Stearoylation cycle regulates the cell surface distribution of the PCP protein Vangl2.

Defects in planar cell polarity (PCP) have been implicated in diverse human pathologies. Vangl2 is one of the core PCP components crucial for PCP signaling. Dysregulation of Vangl2 has been associated with severe neural tube defects and cancers. However, how Vangl2 protein is regulated at the posttranslational level has not been well understood. Using chemical reporters of fatty acylation and biochemical validation, here we present that Vangl2 subcellular localization is regulated by a reversible S-stearoylation cycle. The dynamic process is mainly regulated by acyltransferase ZDHHC9 and deacylase acyl-protein thioesterase 1 (APT1). The stearoylation-deficient mutant of Vangl2 shows decreased plasma membrane localization, resulting in disruption of PCP establishment during cell migration. Genetically or pharmacologically inhibiting ZDHHC9 phenocopies the effects of the stearoylation loss of Vangl2. In addition, loss of Vangl2 stearoylation enhances the activation of oncogenic Yes-associated protein 1 (YAP), serine-threonine kinase AKT, and extracellular signal-regulated protein kinase (ERK) signaling and promotes breast cancer cell growth and HRas G12V mutant (HRasV12)-induced oncogenic transformation. Our results reveal a regulation mechanism of Vangl2, and provide mechanistic insight into how fatty acid metabolism and protein fatty acylation regulate PCP signaling and tumorigenesis by core PCP protein lipidation.

Chemical Inhibitors Targeting the Oncogenic m6A Modifying Proteins.

Epigenetics is brought to RNA, introducing a new dimension to gene expression regulation. Among numerous RNA modifications, N6-methyladenosine (m6A) is an abundant internal modification on eukaryote mRNA first identified in the 1970s. However, the significance of m6A modification in mRNA had been long neglected until the fat mass and obesity-associated (FTO) enzyme was identified as the first m6A demethylase almost 40 years later. The m6A modification influences nearly every step of RNA metabolism and thus broadly affects gene expression at multiple levels, playing a critical role in many biological processes, including cancer progression, metastasis, and immune evasion. The m6A level is dynamically regulated by RNA epigenetic machinery comprising methyltransferases such as methyltransferase-like protein 3 (METTL3), demethylases FTO and AlkB human homologue 5 (ALKBH5), and multiple reader proteins. The understanding of the biology of RNA epigenetics and its translational drug discovery is still in its infancy. It is essential to further develop chemical probes and lead compounds for an in-depth investigation into m6A biology and the translational discovery of anticancer drugs targeting m6A modifying oncogenic proteins.In this Account, we present our work on the development of chemical inhibitors to regulate m6A in mRNA by targeting the FTO demethylase, and the elucidation of their mode of action. We reported rhein to be the first substrate competitive FTO inhibitor. Due to rhein's poor selectivity, we identified meclofenamic acid (MA) that selectively inhibits FTO compared with ALKBH5. Based on the structural complex of MA bound with FTO, we designed MA analogs FB23-2 and Dac51, which exhibit significantly improved activities compared with MA. For example, FB23-2 is specific to FTO inhibition in vitro among over 400 other oncogenic proteins, including kinases, proteases, and DNA and histone epigenetic proteins. Mimicking FTO depletion, FB23-2 promotes the differentiation/apoptosis of human acute myeloid leukemia (AML) cells and inhibits the progression of primary cells in xenotransplanted mice. Dac51 treatment impairs the glycolytic activity of tumor cells and restores the function of CD8+ T cells, thereby inhibiting the growth of solid tumors in vivo. These FTO inhibitors were and will continue to be used as probes to promote biological studies of m6A modification and as lead compounds to target FTO in anticancer drug discovery.Toward the end, we also include a brief review of ALKBH5 demethylase inhibitors and METTL3 methyltransferase modulators. Collectively, these small-molecule modulators that selectively target RNA epigenetic proteins will promote in-depth studies on the regulation of gene expression and potentially accelerate anticancer target discovery.

Cascaded partitioned phase modulation for cross-connection of orbital angular momentum mode and polarization multiplexing channels.

