UCHL3 induces radiation resistance and acquisition of mesenchymal phenotypes by deubiquitinating POLD4 in glioma stem cells.

BACKGROUND: The high degree of intratumoral genomic heterogeneity is a major obstacle for glioblastoma (GBM) tumors, one of the most lethal human malignancies, and is thought to influence conventional therapeutic outcomes negatively. The proneural-to-mesenchymal transition (PMT) of glioma stem cells (GSCs) confers resistance to radiation therapy in glioblastoma patients. POLD4 is associated with cancer progression, while the mechanisms underlying PMT and tumor radiation resistance have remained elusive. METHOD: Expression and prognosis of the POLD family were analyzed in TCGA, the Chinese Glioma Genome Atlas (CGGA) and GEO datasets. Tumorsphere formation and in vitro limiting dilution assay were performed to investigate the effect of UCHL3-POLD4 on GSC self-renewal. Apoptosis, TUNEL, cell cycle phase distribution, modification of the Single Cell Gel Electrophoresis (Comet), γ-H2AX immunofluorescence, and colony formation assays were conducted to evaluate the influence of UCHL3-POLD4 on GSC in ionizing radiation. Coimmunoprecipitation and GST pull-down assays were performed to identify POLD4 protein interactors. In vivo, intracranial xenograft mouse models were used to investigate the molecular effect of UCHL3, POLD4 or TCID on GCS. RESULT: We determined that POLD4 was considerably upregulated in MES-GSCs and was associated with a meagre prognosis. Ubiquitin carboxyl terminal hydrolase L3 (UCHL3), a DUB enzyme in the UCH protease family, is a bona fide deubiquitinase of POLD4 in GSCs. UCHL3 interacted with, depolyubiquitinated, and stabilized POLD4. Both in vitro and in vivo assays indicated that targeted depletion of the UCHL3-POLD4 axis reduced GSC self-renewal and tumorigenic capacity and resistance to IR treatment by impairing homologous recombination (HR) and nonhomologous end joining (NHEJ). Additionally, we proved that the UCHL3 inhibitor TCID induced POLD4 degradation and can significantly enhance the therapeutic effect of IR in a gsc-derived in situ xenograft model. CONCLUSION: These findings reveal a new signaling axis for GSC PMT regulation and highlight UCHL3-POLD4 as a potential therapeutic target in GBM. TCID, targeted for reducing the deubiquitinase activity of UCHL3, exhibited significant synergy against MES GSCs in combination with radiation.

High-resolution timing jitter measurement based on the photonics time stretch technique.

High-resolution jitter measurement is essential for the next generation of electronic communications and sensor systems. However, most electrical timing jitter measurement equipment has a low resolution because of the limitations of electronic processing accuracy. Meanwhile, photonics-based jitter measurement methods have a higher resolution but cannot measure the widely used electrical signals. This work proposes a potential high-resolution jitter measurement method for electrical signals based on the photonics time stretch technique. The jitter information can be magnified in the optical domain and then measured by electrical equipment. The experimental results demonstrate that the jitter of an electrical pulse is magnified from 59.02 ps to 663.29 ps when the magnification factor is 11.24.

Dual-comb fiber laser for stable frequency distribution.

A passive dual-comb laser can generate two optical frequency combs with different repetition frequencies. These repetition differences have high relative stability and mutual coherence through passive common-mode noise suppression without complex tight phase locking from a single-laser cavity. The comb-based frequency distribution requires the dual-comb laser to have a high repetition frequency difference. This paper presents a high repetition frequency difference bidirectional dual-comb fiber laser based on an all-polarization-maintaining cavity configuration and a semiconductor saturable absorption mirror with single polarization output. The proposed comb laser has a standard deviation of 69 Hz and an Allan deviation of 1.17 × 10-7 at τ = 1 s under different repetition frequencies of 12.815 MHz. Moreover, a transmission experiment has been conducted. Owing to the passive common-mode noise rejection capability of dual-comb laser, after passing an 84 km fiber link, the frequency stability of the repetition frequency difference signal is improved by two orders of magnitude than the repetition frequency signal at the receiver side.

Multi-nodes dissemination of stable radio frequency with 10-17 instability over 2000 km optical fiber.

