N-Acetyltransferase 10 represses Uqcr11 and Uqcrb independently of ac4C modification to promote heart regeneration.

Translational control is crucial for protein production in various biological contexts. Here, we use Ribo-seq and RNA-seq to show that genes related to oxidative phosphorylation are translationally downregulated during heart regeneration. We find that Nat10 regulates the expression of Uqcr11 and Uqcrb mRNAs in mouse and human cardiomyocytes. In mice, overexpression of Nat10 in cardiomyocytes promotes cardiac regeneration and improves cardiac function after injury. Conversely, treating neonatal mice with Remodelin-a Nat10 pharmacological inhibitor-or genetically removing Nat10 from their cardiomyocytes both inhibit heart regeneration. Mechanistically, Nat10 suppresses the expression of Uqcr11 and Uqcrb independently of its ac4C enzyme activity. This suppression weakens mitochondrial respiration and enhances the glycolytic capacity of the cardiomyocytes, leading to metabolic reprogramming. We also observe that the expression of Nat10 is downregulated in the cardiomyocytes of P7 male pig hearts compared to P1 controls. The levels of Nat10 are also lower in female human failing hearts than non-failing hearts. We further identify the specific binding regions of Nat10, and validate the pro-proliferative effects of Nat10 in cardiomyocytes derived from human embryonic stem cells. Our findings indicate that Nat10 is an epigenetic regulator during heart regeneration and could potentially become a clinical target.

Cannabidiol represses miR-143 to promote cardiomyocyte proliferation and heart regeneration after myocardial infarction.

Mammalian heart is capable to regenerate almost completely early after birth through endogenous cardiomyocyte proliferation. However, this regenerative capacity diminishes gradually with growth and is nearly lost in adulthood. Cannabidiol (CBD) is a major component of cannabis and has various biological activities to regulate oxidative stress, fibrosis, inflammation, and cell death. The present study was conducted to investigate the pharmacological effects of CBD on heart regeneration in post-MI mice. MI models in adult mice were constructed via coronary artery ligation, which were administrated with or without CBD. Our results demonstrate that systemic administration (10 mg/kg) of CBD markedly increased cardiac regenerative ability, reduced infarct size, and restored cardiac function in MI mice. Consistently, in vitro study also showed that CBD was able to promote the proliferation of neonatal cardiomyocytes. Mechanistically, the expression of miR-143-3p related to cardiomyocyte proliferation was significantly down-regulated in CBD-treated cardiomyocytes, while the overexpression of miR-143-3p inhibited cardiomyocyte mitosis and eliminated CBD-induced cardiomyocyte proliferation. Moreover, CBD enhanced the expression of Yap and Ctnnd1, which were demonstrated as the target genes of miR-143-3p. Silencing of Yap and Ctnnd1 hindered the proliferative effects of CBD. We further revealed that inhibition of the cannabinoid receptor 2 impeded the regulatory effect of CBD on miR-143-3p and its downstream target Yap/Ctnnd1, which ultimately eliminated the pro-proliferative effect of CBD on neonatal and adult cardiomyocytes. Taken together, CBD promotes cardiomyocyte proliferation and heart regeneration after MI via miR-143-3p/Yap/Ctnnd1 signaling pathway, which provides a new strategy for cardiac repair in adult myocardium.

Efficacy and Safety of Ferric Citrate on Hyperphosphatemia among Chinese Patients with Chronic Kidney Disease Undergoing Hemodialysis: A Phase III Multicenter Randomized Open-Label Active-Drug-Controlled Study.