Multi-dimensional orbital angular momentum (OAM) mode multiplexing provides a promising route for enlarging communication capacity and establishing comprehensive networks. While multi-dimensional multiplexing has gained advancements, the cross-connection of these multiplexed channels, especially involving modes and polarizations, remains challenging due to the needs for multi-mode interconversion and on-demand polarization control. Herein, we propose an OAM mode-polarization cross-transformation solution via cascaded partitioned phase modulation, which enables the divergently separated OAM modes to be independently phase-imposed within distinct spatial regions, leading to the synergistic conversion operation of mode and polarization channels. In demonstrations, we implemented the cross-connection of three OAM modes and two polarization multiplexed channels, achieving the mode purity that exceeds 0.951 and polarization contrast up to 0.947. The measured mode insertion losses and polarization conversion losses are below 3.42 and 3.54 dB, respectively. Consequently, 1.2 Tbit/s quadrature phase shift keying signals were successfully exchanged, yielding the bit-error-rates close to 10-6. Incorporating with increased partitioned phase treatments, this approach shows promise in accommodating massive mode-polarization multiplexed channels, which hold the potential to augment networking capability of large-scale OAM mode multiplexing communication networks.

Dual vector millimeter-wave signal generation based on optical carrier suppression modulation and direct detection with one photodetector.

We propose a novel, to the best of our knowledge, scheme for dual vector millimeter-wave (mm-wave) signal generation and transmission, based on optical carrier suppression (OCS) modulation, precoding, and direct detection by a single-ended photodiode (PD). At the transmitter side, two independent vector radio frequency (RF) signals with precoding, generated via digital signal processing (DSP), are used to drive an in-phase/quadrature (I/Q) modulator operating at the optical OCS modulation mode to simultaneously generate two independent frequency-doubling optical vector mm-wave signals, which can reduce the bandwidth requirement of transmitter's components and enhance spectral efficiency. With the aid of the single-ended PD and subsequent DSP at the receiver side, two independent frequency-doubling vector mm-wave signals can be separated and demodulated without data error. Based on our proposed scheme, we experimentally demonstrate the generation, transmission, and detection of 2-Gbaud 30-GHz quadrature-phase-shift-keying (QPSK) and 2-Gbaud 46-GHz QPSK signals over 10-km single-mode fiber-28 (SMF-28) and 1-m wireless transmission. The results indicate that the bit-error ratio (BER) of the dual vector mm-wave signals can each reach the hard-decision forward-error-correction (HD-FEC) threshold of 3.8 × 10-3.

OAM mode-division multiplexing IM/DD transmission at 4.32†Tbit/s with a low-complexity adaptive-network-based fuzzy inference system nonlinear equalizer.

Stochastic nonlinear impairment is the primary factor that limits the transmission performance of high-speed orbital angular momentum (OAM) mode-division multiplexing (MDM) optical fiber communication systems. This Letter presents a low-complexity adaptive-network-based fuzzy inference system (LANFIS) nonlinear equalizer for OAM-MDM intensity-modulation direct-detection (IM/DD) transmission with three OAM modes and 15 wavelength division multiplex (WDM) channels. The LANFIS equalizer could adjust the probability distribution functions (PDFs) of the distorted pulse amplitude modulation (PAM) symbols to fit the statistical characteristics of the WDM-OAM-MDM transmission channel. Therefore, although the transmission symbols in the WDM-OAM-MDM system are subjected to a stochastic nonlinear impairment, the proposed LANFIS equalizer can effectively compensate the distorted signals. The proposed equalizer outperforms the Volterra equalizer with improvements in receiver sensitivity of 2, 1.5, and 1.3 dB for three OAM modes at a wavelength of 1550.12 nm, respectively. It also outperforms a CNN equalizer, with improvements in receiver sensitivity of 1, 0.5, and 0.3 dB, respectively. Moreover, complexity reductions of 67%, 74%, and 99.9% are achieved for the LANFIS equalizer compared with the Volterra, CNN, and ANFIS equalizers, respectively. The proposed equalizer has high performance and low complexity, making it a promising candidate for a high-speed WDM-OAM-MDM system.

Association between frozen embryo transfer and childhood allergy: a retrospective cohort study.