To meet the demand of flexible access for high-precision synchronization frequency, we demonstrate multi-node stable radio frequency (RF) dissemination over a long-distance optical fiber. Stable radio frequency signals can be extracted at any node along the optical fiber, not just at the endpoint. The differential mixing structure (DMS) is employed to avoid the frequency harmonic leakage and enhance the precision. The phase-locked loop (PLL) provides frequency reference for the DMS while improving the signal to noise ratio (SNR) of dissemination signal. We measure the frequency instability of multi-node stable frequency dissemination system (MFDS) at different locations along the 2,000 km optical fiber. The measured short-term instability with average time of 1 s are 1.90 × 10-14 @ 500 km, 2.81 × 10-14 @ 1,000 km, 3.46 × 10-14 @ 1,500 km, and 3.84 × 10-14 @ 2,000 km respectively. The long-term instability with average time of 10,000 s are basically the same at any position of the optical fiber, which is about (6.24 ± 0.05) × 10-17. The resulting instability is sufficient for the propagation of precision active hydrogen masers.

Tri-comb generation with a dual-ring structure.

By introducing a third measurement comb with different repetition frequencies (Δ f r e p ), the tri-comb spectroscopy technique overcomes the ambiguity problem of the original dual-comb spectroscopy technique and eliminates physical delay stages in multidimensional coherent spectroscopy. Nowadays, tri-comb generation based on three frequency-stabilized comb lasers is overly complicated and costly for many potential applications. Previous research on single-cavity dual-combs inspired research on single-cavity tri-combs. However, the currently reported tri-comb structures cannot achieve independently controllable pulses. This paper shows a dual-ring tri-comb seed-source structure using wavelength-based multiplexing in one of the rings. The wavelength and power of the output pulse are independently controlled by using the dual-ring structure. The Δ f r e p of wavelength multiplexing-based dual-comb output can be tuned by adjusting the intra-ring polarization controller (PC). In the case of single-wavelength mode-locking, the PC can be adjusted to achieve a wavelength tuning range of nearly 20 nm. The tri-comb source could offer an attractive alternative solution as a low-complexity light source for field-deployable multi-comb metrology applications.

Michelson interferometer based phase demodulation for stable time transfer over 1556 km fiber links.

Time transfer based on phase modulation schemes has attracted extensive attention in recent years. We propose and experimentally demonstrate an adjustable and stable Michelson interferometer (MI) with a DC phase tracking algorithm for two-way time transfer. Time signal with one pulse per second (1 PPS) is loaded on an optical carrier modulated in phase and demodulated by a Michelson interferometer. The whole compact and cost-effective demodulator is symmetrical with a single coupler to split and recombine optical waves, flexible with one photodetector and a bias tee to separate the DC signal and recovery pulses and stable with a phase modulator to compensate for the drift-phase noise. We show the implementation of modulation and demodulation of the time signal and obtain the stability of 2.31 × 10-11 at 1000 s averaging time. We then demonstrate two-way time transfer over 1556 km lab fibers. The experimental result shows time interval stability of 1 PPS with 5.62 × 10-11 at 1000 s averaging time. It has the potential to transfer time signals in long-distance fiber optic links.

Stable radio frequency transfer over fiber based on microwave photonic phase shifter.

We demonstrate a radio frequency (RF) phase-stable transmission over fiber based on microwave photonic phase shifter. In the proposed system, both assistant RF signals are applied to drive two arms of a dual-drive Mach-Zehnder modulator (DMZM), respectively. An optical bandpass filter is followed to filter out the first-order sideband of optical modulated signal. Due to the phase independence between two optical sidebands, the phase perturbation caused by fiber-length variations can be compensated automatically via controlling the direct-current bias voltage of the DMZM. We have performed RF transfer in a 155 km single-mode fiber with a frequency instability of 3.05 × 10-17 at 10,000 s averaging time.

Tera-sample-per-second single-shot device analyzer.

With the ever-increasing need for bandwidth in data centers and 5G mobile communications, technologies for rapid characterization of wide-band devices are in high demand. We report an instrument for extremely fast characterization of the electronic and optoelectronic devices with 27 ns frequency-response acquisition time at the effective sampling rate of 2.5 Tera-sample/s and an ultra-low effective timing jitter of 5.4 fs. This instrument features automated digital signal processing algorithms including time-series segmentation and frame alignment, impulse localization and Tikhonov regularized deconvolution for single-shot impulse and frequency response measurements. The system is based on the photonic time-stretch and features phase diversity to eliminate frequency fading and extend the bandwidth of the instrument.

Stable radio frequency dissemination via a 1007 km fiber link based on a high-performance phase lock loop.

