Modal instabilities in high power fiber laser oscillators.

Transverse mode competition and instabilities in high-power fiber oscillators have been studied experimentally by monitoring the dynamic power exchanges and characteristic frequencies of the transmitted fundamental mode (FM) and scattered high-order modes (HOMs) of the fiber laser cavity under CW and pulsed pumping. The FM and HOM power evolution indicates the presence of two competing effective laser cavities which result in rich output dynamics and full chaotic operation. The thermal and inversion related contributions to the observed instabilities have been identified by monitoring the associated characteristic instability frequencies under pulsed pumping. It is shown that in the transient regime, both inversion and thermal effects contribute successively to the observed power instabilities. Increasing the pump power leads to full chaotic response through an interplay between transverse and longitudinal mode instabilities.

Highly efficient coupling of crystalline microresonators to integrated photonic waveguides.

Crystalline optical whispering gallery mode resonators made from alkaline earth fluorides can achieve exceptionally large optical finesse, and are used in a variety of applications, from frequency stabilization and narrow linewidth lasers, to low-noise microwave generation or soliton Kerr frequency combs. Here we demonstrate an efficient coupling method to resonators of these materials, which employs photonic integrated waveguides on a chip based on silicon nitride. By converting a mode from silicon nitride to a free-hanging silica waveguide on a silicon chip, coupling to a crystalline resonator is achieved with a high extinction, while preserving a quality factor exceeding 200 million. This compact, heterogeneous integration of ultra-high Q-factor crystalline resonators with photonic waveguides provides a proof of concept for wafer scale integration and robust, compact packaging for a wide range of applications.

Integrated reconfigurable photonic filters based on interferometric fractional Hilbert transforms.

In this paper, we present integrated reconfigurable photonic filters using fractional Hilbert transformers (FrHTs) and optical phase tuning structure within the silica-on-silicon platform. The proposed structure, including grating-based FrHTs, an X-coupler, and a pair of thermal tuning filaments, is fabricated through the direct UV grating writing technique. The thermal tuning effect is realized by the controllable microheaters located on the two arms of the X-coupler. We investigate the 200 GHz maximum bandwidth photonic FrHTs based on apodized planar Bragg gratings, and analyze the reflection spectrum responses. Through device integration and thermal modulation, the device could operate as photonic notch filters with 5 GHz linewidth and controllable single sideband suppression filters with measured 12 dB suppression ratio. A 50 GHz instantaneous frequency measuring system using this device is also schematically proposed and analyzed with potential 3 dB measurement improvement. The device could be configured with these multiple functions according to need. The reconfigurable structure has great potential in ultrafast all-optical signal processing fields.

High power, compact, picosecond MOPA based on single trench fiber with single polarized diffraction-limited output.

We experimentally demonstrate an all-solid Yb-doped 30 µm core diameter single trench fiber. Measurements ensure a robust effective single-mode operation without the need of tight coiling as required for conventional fibers thanks to the ultralow NA (∼0.038) and resonant ring surrounding the core. All-solid and cylindrical design ensures the suitability for mass scale production with the added benefit of all-fiberized device structure. A compact master oscillator power amplifier (MOPA) has been built using this fiber delivering ∼23.5 ps pulses at 13.5 MHz repetition rate delivering up to ∼52 W of average output power corresponding to a pulse energy of ∼3.8 µJ and peak power of >160 kW, while maintaining ∼76% slope efficiency. The output beam exhibits a polarization extinction ratio of more than 15 dB and a M2 less than 1.15.

Ultra-wide detuning planar Bragg grating fabrication technique based on direct UV grating writing with electro-optic phase modulation.

