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Lincomycin derivatives that have a 5-(2-nitrophenyl)-1,3,4-thiadiazol-2-yl thio moiety at the 7-position were synthesized. 5-Substituted 2-nitrophenyl derivatives showed potent antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene. Antibacterial activities of the 4,5-di-substituted 2-nitrophenyl derivatives were generally comparable to those of telithromycin (TEL) against S. pneumoniae with erm gene and clearly superior to those of TEL against S. pyogenes with erm gene. Compounds 6 and 10c that have a methoxy group at the 5-position of the benzene ring exhibited activities comparable to TEL against Haemophilus influenzae. These results suggest that lincomycin derivatives modified at the 7-position would be promising compounds as a clinical candidate. We would like to dedicate this article to the special issue for late Professor Dr. Hamao Umezawa in The Journal of Antibiotics.The Journal of Antibiotics advance online publication, 5 July 2017; doi:10.1038/ja.2017.59.

The synthesis and antibacterial activity of (7S)-7-sulfur-azetidin-3-yl lincomycin derivatives are described. Modification was achieved by a simple reaction of (7R)-7-O-methanesulfonyllincomycin and the corresponding substituted azetidine-2-thiol. Several compounds first showed moderate antibacterial activity against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene as lincomycin derivatives.

Tungsten carbide thin films are used as wear-resistant coatings. For such applications, it is industrially advantageous to form high-quality thin films on substrates with large areas or complex shapes under atmospheric pressure. Herein, we investigated the feasibility of forming tungsten carbide thin films using a mist chemical vapor deposition method. WC1-x thin films with smooth surfaces were obtained at growth temperatures of 650 °C or above, and the elemental composition ratios of C/W and N/W gradually approached 1 and 0, respectively, with increasing growth temperature. The hardness and Young’s modulus of the film obtained at 750 °C were 25 GPa and 409 GPa, respectively. The grown WC1-x films have potential for use as hard coatings.

High-luminance (~1000cd/m2) and high-uniformity see-through eyewear display has been developed by using two in-coupling and one out-coupling reflection volume holograms on optical waveguide glass. This novel volume hologram design achieves an ideal eyewear display for augmented reality with high transparency, high luminance and low power in various environments.

The cell mechanical features are largely regulated by actin cytokeleton. By analyzing the mechanical features, it is possible to evaluate the characteristics of the complicated actin cytoskeleton in diverse cell types. In this study, we examined the sub-membrane mechanical structures of normal fibroblasts TIG-1 cells, and cervical cancer Hela cells using local elasticity mapping method of atomic force microscope. Especially we aimed at clarifying the regulatory mechanisms of sub-membrane actin structures in these cells by activation of actomyosin formation using calyculin A. This technique revealed that TIG-1 and Hela cells bore clearly different sub-membrane mechanical structures. TIG-1 cells had aligned stiff filamentous structures, whereas Hela cells had crooked and relatively soft filaments. The surface stiffness of TIG-1 cells increased slightly by actomyosin formation due to stiffness increase of the aligned filamentous structures. On the other hand, the surface stiffness of Hela cells increased by actomyosin formation due to upregulation of the apical actin filaments. Therefore, the structural and regulatory differences of the apical actin filaments could be demonstrated by atomic force microscopy elasticity mapping analysis.

The synthesis and antibacterial activity of (7S)-7-(5-aryl-1,3,4-thiadiazol-2-yl-thio)-7-deoxylincomycin derivatives are described. These derivatives were mainly prepared by the Mitsunobu reaction of 2,3,4-tris-O-(trimethylsilyl)lincomycin and the corresponding thiols. Exploring structure–activity relationships of the substituent at the 5 position of a thiadiazole ring revealed that compounds with the ortho substituted phenyl group showed improved antibacterial activities against Streptococcus pneumoniae and Streptococcus pyogenes with erm gene compared with the reported compound (1) that had an unsubstituted benzene ring.