INTRODUCTION: Hyperphosphatemia in chronic kidney disease (CKD) patients is positively associated with mortality. Ferric citrate is a potent phosphorus binder that lowers serum phosphorus level and improves iron metabolism. We compared its efficacy and safety with active drugs in Chinese CKD patients with hemodialysis. METHODS: Chinese patients undergoing hemodialysis were randomized into two treatment groups in a 1:1 ratio, receiving either ferric citrate or sevelamer carbonate, respectively, for 12 weeks. Serum phosphorus levels, calcium concentration, and iron metabolism parameters were evaluated every 2 weeks. Frequency and severity of adverse events were recorded. RESULTS: 217 (90.4%) patients completed the study with balanced demographic and baseline characteristics between two groups. Ferric citrate decreased the serum phosphorus level to 0.59 ± 0.54 mmol/L, comparable to 0.56 ± 0.62 mmol/L by sevelamer carbonate. There was no significant difference between two groups (p > 0.05) in the proportion of patients with serum phosphorus levels reaching the target range, the response rate to the study drug, and the changes of corrected serum calcium concentrations, and intact-PTH levels at the end of treatment. The change of iron metabolism indicators in the ferric citrate group was significantly higher than those in the sevelamer carbonate group. There are 47 (40.5%) patients in the ferric citrate group, and 26 (21.3%) patients in the sevelamer carbonate group experienced drug-related treatment emergent adverse events (TEAEs); most were mild and tolerable. Common drug-related TEAEs were gastrointestinal disorders, including diarrhea (12.9 vs. 2.5%), fecal discoloration (14.7 vs. 0%), and constipation (1.7 vs. 7.4%) in ferric citrate and sevelamer carbonate group. CONCLUSION: Ferric citrate capsules have good efficacy and safety in the control of hyperphosphatemia in adult patients with CKD undergoing hemodialysis. Efficacy is not inferior to sevelamer carbonate. The TEAEs were mostly mild and tolerated by the patients.

Low-loss microwave photonic switching for satellite communication.

For traditional switching architecture, packet switching performs fine granularity data packet forwarding, but its digital signal processing (DSP) has high power consumption (PC). All-optical switching provides rapid exchange of wavelength resources, which has coarse granularity. In scenarios where the PC is limited, such as broadband satcom, a switching architecture with lower PC and finer granularity than optical switching would be useful. In this paper, we propose a novel, to the best of our knowledge, low-loss microwave photonic switching architecture that can exchange subband signals across beams and frequency bands. The switching process is realized by exchanging optical carriers instead of payload signals, which does not degrade the signal power, guaranteeing the signal-to-noise ratio (SNR). We conducted a proof-of-concept experiment of 2 × 2 switching with two 1.2-GBaud quadrature phase-shift keying (QPSK) signals; an error vector magnitude (EVM) of or less than 13.87% is realized after forwarding. The proposed system has the advantages of low PC, high SNR, and fine granularity, and is very promising for flexible forwarding in future satcom systems.

Broadband dual-channel channelizer based on a microwave photonic power tunable image rejection down-conversion.

Radiofrequency (RF) channelization has potential high frequency and wideband advantages in frequency-domain channel segmentation and down-conversion reception. In this paper, we propose a compact dual-channel channelizer that can process high-frequency wideband signals. It uses double-polarization double-sideband electro-optic modulation and Hartley structure photoelectric conversion to realize down-conversion channelization of the high-frequency wideband signal. The power matching between two polarization signals can be realized by controlling the modulator bias, so the crosstalk between the two output signals can be suppressed. The proposed channelizer has a compact structure since the electro-optic modulation is based on one single laser and one single integrated modulator. No filters are used in the structure, contributing to a very wide RF operation bandwidth and low constraints of laser wavelength. In the experiment, the single frequency signal pairs from 9 GHz to 15 GHz can achieve an inter-channel image rejection ratio of 53 dB. Furthermore, the channelizer slices multi-octave bandwidth quadrature phase shift keying (QPSK) signals up to 16 GHz with the wideband isolation higher than 10 dB and outputs them to two channels in parallel. The error vector magnitudes (EVM) of 9-17 GHz and 18-26 GHz band QPSK signals are guaranteed to be under 23.58% after channelized separation. To the best of our knowledge, the proposed channelizer provides high inter-channel interference suppression at dual-band adjacent signals with 8 GHz bandwidth for the first time. Therefore, the proposed channelizer has great application value for the reception and processing of millimeter signals in the future.

Light Emitting Diodes Irradiation Regulates miRNA-877-3p to Promote Cardiomyocyte Proliferation.

