Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models.

OBJECTIVE: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (2.0-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO×hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO×hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [3H]-cholesterol and confirmed significant increases of [3H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a-treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a-immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. CONCLUSIONS: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

In-process measurement of a keyhole using a low-coherence interferometer with a high repetition rate.

The shape of an instance hole (keyhole) created via a high-power laser was measured using a low-coherence interferometer with the following parameters: repetition rate, 10 MHz; center wavelength, 1550 nm; absolute spatial resolution, 10 µm; and measurement range, 5 mm. The keyhole was created on a 3-mm-thick stainless-steel plate using a high-power laser with 8-kW peak power and 1070-nm center wavelength. The cross-sectional area of the keyhole was measured to be 0.42 mm × 0.78 mm (width × depth) using the interferometer, and its side dimension was 0.46 mm × 0.78 mm (width × depth).

Identification and Characterization of a New Carboxylesterase 2 Isozyme, mfCES2C, in the Small Intestine of Cynomolgus Monkeys.

In contrast to a single human carboxylesterase 2 (CES2) isozyme (hCE2), three CES2 genes have been identified in cynomolgus monkeys: mfCES2A, mfCES2B, and mfCES2C . Although mfCES2A protein is expressed in several organs, mfCES2B is a pseudogene and the phenotype of the mfCES2C gene has not yet been clarified in tissues. In previous studies, we detected an unidentified esterase in the region of CES2 mobility upon nondenaturing PAGE analysis of monkey intestinal microsomes, which showed immunoreactivity for anti-mfCES2A antibody. The aim of the present study was to identify this unidentified esterase from monkey small intestine. The esterase was separated on nondenaturing PAGE gel and digested in-gel with trypsin. The amino acid sequences of fragmented peptides were analyzed by tandem mass spectrometry. The unidentified esterase was shown to be identical to mfCES2C (XP_015298642.1, predicted from the genome sequence data). mfCES2C consists of 559 amino acid residues and shows approximately 90% homology with mfCES2A (561 amino acid residues). In contrast to the ubiquitous expression of mfCES2A, mfCES2C is only expressed in the small intestine, kidney, and skin. The hydrolytic properties of recombinant mfCES2C, expressed in HEK293 cells, with respect to p-nitrophenyl derivatives, 4-methylumbelliferyl acetate, and irinotecan were similar to those of recombinant mfCES2A. However, mfCES2C showed a hydrolase activity for O-n-valeryl propranolol higher than mfCES2A. It is concluded that the previously unidentified monkey intestinal CES2 is mfCES2C, which shows different hydrolytic properties to mfCES2A, depending on the substrate. SIGNIFICANCE STATEMENT: In the present research, we determined that mfCES2C, a novel monkey CES2 isozyme, is expressed in the small intestine and kidney of the cynomolgus monkey. Interestingly, mfCES2C showed a relatively wide substrate specificity for ester-containing compounds. These findings may, in early stages of drug development, support the use of in vitro-to-in vivo extrapolation for the intestinal hydrolysis of ester drugs in the cynomolgus monkey.

Demonstration of PAM4-OCDM system with electrical amplitude-level pre-tuning and post-equalization for data centers applications.

A PAM4-OCDM system with optical multi-/demultiplexing and electrical pre-/post-processing is proposed for short-reach applications. We experimentally demonstrate, for the first time, a power-efficient 4 OC x 10 GSymbol/s PAM4-OCDM system. The four PSK-OCs are simultaneously generated using a single light source and a passive multiport optical encoder and received by a single optical decoder and cascaded DSP. The effectiveness of the electrical-domain amplitude level pre-tuning and post-equalizer are demonstrated, considering different values of shot and beat noises.

Master-slave carrier recovery for M-QAM multicore fiber transmission.

Master-slave carrier recovery is a digital signal processing technique that uses correlated phase noise in multi-channel receivers to eliminate redundant carrier recovery blocks. In this paper we experimentally investigate the performance of master-slave carrier recovery for multicore fiber transmission in the presence of inter-channel nonlinear interference. Using a triple parallel loop setup we jointly receive three spatial channels in a 7-core fiber for transmission distances of up to 1600 km. We find that an increased launch power causes a moderate penalty on the slave channels. Furthermore, we study the penalty from a non-zero inter-core skew.

