Watt-level green random laser at 532 nm by SHG of a Yb-doped fiber laser.

We have developed a watt-level random laser at 532 nm. The laser is based on a 1064 nm random distributed ytterbium (Yb) gain-assisted fiber laser seed with a 0.35 nm linewidth and 900 mW polarized output power. A study for the optimal length of the random distributed mirror was carried out. A Yb-doped fiber master oscillator power amplifier architecture is used to amplify the random seeder laser without additional spectral broadening up to 20 W. By using a periodically poled lithium niobate crystal in a single-pass configuration, we generate in excess of 1 W random laser at 532 nm by second-harmonic generation (SHG) with an efficiency of 9%. The green random laser exhibits an instability <1%, an optical signal-to-noise ratio >70 dB, a 0.1 nm linewidth, and excellent beam quality.

Watt-level narrow-linewidth fibered laser source at 852 nm for FIB application.

We realize a 1 W all-fibered polarized compact and robust laser source at 852 nm for laser cooling of cesium atoms. The architecture is based on the sum-frequency generation of 1540 and 1908 nm lasers, realized through a periodically poled lithium niobate waveguide with a conversion efficiency of 40%. A linewidth of 20 kHz is achieved with the development of a distributed feedback fiber laser at 1908 nm. The operation of this laser source is demonstrated on a focused ion beam (FIB) experiment based on cold cesium atoms.

Watt-level single-frequency tunable neodymium MOPA fiber laser operating at 915-937 nm.

We have developed a Watt-level single-frequency tunable fiber laser in the 915-937 nm spectral window. The laser is based on a neodymium-doped fiber master oscillator power amplifier architecture, with two amplification stages using a 20 mW extended cavity diode laser as seed. The system output power is higher than 2 W from 921 to 933 nm, with a stability better than 1.4% and a low relative intensity noise.

High-energy femtosecond fiber laser at 976 nm.

We report on a passively mode-locked fiber laser emitting around 976nm. The self-starting mode locking is achieved in an unidirectional ring cavity by means of nonlinear polarization evolution. Stable single-pulse operation is observed for 480mW of average output power. This all-normal dispersion laser generates naturally chirped pulses with 1ps duration. The repetition rate is 40.6MHz, resulting in 12nJ pulse energy. External compression using bulk grating shortens the pulse duration down to 286fs.

Magnetism in iridate heterostructures leveraged by structural distortions.

Fundamental control of magnetic coupling through heterostructure morphology is a prerequisite for rational engineering of magnetic ground states. We report the tuning of magnetic interactions in superlattices composed of single and bilayers of SrIrO3 inter-spaced with SrTiO3 in analogy to the Ruddlesden-Popper series iridates. Magnetic scattering shows predominately c-axis antiferromagnetic orientation of the magnetic moments for the bilayer, as in Sr3Ir2O7. However, the magnetic excitation gap, measured by resonant inelastic x-ray scattering, is quite different between the two structures, evidencing a significant change in the stability of the competing magnetic phases. In contrast, the single layer iridate hosts a more bulk-like gap. We find these changes are driven by bending of the c-axis Ir-O-Ir bond, which is much weaker in the single layer, and subsequent local environment changes, evidenced through x-ray diffraction and magnetic excitation modeling. Our findings demonstrate how large changes in the magnetic interactions can be tailored and probed in spin-orbit coupled heterostructures by engineering subtle structural modulations.

Experimental investigation of Brillouin and Raman scattering in a 2SG sulfide glass microstructured chalcogenide fiber.

In this work, we investigate the Brillouin and Raman scattering properties of a Ge15Sb20S65 chalcogenide glass microstructured single mode fiber around 1.55 microm. Through a fair comparison between a 2-m long chalcogenide fiber and a 7.9-km long classical single mode silica fiber, we have found a Brillouin and Raman gain coefficients 100 and 180 larger than fused silica, respectively.

High power and high energy ultrashort pulse generation with a frequency shifted feedback fiber laser.

The highest average power that has been achieved with a frequency-shifted feedback modelocked fiber laser is reported. Subpicosecond pulses with 40 kW peak power are obtained by this technique for the first time by using external pulse compression. The pulsing is self starting and environmentally stable. The measured pulse energy in modelocked operation is 120 nJ. The pulses could be compressed to 855 fs. The pulse energy was increased to 1muJ with controlled Q-switched modelocking.

