An allosteric inhibitor of the human Cdc34 ubiquitin-conjugating enzyme.

In the ubiquitin-proteasome system (UPS), E2 enzymes mediate the conjugation of ubiquitin to substrates and thereby control protein stability and interactions. The E2 enzyme hCdc34 catalyzes the ubiquitination of hundreds of proteins in conjunction with the cullin-RING (CRL) superfamily of E3 enzymes. We identified a small molecule termed CC0651 that selectively inhibits hCdc34. Structure determination revealed that CC0651 inserts into a cryptic binding pocket on hCdc34 distant from the catalytic site, causing subtle but wholesale displacement of E2 secondary structural elements. CC0651 analogs inhibited proliferation of human cancer cell lines and caused accumulation of the SCF(Skp2) substrate p27(Kip1). CC0651 does not affect hCdc34 interactions with E1 or E3 enzymes or the formation of the ubiquitin thioester but instead interferes with the discharge of ubiquitin to acceptor lysine residues. E2 enzymes are thus susceptible to noncatalytic site inhibition and may represent a viable class of drug target in the UPS.

Stabilizing Fabry-Perot optical frequency comb with differential phase detection and bias compensation.

We present a stable optical frequency comb (OFC) that utilizes a Fabry-Perot phase modulator. The environmental-induced state variation of the OFC is accurately detected by measuring the relative phase changes of beat signals from its upper and lower sidebands. We then compensate for this variation by controlling OFC bias voltage through a homodyne phase-locked loop. The differential phase detection eliminates the common-mode detection noise, enabling long-term stability of the OFC without requiring any additional reference signal. The relative phase change is only 0.056° over 3800 s. Even under a drastic temperature change, the OFC remains stable, validating the effectiveness of the proposed stabilization method.

Highly stable fiber-based photonic delay line with large and tunable delay.

A stable photonic delay line with large and tunable delay is essential for large-distance simulation, beamforming, and diverse photonic signal processing applications. Here, we demonstrate a fiber-based tunable photonic delay line (TPDL) with a maximum delay of 905 µs. Its environmental-related delay jitter is compensated for by a homodyne phase-locked loop (PLL). Precise delay tuning is realized by changing the phase of the reference with a minimum tuning step of 0.5 ps without breaking its locking state. The demonstrated delay line shows exceptional stability, as indicated by an overlapping Allan deviation (ADEV) of 2.06 × 10-17 at the averaging time of 1000 s and the delay jitter below 20 fs. Its high stability, wide delay range, wideband characteristics, and precise tunability make the TPDL an ideal photonic delay line for the above-mentioned applications.

Distributed receiving system with local digitization and combination for SNR enhancement.

We demonstrate an X-band distributed receiving system with 4 remote ends for signal-to-noise ratio (SNR) enhancement. The X-band analog signal received by 4 remote ends is first transmitted to the local end through optical fiber links and is then down-converted with a photonic method for digitization and further coherent combination. Finally, a combined signal with a higher SNR can be obtained. In the proposed system, a frequency-tunable single-tone signal is stably transmitted to the remote end for both down-converting the received signal and for generating a dithered sample clock to eliminate the transmission delay jitter with an unlimited compensation range. Experimentally, X-band binary phase shift keying signals are used for system performance evaluation. After 20 to 25 km transmission, the relative timing drifts between different links are at the order of picoseconds, and a near-theoretical SNR enhancement is achieved. The proposed scheme has a simple remote structure with no need for time synchronization, increasing its signal combining precision, flexibility, and scalability, making it an ideal candidate for long-distance weak signal detection.

Quantitative quasi-distributed vibration sensing by φ-OFDR for multiple events over spatially consecutive sensing spatial resolutions.