RESEARCH QUESTION: Does frozen embryo transfer (FET) increase the risk of allergic diseases in offspring? DESIGN: This study followed up 653 singleton children: 166 born through FET and 487 born through natural conception. Demographic characteristics, perinatal information and allergic diseases of children and their parents were collected through clinical medical systems and questionnaires. Among these 653 children, allergen-specific immunoglobulin E (IgE) testing was performed using peripheral blood samples collected from 207 children: 145 in the FET group and 62 in the natural conception group. The prevalence of allergic diseases and positive rates of allergen-specific IgE testing were compared between the two groups with adjustments for confounding factors. RESULTS: The prevalence of food allergy was significantly higher in children born through FET compared with children born through natural conception (adjusted OR = 3.154, 95% CI 1.895-5.250; P < 0.001). In addition, positive rates of food allergen sensitization were higher in children in the FET group compared with children in the natural conception group (adjusted OR = 5.769, 95% CI 2.859-11.751, P < 0.001). Children in the FET group had a higher positive sensitization rate to at least one allergen compared with children in the natural conception group (adjusted OR = 3.127, 95% CI 1.640-5.961, P < 0.001). No association was observed between FET and other allergic diseases, including asthma (P = 0.136), atopic dermatitis (P = 0.130) and allergic rhinitis (P = 0.922). Allergen sensitization IgE testing indicated no differences between the two groups in terms of positive sensitization rates of other common allergens, including animal and insect allergens (P = 0.627), inhaled outdoor allergens (P = 0.915) and inhaled outdoor allergens (P = 0.544). CONCLUSION: This study suggests that children born through FET have increased risk of developing food allergy in early childhood.

Cpd-A1 alleviates acute kidney injury by inhibiting ferroptosis.

Acute kidney injury (AKI) is defined as sudden loss of renal function characterized by increased serum creatinine levels and reduced urinary output with a duration of 7 days. Ferroptosis, an iron-dependent regulated necrotic pathway, has been implicated in the progression of AKI, while ferrostatin-1 (Fer-1), a selective inhibitor of ferroptosis, inhibited renal damage, oxidative stress and tubular cell death in AKI mouse models. However, the clinical translation of Fer-1 is limited due to its lack of efficacy and metabolic instability. In this study we designed and synthesized four Fer-1 analogs (Cpd-A1, Cpd-B1, Cpd-B2, Cpd-B3) with superior plasma stability, and evaluated their therapeutic potential in the treatment of AKI. Compared with Fer-1, all the four analogs displayed a higher distribution in mouse renal tissue in a pharmacokinetic assay and a more effective ferroptosis inhibition in erastin-treated mouse tubular epithelial cells (mTECs) with Cpd-A1 (N-methyl-substituted-tetrazole-Fer-1 analog) being the most efficacious one. In hypoxia/reoxygenation (H/R)- or LPS-treated mTECs, treatment with Cpd-A1 (0.25 µM) effectively attenuated cell damage, reduced inflammatory responses, and inhibited ferroptosis. In ischemia/reperfusion (I/R)- or cecal ligation and puncture (CLP)-induced AKI mouse models, pre-injection of Cpd-A1 (1.25, 2.5, 5 mg·kg-1·d-1, i.p.) dose-dependently improved kidney function, mitigated renal tubular injury, and abrogated inflammation. We conclude that Cpd-A1 may serve as a promising therapeutic agent for the treatment of AKI.

400 Gbit/s 4 mode transmission for IM/DD OAM mode division multiplexing optical fiber communication with a few-shot learning-based AffinityNet nonlinear equalizer.

Nonlinear impairment in a high-speed orbital angular momentum (OAM) mode-division multiplexing (MDM) optical fiber communication system presents high complexity and strong stochasticity due to the massive optoelectronic devices. In this paper, we propose an Affinity Network (AffinityNet) nonlinear equalizer for an OAM-MDM intensity-modulation direct-detection (IM/DD) transmission with four OAM modes. The labeled training and testing signals from the OAM-MDM system can be regarded as "small sample" and "large target", respectively. AffinityNet can be used to build an accurate nonlinear model using "small sample" based on few-shot learning and can predict the stochastic characteristic nonlinearity of OAM-MDM with a high level of generalization. As a result, the AffinityNet nonlinear equalizer can effectively compensate the stochastic nonlinearity in the OAM-MDM system, despite the large difference between the training and testing signals due to the stochastic nonlinear impairment. An experiment was conducted on a 400 Gbit/s transmission with four OAM modes using a pulse amplitude modulation-8 (PAM-8) signal over a 2 km ring-core fiber (RCF). Our experimental results show that the proposed nonlinear equalizer outperformed the conventional Volterra equalizer with improvements in receiver sensitivity of 1.7, 1.8, 3, and 3.3 dB for the four OAM modes at the 15% forward error correction (FEC) threshold, respectively. In addition, the proposed equalizer outperformed a convolutional neural network (CNN) equalizer with improvements in receiver sensitivity of 0.8, 0.5, 0.9, and 1.4 dB for the four OAM modes at the 15% FEC threshold. In the experiment, a complexity reduction of 37% and 83% of the AffinityNet equalizer is taken compared to the conventional Volterra equalizer and CNN equalizer, respectively. The proposed equalizer is a promising candidate for a high-speed OAM-MDM optical fiber communication system.