Mammalian cardiomyocytes (CMs) maintain a low capacity for self-renewal in adulthood, therefore the induction of CMs cycle re-entry is an important approach to promote myocardial repair after injury. Recently, photobiomodulation (PBM) has been used to manipulate physiological activities of various tissues and organs by non-invasive means. Here, we demonstrate that conditioned PBM using light-emitting diodes with a wavelength of 630 nm (LED-Red) was capable of promoting the proliferation of neonatal CMs. Further studies showed that low-power LED-Red affected the expression of miR-877-3p and promoted the proliferation of CMs. In contrast, silencing of miR-877-3p partially abolished the pro-proliferative actions of LED-Red irradiation on CMs. Mechanistically, GADD45g was identified as a downstream target gene of miR-877-3p. Conditioned LED-Red irradiation also inhibited the expression of GADD45g in neonatal CMs. Moreover, GADD45g siRNA reversed the positive effect of LED-Red on the proliferation of neonatal CMs. Taken together, conditioned LED-Red irradiation increased miR-877-3p expression and promoted the proliferation of neonatal CMs by targeting GADD45g. This finding provides a new insight into the role of LED-Red irradiation in neonatal CMs biology and suggests its potential application in myocardial injury repair.

Photobiomodulation Drives MiR-136-5p Expression to Promote Injury Repair after Myocardial Infarction.

Photobiomodulation (PBM) has emerged as an alternative therapy involved in modulating a variety of biological effects. In this study, we verified whether PBM can affect cardiac physiological activity in mice through noninvasive irradiation using light-emitting diodes at a wavelength of 630 nm (LED-Red). We found that the PBM involved in regulating the repair of injured myocardium is wavelength-limited. LED-Red caused cardiomyocytes (CMs) that had exited the cell cycle to divide and proliferate again, and the cell proliferation ratio increased significantly with the accumulation of intracellular photopower. In addition, LED-Red promoted myocardial revascularization and myocardial regeneration, reduced the area of fibrosis in mice with myocardial infarction (MI), and thus improved cardiac contractile function. In regard to the mechanism, miRNA sequencing analysis showed that low-power LED-Red irradiation could induce differential changes in miRNAs in CMs. Among them, miR-136-5p was identified as a cardiac photo-sensitive miRNA and was obviously inhibited after stimulation, which produced a proliferation-promoting effect on CMs. Subsequent luciferase reporter assays confirmed the involvement of Ino80 as a binding target of miR-136-5p in the regulatory process of CM proliferation. Similarly, LED-Red irradiation elevated intracellular Ino80 expression. After knockdown of Ino80, the proliferation-promoting effect of LED-Red on CMs was inhibited. Collectively, this study demonstrates that LED-Red can promote CM proliferation by inhibiting cardiac photo-sensitive miRNA- miR-136-5p expression through targeting Ino80. The findings provided a new potential strategy for the treatment of ischemic cardiomyopathy (ICD).

Light Emitting Diodes Photobiomodulation Improves Cardiac Function by Promoting ATP Synthesis in Mice With Heart Failure.

Heart failure (HF) is the common consequences of various cardiovascular diseases, often leading to severe cardiac output deficits with a high morbidity and mortality. In recent years, light emitting diodes-based therapy (LEDT) has been widely used in multiple cardiac diseases, while its modulatory effects on cardiac function with HF still remain unclear. Therefore, the objective of this study was to investigate the effects of LED-Red irradiation on cardiac function in mice with HF and to reveal its mechanisms. In this study, we constructed a mouse model of HF. We found that LED-Red (630 nm) was an effective wavelength for the treatment of HF. Meanwhile, the application of LED-Red therapy to treat HF mice improved cardiac function, ameliorate heart morphology, reduced pulmonary edema, as well as inhibited collagen deposition. Moreover, LED-Red therapy attenuated the extent of perivascular fibrosis. Besides, LED-Red irradiation promoted calcium transients in cardiomyocytes as well as upregulated ATP synthesis, which may have positive implications for contractile function in mice with HF. Collectively, we identified that LED-Red exerts beneficial effects on cardiac function in HF mice possibly by promoting the synthesis of ATP.

Generation of rotational orbital angular momentum beams in the radio frequency based on an optical-controlled circular antenna array.