We report on a quantitative quasi-distributed vibration sensing (DVS) system enabled by phase-sensitive optical frequency domain reflectometry (φ-OFDR), which allows for multiple vibration events over consecutive spatial resolutions. To achieve effective crosstalk suppression and mitigation of the instability during the phase extraction, fiber with embedded ultra-weak grating arrays has been adopted as the sensing fiber. It exhibits a particularly customized low spatial duty cycle, that is, high ratio between the size of the gratings and their spacing and the spacing is additionally designed to match the integer multiple of the theoretical spatial resolution. In combination with a rectified frequency-modulated continuous-wave optical probe enabled by the optical phase-locked loop, it allows to achieve quantitative quasi-DVS for multiple events over consecutive sensing spatial resolution as high as ∼2.5 cm along the distance over ∼2200 m. The ability to simultaneously retrieve arbitrary multi-point vibration events over spatially consecutive sensing spatial resolutions with consistently linear response and sensitivity up to a few nano-strain level even at long distances has shown great potentials for the application of φ-OFDR from a practical point of view.

High-resolution measurement of laser frequency drift using stable delayed self-heterodyne interferometry.

We demonstrate a laser frequency drift measurement system based on the delayed self-heterodyne technique. To ensure long-term measurement validity, an ultra-stable optical fiber delay line is realized by monitoring and locking the transmission delay of a probe signal with a well-designed phase-locked loop. The frequency stability indicated by overlapping Allan deviation is 6.39 × 10-18 at 1000-s averaging time, ensuring a real-time measurement resolution of 18.6 kHz. After carefully determining the optimal fiber length, a 5-kHz periodic frequency change with a period of merely 0.5 s is easily detected, proving its high frequency resolution and fast response. At last, the frequency drift characteristics of three different lasers after being powered on are investigated. Thanks to its high precision and long-term stability, the proposed method is ideal for monitoring long-term laser frequency evolution with high precision.

High-precision fiber-optic time transfer with an unlimited compensation range.

We present a fiber-optic time transfer system with high transfer stability and an unlimited compensation range of the delay variation. We first stably transmit a frequency signal from a voltage-controlled oscillator to the remote site. The time signal is then embedded in the frequency signal by simply selecting its one cycle per second with a tunable gate signal. Therefore, the proposed time transfer system inherits both the stability and the unlimited adjustment range of the frequency transfer yet with no need for demodulation. The time deviation of 1.93 ps is achieved at 1000-s averaging. This simple and demodulation-free time transfer system is applicable for scalable distributed applications that require high-precision time synchronization and wide-range delay compensation.

Remote vectorial vibration sensing based on locally stabilized Mach-Zehnder interferometers using multi-core fiber and optical phase-locking.

We report on remote sensing of vectorial vibration based on locally stabilized Mach-Zehnder interferometers (MZIs) using commercial multi-core fiber (MCF). Hexa-MZIs with a shared common reference arm are constructed by a 7-core MCF to acquire remotely vectorial vibration. A set of corresponding local receivers consisting of optical phase-locked loops (OPLLs) for not only eliminating the impact of environmental perturbations but also maintaining the stable operation and relative stability among the MZIs, allows guaranteed stabilized remote sensing. It moreover ensures a linearized phase detection, and thus an improved sensing sensitivity and dynamic range. This way, by exploiting the symmetrically geometric distribution for the cores of 7-core MCF, the proposed all-fiber design can enable highly precise remote extraction of vibration in a vectorial manner with a simplified remote structure. We achieve vectorial remote sensing for vibrations with ∼0.1076° and ∼0.3603 µm precision for the angle and displacement, respectively, over 10 km.

Interval-locked dual-frequency φ-OFDR with an enhanced strain dynamic range and a long-term stability.

We report on an interval-locked dual-frequency phase-sensitive optical frequency-domain reflectometry relying on a common-reference optical phase-locked loop. With a shared unbalanced interferometry, this design allows for synchronizing the frequency drift of two lasers, leading to a steadily stabilized dual frequency with an arbitrary interval. Equivalently to a longer synthetic wavelength, their phase difference is utilized to demodulate the ambient changes of interest with an enhanced dynamic range and long-term stability. With a stabilized interval of 1 THz, it allows for an enhancement in a strain measurement range of up to 193-fold in theory. Demonstration in terms of distributed strain sensing covering a distance of 500 m with a 10 cm spatial resolution has been verified, showing a significant extension in the achievable strain dynamic range with a preserved sensitivity over 1 h.