A direct UV grating writing technique based on phase-controlled interferometry is proposed and demonstrated in a silica-on-silicon platform, with a wider wavelength detuning range than any previously reported UV writing technology. Electro-optic phase modulation of one beam in the interferometer is used to manipulate the fringe pattern and thus control the parameters of the Bragg gratings and waveguides. Various grating structures with refractive index apodization, phase shifts and index contrasts of up to 0.8 × 10(-3) have been demonstrated. The method offers significant time/energy efficiency as well as simplified optical layout and fabrication process. We have shown Bragg gratings can be made from 1200 nm to 1900 nm exclusively under software control and the maximum peak grating reflectivity only decreases by 3 dBover a 250 nm (~32 THz) bandwidth.

High-peak-power, high-energy, high-average-power pulsed fiber laser system with versatile pulse duration and shape.

We present a pulsed fiber laser system with average power up to 265 W, pulse energy up to 10.6 mJ, pulse duration adjustable in the range 500 ps-500 ns, repetition rate fully controllable from single-shot operation up to 1 MHz, and the ability to control peak power independently of pulse energy. The system has a compact, all-spliced construction. Such a versatile laser will have wide applications in materials processing.

Terahertz bandwidth photonic Hilbert transformers based on synthesized planar Bragg grating fabrication.

Terahertz bandwidth photonic Hilbert transformers are proposed and experimentally demonstrated. The integrated device is fabricated via a direct UV grating writing technique in a silica-on-silicon platform. The photonic Hilbert transformer operates at bandwidths of up to 2 THz (~16 nm) in the telecom band, a 10-fold greater bandwidth than any previously reported experimental approaches. Achieving this performance requires detailed knowledge of the system transfer function of the direct UV grating writing technique; this allows improved linearity and yields terahertz bandwidth Bragg gratings with improved spectral quality. By incorporating a flat-top reflector and Hilbert grating with a waveguide coupler, an ultrawideband all-optical single-sideband filter is demonstrated.

Phase controlled integrated interferometric single-sideband filter based on planar Bragg gratings implementing photonic Hilbert transform.

The monolithically integrated all-optical single-sideband (SSB) filter based on photonic Hilbert transform and planar Bragg gratings is proposed and experimentally demonstrated. An SSB suppression of 12 dB at 6 GHz and sideband switching are achieved via thermal tuning. An X-coupler, photonic Hilbert transformer, flat top reflector, and a micro heater are incorporated in a single silicon-on-silica substrate. The device can be thermally tuned by the micro heater on top of the channel waveguide. The device is fabricated using a combination of direct UV grating writing technology and photolithography.

Hollow-bottle optical microresonators.

Selective excitation of whispering-gallery and bottle modes in a robust hollow-bottle optical microresonator, fabricated from a silica microcapillary by a pressure-compensated, "soften-and-compress" method, is demonstrated. Characteristic resonance spectra of bottle modes were obtained by using a tapered fiber coupled at different locations along the hollow bottle. The spectral characteristics (Q-factor, excitation efficiency) are shown to have high tolerance to angular misalignment of the tapered fiber. In addition, introduction of localized losses on the outer surface of the resonator results in selective clean-up of the transmission spectrum and superior performance. A theoretical analysis of modal turning points and associated resonant wavelengths is used to explain the mechanism of mode-suppression and the resultant spectral cleaning.

Whispering gallery mode spectra of channel waveguide coupled microspheres.

Evanescent coupling of light from glass channel waveguides into the whispering gallery modes of glass microspheres of radius 15?m and 100?m is studied experimentally at wavelengths near 1550 nm. Fitting the positions, widths and heights of resonances in the experimental spectra to the characteristic equation for microsphere modes and to universal coupled microresonator theory, we establish sphere radius and index, identify mode numbers, and determine losses. The results provide detailed information for the design of optical devices incorporating microsphere resonators in planar lightwave circuits.

Rare and Common Variants Conferring Risk of Tooth Agenesis.

