Dependence of the V/III Ratio on Indium Incorporation in InGaN Films Grown by Metalorganic Vapour Phase Epitaxy.

InGaN epitaxial layers were grown on c-plane sapphire substrates using the metalorganic vapour phase epitaxy (MOVPE) system at 760 °C. By varying the total flow rate of group-III sources (TMI+TEG) with a fixed molar ratio of group-III sources [TMI/(TMI+TEG)], the influence of V/III ratio were investigated from 4500 to 20000. The grown N-polar InGaN layers were investigated by atomic force microscopy and it is found that the surface roughness decreases with increasing the V/III ratios. High resolution X-ray diffraction analyses show that the phase separation decreases with increasing the V/III ratios. Photoluminescence measurements reveal that the peak position of the band-edge emission shifted toward the shorter wavelength with increasing the V/III ratios. Reciprocal space mapping (RSM) analyses were carried out on InGaN films. At low V/III ratio, the phase separation can be detected in InGaN films.

Analysis of treatment goal alignment between Japanese psoriasis patients and their paired treating physicians.

BACKGROUND: Appropriate goal-oriented treatment strategies are important for optimal treatment outcomes and may prevent under-treatment. As treatment goals vary by patient, a study to examine treatment goals is more meaningful when patients and their physicians are paired. There has not been any study that examines alignment between paired psoriasis patients and physicians in real-world clinical practice using skin clearance as a treatment goal indicator. OBJECTIVES: To evaluate treatment goal alignment between psoriasis patients and their paired physicians, and to quantitatively identify factors associated with goal misalignment. METHODS: The study was a nationwide multicenter cross-sectional observational study. Subjects were physician-reported moderate-to-severe psoriasis patients with a history of systemic treatments, directly paired with their treating physicians. Subjects completed surveys independently. Treatment goals included seven categories, and patient-physician pairs were grouped as 'aligned' or 'misaligned' when the answers were the same or different, respectively. RESULTS: A total of 425 pairs (mean response rate, 94.7%) of responses were collected from 54 sites (64.8% general practitioners or clinics; 35.2% university or large hospitals). Treatment goal misalignment was found in 67.9% of the patient-physician pairs. The misalignment was mainly 'patient predominant' (60.9%) indicating that patients had higher goals ('complete clearance') than physicians. In the multivariate logistic regression analyses, patients' treatment expectation for 'complete clearance' [odds ratio (OR): 1.927; 95% confidential interval (CI): 1.232-3.016] and physician rating of 'level of understanding on treatment options' being low (OR: 1.552, 95% CI; 1.082-2.227) were significant factors for treatment goal misalignment. CONCLUSIONS: The majority of treatment goal misalignment was found between paired psoriasis patients and their treating physicians in Japan. The most important contributing factors to misalignment were patients' treatment expectation for 'complete clearance' and physicians' rating of their patients' 'level of understanding on treatment options' being low.

Effect of sapphire nitridation and group-III source flow rate ratio on In-incorporation into InGaN grown by metalorganic vapor phase epitaxy.

In-composition of N-polar InGaN films on the sapphire substrate with the surface nitridation was investigated. By varying the ratio of the group-III source flow rate from 0.7 to 0.95, the In-composition and the surface morphologies of InGaN films were changed. The In-composition of N-polar InGaN films was affected by the strain relaxation and the surface morphologies.

Preclinical pharmacology of perampanel, a selective non-competitive AMPA receptor antagonist.

