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The treatment of lymphatic anomaly, a rare devastating disease spectrum of mostly unknown etiologies, depends on the patient manifestations1. Identifying the causal genes will allow for developing affordable therapies in keeping with precision medicine implementation2. Here we identified a recurrent gain-of-function ARAF mutation (c.640T>C:p.S214P) in a 12-year-old boy with advanced anomalous lymphatic disease unresponsive to conventional sirolimus therapy and in another, unrelated, adult patient. The mutation led to loss of a conserved phosphorylation site. Cells transduced with ARAF-S214P showed elevated ERK1/2 activity, enhanced lymphangiogenic capacity, and disassembly of actin skeleton and VE-cadherin junctions, which were rescued using the MEK inhibitor trametinib. The functional relevance of the mutation was also validated by recreating a lymphatic phenotype in a zebrafish model, with rescue of the anomalous phenotype using a MEK inhibitor. Subsequent therapy of the lead proband with a MEK inhibitor led to dramatic clinical improvement, with remodeling of the patient's lymphatic system with resolution of the lymphatic edema, marked improvement in his pulmonary function tests, cessation of supplemental oxygen requirements and near normalization of daily activities. Our results provide a representative demonstration of how knowledge of genetic classification and mechanistic understanding guides biologically based medical treatments, which in our instance was life-saving.

In this paper, we report on a passive duplexer based on reflective modulation for single-mode fibers. The component integrates a silicon micromechanical modulator and a photoreceiver in a hybrid assembly. Fabricated by the silicon micromachining technology reflective modulators allow a considerable cost reduction of single mode fiber-optic links as compared to systems operating with active light sources at both link terminals. The micromechanical modulator is characterized by a low insertion loss of less than 3 dB and polarization insensitivity. The ON-OFF ratio is typically 9 dB over a wavelength range from 1260 to 1360 nm. The operation frequency is limited by the mechanical movement of the modulator membrane to 1.3-2 MHz. We report on the characterization of fully packaged duplexer components.

We report on vertical mirrors fabricated by deep reactive ion etching of silicon. The mirror height is 75 /spl mu/m, covering the fiber core of a single-mode fiber when the latter is placed into a groove of equal depth and etched simultaneously with the mirror. To obtain a uniform etch depth, etching is stopped on a buried oxide layer. Using the buried oxide as a sacrificial layer allows to fabricate mirrors with suspension and actuation structures as well as fiber-alignment grooves in one and the same processing step. A minimal mirror thickness of 2.3 /spl mu/m was achieved, resulting in an aspect ratio higher than 30. The verticality was better than 89.3/spl deg/. In the upper part of the mirror a surface roughness below 40 nm rms was obtained. At a wavelength of 1300 nm the reflectivity of the aluminum-coated mirrors was measured to be higher than 76%. Using a reactive ion etched mirror we have fabricated an optical fiber switch with electrostatic actuation. The coupling loss in the bar state of two packaged prototypes was between 0.6 and 1.7 dB and between 1.4 and 3.4 dB in the cross state. The switching time is below 0.2 ms.

Capteur de temperature reparti utilisant la reflectometrie optique dans le domaine temporel. Raman anti Stokes et le comptage de photons

High power pump modules are used for industrial as well as telecom applications such as for fiber lasers and cladding pumped erbium doped fiber amplifiers (EDFA) [Lichtenstein, N., et al., 2004]. Key element of a pump module is a single emitter laser diode, which normally has an aperture of around 90 mum, in order to provide best coupling into an optical multi-mode fiber with a 105 mum core diameter. Increasing the brightness of the pump module lends additional flexibility in the design of fiber lasers and amplifiers and enables higher output power. In this communication we report on two approaches to increase the brightness of our latest generation of high power pump modules. Within the first approach the electro-optical performance of the single emitter laser diode is improved by optimizing Bookham's mature chip technologies such as InGaAs/AlGaAs structures grown by MBE, the ridge-waveguide manufacturing process, the E2 facet passivation and the mounting technology. The combination of improved chip design and new coupling scheme leads to reliable broad area modules with outstanding brightness.

Newly developed wavelength stabilized 980 nm pump lasers demonstrate uncooled operation with >100 mW ex-fiber power over a record -15/spl deg/C to 120/spl deg/C. With uncooled modules using these lasers, low cost optical amplifiers with ultra low power dissipation for metro systems become possible.

It is anticipated that in the near future erbium doped fiber amplifiers (EDFA) will find their way into new optical networking concepts, ranging from WDM systems in the metro sector to loss-compensation in optical switching. In order to be viable, these applications demand a technology, which in comparison to traditional systems is more compact, less costly, and more readily integrated, yet offers comparable performance and reliability. These demands are probably most significant for the EDFA pump laser. Our contribution discusses general reliability issues in pump module packaging, with special emphasis on how they will likely be addressed in future designs. As an example of this emerging trend in pump laser packaging we will present some of the design concepts and the reliability performance of our recently introduced family of un-cooled 980 nm pump modules. For 980 nm pumps, the key target specifications defined by new applications may be summarised as follows: chip reliability < 500 FIT; target package reliability < 500 FIT; wavelength-stabilised output power 200 mW; roadmap to 300 mW; operating case temperature 0/spl deg/C to 70/spl deg/C; power consumption < 1 W; packaging technology opens path to sustainable cost reduction. We and other manufacturers have recognised that these requirements can only be addressed by a significant differentiation of conventional 980 nm module technology, notably the transition to cooler-less operation. Our design features an 8-pin ceramic (Al/sub 2/O/sub 3/) miniDIL housing and a near planar assembly technology. The rated output power of this product family is 200 mW.

