Surface Structure of Organic Semiconductor [ n]Phenacene Single Crystals.

Surface structure relaxation of organic semiconductors affects the properties of organic devices, although such relaxation has not been well explored. Only two examples have been experimentally reported; tetracene shows a large surface relaxation, while rubrene exhibits no relaxation. Therefore, a systematic investigation of the surface relaxation is conducted on [ n]phenacenes ( n = 5, 7, and 9). Electron density analyses are performed based on the synchrotron surface X-ray scattering with the aid of first-principles calculations. The results show little surface relaxation in [ n]phenacenes.

Direct Estimation of the Surface Location of Immobilized Functional Groups for Concerted Catalysis Using a Probe Molecule.

The location of active sites during concerted catalysis by a metal complex and tertiary amine on a SiO2 surface is discussed based on the interaction between the functionalized SiO2 surface and a probe molecule, p-formyl phenylboronic acid. The interactions of the probe molecule with the surface functionalities, diamine ligand, and tertiary amine, were analyzed by FT-IR and solid-state (13)C and (11)B MAS NMR. For the catalyst exhibiting high 1,4-addition activity, the diamine ligand and tertiary amine base exist in closer proximity than in the catalyst with low activity.

Tensile and shear bond strengths of a stainless steel used in orthodontic brackets bonded to bovine enamel using two types of resin cement.

The purpose of this study was to examine the relationship between the bond strength of stainless steel with two types of resin cements (MMA- and composite-based) on bovine enamel depending on the directionality of the applied force. The specimens were either placed in water or subjected to thermal cycles (TC), and the shear or tensile bond strengths (SBS or TBS) were determined. The SBS showed significantly greater than the TBS for both types of cement, and the SBS and TBS for composite-based cement had larger than MMA-based one. No significant difference in SBS was observed in the cements even after being subjected to TC. Cohesive failures of the cement and bovine enamel in the composite-based group, while adhesive failures were observed in MMA-based one. Consequently, the direction of the force at both cements affected the retention of stainless steel, and MMA-based cement was preferred when prioritizing less enamel damages.

Cognitive neural responses in the semantic comprehension of sound symbolic words and pseudowords.

Introduction: Sound symbolism is the phenomenon of sounds having non-arbitrary meaning, and it has been demonstrated that pseudowords with sound symbolic elements have similar meaning to lexical words. It is unclear how the impression given by the sound symbolic elements is semantically processed, in contrast to lexical words with definite meanings. In event-related potential (ERP) studies, phonological mapping negativity (PMN) and N400 are often used as measures of phonological and semantic processing, respectively. Therefore, in this study, we analyze PMN and N400 to clarify the differences between existing sound symbolic words (onomatopoeia or ideophones) and pseudowords in terms of semantic and phonological processing. Methods: An existing sound symbolic word and pseudowords were presented as an auditory stimulus in combination with a picture of an event, and PMN and N400 were measured while the subjects determined whether the sound stimuli and pictures match or mismatch. Results: In both the existing word and pseudoword tasks, the amplitude of PMN and N400 increased when the picture of an event and the speech sound did not match. Additionally, compared to the existing words, the pseudowords elicited a greater amplitude for PMN and N400. In addition, PMN latency was delayed in the mismatch condition relative to the match condition for both existing sound symbolic words and pseudowords. Discussion: We concluded that established sound symbolic words and sound symbolic pseudowords undergo similar semantic processing. This finding suggests that sound symbolism pseudowords are not judged on a simple impression level (e.g., spiky/round) or activated by other words with similar spellings (phonological structures) in the lexicon, but are judged on a similar contextual basis as actual words.

Survey of patient and public perceptions of electronic health records for healthcare, policy and research: study protocol.

BACKGROUND: Immediate access to patients' complete health records via electronic databases could improve healthcare and facilitate health research. However, the possible benefits of a national electronic health records (EHR) system must be balanced against public concerns about data security and personal privacy. Successful development of EHR requires better understanding of the views of the public and those most affected by EHR: users of the National Health Service. This study aims to explore the correlation between personal healthcare experience (including number of healthcare contacts and number and type of longer term conditions) and views relating to development of EHR for healthcare, health services planning and policy and health research. METHODS/DESIGN: A multi-site cross-sectional self-complete questionnaire designed and piloted for use in waiting rooms was administered to patients from randomly selected outpatients' clinics at a university teaching hospital (431 beds) and general practice surgeries from the four primary care trusts within the catchment area of the hospital. All patients entering the selected outpatients clinics and general practice surgeries were invited to take part in the survey during August-September 2011. Statistical analyses will be conducted using descriptive techniques to present respondents' overall views about electronic health records and logistic regression to explore associations between these views and participants' personal circumstances, experiences, sociodemographics and more specific views about electronic health records. DISCUSSION: The study design and implementation were successful, resulting in unusually high response rates and overall recruitment (85.5%, 5336 responses). Rates for face-to-face recruitment in previous work are variable, but typically lower (mean 76.7%, SD 20). We discuss details of how we collected the data to provide insight into how we obtained this unusually high response rate.