Complete experimental characterization of stimulated Brillouin scattering in photonic crystal fiber.

We provide a complete experimental characterization of stimulated Brillouin scattering in a 160 m long solid-core photonic crystal fiber, including threshold and spectrum measurements as well as position-resolved mapping of the Brillouin frequency shift. In particular, a three-fold increase of the Brillouin threshold power is observed, in excellent agreement with the spectrally-broadened Brillouin gain spectrum. Distributed measurements additionally reveal that the rise of the Brillouin threshold results from the broadband nature of the gain spectrum all along the fiber and is strongly influenced by strain. Our experiments confirm that these unique fibers can be exploited for the passive control or the suppression of Brillouin scattering.

Synergistic activation of p53-dependent transcription by two cooperating damage recognition pathways.

High level activation of p53-dependent transcription occurs following cellular exposure to genotoxic damaging agents such as UV-C, while ionizing radiation damage does not induce a similarly potent induction of p53-dependent gene expression. Reasoning that one of the major differences between UV-C and ionizing radiation damage is that the latter does not inhibit general transcription, we attempted to reconstitute p53-dependent gene expression in ionizing irradiated cells by co-treatment with selected transcription inhibitors that alone do not activate p53. p53-dependent transcription can be dramatically enhanced by the treatment of ionizing irradiated cells with low doses of DRB, which on its own does not induce p53 activity. The mechanism of ionizing radiation-dependent activation of p53-dependent transcription using DRB is more likely due to inhibition of gene transcription rather than prolonged DNA damage, as the non-genotoxic and general transcription inhibitor Roscovitine also synergistically activates p53 function in ionizing irradiated cells. These results identify two distinct signal transduction pathways that cooperate to fully activate p53-dependent gene expression: one responding to lesions induced by ionizing radiation and the second being a kinase pathway that regulates general RNA Polymerase II activity.

Photogenotoxicity of hypericin in HaCaT keratinocytes: implications for St. John's Wort supplements and high dose UVA-1 therapy.

Extract of St. John's Wort (Hypericum perforatum) is commonly used as natural remedy for treatment of mild to moderate depression. However, it contains a powerful photoactive component, hypericin, which can cause a severe photodermatitis when eaten by grazing animals (hypericism). In humans, there is evidence that supplementation with St. John's Wort can reduce the minimal erythemal dose (MED) in patients undergoing high dose UVA-1 phototherapy. This is a recent development in phototherapy where the most erythemogenic parts of the UVA spectrum are filtered out, allowing delivery of higher doses of the longer wavelengths of UVA. Although current published evidence suggests that the plasma levels of hypericin are unlikely to cause clinical phototoxicity, it has been established that photoactive compounds can cause DNA damage at sub-toxic and sub-erythemal doses, the effects of which might not be apparent for many years after the event. The present study used HaCaT keratinocytes to investigate the photoclastogenic ability of hypericin on irradiation with UVA. The results show that although the combination of hypericin and UVA light increased the genotoxic burden, when all factors are taken into account, the risk of significant photogenotoxic damage incurred by the combination of Hypericum extracts and UVA phototherapy may be low in the majority of individuals.

Impact of x-ray dose on track formation and data analysis for CR-39-based proton diagnostics.

The nuclear track detector CR-39 is used extensively for charged particle diagnosis, in particular proton spectroscopy, at inertial confinement fusion facilities. These detectors can absorb x-ray doses from the experiments in the order of 1-100 Gy, the effects of which are not accounted for in the previous detector calibrations. X-ray dose absorbed in the CR-39 has previously been shown to affect the track size of alpha particles in the detector, primarily due to a measured reduction in the material bulk etch rate [Rojas-Herrera et al., Rev. Sci. Instrum. 86, 033501 (2015)]. Similar to the previous findings for alpha particles, protons with energies in the range 0.5-9.1 MeV are shown to produce tracks that are systematically smaller as a function of the absorbed x-ray dose in the CR-39. The reduction of track size due to x-ray dose is found to diminish with time between exposure and etching if the CR-39 is stored at ambient temperature, and complete recovery is observed after two weeks. The impact of this effect on the analysis of data from existing CR-39-based proton diagnostics on OMEGA and the National Ignition Facility is evaluated and best practices are proposed for cases in which the effect of x rays is significant.