The orbital angular momentum (OAM) has been widely used in the wireless short-range communication system, but for long-distance communication, the huge difficulty of beam receiving is a great challenge. In this paper, to overcome this challenge, a generation system of radio-frequency rotational orbital angular momentum (RF-ROAM) beams based on an optical-controlled circular antenna array (CAA) is proposed. The ROAM beam is an OAM beam rotating at a certain speed around the beam axis. According to the rotational Doppler effect, the rotation of the OAM beam will induce a frequency shift proportional to the OAM mode and the rotation speed. Thereby, by rotating an OAM beam at a fixed speed scheduled in advance in the transmitting end, the beam can be mode-distinguished by just detecting the frequency shift without receiving the whole wavefront vertical to the beam axis in the receiving end. This provides a partial reception scheme for the OAM-based wireless communication system. The generation system of RF-ROAM beams is proposed and constructed, and the proof-of-concept experiment is performed. In the system, the optical-controlled CAA is constructed to generate the general RF-OAM beam, the optical signal processor (OSP) is employed to control the phase shifts to further control the OAM mode, and the signal with time-varying phase is generated as the rotation factor to control the rotation speed. In the experiment, the RF-ROAM beams with different mode and mode combination are generated and successfully measured by detecting the frequency shift of the signal received in a fixed point.

Data-aided channel equalization scheme for FAST radio over fiber transmission system.

The Five-hundred-meter Aperture Spherical radio Telescope (FAST) located in Guizhou, China, is a very sensitive single dish telescope. Due to the large size of the telescope, optical fiber is used for the transmission of the 3-km astronomical signal from the telescope to the signal processing center. The optical fibers are suspended in the air above the telescope reflector, very easy to slide when the telescope feed cabin moves, resulting in phase drifts for the transmission signal. This phase drift has a negative impact on the observation mode of very long baseline interferometry, and can be compensated by the frequency transfer system in the FAST. In this manuscript, we propose a new phase drift compensation scheme, which is denoted as data-aided channel equalization scheme. The proposed scheme is based on a hypothesis of linear phase relationship between different wavelengths in the same optical fiber, and uses the channel response information of the data-aided channel to conduct signal recovery for the astronomical signal channel. Not only the phase drift, but also the frequency-dependent distortion of the broadband transmission link can be compensated. The proposed scheme has simple transmission structure, and the function part is well modularized, so that the Astronomer users can easily turn it on or off. In the proof-of-concept experiments, the estimation deviation can be significantly reduced by estimated channel responses averaging over training sequence repetitions, showing very high accuracy of the astronomical signal channel estimation.

ALKBH5-mediated m6A mRNA methylation governs human embryonic stem cell cardiac commitment.

N6-methyladenosine (m6A), as the most abundant modification of mammalian messenger RNAs, is essential for tissue development and pathogenesis. However, the biological significance of m6A methylation in cardiac differentiation and development remains largely unknown. Here, we identify that the downregulation of m6A demethylase ALKBH5 is responsible for the increase of m6A methylation and cardiomyocyte fate determination of human embryonic stem cells (hESCs) from mesoderm cells (MESs). In contrast, ALKBH5 overexpression remarkably blocks cardiomyocyte differentiation of hESCs. Mechanistically, KDM5B and RBBP5, the components of H3K4 modifying enzyme complexes, are identified as downstream targets for ALKBH5 in cardiac-committed hESCs. Loss of function of ALKBH5 alters the expression of KDM5B and RBBP5 through impairing stability of their mRNAs, which in turn promotes the transcription of GATA4 by enhancing histone H3 Lys4 trimethylation (H3K4me3) at the promoter region of GATA4. Taken together, we reveal a previously unidentified role of m6A demethylase ALKBH5 in determining cardiac lineage commitment of hESCs.

Photobiomodulation Regulation as One Promising Therapeutic Approach for Myocardial Infarction.

Myocardial infarction refers to myocardial necrosis caused by acute or persistent coronary ischemia and hypoxia. It is considered to be one of the significant crises threatening human health in the world. Following myocardial infarction, collagen gradually replaces the original tissue due to the loss of many cardiomyocytes, myocardial contractile function decreases, and myocardial fibrosis eventually leads to heart failure. Phototherapy is a new treatment which has shown superior efficacy on the nerve, skeletal muscle, skin, and other tissues. Likewise, there is growing evidence that phototherapy also has many positive effects on the heart. Therefore, this article introduces the progress of research on phototherapy as a new therapeutic strategy in the treatment of myocardial infarction. The wavelength of photobiomodulation in the treatment of myocardial infarction is specific, and the influence of light source power and light duration on the tissue presents a bell-shaped distribution. Under these conditions, phototherapy can promote ATP synthesis and angiogenesis, inhibit the inflammatory response, improve heart function, reduce infarct size, and protect myocardium. In addition, we summarized the molecular mechanisms of phototherapy. According to the location of photoreceptors, they can be divided into mitochondrial and nonmitochondrial parts.