We present association results from a large genome-wide association study of tooth agenesis (TA) as well as selective TA, including 1,944 subjects with congenitally missing teeth, excluding third molars, and 338,554 controls, all of European ancestry. We also tested the association of previously identified risk variants, for timing of tooth eruption and orofacial clefts, with TA. We report associations between TA and 9 novel risk variants. Five of these variants associate with selective TA, including a variant conferring risk of orofacial clefts. These results contribute to a deeper understanding of the genetic architecture of tooth development and disease. The few variants previously associated with TA were uncovered through candidate gene studies guided by mouse knockouts. Knowing the etiology and clinical features of TA is important for planning oral rehabilitation that often involves an interdisciplinary approach.

Critical role for glycosphingolipids in Niemann-Pick disease type C.

Niemann-Pick type C (NPC) disease is a cholesterol lipidosis caused by mutations in NPC1 and NPC2 gene loci. Most human cases are caused by defects in NPC1, as are the spontaneously occurring NPC diseases in mice and cats. NPC1 protein possesses a sterol-sensing domain and has been localized to vesicles that are believed to facilitate the recycling of unesterified cholesterol from late endosomes/lysosomes to the ER and Golgi. In addition to accumulating cholesterol, NPC1-deficient cells also accumulate gangliosides and other glycosphingolipids (GSLs), and neuropathological abnormalities in NPC disease closely resemble those seen in primary gangliosidoses. These findings led us to hypothesize that NPC1 may also function in GSL homeostasis. To evaluate this possibility, we treated murine and feline NPC models with N-butyldeoxynojirimycin (NB-DNJ), an inhibitor of glucosylceramide synthase, a pivotal enzyme in the early GSL synthetic pathway. Treated animals showed delayed onset of neurological dysfunction, increased average life span (in mice), and reduced ganglioside accumulation and accompanying neuropathological changes. These results are consistent with our hypothesis and with GSLs being centrally involved in the pathogenesis of NPC disease, and they suggest that drugs inhibiting GSL synthesis could have a similar ameliorating effect on the human disorder.

Adaptive pulse shape control in a diode-seeded nanosecond fiber MOPA system.

We demonstrate active shaping of the driving electrical pulses to a laser diode in order to compensate for the pulse shaping effects of gain saturation in an Yb doped fiber amplifier cascade and to allow the generation of user defined customized output pulse shapes. In particular we demonstrate the generation of square output pulses, which have the potential to significantly increase the maximum pulse energy extractable from an amplifier before the peak power reaches the threshold for SRS, and for high efficiency frequency conversion.

Neurons in Niemann-Pick disease type C accumulate gangliosides as well as unesterified cholesterol and undergo dendritic and axonal alterations.

Niemann-Pick disease type C (NPC) is a lethal neurologic storage disorder of children most often caused by a defect in the protein NPC1. To better understand the disease we thoroughly characterized the cellular and morphological alterations occurring in murine, feline, and human NPC. Using immunocytochemistry and filipin histochemistry we show that both gangliosides and unesterified cholesterol are differentially stored in neurons of the cerebral cortex, cerebellum, and hippocampus, as well as in liver. Double fluorescence labeling revealed that GM2 ganglioside and unesterified cholesterol were partially co-localized in vesicular structures, and triple fluorescence labeling utilizing a LAMP-1 antibody identified many of these organelles as part of the late endosomal/lysosomal pathway. These observations, coupled with the proposed role of NPC1 in intracellular cholesterol movement, suggest that GM3 and GM2 gangliosides as well as unesterified cholesterol may be retrogradely cleared from late endosomes/lysosomes by an NPC1-dependent mechanism. Cellular consequences of the NPC metabolic defect as shown by parvalbumin immunocytochemistry and rapid Golgi staining, respectively, revealed characteristic axonal spheroids on GABAergic neurons and ectopic dendritogenesis that followed a species-specific gradient of: mouse < feline < human. These studies suggest that the homeostatic regulation of gangliosides and cholesterol in neurons is mediated by NPC1 and that perturbations in this mechanism cause a complex neuronal storage disorder.

Quantitative analysis by polymerase chain reaction of growth hormone receptor gene expression in human liver and muscle.

