Krabbe disease is a devastating pediatric leukodystrophy caused by mutations in the galactocerebrosidase (GALC) gene. A significant subset of the infantile form of the disease is due to missense mutations that result in aberrant protein production. The currently used mouse model, twitcher, has a nonsense mutation not found in Krabbe patients, although it is similar to the human 30 kb deletion in abrogating GALC expression. Here, we identify a spontaneous mutation in GALC, GALCtwi-5J, that precisely matches the E130K missense mutation in patients with infantile Krabbe disease. GALCtwi-5J homozygotes show loss of enzymatic activity despite normal levels of precursor protein, and manifest a more severe phenotype than twitcher, with half the life span. Although neuropathological hallmarks such as gliosis, globoid cells and psychosine accumulation are present throughout the nervous system, the CNS does not manifest significant demyelination. In contrast, the PNS is severely hypomyelinated and lacks large diameter axons, suggesting primary dysmyelination, rather than a demyelinating process. Our data indicate that early demise is due to mechanisms other than myelin loss and support an important role for neuroinflammation in Krabbe disease progression. Furthermore, our results argue against a causative relationship between psychosine accumulation, white matter loss and gliosis.
Vibrational contrast imaging of the distribution of complex biological molecules requires the use of techniques that provide broadband spectra with sufficient resolution. Coherent anti-Stokes Raman scattering (CARS) microscopy is currently limited in meeting these requirements due to the presence of a nonresonant background and its inability to target multiple resonances simultaneously. We present nonlinear interferometric vibrational imaging (NIVI), a technique based on CARS that uses femtosecond pump and Stokes pulses to retrieve broadband vibrational spectra over 200 cm–1 (full-width at half maximum). By chirping the pump and performing spectral interferometric detection, the anti-Stokes pulses are resolved in time. This phase-sensitive detection allows suppression of not only the nonresonant background, but also of the real part of the nonlinear susceptibility χ(3), improving the spectral resolution and features to make them comparable to those acquired with spontaneous Raman microscopy, as shown for a material sample and mammary tissue.
A photosensitivity different from that responsible for fiber grating inscription is found in a supercontinuum-generating photonic crystal fiber transmitting intense 818 nm femtosecond pulses. This photosensitivity progressively generates a waveguide at the entrance of the fiber to scatter light of specific wavelengths and is termed as the photoscattering effect. This effect is linked to the ~800 nm photosensitivity in the microlithography of bulk silica glass. While the effect somewhat limits fiber-optic supercontinuum applications, it can be beneficial to produce new photonic devices.In a previous study,1 we reported a relatively surprising photosensitivity for supercontinuum (SC) generating heavily Ge-doped germanosilicate fibers. That is, the prolonged exposure of 800 nm femtosecond pulses produces a multi-millimeter long waveguide at the fiber entrance to dramatically decrease the fiber transmission property over a broad spectral range. This phenomenon resembles the photodarkening effect widely observed in rare-earth doped silica fibers if the Ge dopant plays the role of the rare-earth ions to produce certain absorptive photoproducts.2 Alternatively, it resembles the type I photosensitivity well documented in germanosilicate fiber grating inscription in terms that the waveguide is thermally erasable.3 The observed reduction of fiber transmission may be due to the formation of a structure analogous to a long period grating (LPG), which can attenuate fiber transmission by coupling light from core modes into cladding modes. The nature of the photosensitivity remains controversial mainly because the role of the Ge dopant is unclear. In this work, we report the presence of this photosensitivity in a pure silica photonic crystal fiber (PCF) so that no special photosensitive impurity is essential for such photosensitivity. We study the mechanism underlying the near-infrared photosensitivity, which has not been reported in PCFs, and point out its potential applications.The PCF (LMA-8, Crystal Fibre A/S) under study is an endlessly single-mode pure silica fiber having a cross section of hexagonally arranged 1.7 μm diameter air holes with a pitch size of 4.9 μm. The absence of the central hole results in a core diameter of 8.5 μm, a mode field diameter of 6.0 μm, and a numerical aperture (NA) of 0.10 (at 818 nm). The zero dispersion wavelength of the fiber is estimated to be 1.1 μm. 4 The pump laser is a 250 kHz regenerative amplifier (Reg9000, Coherent) pulsed at 818 nm with ~25 nm full width at half maximum bandwidth. The 1 mm diameter laser beam is coupled into the fiber by a NA of 0.40, 5.0 mm diameter aspheric lens. The pulse energy (pump power) is varied by a neutraldensity filter between 0.04 and 1 μJ (10-250 mW). The pulse width is controlled by a compressor to yield transform-limited 35 fs or positively chirped 210 fs pulses immediately a) htu@uiuc.edu. b) boppart@uiuc.edu. NIH Public Access Author ManuscriptAppl Phys Lett. Author manuscript; available in PMC 2011 February 22. NIH-PA Author Manuscrip...
We present a real-time, multi-dimensional, digital, optical coherence tomography (OCT) acquisition and imaging system. The system consists of conventional OCT optics, a rapid scanning optical delay (RSOD) line to support fast data acquisition rates, and a high-speed A/D converter for sampling the interference waveforms. A 1M-gate Virtex-II field programmable gate array (FPGA) is designed to perform digital down conversion. This is analogous to demodulating and low-pass filtering the continuous time signal. The system creates in-phase and quadrature-phase components using a tunable quadrature mixer. Multistage polyphase finite impulse response (FIR) filtering and down sampling is used to remove unneeded high frequencies. A floating-point digital signal processor (DSP) computes the magnitude and phase shifts. The data is read by a host machine and displayed on screen at real-time rates commensurate with the data acquisition rate. This system offers flexible acquisition and processing parameters for a wide range of multi-dimensional optical microscopy techniques.
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