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Smooth muscle cell (SMC) phenotypic switch from a quiescent 'contractile' phenotype to a dedifferentiated and proliferative state underlies the development of cardiovascular diseases (CVDs); however, our understanding of the mechanism is still incomplete. In the present study, we explored the potential role of ferroptosis, a novel nonapoptotic form of cell death, in SMC phenotypic switch and related neointimal formation. We found that ferroptotic stress was triggered in cultured dedifferentiated SMCs and arterial neointimal tissue of wire-injured mice. Moreover, pro-ferroptosis stress was activated in arterial neointimal tissue of clinical patients who underwent carotid endarterectomy. Blockade of ferroptotic stress via administration of a pharmacological inhibitor or by global genetic overexpression of glutathione peroxidase-4 (GPX4), a well-established anti-ferroptosis molecule, delayed SMC phenotype switch and arterial remodelling. Conditional SMC-specific gene delivery of GPX4 using adreno-associated virus in the carotid artery inhibited ferroptosis and prevented neointimal formation. Conversely, ferroptosis stress directly triggered dedifferentiation of SMCs. Transcriptomics analysis demonstrated that inhibition of ferroptotic stress mainly targets the mitochondrial respiratory chain and oxidative phosphorylation. Mechanistically, ferroptosis inhibition corrected the disrupted mitochondrial homeostasis in dedifferentiated SMCs, including enhanced mitochondrial ROS production, dysregulated mitochondrial dynamics, and mitochondrial hyperpolarization, and ultimately inhibited SMC phenotypic switch and growth. Copper-diacetyl-bis

Compact, low-noise microwave sources are required throughout a wide range of application areas including frequency metrology, wireless-communications and airborne radar systems. And the photonic generation of microwaves using soliton microcombs offers a path towards integrated, low noise microwave signal sources. In these devices, a so called quiet-point of operation has been shown to reduce microwave frequency noise. Such operation decouples pump frequency noise from the soliton’s motion by balancing the Raman self-frequency shift with dispersive-wave recoil. Here, we explore the limit of this noise suppression approach and reveal a fundamental noise mechanism associated with fluctuations of the dispersive wave frequency. At the same time, pump noise reduction by as much as 36 dB is demonstrated. This fundamental noise mechanism is expected to impact microwave noise (and pulse timing jitter) whenever solitons radiate into dispersive waves belonging to different spatial mode families., Here the authors explore the noise spectrum of soliton microcomb when the pump is decoupled from the solitons motion by balancing the Raman shift with the emitted dispersive wave. Based on the analysis of the phase noise and the soliton repetition rate, they identify the uncorrelated thermal fluctuations as underlying mechanism.

Aims Exercise confers protection against cardiovascular ageing, but the mechanisms remain largely unknown. This study sought to investigate the role of fibronectin type-III domain-containing protein 5 (FNDC5)/irisin, an exercise-associated hormone, in vascular ageing. Moreover, the existence of FNDC5/irisin in circulating extracellular vesicles (EVs) and their biological functions was explored. Methods and results FNDC5/irisin was reduced in natural ageing, senescence, and angiotensin II (Ang II)-treated conditions. The deletion of FNDC5 shortened lifespan in mice. Additionally, FNDC5 deficiency aggravated vascular stiffness, senescence, oxidative stress, inflammation, and endothelial dysfunction in 24-month-old naturally aged and Ang II-treated mice. Conversely, treatment of recombinant irisin alleviated Ang II-induced vascular stiffness and senescence in mice and vascular smooth muscle cells. FNDC5 was triggered by exercise, while FNDC5 knockout abrogated exercise-induced protection against Ang II-induced vascular stiffness and senescence. Intriguingly, FNDC5 was detected in human and mouse blood-derived EVs, and exercise-induced FNDC5/irisin-enriched EVs showed potent anti-stiffness and anti-senescence effects in vivo and in vitro. Adeno-associated virus-mediated rescue of FNDC5 specifically in muscle but not liver in FNDC5 knockout mice, promoted the release of FNDC5/irisin-enriched EVs into circulation in response to exercise, which ameliorated vascular stiffness, senescence, and inflammation. Mechanistically, irisin activated DnaJb3/Hsp40 chaperone system to stabilize SIRT6 protein in an Hsp70-dependent manner. Finally, plasma irisin concentrations were positively associated with exercise time but negatively associated with arterial stiffness in a proof-of-concept human study. Conclusion FNDC5/irisin-enriched EVs contribute to exercise-induced protection against vascular ageing. These findings indicate that the exerkine FNDC5/irisin may be a potential target for ageing-related vascular comorbidities.