Loss of m6A methyltransferase METTL3 promotes heart regeneration and repair after myocardial injury.

AIMS: N6-Methyladenosine (m6A), one of the important epigenitic modifications, is very commom in messenger RNAs (mRNAs) of eukaryotes, and has been involved in various diseases. However, the role of m6A modification in heart regeneration after injury remains unclear. The study was conducted to investigate whether targeting methyltransferase-like 3 (METTL3) could replenish the loss of cardiomyocytes (CMs) and improve cardiac function after myocardial infarction (MI). METHODS AND RESULTS: METTL3 knockout mouse line was generated. A series of functional experiments were carried out and the molecular mechanism was further explored. We identified that METTL3, a methyltransferase of m6A methylation, is upregulated in mouse hearts after birth, which is the opposite of the changes in CMs proliferation. Furthermore, both METTL3 heterozygous knockout mice and administration of METTL3 shRNA adenovirus in mice exhibited CMs cell cycle re-entered, infract size decreased and cardiac function improved after MI. Mechanically, the silencing of METTL3 promoted CMs proliferation by reducing primary miR-143 (pri-miR-143) m6A modificaiton, thereby inhibiting the pri-miR-143 into mature miR-143-3p. Moreover, we found that miR-143-3p has targeting effects on Yap and Ctnnd1 so as to regulate CMs proliferation. CONCLUSION: METTL3 deficiency contributes to heart regeneration after MI via METTL3-pri-miR-143-(miR-143)-Yap/Ctnnd1 axis. This study provides new insights into the significance of RNA m6A modification in heart regeneration.

Analog radio of fiber link of 2-Gbaud OOK/BPSK radio frequency-orbital angular momentum beam transmission over 19.4 km.

The 5G mobile communication system provides ultrareliable, low-latency communications at up to 10 Gbps. However, the scale and power consumption of 5G is tremendous owing to a large number of antenna drivers required by the massive multiple-input multiple-output technique. The 6G system will require an architectural paradigm shift to resolve this problem. In this study, we propose an analog RoF downlink scheme for 6G wireless communications. The upcoming oversized base station problem is solved using photonics techniques. The antennas are driven together within the optical domain at a centralized station. The proposed system uses orbital angular momentum (OAM) beams as the generated space-division-multiplexing beams. An RF-OAM beam has a weak coupling effect between different modes, which will dramatically decrease the complexity of the signal processing. In our proof-of-concept experiment, the generated RF-OAM beam was shown to carry a 2-Gbaud OOK/BPSK signal in the Ku-band. Signals were transmitted over a 19.4-km RoF link without dispersion-induced power fading. In addition, by switching the OAM beams, a two-dimensional direction scanning was achieved.

Inhibition of cardiomyocyte differentiation of human induced pluripotent stem cells by Ribavirin: Implication for its cardiac developmental toxicity.

Ribavirin has been proven to be an antiviral treatment, whereas there are still risks of hemolysis and congenital malformation. Abnormal cardiac development contributes to the occurrence and development of many heart diseases. However, there is so far no evidence that ribavirin induces human cardiac developmental toxicity. Herein, we employed the cardiac differentiation model of human induced pluripotent stem cells (hiPSCs) to determine the impact of ribavirin on heart development. Our data showed that ribavirin at clinically high concentrations (5 and 10 µM) significantly inhibited the proliferation and differentiation of hiPSCs from mesoderm to cardiac progenitor cells and cardiac progenitor cells to cardiomyocytes, but not from pluripotent status to mesoderm. Meanwhile, DCFH-DA staining revealed that ribavirin could increase ROS content in the mid-phase of differentiation. In addition, ribavirin treatment (1, 5 and 10 µM) remarkably caused DNA damage which was shown by the increase of γH2AX-positive cells and upregulation of the p53 during the differentiation of hiPSCs from mesoderm to cardiac progenitor cells. Moreover, exposuring to ribavirin (5 and 10 µM) markedly upregulated the expression of lncRNAs Gas5 in both mid-phase and late phase of differentiation and HBL1 in the mid-phase. In conclusion, our results suggest that ribavirin is detrimental in cardiac differentiation of hiPSCs, which may be associated with DNA damage, upregulated p53 and increased Gas5. It may provide the evidence for the rational clinical application of ribavirin.

