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Toxoplasma gondii is a global protozoan pathogen. Clonal lineages predominate in Europe, North America, Africa, and China, whereas highly recombinant parasites are endemic in South/Central America. Far East Asian T. gondii isolates are not included in current global population genetic structure analyses at WGS resolution. Here we report a genome-wide population study that compared eight Japanese and two Chinese isolates against representative worldwide T. gondii genomes using POPSICLE, a novel population structure analyzing software. Also included were 7 genomes resurrected from non-viable isolates by target enrichment sequencing. Visualization of the genome structure by POPSICLE shows a mixture of Chinese haplogroup (HG) 13 haploblocks introgressed within the genomes of Japanese HG2 and North American HG12. Furthermore, two ancestral lineages were identified in the Japanese strains; one lineage shares a common ancestor with HG11 found in both Japanese strains and North American HG12. The other ancestral lineage, found in T. gondii isolates from a small island in Japan, is admixed with genetically diversified South/Central American strains. Taken together, this study suggests multiple ancestral links between Far East Asian and American T. gondii strains and provides insight into the transmission history of this cosmopolitan organism. The population genome structure of Asian Toxoplasma remains incompletely understood. This study analyzes intercontinental genomic admixture in 17 isolates from Japan and China, providing insights into the evolution of parasites and their impact on public health. [ABSTRACT FROM AUTHOR]

An in-depth examination of rheology within the deep sections of polar ice sheets is essential for enhancing our understanding of glacial flow. In this study, we investigate the crystalline textural properties of the 3035-m-long Antarctic deep ice core, with a particular emphasis on its lowermost 20 %. We examine the crystal orientation fabric (COF) and compare it with various other properties from the ice core. In the uppermost approximately 80 % thickness zone (UP80 %), the clustering strength of single pole COF steadily increased, reaching its possible maximum at the bottom of the UP80 %. Below 1800 m in the UP80 %, layers with more or fewer dusty impurities exhibit slower or faster growth of cluster strength. This situation continued until 2650 m. In the remaining lowermost approximately 20 % thickness zone (LO20 %), the trend of the COF clustering strength changed around 2650 m and exhibited substantial fluctuations below this depth. In more impurity-rich layers, stronger clustering is maintained. In impurity-poor layers, relaxation of the COF clustering occurred due to the emergence of new crystal grains with c -axis orientation distinctly offset from the existing cluster, and dynamic recrystallization related to this emergence. The less impure layers show apparent features of bulging and migrating grain boundaries. We argue that the substantial deformational regime of polar ice sheets involves dislocation creep in both UP80 % and LO20 %, with dynamic recrystallization playing a critical role in the LO20 %, particularly in impurity-poor layers, to recover a potential of COF available for the continuation of dislocation-creep-based deformation. Furthermore, we observe that layers and cluster axes of COF rotate meridionally due to rigid-body rotation caused by simple shear strain above subglacial slopes. These features provide vital clues for the development of the 3D structure of polar ice sheets in the deeper part, leading to inhomogeneous deformation between layers in various thickness scales, and the formation of folds, faults and mixing depending on the layers. [ABSTRACT FROM AUTHOR]

Image-enhanced endoscopy (IEE) allows real-time high-contrast imaging of a targeted lesion without any special equipment. Among various IEE technologies, narrow-band imaging, in which a light of shorter wavelength is used, emphasizes the surface and blood vessel patterns on the mucosal surface. This technology has been widely used in endoscopic diagnosis in the gastrointestinal tract. Red dichromatic imaging (RDI) was recently developed; it utilizes lights of longer wavelengths (520–550, 595–610, and 620–640 nm), which have weak light scattering characteristics in contrast to narrow-band imaging. RDI was designed to enhance the visibility of deep-lying blood vessels and areas of bleeding, and it has been installed in the latest Olympus endoscopy system, EVIS X1, as an advanced version of the optical-digital method that was originally developed. Improving the visibility of deep blood vessels allows more accurate evaluation of esophageal varices and the degree of inflammation in ulcerative colitis. Easier identification of a bleeding source makes hemostasis quicker and easier to accomplish during endoscopic resection procedures such as endoscopic submucosal dissection and peroral endoscopic myotomy as well as during treatment of gastrointestinal bleeding from a peptide ulcer or colon diverticulum. The authors herein review the technological development and principles, review the existing literature on RDI, and discuss the utility and effectiveness of this unique IEE technology in gastrointestinal endoscopy. [ABSTRACT FROM AUTHOR]

