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Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the a2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2,encoding the GlyR a2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2?ex8–9). Here, we sequenced 400 males with ASD and identified one de novomissense mutation, p.R153Q, absent from controls. In vitrofunctional analysis demonstrated that the GLRA2?ex8–9protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novomissense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2?ex8–9or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2in non-syndromic ASD, unveil a novel role for GLRA2in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.

Background: Two-dimensional speckle tracking imaging allows noninvasive measurement of left ventricular (LV) strain, rotation, and displacement. We investigated whether LV twist would be depressed in anterior wall myocardial infarction (MI) as a result of reduced apical rotation. Methods: Basal and apical LV short-axis images were acquired in 30 patients with anterior wall MI. Using commercially available 2-dimensional strain software, time domain speckle tracking was performed, and regional LV strain, rotation, and radial displacement were obtained in each plane. LV twist was defined as apical LV rotation relative to the base. Patients were divided into two groups according to global LV systolic function (normal LV ejection fraction [LVEF] group [LVEF >= 45%, n = 16] and abnormal LVEF group [LVEF < 45%, n = 14]). Results: Circumferential strain in the apex was significantly reduced in abnormal LVEF group compared with normal LVEF group (-7.3 +/- 2.6 vs -13.5 +/- 4.1, P < .001). Peak LV twist was significantly reduced in abnormal LVEF group (5.6 +/- 2.6 vs 9.8 +/- 4.0 degrees, P < .005) mainly because of reduced apical rotation. Peak positive and negative twist velocity was also significantly depressed (38.8 +/- 11.3 vs 52.1 +/- 19.3 degree/s, P < .05, and -42.6 +/- 17.8 vs -63.4 +/- 28.0 degree/s, P < .05, respectively). Significant correlation was noted between peak twist and LVEF (r = 0.73, P < .001) and LV end-systolic volume (r = 0.56, P < .001). The twist-displacement loop was markedly distorted in abnormal LVEF group. Conclusions: Systolic twist was decreased and diastolic untwisting was depressed in accordance with LV systolic dysfunction in anterior wall MI. These results suggest the significant impact of global LV systolic function on LV twist and twist-displacement loops in patients with anterior wall MI.

The aim of this study was to determine the normal value of left ventricular (LV) twist, and to examine the effects of aging on LV twist by newly developed 2-dimensional ultrasound speckle-tracking imaging. We acquired basal and apical LV short-axis second harmonic images in 118 healthy volunteers. Using commercially available 2-dimensional strain software, time-domain speckle tracking was performed, and mean value of LV rotation obtained at each plane. LV twist was defined as apical rotation relative to the base. Adequate data were obtained in 113 volunteers. During systole, the LV performs a wringing motion with a counterclockwise rotation at the apex and a clockwise rotation at the base. The mean value of peak twist was 7.7@?+/- 3.5 degrees. Immediately after end systole, rapid untwisting develops. Different LV twist profiles are noted according to age. Peak LV twist was significantly higher, and the rate of LV untwisting significantly reduced and delayed, with advancing age. LV twist can be measured noninvasively by 2-dimensional ultrasound speckle-tracking imaging. The observed reduced and delayed diastolic untwisting with aging may contribute toward the tendency of diastolic dysfunction. This novel method allows the detailed study of diastolic function in various cardiovascular diseases.

Background: Newly developed 2-dimensional (2D) speckle tracking imaging provides simultaneous information on both cardiac rotation and radial displacement throughout the cardiac cycle, thus, providing the opportunity to noninvasively construct twist-displacement loops. The aim of this study was to examine the effect of aging on twist-displacement loops. Methods: Basal and apical 2D left ventricular (LV) short-axis images with high frame rates were acquired in 59 asymptomatic healthy volunteers. Using commercially available software, LV rotation and radial displacement were obtained at each plane by 2D speckle tracking analysis. LV twist was defined as apical LV rotation relative to the base. To adjust intersubject differences in heart rate, the time sequence was normalized to the percentage of systolic and diastolic duration. Volunteers were divided into 3 groups according to age. Results: Twist-displacement loops were characterized by a figure of 8 configuration. There was a linear relation between twist and displacement during systole (r = 0.97), with its slope being significantly larger in the older group compared with the young group. During early diastole, a substantial degree of untwisting developed despite a relatively small reversal of systolic radial displacement, resulting in a much steeper twist-displacement relationship observed in all groups. Subsequent diastolic expansion occurred with more gradual additional untwisting. Conclusion: We found that 2D speckle tracking imaging successfully provides twist-displacement loop, noninvasively. Aging affects the systolic component of the twist-displacement loop. The assessment of twist-displacement loop may be useful for evaluating LV function.