The phototumorigenic potential of broad-band (270-350 nm) and narrow-band (311-313 nm) phototherapy sources cannot be predicted by their edematogenic potential in hairless mouse skin.

The new Philips TL01 narrow-band (311-313 nm) and conventional broad-band (e.g., Philips TL12; 270-350 nm) sources are effective for psoriasis phototherapy, for which treatment regimens are based on a predetermined minimal erythema dose. TL01 phototherapy treatment times are approximately half those with TL12 for psoriasis, whereas the cumulative exposure doses at clearing are similar. We compared the phototumorigenic potential of TL01 and TL12 radiation in mouse skin. Groups of albino Skh-1 hairless mice were exposed for 5 d/week at three dose levels. At each dose level, TL12 and TL01 doses were equally edematogenic. At each dose level, TL01 radiation was significantly more effective at producing first tumors of 1 mm in diameter and multiple tumors. At the lower two dose levels, TL01 radiation produced a significantly greater proportion of squamous cell carcinomas. This study demonstrates that TL01 radiation is more phototumorigenic than TL12 radiation at equally edematogenically weighted doses. This is in contrast with previous reports that edema production by polychromatic sources is predictive of their phototumorigenic effect in Skh-1 mice. The absolute cumulative TL12 dose needed to induce tumors was much less than that for TL01 radiation. The possibility of increased tumor risk with TL01 phototherapy should be considered but must be balanced against the high phototherapeutic efficacy of this source, short treatment times, and the low cumulative doses necessary for clearing of psoriasis.

The phototumorigenic fluoroquinolone lomefloxacin photosensitizes pyrimidine dimer formation in human keratinocytes in vitro.

The fluoroquinolone antibiotic lomefloxacin is phototoxic, photogenotoxic, photomutagenic and photosensitizes tumorigenesis in mouse skin. We have used T4 endonuclease V to demonstrate that lomefloxacin photosensitizes pyrimidine dimer formation in a human keratinocyte line (HaCaT). A possible mechanism for this effect would be triplet-triplet energy transfer. However, there is indirect evidence that the lomefloxacin triplet yield is very low, making this reaction less likely. The finding that lomefloxacin photosensitizes production of highly mutagenic pyrimidine dimers correlates with its ability to initiate skin tumor formation in mice. Until the potential of other fluoroquinolones to photosensitize dimer formation is explored it may be unadvisable to prescribe these antibiotics to patients with defective DNA repair capacity (e.g. xeroderma pigmentosum).

The effect of photofrin on DNA strand breaks and base oxidation in HaCaT keratinocytes: a comet assay study.

Photodynamic therapy (PDT) kills cells via the production of singlet oxygen and other reactive oxygen species. PDT causes chromosomal damage and mutation to cultured cells. However, DNA damage does not contribute to the phototoxic effect. To study the effect of Photofrin-PDT-induced DNA damage, we used the comet assay in combination with endonuclease III and formamidopyrimidine DNA glycosylase and a human keratinocyte cell line to investigate photogenotoxicity and its prevention by tocopherol (TOC). This study shows that PDT induced DNA damage in HaCaT cells at doses allowing cells to survive 7 days after irradiation. alpha-TOC did not prevent the acute cell lysis caused by Photofrin-PDT but did prevent Photofrin-PDT-induced DNA damage. However, the concentration of TOC that conferred protection (100 microM) was higher than is detected in human serum. Base oxidation was also measured using the comet assay. Although TOC could prevent frank DNA strand breaks caused by PDT, it was unable to decrease the level of base oxidation as revealed by enzyme-sensitive sites. It is suggested that the potential genotoxic risk from laser-PDT could be low, and that topical micro-TOC at a high concentration may be useful in preventing some types of DNA damage without preventing acute photolysis after Photofrin-PDT.

Photogenotoxicity of skin phototumorigenic fluoroquinolone antibiotics detected using the comet assay.