Ecotypic divergences of the alpine herb Potentilla matsumurae adapted to fellfield-snowbed habitats across a series of mountain sky islands.

PREMISE: Divergent selection due to environmental heterogeneity can lead to local adaptation. However, the ecological and evolutionary processes of local adaptation that occurs across multiple regions are often unknown. Our previous studies reported on the ecotypic divergence within a local area of variation of Potentilla matsumurae, an alpine herb adapted to the fellfield-snowbed environment. Here we investigated large-scale geographic patterns of ecotypic differentiation in this species to infer local adaptation and selective forces across multiple regions. METHODS: We compiled information on the overall distributions of fellfield and snowbed habitats on the mountains in Japan across the distribution of the species. Next, we conducted common garden experiments to test the adaptive divergence of the fellfield-snowbed plants derived from multiple regions. Finally, we evaluated phylogeographic structures based on cpDNA and allozyme variations and inferred the evolutionary history of ecotype differentiation. RESULTS: The mosaic distribution of the fellfield-snowbed ecotypes across isolated mountaintops constitutes indirect evidence for habitat-specific natural selection. The significant difference in survivorship between the ecotypes observed in a controlled snow environment provides more substantial evidence of local selection. Phylogeographic structures support the hypothesis that ecotypic divergence events from fellfield to snowbed populations occurred independently in at least two distinct regions. CONCLUSIONS: Ecotypic divergence of P. matsumurae has occurred across a series of mountain sky islands. Local selection in snowy environments is a driving force that maintains the divergent ecotypes across multiple mountain regions and can contribute to the diversification of plants in heavy-snow regions.

Long distance crosstalk-supported transmission using homogeneous multicore fibers and SDM-MIMO demultiplexing.

We propose and evaluate the use of spatial-division multiplexing (SDM) multiple input multiple output (MIMO) systems to support long distance transmission using single-mode homogeneous multicore fibers. We show that on a uniform link with per-span inter-core skew compensation, the required SDM-MIMO memory length corresponds to the largest inter-core skew per span on the link. Furthermore, we show that with inter-core skew compensation, the required memory length of the SDM-MIMO is nearly constant with the transmission distance for accumulated crosstalk below -11 dB. We experimentally demonstrate the use of SDM-MIMO with a memory length of 20 ns on a long distance transmission link using 20 GBaud PDM-QPSK signals. We achieve a reach of 9780 km, which corresponds to a 9% improvement over the case without SDM-MIMO. We also show that the use of SDM-MIMO is applicable to the transmission of signals with higher modulation order, achieving transmission reach improvements of 14% for 20 GBaud PDM-16QAM and PDM-64QAM signals.

Volume holographic spatial mode demultiplexer with a dual-wavelength method.

Volume holographic demultiplexers (VHDMs) provide spatial mode demultiplexing using simple optical systems. However, applying VHDM to practical optical communication systems is difficult, as typical holographic media have no sensitivity in the infrared region, which includes optical transmission bands. In this paper, we propose a VHDM scheme combined with a dual-wavelength method (DWM). Using the DWM, VHDMs are able to perform mode demultiplexing in the optical transmission bands. We experimentally demonstrated the basic operation of our proposal using experiments performed at an 850-nm wavelength. In addition, we performed numerical simulations to investigate the application of VHDM to the C-band.

All-optical Nyquist-OTDM to Nyquist-WDM conversion for high-granular flexible optical networks.

We have proposed and experimentally demonstrated all-optical multiplexing (MUX)-format conversion from Nyquist optical time division multiplex (OTDM) to Nyquist wavelength division multiplex (WDM). The system is simply configured with a straight-type phase modulator (PM) driven by a sinusoidal wave and an optical Nyquist filter. In the theoretical investigation, it is proved that the single Nyquist signal is completely converted to Nyquist WDM signal, which consists of two half-baud-rate signals with different carrier frequencies. The theoretical modulation voltage for the phase modulator is slightly lower than Vπ: 0.913 Vπ, and it is experimentally verified. In the experimental demonstrations, 50 Gbaud to 25 Gbaud x 2 and 25 Gbaud to 12.5 Gbaud x 2 conversions are successfully demonstrated with quite low optical signal-to-noise ratio (OSNR) penalties. In addition, cascaded MUX-format conversion is also demonstrated; 50 Gbaud Nyquist signal is converted to four channels of 12.5 Gbaud Nyquist signals.

