Quantum frequency conversion using 4-port fiber-pigtailed PPLN module.

Quantum frequency conversion (QFC), which involves the exchange of frequency modes of photons, is a prerequisite for quantum interconnects among various quantum systems, primarily those based on telecom photonic network infrastructures. Compact and fiber-closed QFC modules are in high demand for such applications. In this paper, we report such a QFC module based on a fiber-coupled 4-port frequency converter with a periodically poled lithium niobate (PPLN) waveguide. The demonstrated QFC shifted the wavelength of a single photon from 780 to 1541 nm. The single photon was prepared via spontaneous parametric down-conversion (SPDC) with heralding photon detection, for which the cross-correlation function was 40.45 ± 0.09. The observed cross-correlation function of the photon pairs had a nonclassical value of 13.7 ± 0.4 after QFC at the maximum device efficiency of 0.73, which preserved the quantum statistical property. Such an efficient QFC module is useful for interfacing atomic systems and fiber-optic communication.

N-Heterocyclic Carbenes with Polyfluorinated Groups at the 4- and 5-Positions from [3 + 2] Cycloadditions between Formamidinates and cis-1,2-Difluoroalkene Derivatives.

We herein report the formation of fluorinated N-heterocyclic carbenes (NHCFs) that bear fluorine atoms at the 4- and 5-positions of the imidazol-2-ylidene ring. Treatment of sodium N,N'-bis(aryl)formamidinates with tetrafluoroethylene followed by the addition of LiBF4 induced a [3 + 2] cycloaddition to afford 4,5-difluorinated imidazolium salts, which served as the precursors for 4,5-difluorinated NHCs. A key feature of this procedure is its applicability to other perfluorinated compounds, which enabled us to incorporate polyfluorinated functional groups at 4- and 5-positions on the imidazol-2-ylidene skeleton. Thus, employing octafluorocyclopentene and hexafluorobenzene led to the formation of 4,4,5,5,6,6-hexafluoro-1,3-diaryl-3,4,5,6-tetrahydrocyclopenta[d]imidazolium (CypIPrF·HBF4) and 4,5,6,7-tetrafluoro-1,3-diarylbenzimidazolium (BIPrF·HBF4) salts, respectively. A thorough NMR analysis of these NHCFs, their selenium adducts, and their tricarbonyl nickel complexes, (NHCF)Ni(CO)3, demonstrated that the fluorine substituents, contrary to expectations, tend to act as electron donors owing to the considerable positive mesomeric effect, while the perfluorocyclopentene-fused and tetrafluorobenzo-fused rings are pure electron acceptors due to their strong negative inductive effect. The unique and increased π-accepting character of the perfluorocyclopentene-fused and tetrafluorobenzo-fused NHCFs in both stoichiometric and catalytic reactions is further demonstrated by employing (NHCF)Ni(CO)3 and (NHCF)AuCl species, respectively. Moreover, an analysis of the % buried volume (%Vbur) values clearly suggests that the modification of the NHC backbone with polyfluorinated groups can drastically alter the electronic properties of the NHC ligand without substantially changing its steric properties. Our experimental results were further corroborated by a series of computational calculations.

Environmental monitoring of trace elements and evaluation of environmental impacts to organisms near a former uranium mining site in Nigyo-toge, Japan.

This study was conducted to find out characteristics of trace element levels and those impacts to organisms at a former uranium (U) mining site. Concentrations of trace elements (Li, Mg, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, As, Se, Rb, Sr, Mo, Cd, Cs, Ba, Pb, Bi, and U) were determined in sediments, water, and three organism types (insects, frogs, and newts) from three zones in the former U mining site, Ningyo-toge in Japan. Concentrations of As and U in the sediments and water samples were the highest at the mill tailings pond (MP) site, where post-U extraction remnants have been accumulated. Additionally, among the organisms analyzed the highest concentrations of these elements/isotopes were found in newts from MP. Considering data analyses of the whole-body element concentrations, bioaccumulation factors, and δ15N values for the organisms, it was concluded that newts might be the most vulnerable species in this location. Further monitoring and more accurate evaluation of the ecological impacts are preferred for this former U mining site.