Iron overload inhibits self-renewal of human pluripotent stem cells via DNA damage and generation of reactive oxygen species.

Iron overload affects the cell cycle of various cell types, but the effect of iron overload on human pluripotent stem cells has not yet been reported. Here, we show that the proliferation capacities of human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs) were significantly inhibited by ferric ammonium citrate (FAC) in a concentration-dependent manner. In addition, deferoxamine protected hESCs/hiPSCs against FAC-induced cell-cycle arrest. However, iron overload did not affect pluripotency in hESCs/hiPSCs. Further, treatment of hiPSCs with FAC resulted in excess reactive oxygen species production and DNA damage. Collectively, our findings provide new insights into the role of iron homeostasis in the maintenance of self-renewal in human pluripotent stem cells.

YAP/TEAD3 signal mediates cardiac lineage commitment of human-induced pluripotent stem cells.

Cardiomyocytes differentiated from human-induced pluripotent stem cells (hiPSCs) hold great potential for therapy of heart diseases. However, the underlying mechanisms of its cardiac differentiation have not been fully elucidated. Hippo-YAP signal pathway plays important roles in cell differentiation, tissue homeostasis, and organ size. Here, we identify the role of Hippo-YAP signal pathway in determining cardiac differentiation fate of hiPSCs. We found that cardiac differentiation of hiPSCs were significantly inhibited after treatment with verteporfin (a selective and potent YAP inhibitor). During hiPSCs differentiation from mesoderm cells (MESs) into cardiomyocytes, verteporfin treatment caused the cells retained in the earlier cardiovascular progenitor cells (CVPCs) stage. Interestingly, during hiPSCs differentiation from CVPC into cardiomyocytes, verteporfin treatment induced cells dedifferentiation into the earlier CVPC stage. Mechanistically, we found that YAP interacted with transcriptional enhanced associate domain transcription factor 3 (TEAD3) to regulate cardiac differentiation of hiPSCs during the CVPC stage. Consistently, RNAi-based silencing of TEAD3 mimicked the phenotype as the cells treated with verteporfin. Collectively, our study suggests that YAP-TEAD3 signaling is important for cardiomyocyte differentiation of hiPSCs. Our findings provide new insight into the function of Hippo-YAP signal in cardiovascular lineage commitment.

Chromatic dispersion immune microwave photonic phase shifter based on double-sideband modulation.

A chromatic dispersion (CD) immune microwave photonic phase shifter (MPPS) based on double-sideband (DSB) modulation is proposed and demonstrated. An optical spectrum processor introduces the phase shift to the MPPS. The DSB signals along two orthogonal polarizations are demodulated to two RF signals with both quadrature amplitude and phase items, transferring the CD-induced power fading to the phase item of the synthetic RF signals. Experimental results show that the RF signals over 14-25 GHz obtain random phase shift in 360° range without a power fading point (PFP) after passing through a dispersion compensation fiber with CD of -331 ps/nm. The phase variation and power variation of the phase-shifted signal are <±5.7° and <±0.9 dB, respectively, at the original PFP at 16 GHz.

Photonic generation of background-free binary and quaternary phase-coded microwave pulses based on vector sum.

A photonic microwave phase-coded pulse generator is proposed and experimentally demonstrated based on the principle of vector sum. The key component of the proposed pulse generator is an integrated polarization-division multiplexing Mach-Zehnder modulator (PDM-MZM) and a 90° hybrid coupler. By properly setting the data sequences applied to the specially biased PDM-MZM, binary and quaternary phase-coded microwave pulses (PCMPs) that are free from the background signals can be generated. Since no filters and polarization adjustment are involved, the proposed pulse generator is characterized by a simple structure, low-loss, flexible frequency tunability and high long-term stability. The experimental results show that background-free 4 Gb/s Barker and Frank PCMPs at 18 GHz and 2 Gb/s Barker and Frank PCMPs at 24 GHz are successfully generated. The calculated pulse compression ratio and peak-to-side lobe ratio are in good agreement with the theoretical values.