Hidden conditional random field-based equalizer for the 3D-CAP-64 transmission of OAM mode-division multiplexed ring-core fiber communication.

As a key technique for achieving ultra-high capacity optical fiber communications, orbital angular momentum (OAM) mode-division multiplexing (MDM) is affected by severe nonlinear impairments, including modulation related nonlinearities, square-law nonlinearity and mode-coupling-induced nonlinearity. In this paper, an equalizer based on a hidden conditional random field (HCRF) is proposed for the nonlinear mitigation of OAM-MDM optical fiber communication systems with 20 GBaud three-dimensional carrierless amplitude and phase modulation-64 (3D-CAP-64) signals. The HCRF equalizer extracts the stochastic nonlinear feature of the OAM-MDM 3D-CAP-64 signals by estimating the conditional probabilities of the hidden variables, thereby enabling the signals to be classified into subclasses of constellation points. The nonlinear impairment can then be mitigated based on the statistical probability distribution of the hidden variables of the OAM-MDM transmission channel in the HCRF equalizer. Our experimental results show that compared with a convolutional neural network (CNN)-based equalizer, the proposed HCRF equalizer improves the receiver sensitivity by 2 dB and 1 dB for the two OAM modes used here, with l = + 2 and l = + 3, respectively, at the 7% forward error correction (FEC) threshold. When compared with a Volterra nonlinear equalizer (VNE) and CNN-based equalizer, the computational complexity of the proposed HCRF equalizer was found to be reduced by 30% and 41%, respectively. The bit error ratio (BER) performance and reduction in computational complexity indicate that the proposed HCRF equalizer has great potential to mitigate nonlinear distortions in high-speed OAM-MDM fiber communication systems.

Photonic-aided W-band dual-vector RF signal generation and detection enabled by bandpass delta-sigma modulation and heterodyne detection.

We propose a photonic-aided dual-vector radio-frequency (RF) signal generation and detection scheme enabled by bandpass delta-sigma modulation and heterodyne detection. With the aid of the bandpass delta-sigma modulation, our proposed scheme is transparent to the modulation format of the dual-vector RF signals and can support the generation, wireless transmission, and detection of both single-carrier (SC) and orthogonal-frequency-division-multiplexing (OFDM) vector RF signals with high-level quadrature-amplitude-modulation (QAM) modulation. With the aid of the heterodyne detection, our proposed scheme can support up to W-band (75-110 GHz) dual-vector RF signal generation and detection. For the validation of our proposed scheme, we experimentally demonstrate the simultaneous generation of a SC-64QAM signal at 94.5 GHz and a SC-128QAM signal at 93.5 GHz and their error-free high-fidelity transmission over a 20-km single-mode fiber 28 (SMF-28) and a 1-m single-input single-output (SISO) wireless link at the W-band. To the best of our knowledge, this is the first time that delta-sigma modulation has been introduced into a W-band photonic-aided fiber-wireless integration system to achieve flexible and high-fidelity dual-vector RF signal generation and detection.

Protein acetylation and related potential therapeutic strategies in kidney disease.

Kidney disease can be caused by various internal and external factors that have led to a continual increase in global deaths. Current treatment methods can alleviate but do not markedly prevent disease development. Further research on kidney disease has revealed the crucial function of epigenetics, especially acetylation, in the pathology and physiology of the kidney. Histone acetyltransferases (HATs), histone deacetylases (HDACs), and acetyllysine readers jointly regulate acetylation, thus affecting kidney physiological homoeostasis. Recent studies have shown that acetylation improves mechanisms and pathways involved in various types of nephropathy. The discovery and application of novel inhibitors and activators have further confirmed the important role of acetylation. In this review, we provide insights into the physiological process of acetylation and summarise its specific mechanisms and potential therapeutic effects on renal pathology.