Periostin plays a critical role in the cell cycle in lung fibroblasts.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with a median survival of only three to 5 years. Fibroblast proliferation is a hallmark of IPF as is secretion of extracellular matrix proteins from fibroblasts. However, it is still uncertain how IPF fibroblasts acquire the ability to progressively proliferate. Periostin is a matricellular protein highly expressed in the lung tissues of IPF patients, playing a critical role in the pathogenesis of pulmonary fibrosis. However, it remains undetermined whether periostin affects lung fibroblast proliferation. METHODS: In this study, we first aimed at identifying periostin-dependently expressed genes in lung fibroblasts using DNA microarrays. We then examined whether expression of cyclins and CDKs controlling cell cycle progression occur in a periostin-dependent manner. We next examined whether downregulation of cell proliferation-promoting genes by knockdown of periostin or integrin, a periostin receptor, using siRNA, is reflected in the cell proliferation of lung fibroblasts. We then looked at whether lung fibroblasts derived from IPF patients also require periostin for maximum proliferation. We finally investigated whether CP4715, a potent inhibitor against integrin αVß3 (a periostin receptor), which we have recently found blocks TGF-ß signaling, followed by reduced BLM-induced pulmonary fibrosis in mice, can block proliferation of lung fibroblasts derived from IPF patients. RESULTS: Many cell-cycle-related genes are involved in the upregulated or downregulated genes by periostin knockdown. We confirmed that in lung fibroblasts, periostin silencing downregulates expression of several cell-cycle-related molecules, including the cyclin, CDK, and, E2F families, as well as transcription factors such as B-MYB and FOXM1. Periostin or integrin silencing slowed proliferation of lung fibroblasts and periostin silencing increased the distribution of the G0/G1 phase, whereas the distribution of the G2/M phase was decreased. Lung fibroblasts derived from IPF patients also required periostin for maximum proliferation. Moreover, CP4715 downregulated proliferation along with expression of cell-cycle-related genes in IPF lung fibroblasts as well as in normal lung fibroblasts. CONCLUSIONS: Periostin plays a critical role in the proliferation of lung fibroblasts and the present results provide us a solid basis for considering inhibitors of the periostin/integrin αVß3 interaction for the treatment of IPF patients.

Concentration ratios of 238U and 226Ra for insects and amphibians living in the vicinity of the closed uranium mine at Ningyo-toge, Japan.

There is still a scarcity of data on the transfer of naturally occurring radionuclides to wildlife in various ecosystems. In the present study, concentration ratios (CRwo-media) of 238U and 226Ra were obtained for grasshoppers, frogs and newts in terrestrial and freshwater ecosystems. Soil, water and animal samples were collected for 2 years in the vicinity of the closed uranium mine at Ningyo-toge, Japan. Three sites with different 238U and 226Ra levels were of interest: (i) pond and its shore (PO); (ii) low-level stream and its shore near overburden dump (OD); and (iii) uranium mill tailings pond and its shore (MP). The activity concentrations in both soil and water were PO ≈ OD < MP for 238U, and PO < OD < MP for 226Ra. Regarding the wildlife, 238U was able to be determined for all samples, but the detection of 226Ra was observed only for part of the samples. The means and standard deviations of CRwo-soil or CRwo-water were then calculated and may indicate the insignificant dependence of CRwo-media on environmental conditions characterized by the tested sites. The present data on CRwo-media were compared to the corresponding data or surrogate data from the IAEA's database, showing both agreement and discrepancy. Our data contribute to enhancing the available data for those radionuclides and animals. In particular, the transfer to amphibians, one of the main links in common food webs, is reported here for the first time.

Cross-Talk between Transforming Growth Factor-ß and Periostin Can Be Targeted for Pulmonary Fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized as progressive and irreversible fibrosis in the interstitium of lung tissues. There is still an unmet need to develop a novel therapeutic drug for IPF. We have previously demonstrated that periostin, a matricellular protein, plays an important role in the pathogenesis of pulmonary fibrosis. However, the underlying mechanism of how periostin causes pulmonary fibrosis remains unclear. In this study, we sought to learn whether the cross-talk between TGF-ß (transforming growth factor-ß), a central mediator in pulmonary fibrosis, and periostin in lung fibroblasts leads to generation of pulmonary fibrosis and whether inhibitors for integrin αVß3, a periostin receptor, can block pulmonary fibrosis in model mice and the TGF-ß signals in fibroblasts from patients with IPF. We found that cross-talk exists between TGF-ß and periostin signals via αVß3/ß5 converging into Smad3. This cross-talk is necessary for the expression of TGF-ß downstream effector molecules important for pulmonary fibrosis. Moreover, we identified several potent integrin low-molecular-weight inhibitors capable of blocking cross-talk with TGF-ß signaling. One of the compounds, CP4715, attenuated bleomycin-induced pulmonary fibrosis in vivo in mice and the TGF-ß signals in vitro in fibroblasts from patients with IPF. These results suggest that the cross-talk between TGF-ß and periostin can be targeted for pulmonary fibrosis and that CP4715 can be a potential therapeutic agent to block this cross-talk.