Perampanel [2-(2-oxo-1-phenyl-5-pyridin-2-yl-1,2-dihydropyridin-3-yl)benzonitrile; E2007] is a potent, selective, orally active non-competitive AMPA receptor antagonist developed for the treatment of epilepsy. Perampanel has a 2,3'-bipyridin-6'-one core structure, distinguishing it chemically from other AMPA receptor antagonist classes. Studies in various physiological systems indicate that perampanel selectively inhibits AMPA receptor-mediated synaptic excitation without affecting NMDA receptor responses. Blocking of AMPA receptors occurs at an allosteric site that is distinct from the glutamate recognition site. Radioligand-binding studies suggest that the blocking site coincides with that of the non-competitive antagonist GYKI 52466, believed to be on linker peptide segments of AMPA receptor subunits that transduce agonist binding into channel opening. As is typical for AMPA receptor antagonists, perampanel exhibits broad-spectrum antiseizure activity in diverse animal seizure models. Perampanel has high oral bioavailability, dose-proportional kinetics, and undergoes oxidative metabolism, primarily via CYP3A4, followed by glucuronidation. The terminal half-life (t½ ) in humans is 105 h; however, in the presence of a strong CYP3A4 inducer (such as carbamazepine), the t½ can be reduced. In sum, perampanel is a selective, centrally acting, negative allosteric modulator of AMPA receptors with good oral bioavailability and favorable pharmacokinetic properties.

Entry point to the Sylvian fissure for the pterional transsylvian approach.

BACKGROUND: Although the anatomy of the Sylvian fissure is understood, there is little information on where to start its dissection in the pterional transsylvian (PT-TS) approach. At small craniotomy using the PT-TS approach, we set the entry point to the Sylvian fissure at 15 mm behind the anterior edge of the craniotomy along the Sylvian fissure and designated this site "point 15." Here we compared the utility of "point 15" with the Sylvian point (point on the Sylvian fissure giving rise to the horizontal and anterior ascending rami) that had been recommended earlier as the entry site for opening the Sylvian fissure. MATERIALS AND METHODS: This study includes 16 patients with 7 ruptured and 9 unruptured anterior circulation aneurysms. We evaluated the usefulness of "point 15" in the PT-TS approach for aneurysmal neck clipping with respect to the adequacy of anatomical exposure and low invasiveness. RESULTS: In 12 patients "point 15" provided for excellent anatomical exposure of the Sylvian fissure; complete neck clipping was possible with minimal brain retraction and damage. In two patients with ruptured aneurysms and thick subarachnoid hemorrhage and in two patients with unruptured aneurysms, the dissection had to be enlarged 3 to 4 mm distally without reaching the Sylvian point. In the latter two patients the Sylvian veins were tethered to frontal and temporal lobes. CONCLUSIONS: The "point 15" was an easily set entry point to the Sylvian fissure. It provided for sufficient anatomical exposure at surgery for anterior circulation aneurysms; additional posterior dissection was required in rare cases. We found that "point 15" was useful in small craniotomies using the PT-TS approach.

Electrochemical isothermal-capacitance-transient spectroscopy: a new depth profiling method of deep levels.

The authors report on a new depth profiling method of deep levels, which we call electrochemical isothermal-capacitance-transient spectroscopy (EICTS). This is combined with electrochemical capacitance-voltage using the Schottky barrier of etchable electrolyte and isothermal-capacitance-transient spectroscopy using the capacitance-transient profile at a fixed temperature. We proved its validity by applying to the ZnSe:N epitaxial film of thickness of more than 1000 nm and comparing the characteristics of an obtained deep level with the results measured by conventional deep-level detection techniques. It is expected that EICTS is very effective to assess the deep levels of wide-bandgap semiconductors that suffer from various point defects and their complexes.

[Off-pump coronary artery bypass in high-risk patients].

In this study, 110 consecutive patients who had undergone off-pump coronary artery bypass (OPCAB) in the past 2 years were evaluated for early results of OPCAB. Patients were classified as a high-risk group (H group: 68 patients consisting of 46 men and 22 women) and a low-risk group (L group: 42 patients consisting of 31 men and 11 women), respectively, and were evaluated for the early operative results. No differences were noted between the H and L groups in the mean number of bypass grafts (2.9 +/- 0.9 in the H group, 2.9 +/- 0.9 in the L group), the rates of complete revascularization (85% in the H group, 93% in the L group), those of various graft materials bypassed, or those of sequential bypass. In all patients, we were able to undergo coronary revascularization by the aortic no-touch technique using arterial grafts exclusively. In the H group, 1 patient (1.5%) died in hospital, but no patients developed cerebral infarction postoperatively, and the frequency of complications was similar to that in the L group. The results of OPCAB for high-risk patients were good, and it was suggested that OPCAB using in situ arterial grafts was very useful particularly in patients with cerebrovascular diseases.

