Gain-of-function mutations in RIT1 cause Noonan syndrome, a RAS/MAPK pathway syndrome.

RAS GTPases mediate a wide variety of cellular functions, including cell proliferation, survival, and differentiation. Recent studies have revealed that germline mutations and mosaicism for classical RAS mutations, including those in HRAS, KRAS, and NRAS, cause a wide spectrum of genetic disorders. These include Noonan syndrome and related disorders (RAS/mitogen-activated protein kinase [RAS/MAPK] pathway syndromes, or RASopathies), nevus sebaceous, and Schimmelpenning syndrome. In the present study, we identified a total of nine missense, nonsynonymous mutations in RIT1, encoding a member of the RAS subfamily, in 17 of 180 individuals (9%) with Noonan syndrome or a related condition but with no detectable mutations in known Noonan-related genes. Clinical manifestations in the RIT1-mutation-positive individuals are consistent with those of Noonan syndrome, which is characterized by distinctive facial features, short stature, and congenital heart defects. Seventy percent of mutation-positive individuals presented with hypertrophic cardiomyopathy; this frequency is high relative to the overall 20% incidence in individuals with Noonan syndrome. Luciferase assays in NIH 3T3 cells showed that five RIT1 alterations identified in children with Noonan syndrome enhanced ELK1 transactivation. The introduction of mRNAs of mutant RIT1 into 1-cell-stage zebrafish embryos was found to result in a significant increase of embryos with craniofacial abnormalities, incomplete looping, a hypoplastic chamber in the heart, and an elongated yolk sac. These results demonstrate that gain-of-function mutations in RIT1 cause Noonan syndrome and show a similar biological effect to mutations in other RASopathy-related genes.

Clinicians in 25 countries prefer to use lower levels of oxygen to resuscitate preterm infants at birth.

AIM: This study determined current international clinical practice and opinions regarding initial fractional inspired oxygen (FiO2 ) and pulse oximetry (SpO2 ) targets for delivery room resuscitation of preterm infants of less than 29 weeks of gestation. METHODS: An online survey was disseminated to neonatal clinicians via established professional clinical networks using a web-based survey programme between March 9 and June 30, 2015. RESULTS: Of the 630 responses from 25 countries, 60% were from neonatologists. The majority (77%) would target SpO2 between the 10th to 50th percentiles values for full-term infants. The median starting FiO2 was 0.3, with Japan using the highest (0.4) and the UK using the lowest (0.21). New Zealand targeted the highest SpO2 percentiles (median 50%). Most respondents agreed or did not disagree that a trial was required that compared the higher FiO2 of 0.6 (83%), targeting the 50th SpO2 percentile (60%), and the lower FiO2 of 0.21 (80%), targeting the 10th SpO2 percentile (78%). Most (65%) would join this trial. Many considered that evidence was lacking and further research was needed. CONCLUSION: Clinicians currently favour lower SpO2 targets for preterm resuscitation, despite acknowledging the lack of evidence for benefit or harm, and 65% would join a clinical trial.

All-fiber 80-Gbit/s wavelength converter using 1-m-long Bismuth Oxide-based nonlinear optical fiber with a nonlinearity gamma of 1100 W-1km-1.

We experimentally demonstrate the use of our fabricated 1-m-long Bi2O3 optical fiber (Bi-NLF) with an ultra-high nonlinearity of ~1100 W-1km-1 for wavelength conversion of OTDM signals. With successfully performed fusion splicing of the Bi-NLF to conventional silica fibers an all-fiber wavelength converter is readily implemented by use of a conventional Kerr shutter configuration. Owing to the extremely short fiber length, no additional scheme was employed for suppression of signal polarization fluctuation induced by local birefringence fluctuation, which is usually observed in a long-fiber Kerr shutter. The wavelength converter, composed of the 1-m Bi-NLF readily achieves error-free wavelength conversion of an 80-Gbit/s input signal.

All fiber-based 160-Gbit/s add/drop multiplexer incorporating a 1-m-long Bismuth Oxide-based ultra-high nonlinearity fiber.

We experimentally demonstrate an all fiber-based, compact add/drop multiplexer (ADM) of a 160 Gbit/s optical time division multiplexed signal using only 1-m length of our fabricated Bi2O3-based step index type optical fiber with an ultra-high nonlinearity of ~1100 W-1.km-1 The ADM is based on the cross phase modulation-induced nonlinear polarization rotation principle and simultaneous add/drop operation was easily achieved by use of a polarization beam splitter after the Bi2O3-based nonlinear fiber. Error-free add/drop operation is readily achieved at multiplexed data rates of both 80 Gbit/s and 160 Gbit/s.

Highly nonlinear bismuth-oxide fiber for smooth supercontinuum generation at 1.5 microm.

Short lengths of highly nonlinear bismuth-oxide fiber are used to generate smooth supercontinuum spanning from 1200 nm to 1800 nm, with sub-0.5 nJ pulse energies. The spectral broadening in a 2-cm length of this fiber was used to compress 150-fs pulses to 25 fs.

Use of 1-m Bi2O3 nonlinear fiber for 160-Gbit/s optical time-division demultiplexing based on polarization rotation and a wavelength shift induced by cross-phase modulation.

We present, for the first time to our knowledge, experimental results of the use of a 1-m-long Bi2O3-based nonlinear fiber (Bi-NLF) with a nonlinear parameter gamma of approximately 1100 W(-1) km(-l) within an all-fiber-based 160Gbit/s optical time-division multiplexing (OTDM) data demultiplexer. Our demultiplexing switch basically uses the principle of the Kerr shutter, and its switching performance is further enhanced by the additional use of the wavelength blueshift of data pulses, which is induced by cross-phase modulation from the control pulse's trailing edge. The OTDM demultiplexer, composed of the 1-m Bi-NLF, readily achieves error-free demultiplexing operation of all 16 channels.

Experimental comparison of a Kerr nonlinearity figure of merit including the stimulated Brillouin scattering threshold for state-of-the-art nonlinear optical fibers.

We introduce a new figure of merit (FOM) including the input pump power limit associated with stimulated Brillouin scattering (SBS) for evaluation of the Kerr nonlinearity efficiency of optical fibers. The new FOM is expressed as gammaL(eff)P(SBS) (gamma is a nonlinearity parameter, L(eff) is effective length, and P(SBS) is the SBS threshold), while the conventional FOM is given by gammaL(eff). Using the new FOM, we perform an efficiency comparison among four types of state-of-the-art nonlinear optical fiber: a Bi2O3-based nonlinear fiber, a silica-based holey fiber, a highly nonlinear dispersion-shifted fiber, and a conventional dispersion-shifted fiber. The Bi2O3-based nonlinear fiber is found to have the best Kerr nonlinearity efficiency owing to the superior nonlinear property of the Bi2O3 glass compared with that of the silica.