Ion-ion coincidence studies on multiple ionizations of N(2) and O(2) molecules irradiated by extreme ultraviolet free-electron laser pulses.

We have investigated multiple ionization of N(2) and O(2) molecules by 52 nm extreme-ultraviolet light pulses at the free-electron laser facility SCSS in Japan. Coulomb break-up of parent ions with charge states up to 5+ is found by the ion-ion coincidence technique. The charge-state dependence of kinetic energy release distributions suggests that the electrons are emitted sequentially in competition with the elongation of the bond length.

Synthesis and antiviral activity of novel anti-VZV 5-substituted uracil nucleosides with a cyclopropane sugar moiety.

A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and 3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.

Synthesis and antiviral activity of novel acyclic nucleosides: discovery of a cyclopropyl nucleoside with potent inhibitory activity against herpesviruses.

A series of acyclic nucleosides with two hydroxymethyl groups mimicking the 3'- and 5'-hydroxyl groups of the 2'-deoxyribose moiety were prepared and evaluated for their antiherpetic activity. Among those, 9-[[cis-1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (3) showed extremely potent antiviral activity against herpes simplex virus type-1 (HSV-1) with good selectivity. Both enantiomers of 3 were synthesized starting from chiral epichlorohydrins, and only one of the enantiomers with 1'S,2'R-configuration (3a) exhibited strong antiherpetic activity (IC50 of 0.020 microg/mL against HSV-1 Tomioka vs 0.81 microg/mL for acyclovir). Enantiomer 3a was also more inhibitory than acyclovir against varicella-zoster virus (VZV) but ineffective against human immunodeficiency virus (HIV). Compound 3a is phosphorylated by HSV-1 thymidine kinase (TK) very efficiently. The relationship between conformation and antiherpetic activity in this series of compounds is discussed.

Evaluation of anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]- guanine (A-5021) in mice.

The anti-herpesvirus activity of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guani ne (A-5021) was evaluated in murine cells and in several murine models of herpes simplex virus (HSV) infection. Against HSV type 1 (HSV-1), A-5021 was 15-30- and 30-60-fold more active, and against HSV type 2 (HSV-2), it was 2- and 8-fold more active than acyclovir and penciclovir in Balb/3T3 cells, respectively. When antiviral compounds were administered orally (once daily) to mice infected intraperitoneally with HSV-1 (Tomioka), A-5021 was more active than acyclovir or famciclovir in spite of its relatively low oral bioavailability. A-5021 was as active as penciclovir when the antiviral compounds were given intravenously (three times daily) to mice infected intraperitoneally with HSV-2 (186). In mice with a cutaneous HSV-1 (KOS) infection, three times daily oral therapy with A-5021 at 25 mg/kg per day produced more significant reduction in severity of skin lesions than equivalent treatment with acyclovir or famciclovir. In mice infected intracerebrally with HSV-1 (Tomioka), complete survival was observed in the group treated intravenously with A-5021 at 25 mg/kg per day (three times daily), while more than 50% of mice died in the groups treated intravenously with acyclovir of up to 100 mg/kg per day (three times daily). Moreover, A-5021 was more effective than acyclovir in clearing infectious virus from the brain. These findings demonstrate that A-5021 has potent anti-HSV activity in several murine models.

Two-source double-slit interference in angle-resolved high-energy above-threshold ionization spectra of diatoms.

When an electron from a diatomic molecule undergoes tunneling-rescattering ionization, a novel form of destructive interference can be realized that involves all four geometric orbits that are available to the electron when it is freed, because both ionization and rescattering may take place at the same or at different centers. We find experimentally and confirm theoretically that in orientation-averaged angle-resolved high-order above-threshold ionization spectra the corresponding destructive interference is visible for O_{2} but not for N_{2}. This effect is different from the suppression of ionization that is well known to occur for O_{2}.

Cold-target recoil-ion momentum spectroscopy for diagnostics of high harmonics of the extreme-ultraviolet free-electron laser light source at SPring-8.