Since its invention, optical frequency comb has revolutionized a broad range of subjects from metrology to spectroscopy. The recent development of microresonator-based frequency combs (microcombs) provides a unique pathway to create frequency comb systems on a chip. Indeed, microcomb-based spectroscopy, ranging, optical synthesizer, telecommunications and astronomical calibrations have been reported recently. Critical to many of the integrated comb systems is the broad coverage of comb spectra. Here, microcombs of more than two-octave span (450 nm to 2,008 nm) is demonstrated through χ(2) and χ(3) nonlinearities in a deformed silica microcavity. The deformation lifts the circular symmetry and creates chaotic tunneling channels that enable broadband collection of intracavity emission with a single waveguide. Our demonstration introduces a new degree of freedom, cavity deformation, to the microcomb studies, and our microcomb spectral range is useful for applications in optical clock, astronomical calibration and biological imaging., Here, the authors demonstrate the use of chaos to obtain 2-octave comb generation. The deformation lifts the circular symmetry and creates chaotic tunneling channels that enable broadband collection of intracavity emission with a single waveguide, introducing a new degree of freedom to microcomb studies.

Pulsed pumping of a silica microcavity is used to generate single-soliton microcombs with conversion efficiency of 54%. Analytical expressions are developed by the Lagrangian approach and applied to model the results.

Optical microresonators with high quality ($Q$) factors are essential to a wide range of integrated photonic devices. Steady efforts have been directed towards increasing microresonator $Q$ factors across a variety of platforms. With success in reducing microfabrication process-related optical loss as a limitation of $Q$, the ultimate attainable $Q$, as determined solely by the constituent microresonator material absorption, has come into focus. Here, we report measurements of the material-limited $Q$ factors in several photonic material platforms. High-$Q$ microresonators are fabricated from thin films of SiO$_2$, Si$_3$N$_4$, Al$_{0.2}$Ga$_{0.8}$As and Ta$_2$O$_5$. By using cavity-enhanced photothermal spectroscopy, the material-limited $Q$ is determined. The method simultaneously measures the Kerr nonlinearity in each material and reveals how material nonlinearity and ultimate $Q$ vary in a complementary fashion across photonic materials. Besides guiding microresonator design and material development in four material platforms, the results help establish performance limits in future photonic integrated systems., Maodong Gao, Qi-Fan Yang and Qing-Xin Ji contributed equally to this work. 9 pages, 4 figures, 1 table

Soliton microcombs based on Kerr nonlinearity in microresonators have been a prominent miniaturized coherent light source. Here, for the first time, we demonstrate the existence of Kerr solitons in an optomechanical microresonator, for which a nonlinear model is built by incorporating a single mechanical mode and multiple optical modes. Interestingly, an exotic vibrational Kerr soliton state is found, which is modulated by a self-sustained mechanical oscillation. Besides, the soliton provides extra mechanical gain through the optical spring effect, and results in phonon lasing with a red-detuned pump. Various nonlinear dynamics is also observed, including limit cycle, higher periodicity, and transient chaos. This work provides a guidance for not only exploring many-body nonlinear interactions, but also promoting precision measurements by featuring superiority of both frequency combs and optomechanics.

