Time-domain measurements reveal spatial aberrations in a sub-surface two-photon microscope.

We show that in a nonlinear microscopy system the effects of chromatic and spherical aberrations are revealed by a difference in the focal positions corresponding to the shortest pulse duration and the minimum lateral resolution. By interpreting experimental results from a high-numerical-aperture two-photon microscope using a previously reported spatio-temporal model, we conclude that the two-photon autocorrelation of the pulses at the focal plane can be used to minimize both the chromatic and spherical aberrations of the system. Based on these results, a possible optimization strategy is proposed whereby the objective lens is first adjusted for minimum autocorrelation duration, and then the wavefront before the objective is modified to maximize the autocorrelation intensity.

Autocorrelation z-scan technique for measuring the spatial and temporal distribution of femtosecond pulses in the focal region of lenses.

In this work we present an Autocorrelation z-scan technique to measure, simultaneously, the spatial and temporal distribution of femtosecond pulses near the focal region of lenses. A second-order collinear autocorrelator is implemented before the lens under test to estimate the pulse width. Signals are obtained by translating a Two Photon Absorption (TPA) sensor along the optical axis and by measuring the second-order autocorrelation trace at each position z. The DC signal, which is typically not considered important, is taken into account since we have found that this signal provides relevant information. Experimental results are presented for different lenses and input wavefronts.

Dual-comb mid-infrared spectroscopy with free-running oscillators and absolute optical calibration from a radio-frequency reference.

By using free-running independent femtosecond OPOs with a repetition-rate difference of 500 Hz we demonstrate methane absorption spectroscopy with spectral coverage simultaneously spanning the methane P, Q and R branches and with a resolution of 0.5 cm-1. Absolute optical frequency calibration with an accuracy of 0.25 cm-1 (0.27 nm) is achieved from simultaneous repetition-rate and carrier-envelope-offset frequency measurements, without the need for any optical reference. The calibration technique allows registration and averaging of consecutively acquired dual-comb spectra, leading to a high quality and low-noise absorbance measurement in good agreement with the HITRAN database.

Kupffer Cells Undergo Fundamental Changes during the Development of Experimental NASH and Are Critical in Initiating Liver Damage and Inflammation.

Non-alcoholic fatty liver disease has become the leading liver disease in North America and is associated with the progressive inflammatory liver disease non-alcoholic steatohepatitis (NASH). Considerable effort has been made to understand the role of resident and recruited macrophage populations in NASH however numerous questions remain. Our goal was to characterize the dynamic changes in liver macrophages during the initiation of NASH in a murine model. Using the methionine-choline deficient diet we found that liver-resident macrophages, Kupffer cells were lost early in disease onset followed by a robust infiltration of Ly-6C+ monocyte-derived macrophages that retained a dynamic phenotype. Genetic profiling revealed distinct patterns of inflammatory gene expression between macrophage subsets. Only early depletion of liver macrophages using liposomal clodronate prevented the development of NASH in mice suggesting that Kupffer cells are critical for the orchestration of inflammation during experimental NASH. Increased understanding of these dynamics may allow us to target potentially harmful populations whilst promoting anti-inflammatory or restorative populations to ultimately guide the development of effective treatment strategies.

Frequency comb metrology with an optical parametric oscillator.

We report on the first demonstration of absolute frequency comb metrology with an optical parametric oscillator (OPO) frequency comb. The synchronously-pumped OPO operated in the 1.5-µm spectral region and was referenced to an H-maser atomic clock. Using different techniques, we thoroughly characterized the frequency noise power spectral density (PSD) of the repetition rate frep, of the carrier-envelope offset frequency fCEO, and of an optical comb line νN. The comb mode optical linewidth at 1557 nm was determined to be ~70 kHz for an observation time of 1 s from the measured frequency noise PSD, and was limited by the stability of the microwave frequency standard available for the stabilization of the comb repetition rate. We achieved a tight lock of the carrier envelope offset frequency with only ~300 mrad residual integrated phase noise, which makes its contribution to the optical linewidth negligible. The OPO comb was used to measure the absolute optical frequency of a near-infrared laser whose second-harmonic component was locked to the F = 2→3 transition of the 87Rb D2 line at 780 nm, leading to a measured transition frequency of νRb = 384,228,115,346 ± 16 kHz. We performed the same measurement with a commercial fiber-laser comb operating in the 1.5-µm region. Both the OPO comb and the commercial fiber comb achieved similar performance. The measurement accuracy was limited by interferometric noise in the fibered setup of the Rb-stabilized laser.

Unique microbial-derived volatile organic compounds in portal venous circulation in murine non-alcoholic fatty liver disease.