Background: Two-dimensional (2D) contrast-enhanced dobutamine stress echocardiography (DSE) is used clinically to diagnose stress-induced wall-motion abnormality (WMA). We hypothesized that contrast-enhanced real-time 3-dimensional (3D) DSE could improve the detection rate of WMA, because from a single full-volume acquisition, multiple segments can be visualized. Methods: We acquired both 2D and 3D DSE in 78 patients with known or suggested coronary artery disease (mean age: 65 years; 44 men). Dobutamine was infused using a standard protocol, and atropine added, if required. For 2D DSE, the intravenous contrast agent was injected at each stage and images displayed in a quadscreen format. For 3D DSE, contrast harmonic 3D data sets (full volumes) were acquired at baseline and peak stress. Using custom software, 3 short-axis views (from apex to base) were created, and wall motion scored using a wall-motion score index using a 16-segment model. A positive stress test was defined as new or worsened WMA or fixed abnormality during stress. Results: Heart rate increased from 72 +/- 13 to 133 +/- 15/min (86 +/- 11% of age-predicted). A total of 1248 segments were analyzed at each stage for both modalities. A single segment at baseline and 5 segments at peak stress could not be assessed with contrast 2D DSE. In contrast, 88 segments at baseline and 39 segments at peak stress could not be assessed with contrast 3D DSE. With 3D DSE, the majority of uninterpretable segments were in the anterior and lateral walls. Significant correlations were noted between wall-motion score index by 2D and 3D DSE at baseline (r = 0.78) and peak stress (r = 0.83). The concordance rate (positive/negative findings) between modalities was 69% (54/78) on a patient basis and 88% (206/234) on a perfusion territory basis. When using 2D DSE results as the gold standard, sensitivity and specificity for detecting WMA by 3D DSE was 58% and 75%, respectively. Sensitivity and specificity values were 67% and 94% for the right coronary artery, 53% and 81% for the left anterior descending coronary artery, and 88% and 100% for the left circumflex coronary artery territory, respectively. Conclusion: Contrast-enhanced 3D DSE was feasible in the majority of patients. However, the moderate concordance between both modalities was a result of: (1) difficulties in visualizing the anterolateral segments because of the relatively large imprint of the transducer; and (2) lower frame rates with 3D DSE resulting in the erroneous diagnosis of dyssynchrony.

An uncommon oxygen absorption/desorption behavior is reported for the cation-stoichiometric cobalt oxide, YBaCo4O7, structurally composed of two kinds of layers of corner-sharing CoO4tetrahedra. We have found that YBaCo4O7absorbs and desorbs oxygen up to 1.5 in a narrow temperature range below 400 °C. The oxygen uptake/release process is highly reversible, being controlled by both temperature and oxygen partial pressure. Such a large low-temperature oxygen-content tunability is of great promise in regard to applications related to, for example, oxygen storage. Materials with similar characteristics are, to a large degree, lacking today.

Using the two-step metalorganic vapor phase epitaxial growth on ZrB2 substrate, we demonstrate violet and UV light-emitting diodes (LEDs). The violet LED shows extremely linear L–I characteristics and a sharp single spectrum with a peak wavelength of 410 nm. In the UV-LED on ZrB2, we confirmed that the vertical conduction through the ZrB2/AlGaN interface is superior to the conventional lateral conduction. The use of ZrB2 substrate is promising for UV light emitting devices with low operating voltage. (© 2003 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

A combined experimental and theoretical study of superconducting, electronic and thermodynamic properties of various isomorphic diborides is reported. The Hc2(T) data of bulk MgB2are analyzed within a two-band model with different couplings and Fermi velocities. No bulk superconductivity was found in TaB2and ZrB2single crystals at temperatures T>1.5 K. Its absence is ascribed to weak electron-phonon coupling strenghth with λ∼0.1 derived both from the comparison of the calculated density of states at the Fermi level and specific heat data as well as from the weak deformation potential.

