Novel two-tiered screening approach identifies synergistic combinations of natural compounds for prostate cancer prevention and treatment.

Prostate cancer (PCa) is the second most common cancer type among American men and it is estimated that in 2023, 34,700 men will die from PCa. Since it can take a considerable amount of time for the disease to progress to clinically evident cancer, there is ample opportunity for effective chemopreventive strategies to be applied for the successful management of PCa progression. In the current study, we have developed a two-tiered metabolomics-based screen to identify synergistic combinations of phytochemicals for PCa chemoprevention. This involves an initial screen for ATP depletion in PCa cells followed by a targeted screen for blocking glutamine uptake in the same cells. One of the phytochemical combinations (enoxolone [ENO] + silibinin [SIL]), identified via this screen, was examined for effects on PCa cell survival, oncogenic signaling and tumor growth in vivo. This combination was found to synergistically reduce cell survival, colony formation and cell cycle progression of PCa cell lines to a greater extent than either agent alone. The combination of ENO and SIL also synergistically reduced tumor growth when administered ad libitum through the diet in a HMVP2 allograft PCa tumor model. Treatment with the combination also significantly reduced STAT3 and mTORC1 signaling pathways in mouse and human PCa cells while significantly reducing levels of critical cell cycle regulatory proteins, contributing to the synergistic inhibition of tumor growth observed. Collectively, the current results demonstrate a novel approach to identifying synergistic combinations of phytochemicals for chemoprevention of PCa and possibly other cancers.

Basigin Deficiency Induces Spontaneous Polycystic Kidney in Mice.

BACKGROUND: Polycystic kidney disease is the most common hereditary kidney disorder with early and frequent hypertension symptoms. The mechanisms of cyst progression in polycystic kidney disease remain incompletely understood. METHODS: Bsg (basigin) heterozygous and homozygous knockout mice were generated using cas9 system, and Bsg overexpression was achieved by adeno-associated virus serotype 9 injection. Renal morphology was investigated through histological and imaging analysis. Molecular analysis was performed through transcriptomic profiling and biochemical approaches. RESULTS: Bsg-deficient mice exhibited significantly elevated arterial blood pressure. Further investigation demonstrated that Bsg deficiency triggers spontaneous cystic formation in mouse kidneys, which shares similar cyst pathological features and common transcriptional regulatory pathways with human polycystic kidney disease. Moreover, Bsg disruption promoted polycystin-1 ubiquitination and degradation, leading to activation of polycystic kidney disease associated cAMP and AMPK signaling pathways in Bsg knockout mouse kidneys. Finally, adeno-associated virus serotype 9 mediated Bsg reexpression reversed cystic progression in Bsg knockout mice in vivo, and Bsg overexpression inhibited the expansion of Madin-Darby canine kidney cysts in vitro. CONCLUSIONS: Our findings show that Bsg deficiency leads to an early-onset spontaneous polycystic kidney phenotype, suggesting that dysregulated Bsg signaling may be a contributing factor in cystogenesis.

The Hypothalamic Epigenetic Landscape in Dietary Obesity.

The hypothalamus in the brain plays a pivotal role in controlling energy balance in vertebrates. Nutritional excess through high-fat diet (HFD) feeding can dysregulate hypothalamic signaling at multiple levels. Yet, it remains largely unknown in what magnitude HFD feeding may impact epigenetics in this brain region. Here, it is shown that HFD feeding can significantly alter hypothalamic epigenetic events, including posttranslational histone modifications, DNA methylation, and chromatin accessibility. The authors comprehensively analyze the chromatin immunoprecipitation-sequencing (ChIP-seq), methylated DNA immunoprecipitation-sequencing (MeDIP-seq), single nucleus assay for transposase-accessible chromatin using sequencing (snATAC-seq), and RNA-seq data of the hypothalamus of C57 BL/6 mice fed with a chow or HFD for 1 to 6 months. The chromatins are categorized into 6 states using the obtained ChIP-seq data for H3K4me3, H3K27ac, H3K9me3, H3K27me3, and H3K36me3. A 1-month HFD feeding dysregulates histone modifications and DNA methylation more pronouncedly than that of 3- or 6-month. Besides, HFD feeding differentially impacts chromatin accessibility in hypothalamic cells. Thus, the epigenetic landscape is dysregulated in the hypothalamus of dietary obesity mice.

Hydrogen sulfide alleviates mitochondrial damage and ferroptosis by regulating OPA3-NFS1 axis in doxorubicin-induced cardiotoxicity.