Identifying collagen VI as a target of fibrotic diseases regulated by CREBBP/EP300.

Fibrotic diseases remain a major cause of morbidity and mortality, yet there are few effective therapies. The underlying pathology of all fibrotic conditions is the activity of myofibroblasts. Using cells from freshly excised disease tissue from patients with Dupuytren's disease (DD), a localized fibrotic disorder of the palm, we sought to identify new therapeutic targets for fibrotic disease. We hypothesized that the persistent activity of myofibroblasts in fibrotic diseases might involve epigenetic modifications. Using a validated genetics-led target prioritization algorithm (Pi) of genome wide association studies (GWAS) data and a broad screen of epigenetic inhibitors, we found that the acetyltransferase CREBBP/EP300 is a major regulator of contractility and extracellular matrix production via control of H3K27 acetylation at the profibrotic genes, ACTA2 and COL1A1 Genomic analysis revealed that EP300 is highly enriched at enhancers associated with genes involved in multiple profibrotic pathways, and broad transcriptomic and proteomic profiling of CREBBP/EP300 inhibition by the chemical probe SGC-CBP30 identified collagen VI (Col VI) as a prominent downstream regulator of myofibroblast activity. Targeted Col VI knockdown results in significant decrease in profibrotic functions, including myofibroblast contractile force, extracellular matrix (ECM) production, chemotaxis, and wound healing. Further evidence for Col VI as a major determinant of fibrosis is its abundant expression within Dupuytren's nodules and also in the fibrotic foci of idiopathic pulmonary fibrosis (IPF). Thus, Col VI may represent a tractable therapeutic target across a range of fibrotic disorders.

Enhanced frequency-modulated continuous-wave generation by injection-locking period-one oscillation in a semiconductor laser with an intensity modulated comb.

We report on an enhanced photonic generation of frequency-modulated continuous-wave (FMCW) signals by injection-locking a semiconductor laser operating in period-one (P1) nonlinear dynamic with an intensity modulated electro-optic frequency comb. When the cavity mode is injection-locked with respect to any of the comb modes, through linearly sweeping the frequency of the injected comb mode while synchronously modulating the injected intensity, the center wavelength of the cavity mode can be tuned following the injected comb mode. This way, it allows maintaining the phase-locking between the cavity mode and comb mode even if beyond the original locking bandwidth of the cavity mode, since it is tuned accordingly. It thus leads to the generation of FMCW signal with efficient phase noise suppression and improved achievable sweep range compared with the limited original injection-locking bandwidth. Such injection enhanced phase-locking is investigated and a demonstration with the injection of -4th order comb mode has realized photonic FMCW generation with enhanced sweep range and suppressed phase noise. Thanks to the flexibility in sweep parameters, this method can also be readily applied for the generation of arbitrary waveforms.

Modeling and optimization of an unbalanced delay interferometer based OPLL system.

We present and establish a versatile analytical model that allows overall analysis and optimization for the phase noise performance of the delay interferometer based optical phase-locked loop (OPLL). It allows considering any type of lasers with arbitrary frequency noise properties while taking into account the contributions from various practical noise sources, thus enabling comprehensive investigation for the complicated interaction among underlying limiting factors. The quantitative analysis for their evolution along with the change of the delay of the interferometer unveils the resulting impact on the fundamental limit and dynamics of the output phase noise, leading to a well-balanced loop bandwidth and sensitivity thus enabling the overall optimization in terms of closed-loop noise performance. The tendencies observed and the results predicted in terms of coherence metrics in numerical verification with different lasers have testified to the precision and effectiveness of the proposed model, which is quite capable of acting as a design tool for the insightful analysis and overall optimization with guiding significance for practical applications.

Optical linear frequency sweep based on a mode-spacing swept comb and multi-loop phase-locking for FMCW interferometry.