Stevioside attenuates bleomycin-induced pulmonary fibrosis by activating the Nrf2 pathway and inhibiting the NF-κB and TGF-ß1/Smad2/3 pathways.

Objective: This study aimed to investigate the effects of stevioside (STE) on pulmonary fibrosis (PF) and the potential mechanisms. Methods: In this study, a mouse model of PF was established by a single intratracheal injection of bleomycin (BLM, 3 mg/kg). The experiment consisted of four groups: control group, BLM group, and STE treatment groups (STE 50 and 100 mg/kg). ELISA and biochemical tests were conducted to determine the levels of TNF-α, IL-1ß, IL-6, NO, hydroxyproline (HYP), SOD, GSH, and MDA. Histopathological changes and collagen deposition in lung tissues were observed by HE and Masson staining. Immunohistochemistry was performed to determine the levels of collagen I-, collagen III-, TGF-ß1- and p-Smad2/3-positive cells. Western blot analysis was used to measure the expression of epithelial-mesenchymal transition (EMT) markers, including α-SMA, vimentin, E-cadherin, and ZO-1, as well as proteins related to the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway, nuclear transcription factor-κB (NF-κB) pathway, and TGF-ß1/Smad2/3 pathway in lung tissues. Results: STE significantly alleviated BLM-induced body weight loss and lung injury in mice, decreased HYP levels, and reduced the levels of collagen I- and collagen III-positive cells, thereby decreasing extracellular matrix (ECM) deposition. Moreover, STE markedly improved oxidative stress (MDA levels were decreased, while SOD and GSH activity were enhanced), the inflammatory response (the levels of TNF-α, IL-1ß, IL-6, and NO were reduced), and EMT (the expression of α-SMA and vimentin was downregulated, and the expression of E-cadherin and ZO-1 was upregulated). Further mechanistic analysis revealed that STE could activate the Nrf2 pathway and inhibit the NF-κB and TGF-ß1/Smad2/3 pathways. Conclusion: STE may alleviate oxidative stress by activating the Nrf2 pathway, suppress the inflammatory response by downregulating the NF-κB pathway, and inhibit EMT progression by blocking the TGF-ß1/Smad2/3 pathway, thereby improving BLM-induced PF.

Dysregulation of iron homeostasis by TfR-1 renders EZH2 wild type diffuse large B-cell lymphoma resistance to EZH2 inhibition.

EZH2 has been regarded as an efficient target for diffuse large B-cell lymphoma (DLBCL), but the clinical benefits of EZH2 inhibitors (EZH2i) are limited. To date, only EPZ-6438 has been approved by FDA for the treatment of follicular lymphoma and epithelioid sarcoma. We have discovered a novel EZH1/2 inhibitor HH2853 with a better antitumor effect than EPZ-6438 in preclinical studies. In this study we explored the molecular mechanism underlying the primary resistance to EZH2 inhibitors and sought for combination therapy strategy to overcome it. By analyzing EPZ-6438 and HH2853 response profiling, we found that EZH2 inhibition increased intracellular iron through upregulation of transferrin receptor 1 (TfR-1), ultimately triggered resistance to EZH2i in DLBCL cells. We demonstrated that H3K27ac gain by EZH2i enhanced c-Myc transcription, which contributed to TfR-1 overexpression in insensitive U-2932 and WILL-2 cells. On the other hand, EZH2i impaired the occurrence of ferroptosis by upregulating the heat shock protein family A (Hsp70) member 5 (HSPA5) and stabilizing glutathione peroxidase 4 (GPX4), a ferroptosis suppressor; co-treatment with ferroptosis inducer erastin effectively overrode the resistance of DLBCL to EZH2i in vitro and in vivo. Altogether, this study reveals iron-dependent resistance evoked by EZH2i in DLBCL cells, and suggests that combination with ferroptosis inducer may be a promising therapeutic strategy.

Insulin-like growth factor binding protein 7 promotes acute kidney injury by alleviating poly ADP ribose polymerase 1 degradation.