BACKGROUND AND AIMS: Non-alcoholic fatty liver disease is now the leading liver disease in North America. The progression of non-alcoholic fatty liver disease to the inflammatory condition, non-alcoholic steatohepatitis is complex and currently not well understood. Intestinal microbial dysbiosis has been implicated in the development of non-alcoholic fatty liver disease and progression of non-alcoholic steatohepatitis. Volatile organic compounds are byproducts of microbial metabolism in the gut that may enter portal circulation and have hepatotoxic effects contributing to the pathogenesis of non-alcoholic steatohepatitis. To test this hypothesis, we measured volatile organic compounds in cecal luminal contents and portal venous blood in a mouse model of non-alcoholic steatohepatitis. METHODS: Gas chromatography-mass spectrometry analysis was conducted on cecal content and portal vein blood for volatile organic compound detection from mice fed a methionine and choline deficient diet, which induces non-alcoholic steatohepatitis. The colonic microbiome was studied by 16S rRNA gene amplification using the Illumina MiSeq platform. RESULTS: Sixty-eight volatile organic compounds were detected in cecal luminal content, a subset of which was also present in portal venous blood. Importantly, differences in portal venous volatile organic compounds were associated with diet-induced steatohepatitis establishing a biochemical link between gut microbiota-derived volatile organic compounds and increased susceptibility to non-alcoholic steatohepatitis. CONCLUSION: Our model creates a novel tool to further study the role of gut-derived volatile organic compounds in the pathogenesis of non-alcoholic steatohepatitis.

High-resolution subsurface microscopy of CMOS integrated circuits using radially polarized light.

Under high numerical aperture (NA) conditions, a linearly polarized plane wave focuses to a spot that is extended along the E-field vector, but radially polarized light is predicted to form a circular spot whose diameter equals the narrower dimension obtained with linear polarization. This effect provides an opportunity for improved resolution in high-NA microscopy, and here we present a performance study of subsurface two-photon optical-beam-induced current solid-immersion-lens microscopy of a complementary metal-oxide semiconductor integrated circuit, showing a resolution improvement by using radially polarized illumination. By comparing images of the same structural features we show that radial polarization achieves a resolution of 126 nm, while linear polarization achieves resolutions of 122 and 165 nm, depending on the E-field orientation. These results are consistent with the theoretically expected behavior and are supported by high-resolution images which show superior feature definition using radial polarization.

Murine models provide insight to the development of non-alcoholic fatty liver disease.

Associated with the obesity epidemic, non-alcoholic fatty liver disease (NAFLD) has become the leading liver disease in North America. Approximately 30 % of patients with NAFLD may develop non-alcoholic steatohepatitis (NASH) that can lead to cirrhosis and hepatocellular carcinoma (HCC). Frequently animal models are used to help identify underlying factors contributing to NAFLD including insulin resistance, dysregulated lipid metabolism and mitochondrial stress. However, studying the inflammatory, progressive nature of NASH in the context of obesity has proven to be a challenge in mice. Although the development of effective treatment strategies for NAFLD and NASH is gaining momentum, the field is hindered by a lack of a concise animal model that reflects the development of liver disease during obesity and the metabolic syndrome. Therefore, selecting an animal model to study NAFLD or NASH must be done carefully to ensure the optimal application. The most widely used animal models have been reviewed highlighting their advantages and disadvantages to studying NAFLD and NASH specifically in the context of obesity.

1-GHz harmonically pumped femtosecond optical parametric oscillator frequency comb.

We present the first example of a femtosecond optical parametric oscillator frequency comb harmonically-pumped by a 333-MHz Ti:sapphire laser to achieve a stabilized signal comb at 1-GHz mode spacing in the 1.1-1.6-µm wavelength band. Simultaneous locking of the comb carrier-envelope-offset and repetition frequencies is achieved with uncertainties over 1 s of 0.27 Hz and 5 mHz respectively, which are comparable with those of 0.27 Hz and 1.5 mHz achieved for 333-MHz fundamental pumping. The phase-noise power-spectral density of the CEO frequency integrated from 1 Hz-64 kHz was 2.8 rad for the harmonic comb, 1.0 rad greater than for fundamental pumping. The results show that harmonic operation does not substantially compromise the frequency-stability of the comb, which is shown to be limited only by the Rb atomic frequency reference used.

Octave-spanning super-continuum from a silica photonic crystal fiber pumped by a 386 MHz Yb:fiber laser.

We report octave-spanning super-continuum generation in a silica photonic crystal fiber (PCF) pumped by a compact, efficient, mode-locked all-normal dispersion Yb:fiber laser. The laser achieved 45% optical-to-optical efficiency by using an optimized resonator design, producing chirped 750 fs pulses with a repetition rate of 386 MHz and an average power of 605 mW. The chirped pulses were compressed to 110 fs with a loss of only 4% by using multiple reflections on a pair of Gires-Tournois interferometer mirrors, yielding an average power of up to 580 mW. The corresponding peak power was 13.7 kW and produced a super-continuum spectrum spanning from 696-1392 nm.

Strain field manipulation in ultrafast laser inscribed BiB3O6 optical waveguides for nonlinear applications.

A novel technique was used to control the spatial overlap of the orthogonal linearly polarized waveguide modes in ultrafast laser inscribed BiB(3)O(6) waveguides. We report that the strain fields induced by the expansion of material in the laser focus can be considered independently in the design of "type II" waveguides guiding orthogonal linearly polarized light. The waveguide with the optimal mode overlap was used for type I birefringently phase-matched second-harmonic generation of a continuous wave laser source at 1047 nm.