Inosine 5′-monophosphate dehydrogenase (IMPDH) is an essential enzyme for the production of guanine nucleotides. Disruption of IMPDH activity has been explored as a therapeutic strategy for numerous purposes, such as for anticancer, immunosuppression, antiviral, and antimicrobial therapy. In the present study, we established a luciferase-based high-throughput screening system to identify IMPDH inhibitors from our chemical library of known bioactive small molecules. The screening of 1400 compounds resulted in the discovery of three irreversible inhibitors: disulfiram, bronopol, and ebselen. Each compound has a distinct chemical moiety that differs from other reported IMPDH inhibitors. Further evaluation revealed that these compounds are potent inhibitors of IMPDHs with kon values of 0.7 × 104 to 9.3 × 104 M−1·s−1. Both disulfiram and bronopol exerted similar degree of inhibition to protozoan and mammalian IMPDHs. Ebselen showed an intriguing difference in mode of inhibition for different IMPDHs, with reversible and irreversible inhibition to each Cryptosporidium parvum IMPDH and human IMPDH type II, respectively. In the preliminary efficacy experiment against cryptosporidiosis in severe combined immunodeficiency (SCID) mouse, a decrease in the number of oocyst shed was observed upon the oral administration of disulfiram and bronopol, providing an early clinical proof-of-concept for further utilization of these compounds as IMPDH inhibitors. [ABSTRACT FROM AUTHOR]

In the asexual stages, Toxoplasma gondii stage converts between acute phase rapidly replicating tachyzoites and chronic phase slowly dividing bradyzoites. Correspondingly, T. gondii differentially expresses two distinct genes and isoforms of the lactate dehydrogenase enzyme, expressing LDH1 exclusively in the tachyzoite stage and LDH2 preferentially in the bradyzoite stage. LDH catalyzes the interconversion of pyruvate and lactate in anaerobic growth conditions and is utilized for energy supply, however, the precise role of LDH1 and LDH2 in parasite biology in the asexual stages is still unclear. Here, we investigated the biological role of LDH1 and LDH2 in the asexual stages, and the vaccine strain potential of deletion mutants lacking LDH1, LDH2, or both genes (Δldh1, Δldh2 and Δldh1/2). Deletion of LDH1 reduced acute parasite virulence, impaired bradyzoite differentiation in vitro, and markedly reduced chronic stage cyst burdens in vivo. In contrast, deletion of LDH2 impaired chronic stage cyst burdens without affecting virulence or bradyzoite differentiation. Deletion of both LDH1 and LDH2 induced a more severe defect in chronic stage cyst burdens. These LDH mutant phenotypes were not associated with any growth defect. Vaccination of mice with a low dose of mutants deleted for LDH elicited effective protective immunity to lethal challenge infection, demonstrating the vaccine potential of LDH deletion mutants. These results suggest that lactate dehydrogenase in T. gondii controls virulence, bradyzoite differentiation, and chronic infection and reveals the potential of LDH mutants as vaccine strains. [ABSTRACT FROM AUTHOR]