The novel biomarker, insulin-like growth factor binding protein 7 (IGFBP7), is used clinically to predict different types of acute kidney injury (AKI) and has drawn significant attention as a urinary biomarker. However, as a secreted protein in the circulation of patients with AKI, it is unclear whether IGFBP7 acts as a key regulator in AKI progression, and if mechanisms underlying its upregulation still need to be determined. Here we found that IGFBP7 is highly expressed in the blood and urine of patients and mice with AKI, possibly via a c-Jun-dependent mechanism, and is positively correlated with kidney dysfunction. Global knockout of IGFBP7 ameliorated kidney dysfunction, inflammatory responses, and programmed cell death in murine models of cisplatin-, kidney ischemia/reperfusion-, and lipopolysaccharide-induced AKI. IGFBP7 mainly originated from kidney tubular epithelial cells. Conditional knockout of IGFBP7 from the kidney protected against AKI. By contrast, rescue of IGFBP7 expression in IGFBP7-knockout mice restored kidney damage and inflammation. IGFBP7 function was determined in vitro using recombinant IGFBP7 protein, IGFBP7 knockdown, or overexpression. Additionally, IGFBP7 was found to bind to poly [ADP-ribose] polymerase 1 (PARP1) and inhibit its degradation by antagonizing the E3 ubiquitin ligase ring finger protein 4 (RNF4). Thus, IGFBP7 in circulation acts as a biomarker and key mediator of AKI by inhibiting RNF4/PARP1-mediated tubular injury and inflammation. Hence, over-activation of the IGFBP7/PARP1 axis represents a promising target for AKI treatment.

Global prevalence of occult hepatitis B: A systematic review and meta-analysis.

The study aimed to investigate the prevalence and risk factors associated with occult hepatitis B virus (HBV) infection (OBI) in the global population. We searched PubMed, Embase, CINAHL, Cochrane and Web of Science from database inception through 27 Dec, 2018. Studies reporting HBV-DNA serological data in previously undiagnosed hepatitis B patients were included. The data were further categorized according to the presence of risk factors. After an initial screening of 2,325 records, we finally included 98 articles about the prevalence of OBI from 34 countries and regions. The OBI prevalence was 0.82% (95% CI:0.69-0.96) in the general population, 16.26% (95% CI:10.97-22.34) in HIV patients, 13.99% (95% CI:8.33-20.79) in patients with other liver diseases, 4.25% (95% CI:1.64-7.87) in haemodialysis patients and 5.14% (95% CI:2.26-9.01) patients with other risk factors. In conclusion, OBI prevalence varies significantly across different populations and nations, which deserve attention from the public health authorities. Our results generate further epidemiological data to identify the population with OBI, which has important clinical implications in finding these high-risk populations to design preventive and management strategies.

Symbol division multiplexing in optical fiber communication systems.

Modern emerging data services and applications have put forward an ever-increasing bandwidth requirement for fiber-optic communication channels. To this end, we propose a novel symbol division multiplexing technology (SDM) by multiplexing/de-multiplexing of multiple quadrature amplitude modulation (QAM) symbols onto one complex constellation point. In our SDM scheme, every 7-bit 128QAM symbol is multiplexed per complex valued signal sequentially according to the optimal many-to-one mapping law, forming a 32QAM in the constellation and achieving an extra 40% gain for symbol capacity in an optical discrete multi-tone transmission system. The experiments prove that the SDM-32QAM successfully mitigates the signal impairments induced by fiber chromatic dispersion and Kerr nonlinearity, thus leading to 3.91-dB superior receiver power sensitivity and 2-dB enhancement of systematic tolerance to fiber nonlinear effect. The results highly motivate a fundamental paradigm in multiplexing techniques for optical fiber communication systems.

Probabilistic neural network equalizer for nonlinear mitigation in OAM mode division multiplexed optical fiber communication.