A single form of GH receptor (GHR) messenger RNA (mRNA) of 4.5 kilobases, encoding the full-length GHR, has been found in man. To measure the absolute number of mRNA molecules encoding the GHR in human tissues, we developed a quantitative polymerase chain reaction assay. An internal control RNA was constructed by inserting a 50-basepair fragment of the rat PRL receptor complementary DNA into a portion of the human GHR complementary DNA. The internal control RNA and the target mRNA were amplified together with the same set of primers. Twenty-four cycles of amplification were used to satisfy an exponential phase of amplification. It was possible to detect as few as 500 molecules of target mRNA/micrograms total RNA. In 3 liver samples obtained from normal donors at the time of transplant, the amount of GHR mRNA ranged from 0.5 +/- 0.1 to 1.4 +/- 0.4 x 10(6) molecules/micrograms total RNA. These results were confirmed by slot blot analysis of the same samples. The number of receptor transcripts did not appear to be correlated with the receptor-binding capacity found in the 3 liver samples. In 7 muscle biopsies, GH receptor mRNA varied between 4.0 +/- 0.4 and 34.6 +/- 1.4 x 10(4) molecules/micrograms total RNA. This technique allows direct measurement of GHR gene expression in human tissues and represents a valuable tool, particularly for tissues such as muscle, in which the receptor protein cannot be measured using conventional binding assays.

Expression of the growth hormone receptor gene in human digestive tissue.

We have examined the forms and the distribution of the messenger ribonucleic acids (mRNAs) encoding the GH receptor (GHR) in human digestive tissues. GHR mRNAs were identified and characterized by Northern blot, dot blot, and in situ hybridization analyses, using complementary DNAs coding for the extracellular part of the human liver GHR. Amplification using the polymerase chain reaction was also used, as tissues express low levels of GHR mRNAs. Our results demonstrate that the GHR gene is expressed in human liver, pancreas, esophagus, stomach, small intestine, and colon. A single 4.5-kilobase mRNA form, which probably encodes the full-length membrane receptor, was detected. GHR mRNA was visualized by in situ hybridization in hepatocytes, exocrine pancreas, and some islet cells; signal was also present in the mucosa of the digestive tract. No specific GH-binding-protein mRNA was found, suggesting that in man, the soluble form of the receptor is generated through proteolytic cleavage of the membrane receptor.

Ferret pyramidal cell dendritogenesis: changes in morphology and ganglioside expression during cortical development.

Pyramidal cell ontogenesis and basilar dendritic differentiation were evaluated concomitantly with ganglioside expression and distribution in ferret cerebral cortex. Layer V neurons began basilar dendritogenesis on postnatal day 1 (P1) with a peak in dendritic arborization occurring at P21. Layer II/III neurons, in contrast, were in early stages of basilar dendritic differentiation at P14, resulting in a complex dendritic arbor at P28. High performance thin-layer chromatography showed numerous changes in ganglioside expression during cortical development, including a decline of GM2 in the mature cortex. The temporal expression and cellular distribution of GM2, GD2, GM1, GD3, and GM3 gangliosides in developing cerebral cortex were determined by immunocytochemistry. GM2 immunoreactivity (IR) was most prominent in layer V neurons between P1 and P21 and in layer II/III neurons between P14 and P28 with staining diminishing to near absent levels in the adult. GM2-IR appeared as punctate structures within the somatodendritic domain and by electron microscopy was shown to be membrane-bound vesicles often in close proximity to the plasmalemma. Expression of GM2, but not of other gangliosides studied, followed two well-documented developmental neurogenic gradients: ventrolateral to dorsomedial and radial (inside-first outside-last). Onset of significant GD2 expression in layer II/III and V pyramidal cells was delayed until P14 and persisted in adult neocortex. GD3 was localized most prominently to glial-like cells, whereas GM1 was primarily localized to white matter. The close temporal and spatial concordance of GM2-IR in cortical pyramidal neurons undergoing dendritogenesis is consistent with its proposed role as a modulator of dendritic differentiation.