The photovoltaic effect of the silicon (Si)/silicon carbide (SiC) quantum dot super lattice (QDSL) and multi-quantum well (QW) strucutres is presented based on numerical simulation and experimental studies. The QDSL and QW structures act as an intermediate layer in a p-i-n Si solar cell. The QDSL consists of a stack of four 4-nm Si nano disks and 2-nm SiC barrier layers embedded in a SiC matrix fabricated with a top-down etching process. The Si nano disks were observed with bright field-scanning transmission electron microscopy. The simulation results based on the 3D finite element method confirmed that the quantum effect on the band structure for the QDSL and QW structures was different and had different effects on solar cell operation. The effect of vertical wave-function coupling to form a miniband in the QDSL was observed based on the solar-cell performance, showing a dramatic photovoltaic response in generating a high photocurrent density Jsc of 29.24 mA/cm2, open circuit voltage Voc of 0.51 V, fill factor FF of 0.74, and efficiency η of 11.07% with respect to a i-QW solar cell with Jsc of 25.27 mA/cm2, Voc of 0.49 V, FF of 0.69, and η of 8.61% and an i-Si solar cell with Jsc of 27.63 mA/cm2, Voc of 0.55 V, FF of 0.61, and η of 10.00%. A wide range of photo-carrier transports by the QD arrays in the QDSL solar cell is possible in the internal quantum efficiency spectra with respect to the internal quantum efficiency of the i-QW solar cell. Copyright © 2015 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Goat farming is important for the livelihood of millions of rural people because it contributes to food security and creation of assets. However, infection of goats with Toxoplasma gondii could be a source of parasite transmission to humans. The information on T. gondii infection of goat was not reported yet in Myanmar. A total of 119 goat serum samples were collected from three cities in the central region of Myanmar for T. gondii antibody survey. With the occurrence value obtained in this first study, a second one, more complete, with larger number (162) of animals and properties, was carried out and the risk factors and prevalence were determined. In both studies the samples were analyzed by the LAT. Of these, 32 (11.4%) samples were showed to be positive. The infection was associated with the presence of cats at the farm (odds ratio [OR] = 4.66, 95% confidential interval [CI] = 1.03–21.06), farming with different animal species (sheep, cattle, and pigs) (OR = 4.33, 95% CI = 1.57–11.94), and farming without good management practices (OR = 0.23, 95% CI = 0.06–0.83). This is the first T. gondii prevalence study in goats in the country. [ABSTRACT FROM AUTHOR]

Background: The glyoxalase pathway, which includes two enzymes, glyoxalase 1 and 2 (Glo1 and Glo2), is a ubiquitous cellular system responsible for the removal of cytotoxic methylglyoxal produced during glycolysis. Protozoan parasites, including Toxoplasma gondii (T. gondii) tachyzoites, produce methylglyoxal because of increased glycolytic fluxes. A Glo1 inhibitor such as curcumin could be considered a drug candidate for anti-protozoan, anti-inflammatory, and anti-cancer therapy. Methods: The T. gondii Glo1 gene (TgGlo1) was cloned and the recombinant protein was produced. Enzyme kinetics of TgGlo1 and five mutants were evaluated by adding methylglyoxal and glutathione to a reaction mixture. Finally, the inhibitory effects of various concentrations of curcumin on recombinant TgGlo1 were evaluated using in vitro cultures of T. gondii. Results: Active recombinant TgGlo1 was successfully produced and the active sites (E166 and E251) of TgGlo1 were verified by point mutagenesis. Curcumin at the tested doses inhibited the enzymatic activity of recombinant TgGlo1 as well as the parasitic propagation of in vitro-cultured T. gondii. The Ki and IC50 were 12.9 ± 0.5 μM and 38.3 ± 0.9 μM, respectively. Conclusion: The inhibitory effect of curcumin on the enzymatic activity of TgGlo1 and parasitic propagation of T. gondii could be explored in the potential development of a potent drug for the treatment of toxoplasmosis. However, considering the fact that curcumin is known to have many effects on other molecules in the micromolar range, further elucidation of curcumin's direct inhibition of the glyoxalase system of T. gondii will be needed. [ABSTRACT FROM AUTHOR]