The design and synthesis of novel 15-membered 11-azalides and 16-membered 11,12-diazalide starting from 16-membered macrolides are reported. A mobile linear dialdehyde was isolated via a cyclic tetraol which was prepared by osmium oxidation of a conjugated diene. One-pot macrocyclization of this dialdehyde with an amine or a diamine afforded corresponding 15-membered azalides or 11,12-diazalide. Fundamental SAR studies of 15-membered 11-azalides disclosed their potentiality as a lead molecule for further chemical modifications. For environmental preservation, sustainable chemistry for synthesis of these azalides is also discussed.

The molecular mechanisms of reduced susceptibility to cefixime in clinical isolates of Neisseria gonorrhoeae , particularly amino acid substitutions in mosaic penicillin-binding protein 2 (PBP2), were examined. The complete sequence of ponA , penA , and por genes, encoding, respectively, PBP1, PBP2, and porin, were determined for 58 strains isolated in 2002 from Japan. Replacement of leucine 421 by proline in PBP1 and the mosaic-like structure of PBP2 were detected in 48 strains (82.8%) and 28 strains (48.3%), respectively. The presence of mosaic PBP2 was the main cause of the elevated cefixime MIC (4- to 64-fold). In order to identify the mutations responsible for the reduced susceptibility to cefixime in isolates with mosaic PBP2, penA genes with various mutations were transferred to a susceptible strain by genetic transformation. The susceptibility of partial recombinants and site-directed mutants revealed that the replacement of glycine 545 by serine (G545S) was the primary mutation, which led to a two- to fourfold increase in resistance to cephems. Replacement of isoleucine 312 by methionine (I312M) and valine 316 by threonine (V316T), in the presence of the G545S mutation, reduced susceptibility to cefixime, ceftibuten, and cefpodoxime by an additional fourfold. Therefore, three mutations (G545S, I312M, and V316T) in mosaic PBP2 were identified as the amino acid substitutions responsible for reduced susceptibility to cefixime in N. gonorrhoeae .

The synthesis and biological evaluation of sixteen-membered macrolides modified at the C-3 position are described. 3-Epi-leucomycin A7 (9), 3-O-acyl-3-epi-leucomycin A7 analogues (11a-11e), 3-O-acylleucomycin A7 analogues (13b-13e) and 3-O-methylleucomycin analogues (16a, 16b and 22) were synthesized via fully protected intermediates (7, 5a, 5b and 20). After appropriate modification, subsequent deprotections were performed to furnish a variety of leucomycin analogues. Methylation of the 3-hydroxyl group was found to improve the pharmacoprofile of leucomycin antibiotics. 3-O-Methylrokitamycin (16b) showed enhanced antibacterial activity in vitro and 3,3''-di-O-methyl-4''-O-(3-methylbutyl)leucomycin V (22) exhibited improved metabolic stability in rat plasma in vitro.

In order to investigate the change in limb alignment in cases of knee flexion deformity, 17 male volunteers aged from 25 to 35 years with no complaints and no knee disorders were selected. The femorotibial angle (FTA), which is the lateral angle at the intersection between the femoral axis and the tibial axis in an anteroposterior radiograph, was employed as an index of limb alignment. FTA in standing on one leg with and without knee flexion was measured. The mean standing FTA was 179.4+/-19 degrees in full extension, which decreased to 176.9+/-2.5 degrees in a mean flexion position of 18+/-3.3 degrees (range 15-25 degrees ) (P0.002), and in all cases, standing FTA in flexion was smaller (more valgus-angulated) than that in full extension. There was a significant positive relationship with a straight regression line (D=0.101KFA + 0.296, R=0.8505) between the angle of knee flexion (KFA) and the difference (D) in standing FTA between full extension and knee flexion. We conclude that limb alignment became more valgus-angulated with an increase in flexion deformity.