In this paper, we propose an active-compensation stable radio frequency (RF) transmission scheme based on a high-performance phase lock loop (PLL). In our PLL, a new structure for phase-detection is designed with only one standard RF signal to obtain a simple structure with no interference from other signals. In addition, different optical wavelengths carrying the same RF signal are utilized in the two directions to suppress Rayleigh scattering. The low phase noise homemade bi-directional erbium doped fiber amplifier (EDFA) module is used to reduce signal-to-noise ratio (SNR) deterioration. Hence, the transmission distance is greatly improved. The effects of polarization mode dispersion and phase noise produced by the EDFA on the transmission distance are discussed. Ultimately, a stable RF signal with 2.4 GHz transmitted over a 1007 km fiber link is obtained. The experimental results demonstrate that frequency instabilities of 1.2×10- 13 at 1s and 5.1×10- 16 at 20000s. Therefore, the system can be used for atomic clocks comparisons and provides frequency standard for time transfer systems over a long-haul fiber.

Stable frequency dissemination over multi-access fiber loop link with optical comb.

An optical comb based stable frequency dissemination system is proposed and experimentally demonstrated over a multi-access optical fiber loop link. In the system, a new technique based on optical-microwave phase locking loop is designed for phase compensation. In the experiment, a mode-locked fiber laser at a repetition rate of 100 MHz is used to provide an optical source at local site, then it transmits along a 150 km fiber loop link. To testify the proposed system, two accessing nodes are measured in the loop link. The dissemination frequency instability is measured at 3.65 × 10-15/1 s and 7.8 × 10-18/1000 s at the intermediate node. The similar performance is shown at the other node. Hence, the system has the potential application in high-precision frequency transmission system via a long-haul multi-access loop link.

Simple and efficient nonlinear polarization evolution mode-locked fiber laser by three-dimensionally manipulating a polarization beam splitter.

A simple and efficient femtosecond nonlinear polarization evolution (NPE) mode-locked laser is presented. Different from conventional NPE fiber lasers, the polarization beam splitter (PBS) is three-dimensionally manipulated to achieve polarization control and state selection in our NPE laser. The polarizer, half-wave plate, and quarter-wave plate from conventional NPE fiber lasers are replaced by this PBS. Thus, the configuration and the system gain of our proposed laser are simply and efficiently improved. As a result, transfer efficiency of 24.17% is experimentally demonstrated. In addition, measured self-started pulses with average power of 49 mW and center wavelength of 1584 nm are generated with single-pulse energy of 1.51 nJ.

Microwave photonic phase-tunable mixer.

Traditional microwave photonic systems cannot implement frequency up-conversion with phase tunable capability, which plays an important role for phase array beamforming. Here, a method that can implement both upconversion and downconversion with a broadband full-degree phase-shift capability by constructing an optical path with a Hilbert transform function is presented. Owing to the Hilbert transform path, the dual-drive Mach-Zehnder modulator (DMZM) bias information, which initially influences the amplitudes of the output signals, are transferred to their phases. As a result, the phase-shift capability of the output radio frequencies (RFs) and intermediate frequencies (IFs) can be achieved by simply adjusting the bias voltage of the DMZM without using an optical filter. Experimental results demonstrate that a 360° phase shift can be achieved when the IF signal below 4-GHz and the RF signal between 8 and 16-GHz are converted into each other.

GVD-insensitive stable radio frequency phase dissemination for arbitrary-access loop link.

We propose and experimentally demonstrate a stable radio frequency (RF) phase dissemination scheme for a long-haul optical fiber loop link based on frequency mixing. Using a single optical source in both directions of the loop link, additional timing jitter caused by group velocity dispersion (GVD) can be eliminated. Impressive scalability provided by the optical link ensures that arbitrary-access node can obtain an RF signal with a stabilized phase to meet the requirements of multiple users. In our experiment, a 2.4 GHz RF signal is distributed to arbitrary points along a 100 km fiber-optic loop link steadily. Stabilities of the recovered signals from two accessing nodes are recorded. The root-mean-square (RMS) phase jitter of the received signal at either accessing node is reduced from 1.87 rad to no more than 0.027 rad during 1800-second measuring time.

Photonic downconversion with tunable wideband phase shift.