[Effect of tracheostomy with imipramine on apneusis attacks in a girl with Rett syndrome].

A girl with Rett syndrome was suffered from severe apneusis attacks, resulting in cardiopulmonary arrest, which required resuscitation. Her apneusis attacks did not respond at all to diazepam, magnesium citrare or tricyclic antidepressants but ceased by tracheostomy with oral imipramine. The breathing abnormality appeared to involve difficulty in terminating inspiration. This supports the idea that a lack of serotonin may cause her apneusis attacks.

Absence of multiple sleep-onset rapid eye movement periods (SOREMPs) is not a specific feature of patients with pathological sleep prolongation.

Purpose: Multiple sleep-onset rapid eye movement periods (SOREMPs) are involved in the pathophysiology of narcolepsy, but it is not clear whether the lack of multiple SOREMPs is associated with the pathophysiology of idiopathic hypersomnia or not. We examined the significance of multiple SOREMPs in patients with pathological sleep prolongation. Methods: Participants were consecutive patients complaining of unexplained sleepiness and agreed to a 3-day-sleep studies; 24 h polysomnography (PSG) followed by standard PSG and multiple sleep latency test (MSLT). Forty-one (26 females, 21.9 ± 8.1 years old, BMI 20.4 ± 2.3 kg/m2) of 54 eligible patients without other sleep pathologies showed pathological sleep prolongation. We subdivided them into those with and without multiple SOREMPs on MSLT and compared clinical and PSG variables between groups. Results: Six of 41 (14.6%) patients showed multiple SOREMPs on MSLT. There were almost no differences in sleep variables between those with and without multiple SOREMPs. We only found shorter mean sleep latency on MSLT and more REM cycles on 24 h PSG in those with multiple SOREMPs (adjusted p = 0.016 and 0.031). The frequencies of REM-related phenomena and clinical symptoms related to idiopathic hypersomnia were not different between groups. Conclusion: Our results indicated that patients with pathological sleep prolongation had the same clinical profiles regardless of the status of SOREMPs, suggesting the absence of multiple SOREMPs, prerequisite for the diagnosis of idiopathic hypersomnia, is not a specific feature of pathological sleep prolongation. Confirmation of sleep prolongation alone could be a diagnostic tool for idiopathic hypersomnia.

Wear Behavior between Aesthetic Restorative Materials and Bovine Tooth Enamel.

Tooth enamel wear occurs because of daily mastication and occlusion. This study investigated the wear behavior of bovine teeth against aesthetic restorative materials in vitro. Abrader specimens were fabricated using four tooth-colored restorative materials (zirconia, lithium disilicate glass ceramic, dental porcelain, and resin composite), with bovine tooth enamel as a control. Flattened bovine tooth enamel was used as the substrate specimen. These materials were characterized by Vickers hardness tests and surface roughness measurements. Two-body wear tests between the abrader and substrate specimens were performed, and the worn topographies were evaluated using a contour-measuring instrument and 3D laser microscope. The restorative materials and bovine tooth enamel had similar surface roughness but different hardness and wear behaviors. Bovine teeth showed the largest wear in tooth-tooth contact as the abrader and substrate specimens. Compared to bovine teeth, zirconia, lithium disilicate glass ceramic, and dental porcelain showed greater hardness and less wear on their surfaces, and less substrate wear of the opposite tooth enamel. The lowest hardness resin composite showed intermediate wear on its surface, resulting in the lowest substrate wear. Accordingly, dentists should pay attention to the selection of restorative materials to reconstruct their morphologies owing to different wear behaviors.

Molecular basis for E-cadherin recognition by killer cell lectin-like receptor G1 (KLRG1).