Crosstalk dynamics in multi-core fibers.

Inter-core crosstalk is a potential limitation on the achievable data-rates in optical fiber transmission systems using multi-core fibers. Crosstalk arises from unwanted coupling between cores of a homogenous multi-core fiber and it's average power has been observed to vary over time by 10s of decibels, potentially requiring an additional performance margin to achieve acceptable outage probability. Most investigations of crosstalk have so far only considered continuous wave laser light or amplified spontaneous emission as sources of crosstalk. In this paper, we theoretically and experimentally investigate the time-dependence of inter-core crosstalk in a homogeneous multi-core fiber when considering signals with various modulation formats and symbol rates. We find that crosstalk power fluctuations depend on the symbol rate, modulation and skew between cores. For carrier-free signals, such as quadrature amplitude modulation, the crosstalk power is nearly constant for expected conditions of multi-core transmission systems. However, carrier-supported signals, such as OOK, always induce time-varying crosstalk powers.

Performance of adaptive DD-OFDM multicore fiber links and its relation with intercore crosstalk.

Adaptive direct-detection (DD) orthogonal frequency-division multiplexing (OFDM) is proposed to guarantee signal quality over time in weakly-coupled homogenous multicore fiber (MCFs) links impaired by stochastic intercore crosstalk (ICXT). For the first time, the received electrical power of the ICXT and the performance of the adaptive DD-OFDM MCF link are experimentally monitored quasi-simultaneously over a 210 hour period. Experimental results show that the time evolution of the error vector magnitude due to the ICXT can be suitably estimated from the normalized power of the detected crosstalk. The detected crosstalk results from the beating between the carrier in the test core and ICXT originating from the carrier and modulated signal from interfering core. The results show that the operation of DD-OFDM systems employing fixed modulation can be severely impaired by the presence of ICXT that may unpredictable vary in both power and frequency. The system may suffer from deleterious impact of moderate ICXT levels over a time duration of several hours or from peak ICXT levels occurring over a number of minutes. Such power fluctuations can lead to large variations in bit error ratio (BER) for static modulation schemes. Here, we show that BER fluctuations may be minimized by the use of adaptive modulation techniques and that in particular, the adaptive OFDM is a viable solution to guarantee link quality in MCF-based systems. An experimental model of an adaptive DD-OFDM MCF link shows an average throughput of 12 Gb/s that represents a reduction of only 9% compared to the maximum throughput measured without ICXT and an improvement of 23% relative to throughput obtained with static modulation.

Few-mode fiber, splice and SDM component characterization by spatially-diverse optical vector network analysis.

This paper discusses spatially diverse optical vector network analysis for space division multiplexing (SDM) component and system characterization, which is becoming essential as SDM is widely considered to increase the capacity of optical communication systems. Characterization of a 108-channel photonic lantern spatial multiplexer, coupled to a 36-core 3-mode fiber, is experimentally demonstrated, extracting the full impulse response and complex transfer function matrices as well as insertion loss (IL) and mode-dependent loss (MDL) data. Moreover, the mode-mixing behavior of fiber splices in the few-mode multi-core fiber and their impact on system IL and MDL are analyzed, finding splices to cause significant mode-mixing and to be non-negligible in system capacity analysis.

Pump-phase-noise-free optical wavelength data exchange between QAM signals with 50-GHz channel-spacing using coherent DFB pump.