Yb:fiber-laser-pumped high-energy picosecond optical parametric oscillator.

We report a high-energy extended-cavity MgO:PPLN optical parametric oscillator, synchronously-pumped by a femtosecond Yb:fiber laser. The oscillator operated at a signal wavelength of 1530 nm with a repetition-frequency of 15.3 MHz (9.8 m length) achieved using intracavity relay-imaging optics. The signal pulses had an average power above 1.0 W, durations of 1.5 ps and energies greater than 70 nJ, making it a potential source for rapid femtosecond waveguide inscription in infrared materials.

Shaping ultrafast laser inscribed optical waveguides using a deformable mirror.

We use a two-dimensional deformable mirror to shape the spatial profile of an ultrafast laser beam that is then used to inscribe structures in a soda-lime silica glass slide. By doing so we demonstrate that it is possible to control the asymmetry of the cross section of ultrafast laser inscribed optical waveguides via the curvature of the deformable mirror. When tested using 1.55 mum light, the optimum waveguide exhibited coupling losses of approximately 0.2 dB/facet to Corning SMF-28 single mode fiber and propagation losses of approximately 1.5 dB.cm(-1). This technique promises the possibility of combining rapid processing speeds with the ability to vary the waveguide cross section along its length.

Towards versatile coherent pulse synthesis using femtosecond laser and optical parametric oscillators.

Pulses from a tunable near-infrared femtosecond optical parametric oscillator and its Ti:sapphire pump laser were phase-locked by matching their carrier-envelope phase-slip frequencies to one quarter of their common pulse repetition frequency. Interferometric second-order cross-correlation and spectral interferometry traces demonstrated their mutual coherence for periods of at least 20 ms, compared with individual coherence times of 0.1 ms estimated from their phase-noise power spectra. This result is a prerequisite for versatile coherent pulse synthesis. Implications for the synthesis of arbitrary waveforms from multi-colour pulses are discussed.

Composite frequency comb spanning 0.4-2.4 microm from a phase-controlled femtosecond Ti:sapphire laser and synchronously pumped optical parametric oscillator.

A repetition-rate-stabilized frequency comb ranging from the violet to the mid-infrared (0.4-2.4 microm) is obtained by phase locking a femtosecond Ti:sapphire laser and a synchronously pumped optical parametric oscillator to a common supercontinuum reference. The locking results have bandwidths lower than 3 kHz. By changing the locking frequencies, different relative and absolute offsets of the constituent frequency combs are achievable.

Mid-infrared methane detection in a photonic bandgap fiber using a broadband optical parametric oscillator.

We demonstrate methane sensing using a photonic bandgap fiber-based gas cell and broadband idler pulses from a periodically-poled lithium niobate femtosecond optical parametric oscillator. The hollow core of the fiber was filled with a methane:nitrogen mixture, and Fourier transform spectroscopy was used to measure transmission spectra in the 3.15-3.35 mum methane absorption region. The method has applications in gas sensing for remote or hazardous environments and potentially at very low concentrations.

Ultrafast-laser inscription of a three dimensional fan-out device for multicore fiber coupling applications.

A fan-out device has been fabricated using ultrafast-laser waveguide-inscription that enables each core of a multicore optical fiber (MCF) to be addressed by a single mode fiber held in a fiber V-groove array (FVA). By utilizing the unique three-dimensional fabrication capability of this technique we demonstrate coupling between an FVA consisting of a one-dimensional array of fibers and an MCF consisting of a two-dimensional array of cores. When coupled to all cores of the MCF simultaneously, the average insertion loss per core was 5.0 dB in the 1.55 mum spectral region. Furthermore, the fan-out exhibited low cross-talk and low polarization dependent loss.

Frequency-doubling in femtosecond laser inscribed periodically-poled potassium titanyl phosphate waveguides.

Frequency doubling has been achieved in femtosecond-laser-inscribed single-mode waveguides written in two periodically-poled potassium titanyl phosphate crystals. A conversion efficiency of 0.22 %W(1) was obtained for first-order quasi-phase matching at 980 nm and an efficiency of 0.02 %W(-1) for third-order quasi-phase matching at 800 nm.

Two-photon optical-beam-induced current solid-immersion imaging of a silicon flip chip with a resolution of 325 nm.

We report high-resolution subsurface imaging of a silicon flip chip by detection of the photocurrent generated by the two-photon absorption of 1530-nm light from a femtosecond Er:fiber laser. The technique combines the focal sensitivity of two-photon excitation with the enhanced optical resolution of high-numerical-aperture solid-immersion imaging. Features on a sub-1-microm scale are clearly resolvable with high contrast, showing a resolution of 325 nm.

Low-threshold femtosecond optical parametric oscillator based on chirped-pulse frequency conversion.

We report what is to our knowledge the first demonstration of a femtosecond optical parametric oscillator based on chirped-pulse frequency conversion in a long crystal of aperiodically poled potassium titanyl phosphate. The minimum pump threshold power was 15 mW, and a signal slope efficiency of 35% was achieved. Continuous tuning from 1190 to 1450 nm was obtained for an average pump power of 800 mW.