In vitro and in vivo antimicrobial activity of TS2037, a novel aminoglycoside antibiotic.

To overcome serious methicillin-resistant Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa infections, we synthesized TS2037, 5,4″-diepi-arbekacin, a novel aminoglycoside antibiotic, and evaluated its biological properties. TS2037 showed broad-range, as well as robust antibacterial activities against Gram-positive and Gram-negative bacteria. The MIC50 and MIC90 of TS2037 against clinical isolates of MRSA (n = 54) were both 0.25 µg/mL, and no resistant strain was observed. The MIC50 and MIC90 of TS2037 against clinical isolates of P. aeruginosa (n = 54) were 1 and 4 µg/mL, respectively. TS2037 and arbekacin, anti-MRSA aminoglycoside, were more stable against AAC(6')-APH(2″), aminoglycoside-6'-N-acetyltransferase and 2″-O-phosphotransferase, produced by resistant S. aureus than gentamicin. Therapeutic efficacies of TS2037 in the mouse models of systemic infection with MRSA were superior to those of arbekacin, vancomycin, and linezolid. The efficacy of TS2037 against systemic infection caused by P. aeruginosa producing AAC(6')-II was superior to those of arbekacin and amikacin. In the nephrotoxicity risk screening, the release of free N-acetyl-ß-D-glucosaminidase from the kidney epithelial cell line after treatment with TS2037 at 2.5 and 5.0 µM were 2.0 and 2.1 (U/L), respectively, which were about two times higher than those of arbekacin. In conclusion, TS2037 exhibited the most potent antibacterial activity among aminoglycosides tested against both MRSA and P. aeruginosa in vitro and in vivo, although its nephrotoxicity risk remains to be improved.

Evaluation of four antiseptics using a novel murine norovirus.

We isolated a novel murine norovirus (MNV), MT30-2 strain, from feces of conventional mice in Japan to evaluate the virucidal activity of four antiseptics. The MNV MT30-2 strain was inactivated by as little as 0.2% (w/v) povidone-iodine (PVP-I) and 0.1% (w/v) sodium hypochlorite (NaOCl) treatment as determined by a novel plaque assay. Importantly, PVP-I reduced the MNV titer by 4 log(10) within 15 s of exposure. The other two antiseptics, benzethonium chloride (BEC) and chlorhexidine gluconate (CHG), did not reduce the MNV titer even when treatment lasted for 60 s. When the virus titer was reduced by PVP-I or NaOCl treatment, the amount of MNV RNA was not reduced, indicating that the presence of viral RNA was not related to the virucidal activity of the antiseptics. PVP-I and NaOCl will be useful in controlling the spread of MNV, which is a common problem in mice colonies. In this study, we isolated a novel MNV and newly revealed that two antiseptics (PVP-I and NaOCl) were able to inactivate MNV at low concentrations and in a short contact time.

ME3738 enhances the effect of interferon and inhibits hepatitis C virus replication both in vitro and in vivo.

BACKGROUND & AIMS: ME3738 (22ß-methoxyolean-12-ene-3ß, 24-diol), a derivative of soyasapogenol B, attenuates liver disease in several animal models of acute and chronic liver injury. ME3738 is thought to inhibit replication of hepatitis C virus (HCV) by enhancing interferon (IFN)-ß production, as determined using the HCV full-length binary expression system. We examined the effect of ME3738 combined with IFN-α on HCV replication using the genotype 1b subgenomic replicon system and an in vivo mouse HCV model. METHODS: HCV replicon cells (ORN/3-5B/KE cells and Con1 cells) were incubated with ME3738 and/or IFN-α, and then intracellular IFN-stimulated genes (ISGs) and HCV RNA replication were analyzed by reverse-transcription-real time polymerase chain reaction and luciferase reporter assay. HCV-infected human hepatocyte chimeric mice were also treated with ME3738 and/or IFN-α for 4 weeks. Mouse serum HCV RNA titer, HCV core antigen, and ISGs expression in the liver were measured. RESULTS: ME3738 induced gene expression of oligoadenylate synthetase 1 and inhibited HCV replication in both HCV replicon cells. The drug enhanced the effect of IFN to significantly increase ISG expression levels, inhibit HCV replication in replicon cells, and reduce mouse serum HCV RNA and core antigen levels in mouse livers. The combination treatment was not hepatotoxic as evident histologically and did not reduce human serum albumin in mice. CONCLUSIONS: ME3738 inhibited HCV replication, enhancing the effect of IFN-α to increase ISG expression both in vitro and in vivo, suggesting that the combination of ME3738 and IFN might be useful therapeutically for patients with chronic hepatitis C.