We have developed a cold-target recoil-ion momentum spectroscopy apparatus dedicated to the experiments using the extreme-ultraviolet light pulses at the free-electron laser facility, SPring-8 Compact SASE Source test accelerator, in Japan and used it to measure spatial distributions of fundamental, second, and third harmonics at the end station.

Experimental retrieval of target structure information from laser-induced rescattered photoelectron momentum distributions.

We have measured two-dimensional photoelectron momentum spectra of Ne, Ar, and Xe generated by 800-nm, 100-fs laser pulses and succeeded in identifying the spectral ridge region (back-rescattered ridges) which marks the location of the returning electrons that have been backscattered at their maximum kinetic energies. We demonstrate that the structural information, in particular the differential elastic scattering cross sections of the target ion by free electrons, can be accurately extracted from the intensity distributions of photoelectrons on the ridges, thus effecting a first step toward laser-induced self-imaging of the target, with unprecedented spatial and temporal resolutions.

Probing molecular symmetry effects in the ionization of N2 and O2 by intense laser fields.

High-resolution electron spectroscopy is used to explore the role played by molecular symmetry in determining the morphology of the energy spectra of electrons ejected when N2 and O2 are irradiated by intense laser fields. In O2, the low-energy part of the electron spectrum is curtailed due to the destructive interference brought about by the antibonding nature of the O2 valence orbital. The high-energy tail of the spectrum is also suppressed by virtue of electron rescattering being of little consequence in O2. In contrast, in N2, which has a bonding valence orbital, the electron dynamics follow the pattern that has been established for atomic ionization in strong optical fields.

Ionization of linear alcohols by strong optical fields.

We have experimentally probed the strong-field ionization dynamics of gas-phase linear alcohols, methanol, ethanol, and 1-propanol, by irradiating them with intense, femtosecond-duration laser pulses of 800 and 400 nm wavelength. Specifically, we make high resolution measurements of the energies of electrons that are ionized by the action of the optical field. Our electron spectroscopy measurements enable us to bifurcate the dynamics into multiphoton ionization and tunneling ionization regimes. In the case of 800 nm irradiation, such bifurcation into different ionization regimes is reasonably rationalized within the framework of the adiabaticity parameter based on the original Keldysh-Faisal-Reiss model of atomic ionization, without recourse to any structure-dependent modifications to the theory. In that sense, our 800 nm spectroscopy indicates that the linear alcohols exhibit atom-like properties as far as strong field ionization dynamics in the multiphoton ionization and tunneling regimes are concerned. We also explore the limitations of this atom-like picture by making measurements with 400 nm photons wherein the ponderomotive potential experienced by the ionized electrons is much less than the photon energy; effects that are purely molecular then appear to influence the strong field dynamics.

Longitudinal study on occlusal force distribution in lower distal-extension removable partial dentures with circumferential clasps.

In this study, longitudinal changes of the occlusal force distribution ratio were examined in lower distal extension removable partial dentures with cast circumferential clasps. Occlusal force applied to the denture base and forces transmitted to the retainers were measured on several separate occasions from the insertion of new dentures to about 4 months after. Two rates of loading were chosen. One was simulated mastication (fast loading rate) and the other was 10 Ns-1 (slow loading rate). Location of the loading points were first premolar (P1), second premolar (P2) and first molar (P3) of the denture. The occlusal force distribution ratio to the retainers was calculated when a load of 20N was applied to the loading point. The results are summarized as follows: (1) The occlusal force distribution ratio at fast loading rate on P1 and P2 was changed until 1 or 1 1/2 months after the insertion of the new dentures, and then became constant. This constant value was 30% on P1, 20% on P2 and 10% on P3. (2) Slow loading rate produced a greater ratio than the fast loading rate on P2 and P3 while there were no remarkable differences in the ratio between both loading rates on P1.

Longitudinal study on forces transmitted from denture base to retainers of lower distal-extension removable partial dentures with conus crown telescopic system.