An important challenge for implementing optical signal processing functions such as wavelength conversion or wavelength data exchange (WDE) is to avoid the introduction of linear and nonlinear phase noise in the subsystem. This is particularly important for phase noise sensitive, high-order quadrature-amplitude modulation (QAM) signals. In this paper, we propose and experimentally demonstrate an optical data exchange scheme through cascaded 2nd-order nonlinearities in periodically-poled lithium niobate (PPLN) waveguides using coherent pumping. The proposed coherent pumping scheme enables noise from the coherent pumps to be cancelled out in the swapped data after WDE, even with broad linewidth distributed feedback (DFB) pump lasers. Hence, this scheme allows phase noise tolerant processing functions, enabling the low-cost implementation of WDE for high-order QAM signals. We experimentally demonstrate WDEs between 10-Gbaud 4QAM (4QAM) signal and 12.5-Gbaud 4QAM (16QAM) signal with 3.5-MHz linewidth DFB pump lasers and 50-GHz channel spacing. Error-free operation is observed for the swapped QAM signals with coherent DFB pumping whilst use of free-running DFB pumps leads to visible error floors and unrecoverable phase errors. The phase noise cancellation in the coherent pump scheme is further confirmed by study of the recovered carrier phase of the converted signals. In addition to pump phase noise, the influence of crosstalk caused by the finite extinction ratio in WDE is also experimentally investigated for the swapped QAM signals.

Optical 8QAM and 8PSK synthesis by cascading arbitrary 2QAM with squared QPSK.

In dynamic optical networking scenarios, it is desirable that the optical transmitter chooses the most suitable modulation format in order to achieve optimal transmission performance. Owing to the ability of switching among different modulation formats, flexible optical transmitters based on reconfigurable optical devices are becoming a key component for the implementation of future flexible optical networks. In this paper, we experimentally demonstrate a flexible 8-ary transmitter to achieve adaptive switching between 8-ary phase-shift keying (8PSK) and circular 8-ary quadrature-amplitude modulation (8QAM) through reconfiguration of two cascaded in-phase/quadrature (IQ) modulators with different driving signals and biasing conditions. An arbitrary binary quadrature-amplitude modulation (2QAM) with constant or non-constant amplitude is proposed and experimentally demonstrated using an IQ modulator. Then, optical 8PSK or 8QAM modulation formats are successfully synthesized when a standard squared QPSK modulator is cascaded with a constant-amplitude or non-constant-amplitude 2QAM, respectively.

Scalable two- and three-dimensional optical labels generated by 128-port encoder/decoder for optical packet switching.

This paper deals with massive number of optical code (OC) label generation and recognition for scalable optical packet switching (OPS) networks. In order to expand the system scalability of code label processing, we develop a record port count 128 x 128 optical encoder/decoder (E/D) and propose a novel three-dimensional (3-D) optical label combining code label with wavelength and polarization. In the experiment, we conduct a proof-of-concept demonstration of 4-code x 2-wavelength x 2-polarization and validate that the 3-D labeling scheme can consequently increase the available number of code label up to more than 1,000 labels. Real-time labeling performance using a field programmable gate array (FPGA)-based processor and crosstalk influence at an optical switch are also experimentally evaluated.

Single parity check-coded 16QAM over spatial superchannels in multicore fiber transmission.

We experimentally investigate single-parity check (SPC) coded spatial superchannels based on polarization-multiplexed 16-ary quadrature amplitude modulation (PM-16QAM) for multicore fiber transmission systems, using a 7-core fiber. We investigate SPC over 1, 2, 4, 5 or 7 cores in a back-to-back configuration and compare the sensitivity to uncoded PM-16QAM, showing that at symbol rates of 20 Gbaud and at a bit-error-rate (BER) of 10-3, the SPC superchannels exhibit sensitivity improvements of 2.7 dB, 2.0 dB, 1.7 dB, 1.3 dB, and 1.1 dB, respectively. We perform both single channel and wavelength division multiplexed (WDM) transmission experiments with 22 GHz channel spacing and 20 Gbaud channel symbol rate for SPC over 1, 3 and 7 cores and compare the results to PM-16QAM with the same spacing and symbol rate. We show that in WDM signals, SPC over hl1 core can achieve more than double the transmission distance compared to PM-16QAM at the cost of 0.91 bit/s/Hz/core in spectral efficiency (SE). When sharing the parity-bit over 7 cores, the loss in SE becomes only 0.13 bit/s/Hz/core while the increase in transmission reach over PM-16QAM is 44 %.