Objective To assess the value of joint fluid analysis for determining cartilage degradation and prognosis in spontaneous osteonecrosis (ON) of the knee. Methods Synovial fluid was obtained from 30 knees with spontaneous ON (26 medial femoral condyles, 4 medial tibial plateaus) as well as from 50 knees with medial compartmental osteoarthritis (OA) as a control. Levels of chondroitin 6-sulfate (C6S), C4S, and hyaluronic acid were measured with high-performance liquid chromatography. The lesion size, appearance of the articular cartilage, and results of magnetic resonance imaging (MRI) were compared with the results of joint fluid analysis. Results The mean ± SD level of C6S was 82.2 ± 36.6 nmoles/ml in joint fluid from ON knees, which was significantly higher than the levels in knees with grade 2 (47.2 ± 20.0 nmoles/ml) and grade 3 (55.8 ± 29.2 nmoles/ml) OA. The C6S:C4S ratio was highest in lesions with mild articular changes and reflected the macroscopic alteration of cartilage overlying the ON lesion. The concentration of C6S in the 9 knees with lesions that covered ≥40% of the condyle (99.0 ± 32.9 nmoles/ml) was higher than that in the 17 knees with lesions that covered

The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31).

Although the literature supports a positive association between substance use and violence, scattered reports suggest a basis for predicting an inverse relationship. Using panel data (N = 2, 222) from subjects tested during early adolescence and three years later, we estimate structural equation models that specify within-wave relationships between substance use and violence constructs, stability of these constructs over time, and lagged effects of each construct on the other. As hypothesized, net of the within-wave positive relationships, substance use was inversely related to later violence. The findings support theoretical orientations that accommodate motivation to use substances to assuage distressful self-feelings (including those that instigate violence).

Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels-Alder reaction of the 3-vinylpyrrole 10 with dienophiles. Chuangxinmycin analogues were synthesized by using some of the functionalized 4-alkylthioindoles as key intermediates.

The nucleophilic addition reaction of N-tosyl-4-oxo-4,5,6,7-tetrahydroindole (12) with the lithium salt of 1-methoxyindole (5), followed by dehydration with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) gave the derivative of 2,4'-bi-1H-indole (9) which provides a new concise synthetic method of an indole pigment of the slime mould, arcyriacyanin A. The compound was first demonstrated here to have unique inhibitory activity to a panel of human cancer cell lines and to inhibit protein kinase C and protein tyrosine kinase.

A three dimensional (3D) analysis code of thermal birefringence in solid-state lasers was developed. Basic equations include thermal conduction, absorption of laser energy, thermal stress and thermal birefringence. Relative phase shifts induced by thermal effects measured and obtained by simulation are in good agreement with quantitatively. Edge effects of thermal birefringence are quantitatively estimated by 3D simulation. Those are unable to be estimated by 2D analysis.

AG205 was identified from high-throughput screening as a potent inhibitor of FabK, the enoyl-ACP reductase in Streptococcus pneumoniae . Specific inhibition of lipid biosynthesis in a macromolecular biosynthesis assay and identification of an Ala141Ser substitution in FabK from spontaneous AG205-resistant mutants indicated that AG205 exerts antibacterial activity against S. pneumoniae through the specific inhibition of FabK.

Sulfur substituted 3-vinylpyrrole 10 was prepared from 3-thio-acetylpyrrole 9 by alkylation with alkyl halide in the presence of propylene oxide. Functionalized 4-alkylthioindoles were made by Diels-Alder reaction of the 3-vinylpyrrole 10 with dienophiles. Chuangxinmycin analogues were synthesized by using some of the functionalized 4-alkylthioindoles as key intermediates.

The Stille coupling reaction of stannylindole 12 with 4-iodoimidazole 13 (or 24) in the presence of PdCl2(PPh3)2 gave the corresponding indole–imidazole coupling product 14 (or 25), thereby affording a new synthetic approach to the alkaloid granulatimide (7), isolated from the Brazilian ascidian Didemnum granulatum, as well as its structural analogues, 10-methylgranulatimide (23), 17-methylgranulatimide (30), 10,17-dimethylgranulatimide (31).

The design and synthesis of novel 14- to 16-membered 11-azalides starting from 16-membered macrolides are reported. A linear 9-formylcarboxylic acid was isolated via a mobile dialdehyde previously reported. Sequential macrocyclization of the formylcarboxylic acid with amino alcohol followed by deprotection afforded corresponding 14- to 16-membered azalides. On the other hand, reductive amination of the formylcarboxylic acid with an azidoamine followed by macrolactam formation with an amine generated from the azide gave 14- to 16-membered azalactams. Among these derivatives, 15-membered azalactams and 16-membered azalides exhibited characteristic in vitro antibacterial activities. Although optimization of 15-membered azalactams including demycarosyl analogues did not provide remarkably promising molecules, SAR studies of 16-membered azalides disclosed that substitution at the 15 position was very important for identification of a clinical candidate.