[Aortic valve replacement for calcified aortic valve and annulus with ultrasonic decalcification].

UNLABELLED: We conducted ultrasonic decalcification on calcified annulus in patients with aortic stenosis (AS) using an ultrasonic operator, Sonopet (UST 2001) prior to aortic valve replacement (AVR). We studied the reliability of this method. SUBJECT AND METHOD: From January 2002 to August 2005, AVR was conducted for AS using the Sonopet in 45 patients, comprising of 18 male and 27 female subjects. The mean age was 73.3 +/- 9.7. RESULT: Artificial valves were successfully inserted at the intra-annular level in 37 patients and at the supra-annular level in 8 patients without conducting annular enlargement. In the patients with narrow annuli of less than 19 mm (23 patients), the preoperative mean annular diameter was 18.2 +/- 1.0 mm, but significantly larger artificial valves with an average diameter of 19.3 +/- 1.5 mm (p=0.003) were successfully inserted. CONCLUSION: AVR was proved to be safe and easy by previous ultrasonic decalcification of the annuls using the Sonopet. This method was very useful because it required no enlargement of aortic annulus.

Negative regulation of cytokine signaling by CIS/SOCS family proteins and their roles in inflammatory diseases.

Immune and inflammatory systems are controlled by multiple cytokines, including interleukins (ILs) and interferons. These cytokines exert their biological functions through Janus tyrosine kinases (JAKs) and STAT transcription factors. The CIS (cytokine-inducible SH2 protein) and SOCS (suppressors of cytokine signaling) are a family of intracellular proteins, several of which have emerged as key physiological regulators of cytokine responses, including those that regulate the inflammatory systems. In this review, we focused on the molecular mechanism of the action of CIS/SOCS family proteins and their roles in inflammatory diseases. Furthermore, we illustrate several approaches for treating inflammatory diseases by modulating extracellular and intracellular signaling pathways.

Antioxidants suppress nitrofurazone-induced proliferation of hepatocytes.

On administration to rats at a subtoxic dose, the antibiotic nitrofurazone (NF) has been shown to increase hepatocyte DNA synthesis and liver weight in a dose-dependent manner, with no histological or biochemical evidence of cell damage or necrosis. Free radicals are implicated in NF metabolism, as well as in the DNA synthesis or cell proliferation induced by a number of other chemicals. In the present study, NF was given alone or concomitantly with the antioxidants N-acetylcysteine or cyanidanol. Antioxidants prevent the effects of free radicals. Co-administration decreased hepatocyte proliferation to the same level as the control. This suppression of NF-induced hepatocyte proliferation by antioxidants therefore strongly suggests that free radical production is involved in this process.

Nitric oxide synergistically potentiates interleukin-1 beta-induced increase of cyclooxygenase-2 mRNA levels, resulting in the facilitation of substance P release from primary afferent neurons: involvement of cGMP-independent mechanisms.

We previously demonstrated that cultured rat dorsal root ganglion (DRG) cells respond to stimulation with interleukin-1 beta (IL-1 beta) by releasing substance P (SP), and this response is regulated via the cyclooxygenase (COX)-2 pathway. In this study, to ascertain the interaction between nitric oxide (NO) and prostaglandins in primary afferent neurons, we investigated the effect of NO on the IL-1 beta-induced release of SP in cultured DRG cells. An NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP), did not in itself evoke SP release. However, it potentiated the IL-1 beta-induced release of SP. Similarly, while SNAP did not elicit the expression of COX-2 mRNA, it potentiated the expression induced by IL-1 beta in cultured DRG cells, and this potentiation was significantly suppressed by the NO scavenger, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl 3-oxide (carboxy-PTIO). Moreover, SNAP also potentiated the expression of COX-2 protein induced by IL-1 beta in cultured DRG cells. The stimulatory effect of SNAP on the IL-1 beta-induced release of SP was completely inhibited on co-incubation with a selective COX-2 inhibitor, NS-398. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ), a potent inhibitor of soluble guanylate cyclase, did not suppress, and a membrane-permeable cGMP analogue, 8-Br-cGMP, did not mimic the stimulatory effects of SNAP in DRG cells. These results suggest that in cultured DRG cells, NO potentiates the IL-1 beta-induced increase in COX-2 expression via a soluble guanylate cyclase-cGMP-independent pathway, resulting in facilitation of SP release. The interaction between NO and COX in primary afferent neurons might contribute to the change in nociceptive perception in inflammatory hyperalgesia.