The killer cell lectin-like receptor G1, KLRG1, is a cell surface receptor expressed on subsets of natural killer (NK) cells and T cells. KLRG1 was recently found to recognize E-cadherin and thus inhibit immune responses by regulating the effector function and the developmental processes of NK and T cells. E-cadherin is expressed on epithelial cells and exhibits Ca(2+)-dependent homophilic interactions that contribute to cell-cell junctions. However, the mechanism underlying the molecular recognition of KLRG1 by E-cadherin remains unclear. Here, we report structural, binding, and functional analyses of this interaction using multiple methods. Surface plasmon resonance demonstrated that KLRG1 binds the E-cadherin N-terminal domains 1 and 2 with low affinity (K(d) approximately 7-12 microm), typical of cell-cell recognition receptors. NMR binding studies showed that only a limited N-terminal region of E-cadherin, comprising the homodimer interface, exhibited spectrum perturbation upon KLRG1 complex formation. It was confirmed by binding studies using a series of E-cadherin mutants. Furthermore, killing assays using KLRG1(+)NK cells and reporter cell assays demonstrated the functional significance of the N-terminal region of E-cadherin. These results suggest that KLRG1 recognizes the N-terminal homodimeric interface of domain 1 of E-cadherin and binds only the monomeric form of E-cadherin to inhibit the immune response. This raises the possibility that KLRG1 detects monomeric E-cadherin at exposed cell surfaces to control the activation threshold of NK and T cells.

Crystal structure of measles virus hemagglutinin provides insight into effective vaccines.

Measles still remains a major cause of childhood morbidity and mortality worldwide. Measles virus (MV) vaccines are highly successful, but the mechanism underlying their efficacy has been unclear. Here we report the crystal structure of the MV attachment protein, hemagglutinin, responsible for MV entry. The receptor-binding head domain exhibits a cubic-shaped beta-propeller structure and forms a homodimer. N-linked sugars appear to mask the broad regions and cause the two molecules forming the dimer to tilt oppositely toward the horizontal plane. Accordingly, residues of the putative receptor-binding site, highly conserved among MV strains, are strategically positioned in the unshielded area of the protein. These conserved residues also serve as epitopes for neutralizing antibodies, ensuring the serological monotype, a basis for effective MV vaccines. Our findings suggest that sugar moieties in the MV hemagglutinin critically modulate virus-receptor interaction as well as antiviral antibody responses, differently from sugars of the HIV gp120, which allow for immune evasion.

Efficient silkworm expression of human GPCR (nociceptin receptor) by a Bombyx mori bacmid DNA system.

Guanine nucleotide-binding protein (G protein) coupled receptors (GPCRs) are frequently expressed by a baculovirus expression vector system (BEVS). We recently established a novel BEVS using the bacmid system of Bombyx mori nucleopolyhedrovirus (BmNPV), which is directly applicable for protein expression in silkworms. Here, we report the first example of GPCR expression in silkworms by the simple injection of BmNPV bacmid DNA. Human nociceptin receptor, an inhibitory GPCR, and its fusion protein with inhibitory G protein alpha subunit (G(i)alpha) were both successfully expressed in the fat bodies of silkworm larvae as well as in the BmNPV viral fraction. Its yield was much higher than that from Sf9 cells. The microsomal fractions including the nociceptin receptor fusion, which are easily prepared by only centrifugation steps, exhibited [35S]GTPgammaS-binding activity upon specific stimulation by nociceptin. Therefore, this rapid method is easy-to-use and has a high expression level, and thus will be an important tool for human GPCR production.

Silkworm expression and sugar profiling of human immune cell surface receptor, KIR2DL1.

Immune cell surface receptors are directly involved in human diseases, and thus represent major drug targets. However, it is generally difficult to obtain sufficient amounts of these receptors for biochemical and structural studies because they often require posttranslational modifications, especially sugar modification. Recently, we have established a bacmid expression system for the baculovirus BmNPV, which directly infects silkworms, an attractive host for the large-scale production of recombinant sugar-modified proteins. Here we produced the human immune cell surface receptor, killer cell Ig-like receptor 2DL1 (KIR2DL1), by using the BmNPV bacmid expression system, in silkworms. By the direct injection of the bacmid DNA, the recombinant KIR2DL1 protein was efficiently expressed, secreted into body fluids, and purified by Ni(2+) affinity column chromatography. We further optimized the expression conditions, and the final yield was 0.2mg/larva. The sugar profiling revealed that the N-linked sugars of the purified protein comprised very few components, two paucimannose-type oligosaccharides, Manalpha1-6Manbeta1-4GlcNAcbeta1-4GlcNAc and Manalpha1-6Manbeta1-4GlcNAcbeta1-4(Fucalpha1-6)GlcNAc. This revealed that the protein product was much more homogeneous than the complex-sugar type product obtained by mammalian cell expression. The surface plasmon resonance analysis demonstrated that the purified KIR2DL1 protein exhibited specific binding to the HLA-Cw4 ligand. Moreover, the CD spectrum showed the proper secondary structure. These results clearly suggested that the silkworm expression system is quite useful for the expression of cell surface receptors that require posttranslational modifications, as well as for their structural and binding studies, due to the relatively homogeneous N-linked sugar modifications.