A microwave photonic frequency downconversion system with wideband and continuous phase-shift function is proposed and experimentally demonstrated. In the proposed system, a radio frequency (RF) and a local oscillator (LO) signal drive two arms of a dual-drive Mach-Zehnder modulator (DMZM). A fiber Bragg grating (FBG) is used for reflecting the first-order sidebands of both RF and LO signals. Due to phase independence between RF and LO optical sidebands, the phase-shifting operation for an output intermediate frequency (IF) signal can be implemented either by adjusting the bias voltage of DMZM or by controlling the optical wavelength of laser. Experimental results demonstrate a full 0° to 360° phase shift, while an RF signal between 12 GHz to 20 GHz is downconverted to IFs below 4 GHz. The phase deviation is measured less than 2°, and the fluctuation of magnitude response is measured less than ±1 dB over a wideband frequency range.

Upregulation of HMGB1 in wall of ruptured and unruptured human cerebral aneurysms: preliminary results.

A growing body of evidence suggests that inflammation plays a crucial role in cerebral aneurysm initiation, progression, and rupture. High-mobility group box 1 (HMGB1) is a non-histone nuclear protein that can serve as an alarmin to drive the pathogenesis of inflammatory disease. The purpose of this study was to investigate the expression of HMGB1 in the wall of ruptured and unruptured human cerebral aneurysms. Human cerebral aneurysms (25 ruptured and 16 unruptured) were immunohistochemically stained for HMGB1. As controls, four specimens of the middle cerebral arteries obtained at autopsy were also immunostained. Immunofluorescence double staining was used to determine HMGB1 cellular distribution. HMGB1 was nearly undetectable in the controls. All aneurysm tissues stained positive for HMGB1 monoclonal antibody, and expression of HMGB1 was more abundant in ruptured aneurysm tissue than unruptured aneurysms (p < 0.05). Furthermore, the expression of HMGB1 had no correlation with aneurysm size and time resected after the rupture. HMGB1 nuclear immunoreactivity was co-localized with immunoreactivity of CD3 in T lymphocytes, CD20 in B lymphocytes, CD68 in macrophages, α-SMA in smooth muscle cells, and CD31 in endothelial cells. Cytoplasmic HMGB1 localization was also detected in macrophages and T lymphocytes. Taken together, HMGB1 is expressed in the wall of human cerebral aneurysms and is more abundant in ruptured aneurysms than in unruptured ones. These data indicate a possible role of HMGB1 in the pathophysiology of human cerebral aneurysms.

Photonic downconversion based on optical carrier bidirectional reusing in a phase modulator.

We propose a novel photonic downconversion method based on optical carrier reusing. In the proposed system, the phase modulator (PM) is placed between two narrowband fiber Bragg gratings (FBGs), which are designed to reflect the optical carrier and transmit the optical sidebands. The optical carrier is modulated in the PM in two directions and is not injected into the photodetector (PD). Thus, the utilization ratio of the optical carrier is enhanced and the power saturation in the PD is avoided. Consequently, the system gain can be improved. In addition, a 2×2 optical coupler is cooperated with a balanced PD behind these two FBGs. Resulting from the subtle design of the phase difference, gain is furthermore doubled and intensity noise can be reduced simultaneously. In the experiments, 29 dB gain improvement is measured compared with the traditional dual-series intensity modulators method. The noise floor is reduced by 12.1 dB.

Third-order intermodulation distortion elimination of microwave photonics link based on integrated dual-drive dual-parallel Mach-Zehnder modulator.

A method to realize a highly linear microwave photonics link is proposed based on the dual-drive dual-parallel Mach-Zehnder modulator (MZM). The scheme theoretically eliminates third-order intermodulation distortion (IMD3) completely by taking all the sidebands in the optical spectrum that cause IMD3 into consideration. Without digital linearization and other optical processors, the method utilizes simple electrical signal phase control. Microwave signals are symmetrically single sideband modulated in the two MZMs. IMD3 suppression of approximately 30 dB is experimentally demonstrated, and the spurious-free dynamic range is improved by 12 dB·Hz2/3.

Differential phase-diversity electrooptic modulator for cancellation of fiber dispersion and laser noise.

Bandwidth and noise are fundamental considerations in all communication and signal processing systems. The group-velocity dispersion of optical fibers creates nulls in their frequency response, limiting the bandwidth and hence the temporal response of communication and signal processing systems. Intensity noise is often the dominant optical noise source for semiconductor lasers in data communication. In this paper, we propose and demonstrate a class of electrooptic modulators that is capable of mitigating both of these problems. The modulator, fabricated in thin-film lithium niobate, simultaneously achieves phase diversity and differential operations. The former compensates for the fiber's dispersion penalty, while the latter overcomes intensity noise and other common mode fluctuations. Applications of the so-called four-phase electrooptic modulator in time-stretch data acquisition and in optical communication are demonstrated.