Orbital angular momentum (OAM) mode-division multiplexing (MDM) is a key technique to achieve ultra-high-capacity optical fiber communications. However, the high nonlinear impairment from optoelectronic devices, such as spatial light modulators, modulators, and photodiodes, is a long-standing challenge for OAM-MDM. In this paper, an equalizer based on a probabilistic neural network (PNN) is presented to mitigate the nonlinear impairment for an OAM-MDM fiber communication system with 32 GBaud Nyquist pulse amplitude modulation-8 (PAM8) intensity-modulation direct-detection (IM-DD) signals. PNN equalizer can calculate the distribution of the nonlinearity using Bayesian decision theory and thus mitigate the stochastic nonlinear impairment of the received signal. Experimental results show that compared with the convolutional neural network (CNN) equalizer, the PNN equalizer improves the receiver sensitivity by 0.6dB and 2dB for two OAM modes with l = + 3 and l = + 4 at the 20% FEC limit, respectively. Moreover, compared with Volterra or CNN equalizers, the PNN equalizer can reduce the computation complexity significantly, which has great potential to mitigate the nonlinear signal distortions in high-speed IM-DD OAM-MDM fiber communication systems.

Demonstration of a highly bandwidth-efficient optical interconnection with symbol division multiplexing pulse amplitude modulation.

A novel symbol division multiplexing (SDM) technology is proposed in an intensity modulation and direct detection (IM/DD) pulse amplitude modulation (PAM) optical interconnection. The SDM-PAM4 symbol is the multiplexing of two standard 3-bit PAM8 symbols based on many-to-one (MTO) mapping, increasing by an extra 50% the line rate compared with a typical PAM4 under the same symbol rate and channel bandwidth. The forward error correction (FEC) based on low-density parity-check coding establishes a mechanism between the codewords of both intra- and inter-SDM-PAM4 symbols, to theoretically support the iterative decoding of symbol de-multiplexing employing an optimized bit-interleaved coded modulation iterative decoding (BICM-ID) system. Furthermore, since SDM evidently reduces the mapping order of the PAM signal, the transmission reliability can be effectively improved by alleviating the impairments mainly caused by fiber chromatic dispersion and Kerr nonlinearity. The experimental results indicate that the SDM-PAM4 can achieve more than 5 dB superior systematic receiver power sensitivity over 10-km single mode fiber transmission, and thus represent an important development in coding and modulation multiplexing techniques for optical interconnection systems.

W-band simultaneous vector signal generation and radar detection based on photonic frequency quadrupling.

In this paper, we propose and experiment with a dual-functional system that can simultaneously implement vector signal generation and radar detection based on frequency quadrupling. In the experimental demonstration, a generated W-band quadrature-phase-shift-keying (QPSK) vector signal is transmitted wirelessly over 1 m with a bit-error rate (BER) below 3.8 × 10-3. A radar working in the W band is investigated with a range resolution of 0.94 cm. To the best of our knowledge, this is the first time that simultaneous QPSK vector signal generation and radar detection in the W band has been realized.

SAF-248, a novel PI3Kδ-selective inhibitor, potently suppresses the growth of diffuse large B-cell lymphoma.

PI3Kδ is expressed predominately in leukocytes and overexpressed in B-cell-related malignances. PI3Kδ has been validated as a promising target for cancer therapy, and specific PI3Kδ inhibitors were approved for clinical practice. However, the substantial toxicity and relatively low efficacy as a monotherapy in diffuse large B-cell lymphoma (DLBCL) limit their clinical use. In this study, we described a novel PI3Kδ inhibitor SAF-248, which exhibited high selectivity for PI3Kδ (IC50 = 30.6 nM) over other PI3K isoforms at both molecular and cellular levels, while sparing most of the other human protein kinases in the kinome profiling. SAF-248 exhibited superior antiproliferative activity against 27 human lymphoma and leukemia cell lines compared with the approved PI3Kδ inhibitor idelalisib. In particular, SAF-248 potently inhibited the proliferation of a panel of seven DLBCL cell lines (with GI50 values < 1 µM in 5 DLBCL cell lines). We demonstrated that SAF-248 concentration-dependently blocked PI3K signaling followed by inducing G1 phase arrest and apoptosis in DLBCL KARPAS-422, Pfeiffer and TMD8 cells. Its activity against the DLBCL cells was negatively correlated to the protein level of PI3Kα. Oral administration of SAF-248 dose-dependently inhibited the growth of xenografts derived from Pfeiffer and TMD8 cells. Activation of mTORC1, MYC and JAK/STAT signaling was observed upon prolonged treatment and co-targeting these pathways would potentiate the activity of SAF-248. Taken together, SAF-248 is a promising selective PI3Kδ inhibitor for the treatment of DLBCL and rational drug combination would further improve its efficacy.