We investigated an intracluster reaction induced by impact of (CS2)n^- (n = 1−8) onto silicon and (La0.7Ce0.3)B6 surfaces at collision energies of 100−2000 eV and 0−100 eV, respectively. Product anions scattered from the surfaces were mass analyzed by a tandem time-of-flight (TOF) mass spectrometer. In the impact onto the silicon surface, the intracluster reaction proceeds via (1) production of S^- by dissociation of the core ion, CS2^-, and (2) production of Sm^- (m = 2,3) by abstractions of S from surrounding CS2 by Sm-1^-. In the impact onto a (La0.7Ce0.3)B6 surface, essentially the same reaction mechanism operates except for the dimer reaction at collision energies less than 50 eV. The two isomers, CS2^-(CS2) and C2S4^-, give S2^-, and the latter dissociates further into C2S2^-. A similar reaction mechanism is found to operate in the intracluster reaction of (OCS)n^-.

Clean and O2adsorbed LaB6(001) surfaces were investigated by metastable impact electron spectroscopy (MIES) and ultraviolet photoelectron spectroscopy (UPS). Two structures appear close to the Fermi level EFand 3 eV below it in the MIE spectrum of the clean LaB6(001) surface (work function; 2.3 eV), and can be assigned to the La(5d) and dangling bond of B(2p), respectively. The peak near EForiginates mainly from auto-detachment process between He*(1s2s) and La(5d). The results suggest that the clean LaB6(001) surface is terminated with La. Particular emphasis was paid to changes of these spectral features as a function of oxygen exposure. Both structures disappear at 1.5 L. It is concluded that O2is dissociated at the La-terminated surfaces. Two oxygen-induced peaks appear in the MIES and UPS(HeII) spectra at 5.8 and 7.5 eV binding energy. It is concluded that O2is dissociated at the La-terminated surfaces. Their origin is discussed on the basis of two mechanisms for the interaction of O2with LaB6surfaces.

Germ-line chimerism was successfully induced by blastoderm transplantation from donor triploid crucian carp, which reproduces gynogenetically, to recipient diploid goldfish, which reproduces bisexually. Lower part of donor blastoderm including primordial germ cells (PGCs) was sandwiched between recipient blastoderm at the mid- to late-blastula stage. When donor grafts were prepared from intact embryos or ventralized ones by removing vegetal yolk hemisphere at the 1- to 2-cell stage, malformations including double axes were observed in the resultant chimeras transplanted with grafts from intact embryos at the hatching stage, while a few malformations in those from ventralized embryos. PGCs originated from donor grafts were observed around the gonadal anlage at 10 days post-fertilization in chimeras. When ploidy of erythrocytes and epidermal cells in chimeric fish was examined by flow-cytometry, no triploid cells were detected at 1- and 5-year-old chimeras. Three-year-old chimeric fish (n= 5) laid eggs originated from the donor together with those from the recipient. The frequency of eggs from the donor crucian carp blastoderm varied from 3.1 to 89.3% between chimeras.

Leptin, a hormone derived from adipose tissue, regulates energy homeostasis and body weight. In the mouse, serum leptin levels, when measured by radioimmunoassay (RIA), increase by a factor of more than 50 times during pregnancy, compared with those in the non-pregnant state. It is well known that mouse placenta produces the secretory isoform of the leptin receptor, OB-Re. In order to investigate the issue of whether serum leptin levels are actually increased during pregnancy or whether the increased OB-Re concentration plays a role in this phenomenon, serum leptin levels were determined by the immunoprecipitation of leptin using anti-leptin antibody, and were found to be increased only by about ten times during pregnancy. To investigate the influence of OB-Re on leptin measurement by the RIA procedure, serum leptin levels were measured by the RIA after the addition of OB-Re to the serum. The apparent values of leptin levels increased in parallel with the amount of OB-Re added to the serum. Leptin levels, as determined by the RIA, might therefore provide artificially high values when serum levels of the secretory form of OB-R are high, in cases, for example, such as the last period of pregnancy in mice.