We report on the generation of a highly coherent broadband optical linear frequency sweep (LFS) using mode-spacing swept comb and multi-loop composite optical phase-locked loop (OPLL). We exploit a specially designed agile opto-electronic frequency comb as a sweeping reference, whose mode-spacing is capable of arbitrary frequency sweep while preserving a stable phase and power distribution per mode. By locking a continuous-wave (CW) laser to any of its modes using composite OPLL with a large loop bandwidth, it allows the extraction of the optical LFS at high-order modes in a coherent manner with a multiplied sweep range and rate. With such capability, only intermediate frequency LFS with smaller bandwidth is required to yield a broadband LFS while inheriting the coherence and precision from the comb. We achieve optical LFS of 60 GHz at 6 THz/s sweep rate with a nine-folded sweep bandwidth of the driving signal. Fourier transform-limited spatial resolution at more than 80 times of the intrinsic coherence length of the CW laser is demonstrated in an OFMCW interferometry, verifying the high coherence with more than 4 orders of magnitude improvement in spatial resolution. The characteristics in terms of agility, coherence, and precision are discussed together with the potential limitations. The proposed method is capable of generating arbitrary frequency-modulated optical waveforms with a multiplied bandwidth, showing attractive potential in future metrology applications.

Generation and transmission of phase-stable coherent multi-band linear frequency modulated signals.

We present a coherent multi-band linear frequency modulated (LFM) signal generation and transmission system based on dual optical frequency combs (OFCs). In the proposed scheme, the two OFCs are phase-locked to ensure high coherence of the generated multi-band LFM signals. A round-trip phase correction is adopted to stabilize the time delay of the fiber transmission and enable the system to resist temperature variation. In the demonstration experiment, the generated multi-band LFM signals across L, S, and C frequency bands has a bandwidth of 200 MHz in each band. The root-mean-square (RMS) phase deviation of the multi-band signal is below 4×10-3rad after 1.2 km fiber transmission. During 1°C temperature variation, the RMS phase drift is suppressed from 1 rad to 0.1 rad. The high signal coherence between different bands and the capability of resisting temperature variation are highly desired for a multi-band distributed radar system.

Sub-terahertz photonic frequency divider with a large division ratio based on phase locking.

We present a photonic frequency divider with a large division ratio for microwave signals up to sub-terahertz. A high-operating frequency and a large frequency division ratio have both been achieved by phase-locking a Fabry-Perot frequency comb to the input signal that is to be divided. The input signals ranging from 50.10 GHz to 200.10 GHz are all divided to 2.5 GHz signals, which can be further divided into lower- frequency signals easily. The proposed divider is free of high-speed electrical devices, thanks to the intermediate-frequency detection and feedback control in the phase locking process. Moreover, the phase noise caused by the photonic frequency division is negligible at low offset frequencies, proving that the divider has superior long-term stability. This flexible, cost-efficient, and stable photonic frequency divider is an ideal candidate for frequency division at the remote end of a high-precision frequency transfer system.

Remote Michelson interferometric phase sensor based on dual-core fiber transmission and linear phase demodulation.

We present a remote Michelson interferometric phase sensor based on dual-core fiber transmission and linear phase demodulation. The former allows for synchronous transmission of both sensing signal and reference lights, enabling efficient suppression for the environmental disturbances along the transmission link and for the incoherent phase noise between the two lights. The latter is conducted by two optical phase-locked loops, one of which consists of a fiber stretcher that is used to eliminate the residual phase noises, thus stabilizing the operation point while the other relies on a phase modulator that is used to track the remote phase changes, thus achieving a highly linearized phase demodulation. A remote phase sensing over a 20 km fiber link with less than 3% nonlinear phase error over 3π range has been readily realized, corresponding to more than 10 times extension in a linear phase demodulation range. The proposed system shows great potential in the field of remote phase sensing for a variety of physical quantities.

Dual-frequency Doppler velocimeter based on delay interferometric optical phase-locking.