A sub-10 nm, high-density, periodic silicon nanodisk (Si-ND) array with a SiC interlayer has been fabricated using a new top-down process that involves a 2D array of a bio-template etching mask and damage-free neutral beam etching. Optical and electrical measurements were carried out to clarify the formation of mini-bands due to wavefunction coupling. We found that the SiC interlayer could enhance the optical absorption coefficient in the layer of Si-NDs due to the stronger coupling of wavefunctions. Theoretical simulation also indicated that wavefunction coupling was effectively enhanced in Si-NDs with a SiC interlayer, which precisely matched the experimental results. Furthermore, the I-V properties of a 2D array of Si-NDs with a SiC interlayer were studied through conductive AFM measurements, which indicated conductivity in the structure was enhanced by strong lateral electronic coupling between neighboring Si-NDs. We confirmed carrier generation and less current degradation in the structure due to high photon absorption and conductivity by inserting the Si-NDs into p-i-n solar cells. [ABSTRACT FROM AUTHOR]

We have fabricated GaAs nanodisk (ND) structures by using a combination of neutral beam etching process and atomic hydrogen-assisted molecular beam epitaxy regrowth. We have observed clear photoluminescence (PL) emissions from GaAs NDs. The peak energy showed a blueshift due to the quantum confinement in three spatial dimensions, and it agreed with the theoretically estimated transition energy. The PL results also showed that the cap-layer disks act as radiative recombination centers. We have confirmed that the PL emission originates from the GaAs NDs, and our approach is effective for the fabrication of high quality ND structures. [ABSTRACT FROM AUTHOR]

We study picosecond transient photoluminescence (PL) in Si-nanodisk (Si-ND) arrays fabricated using bio-nano-templates. The PL time profiles show multi-exponential decaying kinetics depending on the disk density. We attribute the fastest decaying component with a decay time of 40 ps observed only in the high-density Si-ND array to the electron transfer among the Si-NDs. [ABSTRACT FROM AUTHOR]

For the last couple of years, a method that permits the collection of precise positional information of transcriptional start sites (TSSs) together with digital information of the gene-expression levels in a high-throughput manner was established. We applied this novel method, ‘tss-seq’, to elucidate the transcriptome of tachyzoites of the Toxoplasma gondii, which resulted in the identification of 124 000 TSSs, and they were clustered into 10 000 transcription regions (TRs) with a statistics-based analysis. The TRs and annotated ORFs were paired, resulting in the identification of 30% of the TRs and 40% of the ORFs without their counterparts, which predicted undiscovered genes and stage-specific transcriptions, respectively. The massive data for TSSs make it possible to execute the first systematic analysis of the T. gondii core promoter structure, and the information showed that T. gondii utilized an initiator-like motif for their transcription in the major and novel motif, the downstream thymidine cluster, which was similar to the Y patch observed in plants. This encyclopaedic analysis also suggested that the TATA box, and the other well-known core promoter elements were hardly utilized. [ABSTRACT FROM PUBLISHER]

The aim of the present study using near-infrared spectroscopy (NIRS) is to evaluate the correlation of cerebral (parieto-temporal lobe) hemoglobin changes and vertiginous sensation during unilateral caloric stimulation. During the hot water (44° C) stimulus, cerebral hemoglobin was increased bilaterally, but it was dominant ipsilaterally. During the unilateral cold water (30° C) stimulus, cerebral hemoglobin was decreased on both sides, especially on the ipsilateral side. Vertigious sensation was strong in cases with marked left-right difference of cerebral hemoglobin changes. The usefulness of NIRS to investigate the relationship between peripheral vestibular organ and vestibular cortex was verified. [ABSTRACT FROM AUTHOR]

Conclusions. A lengthy alteration of gravity direction produced different effects on the intrinsic horizontal and vertical optokinetic oculomotor systems. Objective. To examine both optokinetic nystagmus (OKN) and optokinetic after-nystagmus (OKAN) in a 6 h 6° head-down bedrest study, in which the subjects were kept lying under simulated micro-gravity conditions. Subjects and methods. In six normal healthy adults, we repeatedly (five times) and comparatively studied OKN and OKAN evoked by horizontal and vertical stimuli. Stage 1 was an upright sitting position. During the 6 h bedrest condition, we studied OKN and OKAN in 90° recumbent lateral positions (stages 2, 3, and 4). In stage 5 the subject returned to an upright position. Results. We confirmed that the change in gravity direction had various effects on the condition of OKN and OKAN. Also, we found that it took more than 3 h to reach a desirable level of systemic adaptive modification to the unique environmental condition. We considered that the early change was basically due to the changes in sensory inputs through the otolith organs, and the latter changes represented the adaptive process of the spatial orientation system. During the tilt, the occurrence rates of both horizontal and vertical OKANs were decreased; however, the conditions of these changes were different. [ABSTRACT FROM AUTHOR]