We present a fully packaged duplexer implementing a reflective Fabry-Perot modulator realised by silicon surface micromachining. The device demonstrates excellent performance for bit rates up to 2.8 Mbit/s. Relaxed positioning tolerances, a fiber to fiber loss below 3 dB, an extinction ratio better than 12 dB, and the potential for low cost fabrication make this device very attractive for use in economical optical links.

We report on vertical mirrors fabricated by deep reactive ion etching of silicon. In view of their application in fiber optical switches the mirror height is 75 /spl mu/m. So the mirror covers well the fiber core of a single mode fiber, when the fiber is placed in a groove of the same depth and etched at the same time as the mirror. A minimal mirror thickness of 2.3 /spl mu/m was achieved, resulting in an aspect ratio over thirty. The verticality was better than 89.3/spl deg/. The surface roughness of the etched surface is 36 nm rms. For an increased reflectivity the silicon mirrors are coated with aluminium. Their reflectivity was measured to be 76%. To obtain an uniform etch depth, etching is stopped on a buried oxide layer. This allows to integrate at the same time mirrors with suspension and actuation structures as well as fiber-alignment grooves in one processing step. Using this technology we have fabricated a fiber optical switch with promising performance: The coupling loss in the OFF position is 2.5 dB and 4 dB in the ON position. The switching time is below 0.2 ms.

Optical coupling from single mode fibers to integrated waveguides of semiconductor optoelectronic devices with less than 0.5 dB packaging loss generally requires positioning accuracies on the order of ±0.5 to ±1.5 μm. Laser welding is widely used for fixing because it guarantees long term stability, and it is the preferred method for hermetic packaging [1-3]. Furthermore, no thermal strain on the module parts and precise positioning of the welds are attractive features of this technique. A Nd:YAG laser equipped with fiber guided energy distribution to the welding heads is generally used. However, commercial laser systems do not guarantee a stable distribution of the energy into the different arms. This leads to different volumes and temperatures of the melted material in the weld spots, preventing a simultaneous solidification and cooling process. Hence, an unequal shrinking of the welding spots occurs, resulting in a shift of a few microns of the welded parts, strongly increasing the assembly loss. However, the shrinking of welding spots can be turned into an advantage by using it for readjustment purposes.

A new generation of wavelength stabilised, uncooled 980 nm pump modules in MiniDIL housings is presented, enabling 400 mW ex-fibre power over a temperature range of 10/spl deg/C to 70/spl deg/C. At 100/spl deg/C 200 mW power is still obtained with a robust fibre coupling scheme.

The simulated annealing algorithm is applied to the design of binary holographic optical elements for the connection of single-mode structures. The system energy used with the simulated annealing algorithm is the absolute square of the overlap between the transmitted wave front and the modal characteristics of the receiving device; the system variables are the binary states of the hologram pixels. The plausibility of the obtained binary patterns is discussed for examples involving plane and spherical modal characteristics. The ability of the annealing process to avoid local minimum trapping is demonstrated.

A novel fiber-optic Doppler velocimeter is presented. By suitably controlling the polarization state of the local oscillator, illuminating beam, and signal light, balanced mixing with a noise reduction of 30 dB as compared to unbalanced mixing can be realized. The remaining noise level is predominantly due to shot noise. Allowing for losses in the receiving optics and for nonperfect mixing efficiency, the minimum detectable signal power is estimated to be 10/sup -18/ W-Hz/sup -1/. The high sensitivity of the system is demonstrated by the detection of light scattered from a distant moving object. >

A fiberoptic acoustic sensor constructed in the Mach-Zehnder arrangement for use in a resonant photoacoustic cell is reported. Tests indicate a minimum detectable concentration of 0.5 ppm NOT, in Ar for an input power of 50 mW. This extrapo-lates for 500 mW input to a minimum detectable concentration of 50 ppb.

Opto- acoustic Fiber SensorQ. Munir, H.P. Weber, and R. BattigInstitute of Applied Physics, University of Bern,SwitzerlandAbstractAn optoacoustic sensor for trace analysis in gases was constructed and experimentallytested. The crucial element in such systems, the highly sensitive electronic microphone,was replaced by a fiberoptic interferometer in the Mach -Zehnder configuration. The fiber ofthe sensing arm was wrapped onto a thin foil arranged close to the cylindrical walls of theacoustic cell. Thus the acoustical waves generated by the absorbed light were transferredto an elongation of the fiber. The cell was operated at one of its resonances. A sensitivi-ty of ~ 50 ppb was evaluated for an input power of 500 mW radiation of an Ar -laser for thedetection of NO2 in an inert buffer gas. Presently the minimum observable power is 7.10 -8W /cm I. Details on this device are described in