Translation ability of mitochondrial tRNAsSer with unusual secondary structures in an in vitro translation system of bovine mitochondria.

BACKGROUND: Metazoan mitochondrial (mt) tRNAs are structurally quite different from the canonical cloverleaf secondary structure. The mammalian mt tRNASerGCU for AGY codons (Y = C or U) lacks the entire D arm, whereas tRNASerUGA for UCN codons (N = A, G, C or U) has an extended anti-codon stem. It has been a long-standing problem to prove experimentally how these tRNAsSer work in the mt translation system. RESULTS: To solve the above-mentioned problem, we examined their translational abilities in an in vitro bovine mitochondrial translation system using transcripts of altered tRNASer analogues derived from bovine mitochondria. Both tRNASer analogues had almost the same ability to form ternary complexes with mt EF-Tu and GTP. The D-arm-lacking tRNASer GCU analogue had considerably lower translational activity than the tRNASerUGA analogue and produced mostly short oligopeptides, up to a tetramer. In addition, tRNASerGCU analogue was disfavoured by the ribosome when other tRNAs capable of decoding the cognate codon were available. CONCLUSION: Both mt tRNASerGCU and tRNASerUGA analogues with unusual secondary structure were found to be capable of translation on the ribosome. However, the tRNASerGCU analogue has some molecular disadvantage on the ribosome, which probably derives from the lack of a D arm.

Induction of the cytokine signal regulator SOCS3/CIS3 as a therapeutic strategy for treating inflammatory arthritis.

Immune and inflammatory systems are controlled by multiple cytokines, including ILs and INFs. These cytokines exert their biological functions through Janus tyrosine kinases and STAT transcription factors. One such cytokine, IL-6, has been proposed to contribute to the development of rheumatoid arthritis (RA). We found that STAT3 was strongly tyrosine phosphorylated in synovial tissue of RA patients, but not those with osteoarthritis. Blockade of the IL-6-gp130-JAK-STAT3-signaling pathway might therefore be beneficial in the treatment of RA. We show here that the mRNA for the endogenous cytokine signaling repressor CIS3/SOCS3 is abundantly expressed in RA patients. To determine whether CIS3 is effective in treating experimental arthritis, a recombinant adenovirus carrying the CIS3 cDNA was injected periarticularly into the ankle joints of mice with antigen-induced arthritis or collagen-induced arthritis (CIA). Periarticular injection of CIS3 adenovirus drastically reduced the severity of arthritis and joint swelling compared with control groups. CIS3 was more effective than a dominant-negative form of STAT3 in the CIA model. Thus, induction of CIS3 could represent a new approach for effective treatment of RA.

A role for neuromedin U in stress response.

Neuromedin U (NMU) is a hypothalamic peptide that has been recently found to reduce food intake, but few is known about its other functions in the central nervous system. We here studied behavioral activities induced by an intracerebroventricular (ICV) administration of NMU in rats and mice. NMU increased gross locomotor activity, face washing behavior, and grooming. NMU-induced stress response was significantly abolished by pretreatment with an antagonist of corticotropin-releasing hormone (CRH), alpha-helical CRH (9-41) (alpha-hCRH), or anti-CRH IgG. NMU did not induce locomotor activity in CRH knockout mice. NMU that interacts anatomically and/or functionally with the CRH system is a novel physiological regulator of stress response.

Suppressor of cytokine signaling-3 is a biomechanical stress-inducible gene that suppresses gp130-mediated cardiac myocyte hypertrophy and survival pathways.