Significance Microlasers in near-degenerate supermodes play a pivotal role for studies of non-Hermitian physics, novel light sources, and advanced sensors. However, the widely observed beating phenomena and the single-mode nature of the stimulated scattering have been generating the lasing characteristic dilemma. In this article, we experimentally elucidate the lasing spectral paradox by investigating the lasing dynamics of supermode Raman microlasers. The single-mode lasing behavior is confirmed, and the beating signal has been recognized as the transient interference during the lasing switching between the supermodes with the help of the self-injection technique. This work provides an insightful guidance for microlaser-based precision measurements and paves the way to reconfigurable light sources., Microlasers in near-degenerate supermodes lay the cornerstone for studies of non-Hermitian physics, novel light sources, and advanced sensors. Recent experiments of the stimulated scattering in supermode microcavities reported beating phenomena, interpreted as dual-mode lasing, which, however, contradicts their single-mode nature due to the clamped pump field. Here, we investigate the supermode Raman laser in a whispering-gallery microcavity and demonstrate experimentally its single-mode lasing behavior with a side-mode suppression ratio (SMSR) up to 37 dB, despite the emergence of near-degenerate supermodes by the backscattering between counterpropagating waves. Moreover, the beating signal is recognized as the transient interference during the switching process between the two supermode lasers. Self-injection is exploited to manipulate the lasing supermodes, where the SMSR is further improved by 15 dB and the laser linewidth is below 100 Hz.

BACKGROUND: Arthroscopic anterior cruciate ligament reconstruction (ACLR) is the best treatment choice for returning to pre-injury activities following ACL rupture. Although allografts are considered an effective alternative to autografts, there is still controversy regarding the safety and effectiveness of this procedure, especially concerning the risk of postoperative infection and disease transmission. The purpose of this study was to compare the efficacy outcomes and safety between allografts and autografts in primary ACLR. METHODS: The retrospective analysis involved 112 patients (58 patients received allogeneic tendons and 54 patients received autologous hamstring tendons) who underwent primary ACLR. All patients were followed up and evaluated on admission and at 1 week, 3 months, 6 months, and 1 year postoperatively. The efficacy outcome of the ACLR was evaluated by International Knee Documentation Committee (IKDC) score and physical examinations (Lachman test, anterior drawer test, and pivot shift test). The safety outcome of allografts and autografts was compared by investigating the occurrence of postoperative complications, including postoperative inflammation and potential disease transmission. The benefits of each operation for surgeons and patients were also analyzed, including the length of surgical incision and operative time. RESULTS: There was no significant difference in the demographic and clinical characteristics between the allograft and autograft groups. The two cohorts proved to be similar in terms of the acute or chronic nature of the cruciate ligament and the incidence of concomitant meniscal surgery. Arthroscopic ACLR was performed in all patients. The physical examinations were all positive before surgery and negative immediately after the operation. The KT-1000 and IKDC scores of two groups significantly decreased than pre-operative ones (P0.05). At final follow-up, all patients had returned to their pre-injury activities. Allografts showed no increased risk for postoperative infection or potential disease transmission relative to autografts. CONCLUSIONS: The outcomes of reconstructed ACL with allografts were similar to those of autographs. Moreover, the safety of allografts showed to be comparable to that of autografts, especially concerning postoperative infection and disease transmission. Therefore, the surgical option should be chosen wisely according to the patient’s condition.

Optical frequency combs have a wide range of applications in science and technology(1). An important development for miniature and integrated comb systems is the formation of dissipative Kerr solitons in coherently pumped high-quality-factor optical microresonators(2-9). Such soliton microcombs(10) have been applied to spectroscopy(11-13), the search for exoplanets(14,15), optical frequency synthesis(16), time keeping(17) and other areas(10). In addition, the recent integration of microresonators with lasers has revealed the viability of fully chip-based soliton microcombs(18,19). However, the operation of microcombs requires complex startup and feedback protocols that necessitate difficult-to-integrate optical and electrical components, and microcombs operating at rates that are compatible with electronic circuits-as is required in nearly all comb systems-have not yet been integrated with pump lasers because of their high power requirements. Here we experimentally demonstrate and theoretically describe a turnkey operation regime for soliton microcombs co-integrated with a pump laser. We show the appearance of an operating point at which solitons are immediately generated by turning the pump laser on, thereby eliminating the need for photonic and electronic control circuitry. These features are combined with high-quality-factor Si3N4 resonators to provide microcombs with repetition frequencies as low as 15 gigahertz that are fully integrated into an industry standard (butterfly) package, thereby offering compelling advantages for high-volume production.