This clinical case report presents a new technique for reconstructing the vertical and horizontal dimensions of the alveolar ridge using a mandibular bone block at sites planned for single implants. Augmentation was eased with the use of a mandibular bone block, which was shaped after placement with a round bur to passively fit the dimensions of the defect, at the recipient site. After treatment, approximately 7 mm of horizontal and 3 mm of vertical augmentation were gained. Histologic observation showed that the grafted bone was well integrated with the original bone. The volume of tissue gained was sufficient for placing an implant in an optimal position. The gain in the vertical and horizontal dimensions allowed an esthetic result with a single-tooth crown.

The design and synthesis of 16-membered macrolides modified at the C-3 position are described. Starting from fully protected intermediate ( 5 ), appropriate modifications including Heck reaction were performed to furnish 3- O -(3-aryl-2-propenyl)leucomycin A 7 analogues ( 9a – 9m ). These leucomycin A 7 derivatives showed improved in vitro antibacterial activities against clinically important pathogens including erythromycin-resistant Streptococcus pneumoniae (ERSP). SAR analysis of derivatives modified at the C-3 and C-3″ positions suggested that single modification at C-3 or C-3″ was effective for in vitro antibacterial activity.

Design and synthesis of 16-membered macrolides modified at the C-12 and 13 positions are described. The compounds we report here have an arylalkylamino group attached to the C-12 position of the macrolactone. Both types of derivatives, 12,13-cyclic carbamates and non-carbamate analogues, were synthesized via 12-amino-13-hydroxy intermediates derived from 12,13-epoxide that was prepared by selective epoxidation at the C-12 and C-13 positions. 4′-Hydroxyl analogues were also prepared by acidic hydrolysis of a neutral sugar. These compounds were evaluated for in vitro antibacterial activity against respiratory tract pathogens. Some of these analogues exhibited an improved activity compared with the corresponding parent compound.

The design and synthesis of novel 15-membered 11-azalides and 16-membered 11,12-diazalide starting from 16-membered macrolides are reported. A mobile linear dialdehyde was isolated via a cyclic tetraol which was prepared by osmium oxidation of a conjugated diene. One-pot macrocyclization of this dialdehyde with an amine or a diamine afforded corresponding 15-membered azalides or 11,12-diazalide. Fundamental SAR studies of 15-membered 11-azalides disclosed their potentiality as a lead molecule for further chemical modifications. For environmental preservation, sustainable chemistry for synthesis of these azalides is also discussed.

4-Pyridone derivatives were identified as potent inhibitors of FabI, the enoyl-acyl carrier protein reductase in Escherichia coli and Staphylococcus aureus. 1-Substituted derivatives of a hit compound exhibited potent antibacterial activities against S. aureus. Target specificity of 4-pyridone derivatives was confirmed by the strong inhibition of lipid synthesis in macromolecular biosynthesis assay and also by the reduced antimicrobial activity against triclosan-resistant S. aureus isolates possessing a point mutation (Ala95Val) in FabI. Two 4-pyridone compounds exhibited strong antibacterial activities against 30 clinical isolates of methicillin-resistant S. aureus (MRSA) with MIC(90) of 0.5 and 2 mug/ml, respectively. Moreover, they retained activity against S. aureus with a mutation affecting FabI residue 204, which was recently found to be associated with triclosan resistance in clinical isolates of S. aureus. In conclusion, we have identified a novel chemical series, 4-pyridone derivatives, as specific inhibitors of FabI with potent antibacterial activity against S. aureus.