We present a dual-frequency laser Doppler velocimeter (DF-LDV) relying on a DF laser source (DFLS) generated by optical phase-locking two individual lasers to a common unbalanced Mach-Zehnder interferometer, which allows achieving high stability regardless of the DF separation of the lasers. This DFLS is evaluated using an optical frequency comb, testifying to the generation of DFLS with large DF separation up to terahertz with flexible tunability and high stability. Demonstration of DF-LDV using the DFLS of ${\sim}1.024\; {\rm THz}$ separation has achieved $1.62 \times {10^{- 2}}$ mm/s velocity resolution even for a slow velocity of $1.8\; {\rm mm}/{\rm s}$ in a mere 5 s acquisition time, confirming the high resolution and efficient speckle noise suppression enabled by the proposed DF-LDV. Featuring high precision, flexibility, and robustness, this method is particularly attractive from the practical point of view.

Theoretical analysis for fiber-optic distribution of RF signals based on phase-locked loop.

We establish an analytical model for the stable dissemination of radio-frequency (RF) signals via fiber-optic links. Based on the phase-locked loop theory, the contributions from the photonic RF source, transmission-path, and additional system noise have been taken into account, leading to the quantitative analysis of the phase noise evolution in the transmission link. Furthermore, the theoretical analysis reveals the relation between the system instability and the frequency of the transmitted signal, which is further verified. Assisted with the proposed model, the optimization for stabilized dissemination of RF signals with a certain length of transmission link or any specified noise floors can be achieved with minimized timing jitter performance, testifying the potential high stability obtained thanks to the higher transmitted signal frequencies. This quantitative model, enabling precise prediction of the frequency instability and timing jitter from the residual phase noise, can be a useful guide in designing a fiber-optic distribution system and evaluating its fundamental limits.

Remote broadband RF signal down-conversion with stable phase and high efficiency using a sideband optical phase-locked loop.

We propose a phase-stable high-efficiency down-conversion approach for broadband radio frequency signals transmitted from a remote site. A high power coherent optical local oscillator signal is used at the local site to increase the conversion gain and the spurious-free dynamic range (SFDR) at the same time. A sideband optical phase-locked loop ensures the suppression of the phase noise induced by the fiber transmission and the relative frequency drift of the remote and local lasers, which are essential for the signal transmission and the down-conversion. We first experimentally demonstrate the down-conversion of a single frequency signal at 16.45 GHz to a 250 MHz intermediate frequency (IF) signal with 3 dB gain and 103 dB/Hz2/3 SFDR after 10 km fiber transmission. Then we show the broadband down-conversion capability by down-converting a 1 GHz wide linear frequency modulated pulse signal centered at 11 GHz to 1 GHz with 3 dB gain. Along with a positive gain, the SFDR of the IF signal down-converted from 5 GHz to 40 GHz has reached 97.6 dB/Hz2/3 on average. This approach is suitable for weak broadband remote signal down-conversion with a simple-structured remote end.

Distribution of optical-comb-based multi-frequency microwave signals over 100†km optical fiber with high phase stability.

We demonstrate a long-distance multi-frequency microwave distribution system over an optical fiber link with high phase stability based on transferring an optical frequency comb (OFC). The phase fluctuation induced by the transmission link variations is detected by applying a reference OFC and is then compensated with the proposed optical voltage-controlled oscillator (OVCO) by adjusting the phase of the repetition rate of the transmitted OFC. By applying the OVCO, we perform the OFC-based multi-frequency microwave distribution over a 100 km standard single-mode fiber. The performance of the transmission system can be exhibited by evaluating the repetition rate (10.015 GHz) and second harmonic frequency (20.03 GHz) signals achieved at the remote end. The residual phase noise of the 10.015 GHz and 20.03 GHz signal is -64 dBc/Hz and -58 dBc/Hz at 1 Hz frequency offset from the carrier, respectively. The fractional frequency instability is 1.4×10-16 and 2.4×10-16 at 10000 s averaging time, respectively. And the timing jitter in the frequency range from 0.01 Hz to 1 MHz reaches 88 fs and 87 fs, respectively. Based on the phase-locked loop theory, we conduct a simulation model of the transmission system and the simulated results match well with experiments. It shows that by detecting the phase fluctuation with higher harmonic frequency signals in the simulation system, the performance of the transmission system can be further improved.