Ice cores from the relatively low-lying ice caps in Svalbard have not been widely exploited in climatic studies owing to uncertainties about the effect of meltwater percolation. However, results from two new Svalbard ice cores, at Lomonosovfonna and Austfonna, have shown that with careful site selection, high-resolution sampling and multiple chemical analyses it is possible to recover ice cores from which part of the annual signals are preserved, despite the considerable meltwater percolation. The new Svalbard ice cores are positioned in different parts of Svalbard and cover the past 800 years. In this paper we focus on the last 400 years. The δ18O signals from the cores are qualitatively similar over most of the twentieth century, suggesting that they record the same atmospheric signal. Prior to AD 1920, the Austfonna ice core exhibits more negative δ18O values than Lomonosovfonna, although there are intermittent decadal-scale periods throughout the record with similar values. We suggest that the differences reflect the effect of the inversion layer during the winter. The pattern in the δ18O records is similar to the Longyearbyen air-temperature record, but on an annual level the correlation is low. The Austfonna record correlates well with the temperature record from the more distant and southwesterly located Jan Mayen. A comparison of the ice-core and sea-ice records from this period suggests that sea-ice extent and Austfonna δ18O are related over the past 400 years. This may reflect the position of the storm tracks and their direct influence on the relatively low-altitude Austfonna. Lomonosovfonna may be less sensitive to such changes and primarily record free atmospheric changes instead of variations in sea-ice extent, the latter is probably a result of its higher elevation. [ABSTRACT FROM AUTHOR]

Two competing models for fibroblast growth factor (FGF) receptor (FGFR) dimerization have recently emerged based on ternary FGF-FGFR-heparin crystal structures. In the symmetric two-end model, heparin promotes dimerization of two FGF-FGFR complexes by stabilizing bivalent interactions of the ligand and receptor through primary and secondary sites and by stabilizing direct receptor-receptor contacts. In the asymmetric model, there are no protein-protein contacts between the two FGF-FGFR complexes, which are bridged solely by heparin. To identify the correct mode of FGFR dimerization, we abolished interactions at the secondary ligand-receptor interaction site, which are observed only in the symmetric two-end model, using site-directed mutagenesis. Cellular studies and real-time binding assays, as well as matrix-assisted laser desorption ionization—time of flight analysis, demonstrate that loss of secondary ligand-receptor interactions results in diminished FGFR activation due to decreased dimerization without affecting FGF-FGFR binding. Additionally, structural and biochemical analysis of an activating FGFR2 mutation resulting in Pfeiffer syndrome confirms the physiological significance of receptor-receptor contacts in the symmetric two-end model and provides a novel mechanism for FGFR gain of function in human skeletal disorders. Taken together, the data validate the symmetric two-end model of FGFR dimerization and argue against the asymmetric model of FGFR dimerization. [ABSTRACT FROM AUTHOR]

We made a tissue phantom with double-peak particle size distribution, which has polystyrene particles of cell nuclear site and mitochondrial size, and measured the spectrum from the tissue phantom using a single optical fiber. In this paper we investigate the characterization method for the tissue phantom with double-peak particle size distribution by comparing the measured spectra with the calculated ones using the Monte Carlo (MC) method. It is first shown that the Mie phase function characterizes better than the Henyey-Greenstein (H-G) phase function in MC calculation. Next, we compare the measurement spectra with those obtained by modeling as single-peak, conventional modelling for particle size distribution, and for double-peak particle size distribution. The single-peak modeling is found to cause considerable error for the tissue phantom with double-peak particle size distribution, which seems to simulate a biological tissue. We suggest that if one simulates the particle size distribution of a biological tissue by conventional modeling, the accuracy of estimation will be lower. [ABSTRACT FROM AUTHOR]