The purpose of this study was to perform longitudinal measurement of forces transmitted from the denture base to retainers of lower distal-extension removable partial dentures with a conus crown telescopic system. The experimental denture was embedded with a force-detecting unit which could detect a change in lateral and vertical forces transmitted from denture base to retainers at the same time. Forces were measured during chewing of food on several separate occasions from the insertion of new dentures to about 3 months after. Max.ver (maximal mean value of vertical force) and Max.lat (maximal mean value of lateral force) were calculated from the peak level of all strokes of chewing of food at the minimum of the interocclusal distance. The results are summarized as follows: (i) There were no significant changes of Max.ver and Max.lat; (ii) There were no significant differences of Max.ver between subjects the value of which was about 20 N; (iii) There were significant differences of Max.lat between subjects the value of which was less than 15 N.

Mode of action of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl) cycloprop-1'-yl]methyl]guanine (A-5021) against herpes simplex virus type 1 and type 2 and varicella-zoster virus.

The mode of action of (1'S,2'R)-9-([1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl)guanine (A-5021) against herpes simplex virus type 1 (HSV-1), HSV-2, and varicella-zoster virus (VZV) was studied. A-5021 was monophosphorylated at the 2' site by viral thymidine kinases (TKs). The 50% inhibitory values for thymidine phosphorylation of A-5021 by HSV-1 TK and HSV-2 TK were comparable to those for penciclovir (PCV) and lower than those for acyclovir (ACV). Of these three agents, A-5021 inhibited VZV TK most efficiently. A-5021 was phosphorylated to a mono-, di-, and triphosphate in MRC-5 cells infected with HSV-1, HSV-2, and VZV. A-5021 triphosphate accumulated more than ACV triphosphate but less than PCV triphosphate in MRC-5 cells infected with HSV-1 or VZV, whereas HSV-2-infected MRC-5 cells had comparable levels of A-5021 and ACV triphosphates. The intracellular half-life of A-5021 triphosphate was considerably longer than that of ACV triphosphate and shorter than that of PCV triphosphate. A-5021 triphosphate competitively inhibited HSV DNA polymerases with respect to dGTP. Inhibition was strongest with ACV triphosphate, followed by A-5021 triphosphate and then (R,S)-PCV triphosphate. A DNA chain elongation experiment revealed that A-5021 triphosphate was incorporated into DNA instead of dGTP and terminated elongation, although limited chain extension was observed. Thus, the strong antiviral activity of A-5021 appears to depend on a more rapid and stable accumulation of its triphosphate in infected cells than that of ACV and on stronger inhibition of viral DNA polymerase by its triphosphate than that of PCV.

Antiherpesvirus activities of (1'S,2'R)-9-[[1',2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]guanine (A-5021) in cell culture.

Antiherpetic activity of (1'S,2'R)-9-([1',2'-bis(hydroxymethyl)cycloprop-1'yl]methyl)guanine (A-5021) was compared with those of acyclovir (ACV) and penciclovir (PCV) in cell cultures. In a plaque reduction assay using a selection of human cells, A-5021 showed the most potent activity in all cells. Against clinical isolates of herpes simplex virus type 1 (HSV-1, n = 5) and type 2 (HSV-2, n = 6), mean 50% inhibitory concentrations (IC50s) for A-5021 were 0.013 and 0.15 microgram/ml, respectively, in MRC-5 cells. Corresponding IC50s for ACV were 0.22 and 0.30 microgram/ml, and those for PCV were 0.84 and 1.5 micrograms/ml, respectively. Against clinical isolates of varicella-zoster virus (VZV, n = 5), mean IC50s for A-5021, ACV, and PCV were 0.77, 5.2, and 14 micrograms/ml, respectively, in human embryonic lung (HEL) cells. A-5021 showed considerably more prolonged antiviral activity than ACV when infected cells were treated for a short time. The selectivity index, the ratio of 50% cytotoxic concentration to IC50, of A-5021 was superior to those of ACV and PCV for HSV-1 and almost comparable for HSV-2 and VZV. In a growth inhibition assay of murine granulocyte-macrophage progenitor cells, A-5021 showed the least inhibitory effect of the three compounds. These results show that A-5021 is a potent and selective antiviral agent against HSV-1, HSV-2, and VZV.