The gp130 cytokine receptor activates a cardiomyocyte survival pathway during the transition to heart failure following the biomechanical stress of pressure overload. Although gp130 activation is observed transiently during transverse aortic constriction (TAC), its mechanism of inactivation is largely unknown in cardiomyocytes. We show here that suppressor of cytokine signaling 3 (SOCS3), an intrinsic inhibitor of JAK, shows biphasic induction in response to TAC. The induction of SOCS3 was closely correlated with STAT3 phosphorylation, as well as the activation of an embryonic gene program, suggesting that cardiac gp130-JAK signaling is precisely controlled by this endogenous suppressor. In addition to its cytoprotective action, gp130-dependent signaling induces cardiomyocyte hypertrophy. Adenovirus-mediated gene transfer of SOCS3 to ventricular cardiomyocytes completely suppressed both hypertrophy and antiapoptotic phenotypes induced by leukemia inhibitory factor (LIF). To our knowledge, this is the first clear evidence that these two separate cardiomyocyte phenotypes induced by gp130 activation lie downstream of JAK. Three independent signaling pathways, STAT3, MEK1-ERK1/2, and AKT activation, that are coinduced by LIF stimulation were completely suppressed by SOCS3 overexpression. We conclude that SOCS3 is a mechanical stress-inducible gene in cardiac muscle cells and that it directly modulates stress-induced gp130 cytokine receptor signaling as the key molecular switch for a negative feedback circuit for both myocyte hypertrophy and survival.

A mutant form of JAB/SOCS1 augments the cytokine-induced JAK/STAT pathway by accelerating degradation of wild-type JAB/CIS family proteins through the SOCS-box.

Cytokines exert biological functions by activating Janus tyrosine kinases (JAKs), and JAK inhibitors JAB (also referred to as SOCS1 and SSI1) and CIS3 (SOCS3) play an essential role in the negative regulation of cytokine signaling. We have found that transgenic (Tg) mice expressing a mutant JAB (F59D-JAB) exhibited a more potent STAT3 activation and a more severe colitis than did wild-type littermates after treatment with dextran sulfate sodium. We now find that there is a prolonged activation of JAKs and STATs in response to a number of cytokines in T cells from Tg mice with lck promoter-driven F59D-JAB. Overexpression of F59D-JAB also sustained activation of JAK2 in Ba/F3 cells. These data suggested that F59D-JAB up-regulated STAT activity by sustaining JAK activation. To elucidate molecular mechanisms related to F59D-JAB, we analyzed the effects of F59D-JAB on the JAK/STAT pathway using the 293 cell transient expression system. We found that the C-terminal SOCS-box played an essential role in augmenting cytokine signaling by F59D-JAB. The SOCS-box interacted with the Elongin BC complex, and this interaction stabilized JAB. F59D-JAB induced destabilization of wild-type JAB, whereas overexpression of Elongin BC canceled this effect. Levels of endogenous JAB and CIS3 in T cells from F59D-JAB Tg-mouse were lower than in wild-type mice. We propose that F59D-JAB destabilizes wild-type, endogenous JAB and CIS3 by chelating the Elongin BC complex, thereby sustaining JAK activation.

Proteomic analysis of the mammalian mitochondrial ribosome. Identification of protein components in the 28 S small subunit.