The fluoroquinolone (FQ) antibiotics photosensitize human skin to solar UV radiation and are reported to photosensitize tumor formation in mouse skin. As tumor initiation will not occur without genotoxic insult, we examined the potential of ciprofloxacin, lomefloxacin, fleroxacin, BAYy3118 (a recently developed monofluorinated quinolone) and a nalidixic acid to photosensitize DNA damage in V79 hamster fibroblasts in vitro. Cells were exposed to 37.5 kJ/m2 UVA (320-400 nm; glass filtered Sylvania psoralen + UVA (PUVA) tubes; calibrated Waldmann radiometer) at 4 degrees C in the presence of FQ and immediately afterwards embedded in agarose, lysed and placed in an electrophoretic field at pH 12. Under these denaturing conditions, the presence of DNA single-strand breaks (SSB), alkali-labile sites (ALS) and double-strand breaks (DSB) can be visualized as DNA migrating away from the nucleus (characteristic "comet" appearance) after staining with a specific fluorochrome. At FQ concentrations that induced minimal loss of cell viability (neutral red uptake assay) the compounds tested induced comets with a rank order of BAYy3118 > norfloxacin > ciprofloxacin > lomefloxacin > fleroxacin > nalidixic acid. If cells were incubated after treatment for 1 h at 37 degrees C, the comet score decreased, suggesting efficient removal of SSB/ALS/DSB. Addition of the DNA polymerase(alpha) inhibitor, aphidicolin, to cells treated with either ciprofloxacin alone or ciprofloxacin + UVA resulted in an accumulation of SSB due to the endo/exonuclease steps of excision repair. We have demonstrated that the FQ are photogenotoxic in mammalian cells but the FQ-photosensitized SSB are efficiently repaired. Preliminary evidence that ciprofloxacin photosensitizes the formation of DNA lesions warranting excision repair may indicate production of more mutagenic lesions.

Comparative potency of broad-band and narrow-band phototherapy sources to induce edema, sunburn cells and urocanic acid photoisomerization in hairless mouse skin.

The Philips TL01 narrow-band (311-313 nm) fluorescent lamp provides effective phototherapy for psoriasis and atopic eczema while emitting less erythemogenic radiation than conventional broad-band (e.g. Philips TL12; 270-350 nm) sources. We studied the potency of TL01 and TL12 radiation to induce edema and sunburn cells (SBC) and to photoisomerize naturally occurring trans-urocanic acid (UCA) to cis-UCA in hairless mouse skin. Cis-UCA has immunosuppressive properties and is a putative mediator of UV-induced suppression of immune responses. For each source, there was UV dose dependence for all three responses. Within the dose ranges used, the potency ratio of TL12:TL01 radiation to induce equivalent edema and SBC was about 6:1. However, the potency ratio to induce cis-UCA was less than 2.3:1. Therefore, at a given level of edema or SBC induction, TL01 was more efficient than TL12 at UCA photoisomerization. The TL01 induction of immunomodulating cis-UCA, while causing minimal skin injury, may relate to the therapeutic efficacy of this source in skin conditions with an immunological component.

Action spectra for the trans to cis photoisomerisation of urocanic acid in vitro and in mouse skin.

Urocanic acid (UCA) is a major UV chromophore in the upper layers of the skin where it is found predominantly as the trans isomer. UV irradiation induces photoisomerisation of trans-UCA to cis-UCA which has been shown to mimic some of the immunosuppressive properties of UV exposure. We examined the wavelength dependence for trans-UCA to cis-UCA photoisomerisation in vitro and in mouse skin in vivo over the spectral range 270-340 nm. The resulting action spectra were very similar with maximal effectiveness at 300-315 nm and equal activity at 270 nm and 325-330 nm, demonstrating that UVA-II radiation (320-340 nm) is efficient at UCA photoisomerisation. These action spectra differed markedly from the trans-UCA absorption spectrum in vitro and also the reported action spectrum for UV suppression of contact hypersensitivity in mice. These findings suggest that the relationship between cis-UCA formation in skin and UV-induced immunosuppression may be complex.

Photohaemolysis assay for drug phototoxicity complicated by 'bleaching' of released haemoglobin.