A record Q-factor of 1.1 billion is demonstrated in on-chip silica whispering-gallery resonators. Using the devices, sub-milliwatt parametric oscillation threshold is measured in 9 GHz free-spectral-range devices.

The phase noise of the soliton repetition rate is experimentally characterized in silica microresonators. In conjunction with dispersive wave quieting of pump technical noise, spatio-temporal fluctuations of distinct transverse modes set a limit to performance.

Melatonin has been previously shown to prevent nonalcoholic fatty liver disease (NAFLD), yet the underlying mechanisms are poorly understood. Here, we identified a previously unknown regulatory action of melatonin on apoptosis signal-regulating kinase 1 (ASK1) signaling pathway in the pathogenesis and development of NAFLD. Although melatonin administration did not alter food intake, it significantly alleviated fatty liver phenotypes, including the body weight gain, insulin resistance, hepatic lipid accumulation, steatohepatitis, and fibrosis in a high-fat diet (HFD)-induced NAFLD mouse model (in vivo). The protection of melatonin against NAFLD was not affected by inactivation of Kupffer cell in this model. In NAFLD mice liver, ASK1 signal cascade was substantially activated, evidence by the enhancement of total ASK1, phospho-ASK1, phospho-MKK3/6, phospho-p38, phospho-MKK4/7, and phospho-JNK. Melatonin treatment significantly suppressed the ASK1 upregulation and the phosphorylation of ASK1, MKK3/6, MKK4/7, p38, and JNK. Mechanistically, we found that lipid stress triggered the interaction between ASK1 and TNF receptor-associated factors (TRAFs), including TRAF1, TRAF2, and TRAF6, which resulted in ASK1 deubiquitination and thereby increased ASK1 protein stability. Melatonin did not alter ASK1 mRNA level; however, it activated a scaffold protein β-arrestin-1 and enabled it to bind to ASK1, which antagonized the TRAFs-mediated ASK1 deubiquitination, and thus reduced ASK1 protein stability. Consistent with these findings, knockout of β-arrestin-1 in mice partly abolished the protection of melatonin against NAFLD. Taken together, our results for the first time demonstrate that melatonin safeguards against NAFLD by eliminating ASK1 activation via inhibiting TRAFs-mediated ASK1 deubiquitination and stabilization in a β-arrestin-1 dependent manner.

While soliton microcombs offer the potential for integration of powerful frequency metrology and precision spectroscopy systems, their operation requires complex startup and feedback protocols that necessitate difficult-to-integrate optical and electrical components. Moreover, CMOS-rate microcombs, required in nearly all comb systems, have resisted integration because of their power requirements. Here, a regime for turnkey operation of soliton microcombs co-integrated with a pump laser is demonstrated and theoretically explained. Significantly, a new operating point is shown to appear from which solitons are generated through binary turn-on and turn-off of the pump laser, thereby eliminating all photonic/electronic control circuitry. These features are combined with high-Q $Si_3N_4$ resonators to fully integrate into a butterfly package microcombs with CMOS frequencies as low as 15 GHz, offering compelling advantages for high-volume production., Comment: Boqiang Shen, Lin Chang, Junqiu Liu, Heming Wang and Qi-Fan Yang contributed equally to this work

High optical quality (Q) factors are critically important in optical microcavities, where performance in applications spanning nonlinear optics to cavity quantum electrodynamics is determined. Here, a record Q factor of over 1.1 billion is demonstrated for on-chip optical resonators. Using silica whispering-gallery resonators on silicon, Q-factor data is measured over wavelengths spanning the C/L bands (100 nm) and for a range of resonator sizes and mode families. A record low sub-milliwatt parametric oscillation threshold is also measured in 9 GHz free-spectral-range devices. The results show the potential for thermal silica on silicon as a resonator material.

Optical absorption and nonlinear index are important performance drivers in devices like microcombs and parametric oscillators. Here we use resonance-enhanced nonlinear spectroscopy to characterize absorption limits and nonlinear index for some integrated photonic materials. (c) 2021 The Author(s)