CCD is a continuum of MOS capacitors, so its big capacitance becomes one of the major disadvantages compared with CMOS image sensor, that cause not only large power dissipation but also other problems, such as generating an electro magnetic interference. We have developed a CCD linear image sensor with thin single-layer electrodes for the purpose of reducing the CCD capacitance. A two phase pulse drive CCD is fabricated with single layer poly Si electrode that has narrow electrode gaps and thinner electrode thickness. At the sensor that has 2.625um pitch 10k pixel linear array with a single sided CCD register, the coupling capacitance has been reduced to totally less than 40% compared to the conventional two layer CCD electrode structure, due to non electrode overlapping and thin thickness of the CCD electrodes. The total power consumption for CCD drive is reduced to 45% of conventional CCD and high transfer efficiency (>99%) is obtained at 20MHz. Moreover, the size of the area around CCD for the contact between electrode and clock applying wire is reduced by eliminating second layer electrode. The flatness above the silicon surface is also improved for better image quality.

The aim of this study was to examine the prognostic value of monitoring end-tidal carbon dioxide (ETCO(2)) levels for patients in cardiogenic shock undergoing percutaneous cardiopulmonary support (PCPS). Fifteen patients in whom PCPS was used to treat cardiogenic shock were enrolled in this study. For hemodynamic measurements, a thermodilution catheter was inserted into the pulmonary artery and an infrared absorption sensor was placed in the main stream of exhaled air between the respiration tube and the respirator to measure ETCO(2) levels. Nine patients (group II, 60%) died of multiple organ failure. In the six survivors (group I), there was a significant increase in average ETCO(2) level from 8.8 +/- 3.9 mmHg before treatment to 20.5 +/- 2.1 mmHg 24 h after the start of PCPS compared with values in group II patients (8.8 +/- 3.9 mmHg, P = 0.0411). Also, serum lactate concentrations fell significantly in group I patients (group I 2.8 +/- 0.47 mmol/l, group II 9.0 +/- 2.31 mmol/l, P = 0.0435). The mean ETCO(2) level in group I patients gradually returned to 23 mmHg, which was within the normal healthy range; these patients were successfully weaned from PCPS. These results suggest that, in cardiogenic shock patients, ETCO(2) level is a possible index of cardiac recovery during PCPS support.

The Stille coupling reaction of the stannylindole 13 with the 5-iodoimidazole derivative 14 (or 27) in the presence of PdCl(2)(PPh(3))(2) gave the corresponding indole-imidazole coupling product 15 (or 28), thereby affording a synthetic approach to 10-methylgranulatimide (7), 15-methylgranulatimide (11), and 10, 15-dimethylgranulatimide (12), as well as 10-methylisogranulatimide B (5).

Although antibiotic-loaded hydroxyapatite blocks have been used for the treatment of chronic osteomyelitis, their long-term potential for releasing antibiotic into human bones is not well known. Five patients with chronic osteomyelitis due to methicillin-resistant Staphylococcus aureus (MRSA) infection were effectively treated with local implantation of vancomycin-loaded hydroxyapatite blocks. Blocks were removed during the following reconstructive surgeries when the releasing capability of the blocks, and the bacteriocidal activity of the remaining vancomycin in these blocks could be evaluated. Vancomycin was rapidly released within 1 month after implantation, and by 3 months 90% of vancomycin had leaked from the blocks. At 18 months vancomycin still remained in a bacteriocidal form in the hydroxyapatite blocks, though the blocks had no releasing potential or the eluted vancomycin had been changed to a different form. Vancomycin-loaded porous hydroxyapatite blocks would be useful for the treatment of chronic osteomyelitis or implant-associated osteomyelitis due to MRSA.

A long-term follow-up study was performed on 75 knees of 53 patients after high tibial valgus osteotomy. The earlier results have previously been reported. There were 15 knees in 11 men and 60 knees in 42 women. The follow-up period ranged from 15 to 28 years with a mean of 19 +/- 3 years. The age at osteotomy ranged from 46 to 73 years with a mean of 59.6 +/- 6.7 years. The diagnosis was medial compartmental osteoarthritis (OA) in 68 knees (46 patients) and spontaneous osteonecrosis of the medial femoral condyle in 7 knees (7 patients). Valgus osteotomy was performed above the tibial tuberosity, with removal of a laterally based wedge in all cases, aiming for anatomical valgus angulation of 10 degrees . The American Knee Society Score showed a Knee Score of 37 +/- 20 and a Function Score of 38 +/- 16 preoperatively and 87 +/- 13 and 80 +/- 19 at the final 15 to 28 years' follow-up. The femoro-tibial angle in standing was 186 +/- 6.5 degrees (6 degrees of anatomical varus angulation) before and 171 +/- 7.5 degrees (9 degrees of anatomical valgus angulation) at final follow-up (p < 0.0001), with no apparent loss of limb alignment.