The mammalian mitochondrial ribosome (mitoribosome) has a highly protein-rich composition with a small sedimentation coefficient of 55 S, consisting of 39 S large and 28 S small subunits. In the previous study, we analyzed 39 S large subunit proteins from bovine mitoribosome (Suzuki, T., Terasaki, M., Takemoto-Hori, C., Hanada, T., Ueda, T., Wada, A., and Watanabe, K. (2001) J. Biol. Chem. 276, 21724-21736). The results suggested structural compensation for the rRNA deficit through proteins of increased molecular mass in the mitoribosome. We report here the identification of 28 S small subunit proteins. Each protein was separated by radical-free high-reducing two-dimensional polyacrylamide gel electrophoresis and analyzed by liquid chromatography/mass spectrometry/mass spectrometry using electrospray ionization/ion trap mass spectrometer to identify cDNA sequence by expressed sequence tag data base searches in silico. Twenty one proteins from the small subunit were identified, including 11 new proteins along with their complete cDNA sequences from human and mouse. In addition to these proteins, three new proteins were also identified in the 55 S mitoribosome. We have clearly identified a mitochondrial homologue of S12, which is a key regulatory protein of translation fidelity and a candidate for the autosomal dominant deafness gene, DFNA4. The apoptosis-related protein DAP3 was found to be a component of the small subunit, indicating a new function for the mitoribosome in programmed cell death. In summary, we have mapped a total of 55 proteins from the 55 S mitoribosome on the two-dimensional polyacrylamide gels.

Internucleobase-interaction-directed self-assembly of nanofibers from homo- and heteroditopic 1,omega-nucleobase bolaamphiphiles.

The complementary 1,omega-thymine, 1,omega-adenine, and 1,omega-(thymine, adenine) bolaamphiphiles, [N,N'-bis[3-(2,4-dihydroxy-5-methylpyrimidine-1-yl)propionyl]1,n-diaminoalkane [T-n-T (n = 10, 11, 12)], N, N'-bis[3-(6-aminopurine-9-yl)propionyl]1,n-diaminoalkane [A-n-A (n = 10, 11, 12)], and N-[3-(2,4-dihydroxy-5-methylpyrimidine-1-yl)propionyl], N'-[3-(6-aminopurine-9-yl)propionyl]1,n-diaminoalkane [T-n-A (n = 10, 11, 12)], respectively] have been synthesized. The spontaneous homo- and heteroassembly of these nucleobase-based bolaamphiphiles has been studied by light microscopy, energy-filtering transmission electron microscopy, FT-IR, and powder X-ray diffraction analyses. The achiral T-10-T bolaamphiphile produced in 10% ethanolic/aqueous solutions unprecedented double-helical ropes of 1-2 microm in widths and several hundred micrometers in length, whereas the complementary homologue A-10-A gave only microcrystalline solids of 1-10 microm in size. In contrast, an equimolar mixture of T-10-T and A-10-A yielded supramolecular fibers of 15-30 nm in width. (1)H NMR, CD, and UV studies of solution photoreactions of T-10-T suggested that under natural light the chiral rope formation is triggered by photodimerization of trace amounts of the thymine moieties in the T-10-T assemblies. Complementary hydrogen bond formation between the thymine-adenine heterobase pairs was found to prevent such a photoreaction and resulted in no chiral rope formation. The heteroditopic T-12-A bolaamphiphile self-assembled to form supramolecular fibers. Multilamellar organization was proposed for the homo- and heteroassemblies made of T-n-T and A-n-A.

Histopathological and immunohistochemical studies on arteritis induced by fenoldopam, a vasodilator, in rats.

Fenoldopam, a dopaminergic (DA1) agonist, has been reported to induce medial necrosis and adventitial inflammatory response in the splanchnic arteries in rats. This study was carried out to clarify the detailed time course of the inflammatory responses, using antibodies for the inflammatory cell markers, CD3 (T cell), CD20 (B cell) and ED-1 (macrophage), and inflammatory serum factors, IgG, IgM and C3. Rats were administered fenoldopam for 24 hours by intravenous infusion. Histopathologically, medial necrosis with hemorrhage was observed at the end of infusion, but it almost disappeared on day 7 post-infusion. Adventitial inflammatory responses with ED-1-, CD3- and CD20-positive cells were very slight at the end of infusion, became prominent with marked fibrosis on days 3 and 5, decreased on day 7, and subsided on day 14. The serum factors were first present in the area of medial necrosis, then shifted to the subendothelial space or cytoplasm of smooth muscle cells, and disappeared on day 14 post-infusion. Gaps in the external elastic lamina were observed on days 3 and 5 post-infusion, and IgG and IgM were present outside the gaps in the adventitia. These results provided us with more detailed information on the inflammatory responses following medial damage induced by vasodilators.