The phototoxic potential of several non-steroidal anti-inflammatory drugs and quinolone antibiotics was assessed using the photohaemolysis assay. In this system, human erythrocytes are irradiated (UVA radiation 320-400 nm) from below in the presence of suspected photosensitizers. Photohaemolysis with ketoprofen, tiaprofenic acid or nalidixic acid was initially concentration dependent, but photohaemolysis apparently decreased at higher drug concentrations. As erythrocytes were irradiated from below any optical screening at high drug concentrations was discounted. Other phototoxic drugs can oxidize haemoglobin to methaemoglobin resulting in a decrease in absorption and an artificially lowered photohaemolysis level. However, in the present experiments, the use of Drabkin's solution overcame this effect as haemoglobin and most of its oxidized derivatives were converted into a single derivative, namely cyanmethaemoglobin. Further possibilities are that photosensitized damage to haemoglobin results in the formation of intracellular Heinz bodies and/or bleaching of released haemoglobin. The latter hypothesis was tested by irradiating free haemoglobin in the presence of drugs. The results suggested that certain phototoxic agents cause 'bleaching' of the haemoglobin and formation of a derivative that fails to react with Drabkin's solution. If only high concentrations of these drugs are used in the photohaemolysis assay, this increases the risk of false negative results. It is therefore suggested that both photohaemolysis and photosensitized 'bleaching' of haemoglobin should be investigated when using this assay for screening drug phototoxicity.

Comparison of an in vitro cellular phototoxicity model against controlled clinical trials of fluoroquinolone skin phototoxicity.

Many therapeutic drugs induce phototoxic skin responses following exposure to solar or artificial ultraviolet radiation sources. Several in vitro model systems have been developed to predict drug phototoxicity but none have been conducted in parallel with controlled clinical phototoxicity studies on systemically administered pharmaceuticals. The in vitro phototoxicity of eight fluoroquinolone (FQ) antibiotics (ciprofloxacin, grepafloxacin, lomefloxacin, norfloxacin, ofloxacin, trovafloxacin, BAYy3118, moxifloxacin) was determined by exposing Chinese hamster fibroblasts to UVA radiation. Cell damage was quantified with standard MTT or neutral red assays and an in vitro phototoxic index calculated (PI(vit)=% cell viability with UVA alone /% cell viability with UVA+FQ) for each endpoint. Clinical photosensitizing ability of the eight systemically administered FQ was investigated using double-blind, placebo and positive controlled, clinical skin phototesting of normal subjects. Minimal erythema doses at 365+/-30nm were determined before and after 6-7 days of FQ ingestion and PI(clin) (minimal erythema dose without FQ/minimal erythema dose with FQ) calculated. Linear regression analysis of PI(vit) vs PI(clin) gave correlations of up to 0.893. Principal components analysis of PI(vit), daily dose, plasma levels and photophysical (absorption) properties of the eight FQ showed that phototoxic (arbitrarily defined as PI(clin)> or =2) and non-phototoxic (PI(clin)<2) FQ could be completely discriminated using these parameters, and that the in vitro models were able to rank the relative phototoxic potential of the eight FQ.

In vitro phototoxicity of nifedipine: sequential induction of toxic and non-toxic photoproducts with UVA radiation.

Anecdotal reports suggest that the dihydropyridine calcium antagonist, nifedipine (NIF), may be phototoxic in human skin. We have studied NIF phototoxicity in vitro using UVA fluorescent tubes (Sylvania PUVA). NIF was phototoxic to Candida albicans and induced photohaemolysis both with NIF present during irradiation and with pre-irradiated drug. In V79 hamster fibroblasts, NIF (10 micrograms ml-1) was phototoxic MTT assay) 24 h after irradiation (0-112 kJ m-2); at 7.5 kJ m-2, about 70% of cells were damaged whilst at 37.5 kJ m-2, only about 45% of cells were damaged. A similar pattern was seen with pre-irradiated NIF. Absorption spectroscopy showed that the NIF absorption maximum (Amax approximately 340 nm) blue-shifted to 314 nm at low UVA doses (7.5 kJ m-2 or less) and red-shifted to 345 nm at higher doses (isosbestic point, 325 nm). Thin layer chromatography of irradiated NIF showed a single photoproduct (PP1; Amax approximately 314 nm) formed at 7.5 kJ m-2 or less which disappeared at higher UVA doses to give further photoproducts. PP1 was highly dark toxic to V79 cells (50% damage at about 5 micrograms ml-1) but PP1 pre-irradiated with UVA was non-toxic. Preliminary gas chromatography-mass spectroscopy studies suggest that PP1 is the nitroso derivative of NIF. These results indicate that NIF phototoxicity in vitro is partially mediated by initial formation of a toxic photoproduct (PP1) but, paradoxically, subsequent UVA irradiation may reduce phototoxicity. The NIF concentrations required to induce in vitro phototoxicity are much greater than therapeutic plasma levels. Unless there is skin accumulation of NIF or PP1, our in vitro results suggest that NIF may not be an important skin-photosensitizing agent in vivo.