Tricyclic pharmacophore-based molecules as novel integrin alphavbeta3 antagonists. Part IV: preliminary control of alphavbeta3 selectivity by meta-oriented substitution.

To establish the in vivo efficacy of alphavbeta3/alphaIIbbeta3 dual antagonists possessing a tricyclic pharmacophore, a corresponding alphavbeta3-selective antagonist was required as a control. We initially took two synthetic approaches to obtain alphavbeta3-selective antagonists based on the RGD recognition pattern or on modification of the dihedral angle between the central benzene ring and the adjacent heterocycle, but both proved unsuccessful. However, synthesis of novel antagonists with meta-substitution of the central benzene ring generated weak selectivity for alphavbeta3 over alphaIIbbeta3 for the first time in the family of compounds with the tricyclic pharmacophore. Optimization of meta-oriented antagonists furnished an alphavbeta3-selective antagonist exhibiting inhibitory activity not only in a receptor-binding assay, but also in a cell adhesion assay.

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part III: synthesis of potent antagonists with alpha(v)beta3/alpha(IIb)beta3 dual activity and improved water solubility.

In order to optimize our novel integrin alpha(v)beta3/alpha(IIb)beta3 dual antagonists, spatial screening at the N-terminus was performed. The alpha(v)beta3 antagonistic activity varied depending on the space that was occupied by the N-terminus, but high potency against alpha(IIb)beta3 was well maintained. The (3S)-aminopiperidine analogue had the strongest activity against alpha(v)beta3, and the S isomer at piperidine was more potent than the R isomer. Compounds selected on the basis of SAR analysis of a novel lead compound showed acceptable early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profiles and sufficient water solubility for use as infusion drugs. Docking studies with the alpha(v)beta3 receptor were performed to confirm the SAR findings.

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 1: design and synthesis of a lead compound exhibiting alpha(v)beta3/alpha(IIb)beta3 dual antagonistic activity.

In order to generate novel compounds with integrin alpha(v)beta3-antagonistic activity together with antiplatelet activity, tricyclic pharmacophore-based molecules were designed and synthesized. Although piperazine-containing compounds initially prepared were selective alpha(IIb)beta3 antagonists, replacement of piperazine with piperidine furnished a potent alpha(v)beta3/alpha(IIb)beta3 dual antagonist. Structure-activity relationship (SAR) studies provided clues for further development of tricyclic pharmacophore-based integrin antagonists.

Tricyclic pharmacophore-based molecules as novel integrin alpha(v)beta3 antagonists. Part 2: synthesis of potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists.

We synthesized 4-aminopiperidine derivatives of our prototype integrin alpha(v)beta3 antagonist 1 in an attempt to increase the activity and water solubility. Introduction of one or two hydrophilic moieties into the central aromatic ring and/or the benzene ring at the C-terminus of 1 increased water solubility and enhanced inhibition of cell adhesion. The results of a structure-activity relationships (SAR) study indicated that the torsion angle between the central aromatic ring and the piperidine ring, and the acidity at the sulfonamide moiety, might be important for alpha(v)beta3 receptor binding activity. Some of these compounds are novel and potent alpha(v)beta3/alpha(IIb)beta3 dual antagonists with acceptable water solubility and a satisfactory early absorption, distribution, metabolism, excretion, and toxicity (ADMET) profile.

A proof of the specificity of kanamycin-ribosomal RNA interaction with designed synthetic analogs and the antibacterial activity.

The binding specificity of designed synthetic kanamycins with model RNA sequences (wild-type and point-mutated type) derived from the 16S ribosomal A-site was evaluated using surface plasmon resonance imaging. It was observed that kanamycins have nonspecific and multiple interactions with RNA hairpins and that the binding potency is not always proportional to the antimicrobial activity.