Identification of novel and potent 2-amino benzamide derivatives as allosteric glucokinase activators.

The identification and structure-activity-relationships (SARs) of novel 2-amino benzamide glucokinase activators are described. Compounds in this series were developed to be potent GK activators, and their binding mode to the GK protein was determined by crystal structure analysis. In vivo pharmacokinetic and acute in vivo efficacy studies of compound 18 are also described.

Discovery of novel 3,6-disubstituted 2-pyridinecarboxamide derivatives as GK activators.

A novel class of 3,6-disubstituted 2-pyridinecarboxamide derivatives was designed based on X-ray analysis of the 2-aminobenzamide lead class. Subsequent chemical modification led to the discovery of potent GK activators which eliminate potential toxicity concerns associated with an aniline group of the lead structure. Compound 7 demonstrated glucose lowering effect in a rat OGTT model.

Discovery of novel 2-(pyridine-2-yl)-1H-benzimidazole derivatives as potent glucokinase activators.

The synthesis and structure-activity-relationships (SARs) of novel 2-(pyridine-2-yl)-1H-benzimidazole glucokinase activators are described. Systematic modification of benzimidazole lead 5a identified from a high-throughput screening led to the discovery of a potent and metabolically stable glucokinase activator 16p(R) with greater structural diversity from GKAs reported to date. The compound also demonstrated acute oral glucose lowering efficacy in rat OGTT model.

Discovery and structure-activity relationships of a novel class of quinazoline glucokinase activators.

We describe design, syntheses and structure-activity relationships of a novel class of 4,6-disubstituted quinazoline glucokinase activators. Prototype quinazoline leads (4 and 5) were designed based on the X-ray analyses of the previous 2-aminobenzamide lead classes. Modifications of the quinazoline leads led to the identification of a potent GK activator (21d).

Discovery of potent and orally active 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as novel allosteric glucokinase activators.

Identification and synthesis of novel 3-alkoxy-5-phenoxy-N-thiazolyl benzamides as glucokinase activators are described. Removal of an aniline structure of the prototype lead (2a) and incorporation of an alkoxy or phenoxy substituent led to the identification of 3-Isopropoxy-5-[4-(methylsulfonyl)phenoxy]-N-(4-methyl-1,3-thiazol-2-yl)benzamide (27e) as a novel, potent, and orally bioavailable GK activator. Rat oral glucose tolerance test indicated that 27e exhibited a glucose-lowering effect after 10 mg/kg oral administration.

Structure-activity relationships of 3,5-disubstituted benzamides as glucokinase activators with potent in vivo efficacy.

The optimization of our lead GK activator 2a to 3-[(1S)-2-hydroxy-1-methylethoxy]-5-[4-(methylsulfonyl)phenoxy]-N-1,3-thiazol-2-ylbenzamide (6g), a potent GK activator with good oral availability, is described, including to uncouple the relationship between potency and hydrophobicity. Following oral administration, this compound exhibited robust glucose lowering in diabetic model rodents.

The design and optimization of a series of 2-(pyridin-2-yl)-1H-benzimidazole compounds as allosteric glucokinase activators.

The optimization of a series of benzimidazole glucokinase activators is described. We identified a novel and potent achiral benzimidazole derivative as an allosteric GK activator. This activator was designed and synthesized via removal of the chiral center of the lead compound, 6-(N-acylpyrrolidin-2-yl)benzimidazole. The activator exhibited good PK profiles in rats and dogs, and significant hypoglycemic efficacy at 1 mg/kg po dosing in a rat OGTT model. The binding site and binding mode of the benzimidazole class of GKA with GK protein was confirmed by X-ray crystallographic analysis.