PbZrTiO3(PZT) is one of the most promising ferroelectric materials for ferroelectric random access memory (FeRAM). But, there is a problem that the PZT ferroelectric properties are degraded with platinum (Pt) electrodes after annealing in a hydrogenous atmosphere during LSI fabrication. This degradation has been attributed to the catalytic nature of Pt, which dissociates H2into protons which then migrate into the PZT and reduce it at elevated temperature. In this theory, it is unclear how Pt and PZT physically interact at the interface. Also, the mechanism concerning the generation of an interfacial layer of oxygen vacancies has not been addressed, which creates some ambiguity in the model. We researched the interface using secondary ion mass spectroscopy (SIMS) and field-emission type transmission electron microscopy (FE-TEM) in order to more clearly understand its impact on the degradation mechanism. We have verified atomically that annealing a Pt/PZT/Pt capacitor results in Pb diffusion from the PZT into the Pt electrode and Pt diffusion from the electrode into the PZT. We next verified that the interdiffusion is not a usual thermal interdiffusion process, but appears rather to be generated by the reaction with hydrogen on both top and bottom Pt electrodes. Finally, we present a model of how the effects of hydrogen reduction combine with the Pt catalysis to form oxygen vacancies. Lead and Pt interdiffuse easily through these vacancies at both interfaces. The model presented here can predict the distribution of vacancies and demonstrates the limitations of the recovery anneal. It also supplements our understanding of the degradation process and provides additional credibility to the above theory.

We have already reported that the activation of extracellular signal-regulated kinase (Erk) is critical in the stimulation of cell proliferation during the promotion stage of urethane-induced lung tumorigenesis in mice. Also, we have found that vitamin E suppresses lung tumorigenesis by inhibiting cell proliferation at the promotion stage. However, it is still unclear whether this inhibitory effect at the promotion stage is based on the antioxidative effect of vitamin E or not. In order to address this question, we examined the inhibitory effect of alpha-tocopheryloxybutyric acid (TSE), an ether derivative of vitamin E that cannot act as an antioxidant in vivo, on cell proliferation and the activation of Erk during promotion of lung tumorigenesis. On day 30 after urethane injection (750 mg/kg, i. p.) in A/J mice, TSE or vitamin E at 100 micromol/kg, p.o. was administered. Twenty-four hours after the final administration, the mice were killed to analyze cell proliferation and related parameters. The labeling index of proliferating cell nuclear antigen (a marker of cell proliferation) and ornithine decarboxylase activity (a marker of the promotion stage in lungs) were attenuated by treatment with TSE or vitamin E. TSE or vitamin E treatment also inhibited urethane-induced activation of Erk and suppressed the activation of other essential members of the Erk cascade (Ras, Raf and Mek). These results suggest that vitamin E inhibits cell proliferation and activation of the Erk cascade during promotion of urethane-induced lung tumorigenesis in mice, independent of its antioxidative effect.

Single crystals of rare-earth hexaborides, LaB6, CeB6, PrB6, NdB6, and SmB6, were prepared by the floating zone method. Their crystal quality increased as the atomic number of the rare-earth metals increased. The difference in the quality was explained from the high-temperature hardness and the growth temperature.

The mechanism of stimulated F⁺ desorption has been investigated from fluorinated TiC(111) and CaF2 surfaces by He⁺, Ne⁺, Ar⁺, H⁺, and D⁺ irradiation. Upon He⁺ irradiation, the F⁺ ion is ejected from the surface of CaF2 via both kinetic and potential sputtering, whereas the potential sputtering of F⁺ is dominant from the fluorinated TiC(111) surface. The kinetically sputtered F⁺ ion from the metal surface undergoes efficient resonant neutralization due to the band effect. The probability for potential sputtering of F⁺ from the F/TiC(111) surface is dependent upon the primary ion species on the order of He⁺ > Ne⁺ ≫ Ar⁺. The F⁺ desorption is not simply related to the ionization potential of the projectile as evidenced by the fact that H⁺, though having the ionization potential smaller than Ar⁺ induces F⁺ emission with the yield about 70 times as large as that by Ar⁺ and almost one-fourth that by He⁺. The comparison between H⁺ and D⁺ irradiations clearly shows that the swifter ion leads to a higher F⁺ emission probability. From these facts, it is concluded that the F⁺ emission is initiated by formation of the F 2s core−hole state having the antibonding character as a consequence of the nonadiabatic transition of the primary ion's hole during collision. The ionization of the core-excited fluorine occurs due to the intra-atomic Auger decay (autoionization) after breakage of the chemisorptive bond, so that the resulting F⁺ ion can avoid efficient reneutralization even at metal surfaces.