Prognostic values of B7-H3, B7-H4, and HHLA2 expression in human pancreatic cancer tissues based on mIHC and spatial distribution analysis.

BACKGROUND: Pancreatic cancer (PC) is one of the most malignant solid tumors and its 5-year survival rate remains poor. Although immunotherapy has achieved certain therapeutic efficacy in some clinical trials, such treatment still shows low responses and overall remission rate. Therefore, it is urgently necessary to dissect the tumor microenvironment and optimize the immunotherapeutic strategies against this malignancy. METHODS: Using the multi-color immunohistochemistry assay, we investigated the expressions of B7-H3, B7-H4, HHLA2, CD8, and CD68 in 63 cases of PC tissues in a tissue microarray. Moreover, we analyzed immunolocalization features, clinical associations and prognostic values of these molecules. RESULTS: The expressions of B7-H3, B7-H4, and HHLA2 could be detected in cytokeratin staining positive (CK+) cancer epithelial cells, CD68+tumor-associated macrophages (TAMs), and even other cells defined as CK-CD8-CD68-. Higher expression of B7-H3 in tumor cells could predict a better survival of the PC patients. A positive correlation was found between the expressions of B7-H3 and HHLA2 in tumor cells, while there was a negative correlation between the expressions of B7-H4 and HHLA2 in tumor cells. A positive correlation was found between the expressions of B7-H3 and B7-H4 or HHLA2 in CD68+TAMs, but not B7-H4 and HHLA2. Tumor-infiltrating CD8+T cells in combination with CD68+TAMs could serve as an important predictor for the postoperative prognosis of PC patients. Higher expression of B7-H3, or HHLA2 in CD68+TAMs could serve as an important predictor for poorer prognosis of PC patients. Patients with B7-H3lowB7-H4low, B7-H3lowHHLA2low, or B7-H4lowHHLA2low on CD68+TAMs could have a better postoperative prognosis compared with the other sub-populations in the combinational analysis. CONCLUSIONS: Taken together, our study indicated variable expressions and prognostic values of B7-H3, B7-H4, and HHLA2, in human PC tissues, and demonstrated that these co-stimulator molecules expressed by CD68+TAMs could be used as important bio-markers for the prognostic prediction of PC patients. Moreover, these results supported that the evaluation of these markers could be used as essential candidate targets for immunotherapy against PC.

Mild and moderate cardioembolic stroke patients may benefit more from direct mechanical thrombectomy than bridging therapy: A subgroup analysis of a randomized clinical trial (DIRECT-MT).

Background: The benefit of intravenous alteplase before endovascular thrombectomy is unclear in patients with acute cardioembolic stroke. Methods: We collected cardioembolic (CE) stroke patient data from the multicentre randomized clinical trial of Direct Intra-arterial Thrombectomy to Revascularize Acute Ischaemic Stroke Patients with Large Vessel Occlusion Efficiently in Chinese Tertiary Hospitals (DIRECT-MT). The primary outcome was the 90-day modified Rankin Scale (mRS) score. Five subgroups of cardioembolic stroke patients were analyzed. A multivariable ordinal logistic regression analysis analyzed the difference in the primary outcome between the direct mechanical thrombectomy (MT) and bridging therapy groups. An interaction term was entered into the model to test for subgroup interaction. The DIRECT-MT trial is registered with clinicaltrials.gov Identifier: NCT03469206. Results: A total of 290 CE stroke patients from the DIRECT-MT trial were enrolled in this study: 146 patients in the direct MT group and 144 patients in the bridging therapy group. No difference between the two treatment groups in the primary outcome was found (adjusted common odds ratio, 1.218; 95% confidence interval, 0.806 to 1.841; P = 0.34). In the subgroup analysis, CE stroke patients with an NIHSS ≤ 15 in the direct MT group were associated with better outcomes (47 vs. 53, acOR, 3.14 [1.497, 6.585]) and lower mortality (47 vs. 53, aOR, 0.16 [0.026, 0.986]) than those in the bridging therapy group, while there were no significant differences between the two treatment groups in the outcome and mortality of CE stroke patients with an NIHSS >15. Conclusion: Mild and moderate cardioembolic stroke patients may benefit more from direct mechanical thrombectomy than bridging therapy. This need to be confirmed by further prospective studies in a larger number of patients.