Experimental investigation of phase-sensitive amplification of data signals in a four-mode fiber-based PSA.

In this Letter, we investigate the influence of the phase and power of pump and signal waves on the gain of a four-mode phase-sensitive amplifier (PSA) built with a highly nonlinear fiber (HNLF), using a copier + PSA scheme to generate phase- and frequency-correlated idler waves. Using such an amplifier, low-noise amplification of a 10 Gsymbol/s quadrature phase-shift keying (QPSK) signal, with net gain of ∼20 dB and less than 1 dB optical signal-to-noise ratio (OSNR) penalty at a bit error ratio (BER) of 10(-3), was achieved. We also verified an additional net gain of 11.6 dB when switching from phase-insensitive to phase-sensitive operation, which is in good agreement with theoretical predictions of 12 dB.

Bioactivation of loxoprofen to a pharmacologically active metabolite and its disposition kinetics in human skin.

Loxoprofen (LX) is a prodrug-type non-steroidal anti-inflammatory drug which is used not only as an oral drug but also as a transdermal formulation. As a pharmacologically active metabolite, the trans-alcohol form of LX (trans-OH form) is generated after oral administration to humans. The objectives of this study were to evaluate the generation of the trans-OH form in human in vitro skin and to identify the predominant enzyme for its generation. In the permeation and metabolism study using human in vitro skin, both the permeation of LX and the formation of the trans-OH form increased in a time- and dose-dependent manner after the application of LX gel to the skin. In addition, the characteristics of permeation and metabolism of both LX and the trans-OH form were examined by a mathematical pharmacokinetic model. The Km value was calculated to be 10.3 mm in the human in vitro skin. The predominant enzyme which generates the trans-OH form in human whole skin was identified to be carbonyl reductase 1 (CBR1) by immunodepletion using the anti-human CBR1 antibody. The results of the enzyme kinetic study using the recombinant human CBR1 protein demonstrated that the Km and Vmax values were 7.30 mm and 402 nmol/min/mg protein, respectively. In addition, it was found that no unknown metabolites were generated in the human in vitro skin. This is the first report in which LX is bioactivated to the trans-OH form in human skin by CBR1. Copyright © 2015 John Wiley & Sons, Ltd.

Chromatic dispersion monitoring and adaptive compensation using pilot symbols in an 8 x 12.5 Gbit/s all-optical OFDM system.

We propose and experimentally demonstrate a novel technique for chromatic dispersion (CD) monitoring and adaptive compensation in an 8 x 12.5 Gbit/s all-optical orthogonal frequency-division multiplexing (AO-OFDM) system by using two pilot symbols and a virtually imaged phased array (VIPA) for a tunable CD compensator. The two pilot symbols are added to the first and the last sub-channels of the OFDM signal, and their relative time delay is detected and used for CD estimation at the CD monitoring circuit. The monitored CD value is fed to VIPA for CD compensation. In the experiments, the relative time delay between the two pilot symbols was successfully observed, and the adaptive CD compensation drastically improved the bit-error-rate (BER) from over 10(-5) to under 10(-9). The estimated CD values showed less than 10 ps/nm difference from the values measured by a photonic dispersion analyzer, which is accurate enough since the AO-OFDM system can keep BER<10(-9) upto 20 ps/nm residual CD.

Moving the boundary between wavelength resources in optical packet and circuit integrated ring network.

Optical packet and circuit integrated (OPCI) networks provide both optical packet switching (OPS) and optical circuit switching (OCS) links on the same physical infrastructure using a wavelength multiplexing technique in order to deal with best-effort services and quality-guaranteed services. To immediately respond to changes in user demand for OPS and OCS links, OPCI networks should dynamically adjust the amount of wavelength resources for each link. We propose a resource-adjustable hybrid optical packet/circuit switch and transponder. We also verify that distributed control of resource adjustments can be applied to the OPCI ring network testbed we developed. In cooperation with the resource adjustment mechanism and the hybrid switch and transponder, we demonstrate that automatically allocating a shared resource and moving the wavelength resource boundary between OPS and OCS links can be successfully executed, depending on the number of optical paths in use.