentachlorophenol (PCP)), parabens (methylparaben (MPB), ethylparaben (EPB) propylparaben (PPB) and butylparaben (BuPB)), or bis- and benzoylphenols (bisphenols A and B and p-hydroxybenzophenone (pHBP)) by means of a DNA microarray assay first to evaluate the estrogenic activity of these chemicals and then to understand the structural basis for the activity. By selecting a set of 120 genes showing greater statistical reliability for estrogen, a more reliable assay for each of the chemicals was achieved and, for the chemicals for which data were available, the results were consistent with those of previously reported estrogen receptor-binding and yeast two-hybrid assays except for chlorinated and few other phenols. Evaluation of the chemicals based on gene function indicated that the genes related to proliferation, transcription and transport were mostly up-regulated while significant numbers of genes related to enzymes and signaling were down-regulated. The genes related to transcription showed the highest degree of variation among the six functional categories (enzymes, signaling, proliferation, transcription, transport and others) for the chemicals with relatively high levels of estrogenic activity. These results indicate that the variations in chemicals and their biological effects can be monitored by the appropriate grouping of estrogen-responsive genes.

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