The p53 tumor suppressor gene can induce either apoptosis or a permanent growth arrest (also termed senescence) phenotype in response to cellular stresses. We show that the increase in intracellular reactive oxygen species (ROS) associated with the magnitude of p53 protein expression correlated with the induction of either senescence or apoptosis in both normal and cancer cells. ROS inhibitors ameliorated both p53dependent cell fates, implicating ROS accumulation as an effector in each case. The absence of Bax or PUMA strongly inhibited both p53-induced apoptosis and ROS increase, indicating an important role these p53 targets affecting mitochondrial function genes in p53-mediated ROS accumulation. Moreover, physiological p53 levels in combination with an exogenous ROS source were able to convert a p53 senescence response into apoptosis. All of these findings establish a critical role of ROS accumulation and mitochondrial function in p53-dependent cell fates and show that other ROS inducers can collaborate with p53 to influence these fate decisions. Thus, our studies imply that therapeutic agents that generate ROS are more likely to be toxic for normal cells than p53-negative tumor cells and provide a rationale for identifying therapeutic agents that do not complement p53 in ROS generation to ameliorate the cytotoxic side effects in normal cells. [ABSTRACT FROM AUTHOR]

We directly sequenced PCR fragments amplified from a porcine thyroid cDNA library with various synthetic primers based on the nucleotide sequence of bovine thyrotropin receptor (bTSHR) cDNA. A nucleotide sequence of 2410 bp was determined and its deduced amino acid sequence contained an open reading frame coding 764 amino acids, which showed 91.8% and 89.5% similarity to bTSHR and human TSH receptor, respectively. A hydrophobicity plot of the porcine protein suggested that it had a putative signal peptide and seven transmembrane domains. Chinese hamster ovary cells stably transfected with the cDNA could be specifically bound to bovine TSH (bTSH) and increased the intracellular cAMP level in response to bTSH and Graves' disease patients' sera stimulation. Clin Chem Lab Med 2003; 41(6):796-803. [ABSTRACT FROM AUTHOR]

Binding specificity between fibroblast growth factors (FGFs) and their receptors (FGFRs) is essential for mammalian development and is regulated primarily by two alternatively spliced exons, IIIb ("b") and IIIc ("c"), that encode the second half of Ig-like domain 3 (D3) of FGFRs. FGF7 and FGF10 activate only the b isoform of FGFR2 (FGFR2b). Here, we report the crystal structure of the ligand-binding portion of FGFR2b bound to FGF10. Unique contacts between divergent regions in FGF10 and two b-specific loops in D3 reveal the structural basis by which alternative splicing provides FGF10-FGFR2b specificity. Structure-based mutagenesis of FGF10 confirms the importance of the observed contacts for FGF10 biological activity. Interestingly, FGF10 binding induces a previously unobserved rotation of receptor Ig domain 2 (D2) to introduce specific contacts with FGF10. Hence, both D2 and D3 of FGFR2b contribute to the exceptional specificity between FGF10 and FGFR2b. We propose that ligand-induced conformational change in FGFRs may also play an important role in determining specificity for other FGF-FGFR complexes. [ABSTRACT FROM AUTHOR]

Objective assessment of gastrointestinal mucosal color is extremely important in the endoscopic diagnosis of digestive tract disease. In this paper, we propose a method to clarify the spectral characteristics of gastric and colon cancer. A large number of spectral reflectance data of mucous membrane are measured by the endoscopic spectroscopy system (ESS) in the National Cancer Center Hospital East, Kashiwa, Japan and the Department of Internal Medicine, SelfDefense Force Center Hospital, Tokyo, Japan. We assume that early cancer appears primarily in the spectral data of short wavelength, because it is usually present in a superficial cell where short wavelength light is scattered more strongly than long wavelength light. To identify the features in the short wavelength components, the spectral reflectance was divided by the reflectance of a long wavelength. We investigated the possibility of distinguishing early cancer from normal spectral data through statistical analysis, employing the projection axis as the mean difference between them. Early cancer and normal spectral data were projected on the projection axis, and the Student's T-test was applied to evaluate the mean of the distribution between these data. [ABSTRACT FROM AUTHOR]