Reduced food intake is the main cause of low growth hormone receptor expression in uremic rats.

To examine the respective effects of reduced food intake and of uremia on the growth defect in uremic rats, we have studied the expression of GH receptors in three groups of male rats: Group 1, rats fed ad libitum; Group 2, food-restricted to be pair-fed with uremic rats; Group 3, uremic rats. Animals were studied for a time period of 9 days starting 1 week after surgery (sham operation in rats of Groups 1 and 2, 5/6 nephrectomy in rats of Group 3). The gain in body length and weight of pair-fed controls and of uremic rats was comparable and significantly lower than that of rats fed ad libitum. IGF-1 plasma levels were low in rats of groups 2 and 3. Low food intake (50% that of rats fed ad libitum) resulted in a reduced number of GH receptors in liver membranes and a low plasma level of GH-binding protein (GHBP); GH receptor gene expression in the liver, as analyzed by Northern blots, was not significantly lower in normal food-restricted animals. In uremic rats, the low level of GH binding to liver membranes was comparable to that found in pair-fed controls; but the level of GHBP activity was normal, not different from the values found in rats fed ad libitum. However, expression of the liver GHBP mRNA was reduced in uremic rats. In uremia, the GH receptor dysfunction is not only at a transcriptional level but also at a post-transcriptional level. These findings suggest that uremia, as such, is not primarily responsible for the growth failure.(ABSTRACT TRUNCATED AT 250 WORDS)

GM2 ganglioside as a regulator of pyramidal neuron dendritogenesis.

One of the most profound events in the life of a neuron in the mammalian CNS is the development of a characteristic dendritic tree, yet little is understood about events controlling this process. Pyramidal neurons of the cerebral cortex are known to undergo a single explosive burst of dendritic sprouting immediately after completing migration to the cortical mantle, and following maturation there is no evidence that new, primary dendrites are initiated. Yet in one group of rare genetic diseases--Tay-Sachs disease and related neuronal storage disorders--cortical pyramidal neurons undergo a second period of dendritogenesis. New dendritic membrane is generated principally at the axon hillock and in time is covered with normal-appearing spines and synapses. In our studies of normal brain development and storage diseases we consistently find one feature in common in cortical pyramidal neurons undergoing active dendritogenesis: They exhibit dramatically increased expression of GM2 ganglioside localized to cytoplasmic vacuoles within neuronal perikarya and proximal dendrites. There is also evidence that the increase in GM2 precedes dendritic spouting, and that after dendritic maturation is complete (in normal brain) the GM2 levels in neurons become substantially reduced. These findings are consistent with GM2 ganglioside playing a pivotal role in the regulation of dendritogenesis in cortical pyramidal neurons.

[Growth hormone receptor]. / Le récepteur de l'hormone de croissance.

Growth hormone (GH) exerts multiple actions and GH receptors have been demonstrated in a variety of tissues. Changes in the number of hepatic GH receptors have been demonstrated in several models of growth failure in rats. Cloning of the rabbit and human liver GH receptor has shown that the receptor is a single polypeptide chain of 620 amino acids, made of an extracellular hormone-binding domain, with 7 cysteines and 5 potential glycosylation sites, a unique transmembrane domain and a long cytoplasmic domain. The GH receptor belongs to a new family including prolactin and cytokine receptors. Signal transduction pathways are unknown for these receptors, which do not possess any consensus sequences homologous to tyrosine kinases. The GH-binding protein (GH-BP), identified in plasma of man and other species, corresponds to the extracellular binding domain of the membrane GH receptor. Evaluation of the GH-BP is a direct approach to the GH receptor in man in vivo. Complete absence of GH binding activity has been found in the plasma of patients with Laron dwarfism, in particular those for whom a mutation in the GH receptor gene has been demonstrated.