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.

Targeted protein degradation in hematologic malignancies: latest updates from the 2023 ASH annual meeting.

Protein degraders, emerging as a novel class of therapeutic agents, have gained widespread attention due to their advantages. They have several advantages over traditional small molecule inhibitors, including high target selectivity and ability to target "undruggable" targets and overcome inhibitor drug resistance. Tremendous research and development efforts and massive investment have resulted in rapid advancement of protein degrader drug discovery in recent years. Here, we overview the latest clinical and preclinical updates on protein degraders presented at the 2023 ASH Annual Meeting.

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.

Nondestructive and high-resolution monitoring of inflammation-type skull defects regeneration on adult zebrafish with optical coherence tomography.

Optimized animal models and effective imaging techniques are exceedingly important to study cranial defects in bone loss due to chronic inflammation. In this study, the assessment procedure on a zebrafish inflammation-type skull defects model was monitored in vivo with spectral-domain optical coherence tomography (SD-OCT), and the efficacy of etidronate disodium in bone regeneration was assessed. An acute skull defect injury model was established in adult zebrafish using a stereotaxic craniotomy device. SD-OCT imaging was performed immediately following the mechanical injury. Both SD-OCT and immunohistochemistry results demonstrated an increase in inflammation-induced skull destruction within 5 days, which was confirmed by pathological experiments.

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.

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.

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.

A prospective observational cohort study of the efficacy of tofacitinib plus iguratimod on rheumatoid arthritis with usual interstitial pneumonia.

Objectives: This study aims to assess the efficacy of tofacitinib (TOF) plus iguratimod (IGU) in rheumatoid arthritis (RA) with usual interstitial pneumonia (UIP) (RA-UIP). Methods: This was a prospective observational cohort, single-center study. Data from 78 RA-UIP patients treated with TOF plus IGU, IGU plus conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs), and csDMARDs were analyzed. Clinically relevant responses in RA activity assessment, pulmonary function tests (PFTs), and high-resolution computed tomography (HRCT) assessment at baseline and follow-up were compared between groups to evaluate the efficacy of TOF plus IGU. Results: A total of 78 patients were followed up for at least 6 months after treatment. There were significant changes in sedimentation rate (ESR), C reactive protein (CRP), and disease activity score (DAS) 28-CRP during the follow-up within each treatment group, but there was no statistically significant difference between the two groups. After 6 months of TOF plus IGU treatment, forced vital capacity (FVC)% (84.7 ± 14.7 vs. 90.7 ± 15.4) and HRCT fibrosis score (7.3 ± 3.4 vs. 7.0 ± 5.6) showed a significant improvement compared to the csDMARDs group (P = 0.031, P = 0.015). The TOF plus IGU-treated patients had a significantly higher regression and lower deterioration than the csDMARDs-treated patients (P = 0.026, P = 0.026) and had a significantly higher response (regression + stability), with overall response rates of 66.7% (16/24) vs. 35.7% (10/28) (P = 0.027), respectively. Conclusion: Our results indicate that TOF plus IGU can simultaneously relieve RA and RA-UIP and be better than the csDMARDs with a higher response rate in RA-UIP, which may be a potential choice for "dual treat-to-target".

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.

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.

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.

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.

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.

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.

Inhibition of Cancer Cell Adhesion, Migration and Proliferation by a Bispecific Antibody that Targets two Distinct Epitopes on αv Integrins.

Members of the αv family of integrins regulate activation of transforming growth factor beta (TGFß) and are directly involved in pro-tumorigenic phenotypes. Thus, αv integrins may be therapeutic targets for fibrosis and cancer, yet the isolation of selective inhibitors is currently a challenge. We generated synthetic antibodies selective for αv integrins by phage display selections on cell lines that displayed integrin heterodimers. We identified antibodies that targeted two distinct epitopes on cell-surface αv integrins and partially inhibited cell adhesion mediated by interactions between integrins and the latency-associated peptide, part of the pro-form of TGFß. Using the isolated antibody paratope sequences we engineered a bispecific antibody capable of binding to both epitopes simultaneously; this antibody potently and completely inhibited cell adhesion mediated by integrins αvß1, αvß3 and αvß5. In addition, the bispecific antibody inhibited proliferation and migration of lung carcinoma lines, where the highest and lowest potencies observed correlated with integrin-αv cell surface expression levels. Taken together, our results demonstrate that phage display selections with live cells can yield high quality anti-integrin antibodies, which we used as biparatopic building blocks to construct a bispecific antibody that strongly inhibited integrin function and may be a therapeutic candidate for cancer and fibrosis.

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.

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.

Rational design of SphK inhibitors using crystal structures aided by computer.

Sphingosine kinases (SphKs) are lipid kinases that catalyze the phosphorylation of sphingosine (Sph) to sphingosine-1-phosphate (S1P). As a bioactive lipid, S1P plays a role outside and inside the cell to regulate biological processes. The overexpression of SphKs is related to a variety of pathophysiological conditions. Targeting the S1P signaling pathway is a potential treatment strategy for many diseases. SphKs are key kinases of the S1P signaling pathway. The SphK family includes two isoforms: SphK1 and SphK2. Determination of the co-crystal structure of SphK1 with various inhibitors has laid a solid foundation for the development of small molecule inhibitors targeting SphKs. This paper reviews the differences and connections between the two isoforms and the structure of SphK1 crystals, especially the structure of its Sph "J-shaped" channel binding site. This review also summarizes the recent development of SphK1 and SphK2 selective inhibitors and the exploration of the unresolved SphK2 structure.