In this study we investigated the effects of 24R,25-dihydroxyvitamin D(3) [24R,25(OH)(2)D(3)] on N,N'-dimethylhydrazine (DMH)-induced rat colon carcinogenesis. For experiments 1 and 2, 50 F344 male, 6-week-old rats were divided into five groups in each experiment. Animals were given s.c. injections of DMH once a week for 4 weeks. Those in groups 1-5 were given 24R,25(OH)(2)D(3) in the diet (10, 5, 2.5, 1.25 or 0 p.p.m., respectively) during the post-initiation stage in experiment 1 and during the initiation stage in experiment 2. At termination, the numbers of aberrant crypt foci (ACF) in the rat colonic mucosa were decreased dose-dependently in rats treated with 24R,25(OH)(2)D(3) during the post-initiation stage, but not in the initiation stage. For experiment 3, 15 male, 9-week-old rats were divided into three groups and given 24R,25(OH)(2)D(3) in the diet (10, 5 or 0 p.p.m.). Animals were injected with 5-bromo-2'-deoxyuridine (BrdU) i.p. 1 h before death to examine DNA synthesis in the colon mucosa. BrdU labeling indices were decreased dose-dependently in colonic crypts of rats treated with 24R, 25(OH)(2)D(3). In experiment 4, using the multicarcinogenic protocol we could analyze our data with respect to not only one separate organ, but at the organism level. Sixty-eight male, 6-week-old rats were treated with DMH, N-methylnitrosourea, 2, 2'-dihydroxy-di-n-propylnitrosamine, diethylnitrosamine and N-butyl-N-(4-hydroxybutyl)nitrosamine in weeks 1-4 and were then given 24R,25(OH)(2)D(3) in the diet (5, 1 or 0 p.p.m.) throughout weeks 5-30. Examination of the development of tumors and preneoplastic lesions in various organs revealed that 24R, 25(OH)(2)D(3) inhibited colonic tumor development significantly but exerted no effects on tumor induction in other organs. In conclusion, these results strongly indicate that 24R,25(OH)(2)D(3) inhibits colon carcinogenesis specifically, without any enhancement of carcinogenesis in other organs, when administered in the post-initiation phase.

X-ray photoelectron spectroscopy was used to investigate the initial stages of oxygen adsorption on the (100) surface of a single crystal of lanthanum hexaboride. Numerous previous studies had not resolved the issue of whether oxygen adsorbs at lanthanum sites, boron sites, or both. We find that oxygen adsorption markedly alters the La3d lineshapes, whereas the B1s peak is unaffected. On the clean surface the La3d3/2peak is split into two components at binding energies of 854.7 and 851.8eV, a splitting that is typical of rare-earth metals and their compounds. The two components are associated with two different final states. In one final state the 3d core hole is poorly screened (854.7eV) and in the other it is well-screened (851.8eV). The relative intensity of the two components is known to be very sensitive to the chemical environment of the rare earth atom and a 10L O2exposure at room temperature produces a large increase in the relative intensity of the well-screened component. Annealing the surface to 600°C and then to 700°C produces sharp c(2×2) and p(2×1) LEED patterns respectively. The La3d peaks associated with the two LEED patterns are similar to those observed after the initial 300K 10L O2exposure, indicating oxygen bonding to La in both overlayer structures. Thus while the XPS data clearly reveal oxygen adsorption at La sites, there is no indication of adsorption at boron sites for low O2exposures. More extensive oxidation at higher temperatures shows formation of both boron and lanthanum oxides.

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