Hydrostatic pressure effect on chicken myofibrils was studied. Some of myofibrillar proteins were solubilized by pressure application above 200 MPa. Most of them were derived from thin filament; namely, actin, tropomyosin, and troponin components. Myosin heavy chain was hardly solubilized in 0.1 M NaCl, while its solubilization occurred in 0.2 M NaCl at 200–300 MPa. Solubilization of myosin dependend on magnitude of applied pressure and duration of treatment, and also salt concentration and pH. The maximal solubilization of myosin occurred at 200 MPa in 0.2 M NaCl at pH 7. Myofibrils in 0.1–0.2 M NaCl with a protein concentration of 40 mg/ml formed a gel by pressure application. The gel strength at 0.1 M NaCl increased with pressure, while it remained almost at the same level in 0.2 M NaCl. The intrinsic structure of myofibril was retained after pressure treatment in 0.1 M NaCl; however, pressure-induced disruption of myofibrillar structure occurred in 0.2 M NaCl.

In the present study, the adjuvant effect of zymosan on human immunodeficiency virus type-1 (HIV-1)-specific DNA vaccine and the mechanism of this enhancement were studied in a murine model. We coinoculated zymosan with our candidate HIV-1 specific DNA vaccine (pCMV160IIIB) into skeletal muscles of BALB/c mice. Higher levels of both humoral immune response and HIV-specific delayed-type hypersensitivity (DTH) response were observed when zymosan was coinoculated with pCMV160IIIB compared with that obtained using pCMV160IIIB alone. HIV-specific cytotoxic T lymphocyte (CTL) activity was also enhanced. This enhancing activity was suppressed when coinoculated to the fifth complement (C5)-deficient DDD and AKR mice. The enhanced activity was also suppressed when anti-C3 antibody was inoculated to mice intramuscularly. There was significant induction of immunoglobulin G2a (IgG2a) and interferon-gamma (IFN-gamma) in pCMV160IIIB vaccine with zymosan. These results suggest that zymosan-mediated DNA vaccination enhances helper T cell (Th) 1-mediated immunity. The effect is suggested to be based on the consequences of its recruitment and activation of macrophages, dendritic cells or antigen-presenting cells (APC) through complement activation, especially through the alternative pathway. Taken together, these results suggest that zymosan can be an effective immunological adjuvant in DNA vaccination against HIV-1.

We report the high-sensitivity measurements of 2D thermal birefringence distribution in LD pumped Nd:glass (HAP4) laser under lasing at 1054 nm and non lasing conditions. The thermal birefringence was reduced under the lasing condition compared to the non lasing condition. By inserting a 90 degree(s) quartz rotator between two identically LD pumped Nd:glass rods, almost perfect birefringence compensation was achieved with very little residual birefringence. A considerable reduction of birefringence loss from over 20% before compensation to less than 1% after compensation was observed.

— A full-color eyewear display with over 85% see-through transmittance with a 16° horizontal field of view was developed. Very low color crosstalk, less than 0.008 Δu′v′ uniformity, and 120% NTSC color gamut were achieved. Waveguides with two in- and out-coupling reflection volume hologram elements enabled a simple configuration that has an optical engine beside the user's temples. The reflection volume hologram elements used on the waveguides realized a small thickness of 1.4 mm for each waveguide, and an out-coupling reflection volume hologram used as an optical combiner contributed a high see-through transmittance of 85% due to its wavelength selectivity. However, there are technical challenges in achieving a reasonable screen size and quality color images with optics that utilize holographic waveguides because holograms have large chromatic dispersions compared to conventional optical elements such as lenses and mirrors. Approaches to overcome these issues are described.