The cyclin-dependent kinase (CDK) inhibitor p21Waf1/CiP1/Sdi1 was identified initially as a gene induced in senescent cells and itself has been shown to cause permanent growth arrest/senescence. Reactive oxygen species (ROS), a byproduct of oxidative processes, can also induce an irreversible growth arrest similar to senescence. Here we show that p21 increased intracellular levels of ROS both in normal fibroblasts and in p53-negative cancer cells. N-acetyl-L-cysteine, an ROS inhibitor, rescued p21-induced senescence, showing that ROS elevation is necessary for induction of the permanent growth arrest phenotype. p16Ink4a, a CDK4- and CDK6-specific inhibitor, failed to increase ROS levels, and cell cycle arrest induced by p16 was reversible following its down-regulation, demonstrating the specificity of this p21 effect. A p21 mutant that tacked the ability to bind proliferating cell nuclear antigen (PCNA) retained the ability to induce both ROS and permanent growth arrest. All of these findings establish that p21 mediates senescence by a mechanism involving ROS accumulation which does not require either its PCNA binding or the CDK inhibitory functions shared with p16. [ABSTRACT FROM AUTHOR]

The localization of Ca2+-ATPase activity was examined ultracytochemically in the endolymphatic sac (ES) of the 1-day-old chick. The reaction products showing Ca2+-ATPase activity were localized along the microvilli and the apical cell membranes of the epithelial cells of the ES. The lateral cell membranes also showed mild activity. These reactions were completely abolished when either Ca2+ or ATP was omitted from the incubation medium. The results suggest that Ca2+-ATPase plays a significant role as a Ca2+ pump for regulation of the Ca2+ concentration in the endolymph of the ES. [ABSTRACT FROM AUTHOR]

The human homologue of fz1 (Hfz1) was cloned from a cDNA library. Hfz1 was shown to couple to Wnt signal transduction pathways by its ability to enhance Wnt induced TCF dependent transcription in both autocrine and paracrine modes. Enhanced TCF dependent signaling was dose dependent with respect to both Wnt-3A and Hfz1. Moreover, Hfz1 deletion mutants with truncated carboxy termini showed markedly reduced capacity to enhance Wnt signal transduction. Specificity was demonstrated with respect to signal transduction by different Wnts. While Wnt-3a, -3, -1 and to a lesser extent Wnt-2 cooperated with Hfz1 in the paracrine assay for TCF dependent signaling, neither Wnt-4, -5a, -5b, -6, -7a nor -7b did so, despite similar levels of expression. However, coimmunoprecipitation of Hfz1 with both Wnt-3a and Wnt-5a indicated that TCF dependent signaling in response to Wnts is not determined solely by their ability to bind the receptor. All of these findings provide strong evidence that Hfz1 is a functional partner for certain Wnts in inducing TCF dependent transcription. [ABSTRACT FROM AUTHOR]

We have shown previously that wild type p53 can rapidly induce replicative senescence in EJ human bladder carcinoma cells lacking functional p53. A major effector of p53 functions is p21Waf1/Cip1/Sdi1, a potent cyclin-dependent kinase inhibitor. p21Waf1/Cip1/Sdi1 has been shown to be involved in both p53 dependent and independent control of cell proliferation, differentiation and death. To directly investigate the effects of p21Waf1/Cip1/Sid1 in the p53 response observed in EJ tumor cells, we established p21Waf1/Cip1/Sdi1 inducible lines using the tetracycline-regulatable vector system. p21Waf1/Cip1/Sdi1 induction caused irreversible cell cycle arrest in both G1 and G2/M, and diminished Cdk2 kinase activity. In addition, p21Waf1/Cip1/Sdi1 induction led to morphological alterations characteristic of cells undergoing replicative senescence with morphological, biochemical and ultrastructural markers of the senescent phenotype. Furthermore, sustained p21Waf1/Cip1/Sdi1 induction sensitized EJ cells to apoptotic cell death induced by mitomycin C, a cross-linking DNA damaging agent. These findings support the function of p21Waf1/Cip1/Sdi1 as an inducer of replicative senescence and a major mediator of this phenomenon in response to p53. Moreover, our results imply that therapeutic intervention in human cancers might be aimed at sustained elevation of p21Waf1/Cip1/Sdi1 expression. [ABSTRACT FROM AUTHOR]

We used light microscopy to study 87 human temporal bones (from 47 cases) with no known otological disorders, and found that certain cases had sclerotic changes around the endolymphatic duct and sac. Changes included fibrosis, hyalinization, psammoma formation, and thickened vascular walls. The findings were subjected to statistical analysis, which indicated that most of the changes could be positively correlated with increases in age. [ABSTRACT FROM AUTHOR]

The effect of the chronic administration of diazepam on vestibular compensation (post-unilateral labyrinthectomy) was studied in squirrel monkeys. An intramuscular injection of diazepam (2 mg/kg) was given daily for a period of 4 weeks post-operatively. After daily injection, reduction of the slow-phase eye velocity (SPEV) of spontaneous nystagmus and enhancement of locomotor body dysequilibrium were found in the early post-operative stage. However, these pharmacological effects decreased gradually and almost no remarkable effect was found about 3 weeks after surgery. When compared to control animals, no marked differences was found in SPEV reduction of spontaneous nystagmus in injected animals during the vestibular compensation period. Platform runway tests showed that the average number of calendar days needed to regain the pre-operative level of locomotor balance function in the group injected with diazepam was even less than that of the control group. Thus, post-operative daily diazepam injections did not retard the vestibular compensation. The possible neural mechanism responsible for this phenomenon is discussed. [ABSTRACT FROM AUTHOR]

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The present experimental results in squirrel monkeys indicated that the performance of psycho-physically advanced locomotor task (squirrel monkey rail test) was severely impaired after the placement of the medium to relatively large surgical lesions in the unilateral vestibular nuclei area, and therefore, confirmed that this brain-stem structure is essential for the signal relay and/or input coordination. The severest locomotor disability was found 10-14 days after the surgery; thereafter, squirrel monkeys showed very gradual and only limited degree of performance recovery. The post-ablative performance levels were no better than 1/5 of their pre-ablative performance levels. [ABSTRACT FROM AUTHOR]

Simultaneous application of the rotatory stimulus with a constant angular acceleration (1∘/sec) did not clearly improve the optokinetic pursuing ability in squirrel monkeys, even though the directions of vestibular and visual stimuli matched. When the directions of vestibular stimulus and visual stimulus conflicted, the optokinetic pursuing ability markedly declined regardless of the stimulus magnitude. The inter-individual difference was large in that situation. For the vestibular-visual coordination, the active head movement condition is considered to be natural and important as a biological function. [ABSTRACT FROM AUTHOR]

Damped pendular rotation nystagmus was studied in squirrel monkeys before and after otolith end organ ablation (two-stage operations). After each operation, the nystagmic slow phase eye speed toward the operated side was reduced (to about 73% of that before the operation) and that to the nonoperated side did not show any marked change. A few subjects showed spontaneous nystagmus with amphetamine administration but only in dark (could not be found in light) immediately after the operation, and it disappeared rapidly. Therefore, this post-ablative reduction of the slow phase eye speed is considered to result from the loss of inputs from the otolith end organs. [ABSTRACT FROM AUTHOR]

Vestibular end organ mapping (surface preparation) was performed in squirrel monkeys by using succinic dehydrogenase staining. Comparing sensory hair cell counts and surface area measurements of the squirrel monkey to those of man and the guinea pig, the values obtained from the squirrel monkey were between those of man and the guinea pig. When regional (central versus peripheral) cell density was compared, the density of the peripheral area was 1.62 × more on the average than that of the central portion. [ABSTRACT FROM AUTHOR]