Ferroptosis is a major cause of cardiotoxicity induced by doxorubicin (DOX). Previous studies have shown that hydrogen sulfide (H2S) inhibits ferroptosis in cardiomyocytes and myoblasts, but the underlying mechanism has not been fully elucidated. In this study, we investigated the role of H2S in protecting against DOX-induced cardiotoxicity both in vivo and in vitro, and elucidated the potential mechanisms involved. We found that DOX downregulated the expression of glutathione peroxidase 4 (GPX4) and NFS1, and upregulated the expression of acyl-coenzyme A synthetase long-chain family member 4 (ACSL4) expression level, resulting in increased lipid peroxidation and ferroptosis. Additionally, DOX inhibited MFN2 expression and increased DRP1 and FIS1 expression, leading to abnormal mitochondrial structure and function. In contrast, exogenous H2S inhibited DOX-induced ferroptosis by restoring GPX4 and NFS1 expression, and reducing lipid peroxidation in H9C2 cells. This effect was similar to that of the ferroptosis antagonist ferrostatin-1 (Fer-1) in protecting against DOX-induced cardiotoxicity. We further demonstrated that the protective effect of H2S was mediated by the key mitochondrial membrane protein optic atrophy 3 (OPA3), which was downregulated by DOX and restored by exogenous H2S. Overexpression of OPA3 alleviated DOX-induced mitochondrial dysfunction and ferroptosis both in vivo and in vitro. Mechanistically, NFS1 has an inhibitory effect on ferroptosis, and NFS1 deficiency increases the susceptibility of cardiomyocytes to ferroptosis. OPA3 is involved in the regulation of ferroptosis by interacting with NFS1. Post-translationally, DOX promoted OPA3 ubiquitination, while exogenous H2S antagonized OPA3 ubiquitination by promoting OPA3 s-sulfhydration. In summary, our findings suggested that H2S protects against DOX-induced cardiotoxicity by inhibiting ferroptosis via targeting the OPA3-NFS1 axis. This provides a potential therapeutic strategy for the treatment of DOX-induced cardiotoxicity.

Highly-twisted states of light from a high quality factor photonic crystal ring.

Twisted light with orbital angular momentum (OAM) has been extensively studied for applications in quantum and classical communications, microscopy, and optical micromanipulation. Ejecting high angular momentum states of a whispering gallery mode (WGM) microresonator through a grating-assisted mechanism provides a scalable, chip-integrated solution for OAM generation. However, demonstrated OAM microresonators have exhibited a much lower quality factor (Q) than conventional WGM resonators (by >100×), and an understanding of the limits on Q has been lacking. This is crucial given the importance of Q in enhancing light-matter interactions. Moreover, though high-OAM states are often desirable, the limits on what is achievable in a microresonator are not well understood. Here, we provide insight on these two questions, through understanding OAM from the perspective of mode coupling in a photonic crystal ring and linking it to coherent backscattering between counter-propagating WGMs. In addition to demonstrating high-Q (105 to 106), a high estimated upper bound on OAM ejection efficiency (up to 90%), and high-OAM number (up to l = 60), our empirical model is supported by experiments and provides a quantitative explanation for the behavior of Q and the upper bound of OAM ejection efficiency with l. The state-of-the-art performance and understanding of microresonator OAM generation opens opportunities for OAM applications using chip-integrated technologies.

High-performance Kerr microresonator optical parametric oscillator on a silicon chip.

Optical parametric oscillation (OPO) is distinguished by its wavelength access, that is, the ability to flexibly generate coherent light at wavelengths that are dramatically different from the pump laser, and in principle bounded solely by energy conservation between the input pump field and the output signal/idler fields. As society adopts advanced tools in quantum information science, metrology, and sensing, microchip OPO may provide an important path for accessing relevant wavelengths. However, a practical source of coherent light should additionally have high conversion efficiency and high output power. Here, we demonstrate a silicon photonics OPO device with unprecedented performance. Our OPO device, based on the third-order (χ(3)) nonlinearity in a silicon nitride microresonator, produces output signal and idler fields widely separated from each other in frequency ( > 150 THz), and exhibits a pump-to-idler conversion efficiency up to 29 % with a corresponding output idler power of > 18 mW on-chip. This performance is achieved by suppressing competitive processes and by strongly overcoupling the output light. This methodology can be readily applied to existing silicon photonics platforms with heterogeneously-integrated pump lasers, enabling flexible coherent light generation across a broad range of wavelengths with high output power and efficiency.

ELF4 is a critical component of a miRNA-transcription factor network and is a bridge regulator of glioblastoma receptor signaling and lipid dynamics.

BACKGROUND: The loss of neurogenic tumor suppressor microRNAs miR-124, miR-128, and miR-137 is associated with glioblastoma's undifferentiated state. Most of their impact comes via the repression of a network of oncogenic transcription factors. We conducted a high-throughput functional siRNA screen in glioblastoma cells and identify E74 like ETS transcription factor 4 (ELF4) as the leading contributor to oncogenic phenotypes. METHODS: In vitro and in vivo assays were used to assess ELF4 impact on cancer phenotypes. We characterized ELF4's mechanism of action via genomic and lipidomic analyses. A MAPK reporter assay verified ELF4's impact on MAPK signaling, and qRT-PCR and western blotting were used to corroborate ELF4 regulatory role on most relevant target genes. RESULTS: ELF4 knockdown resulted in significant proliferation delay and apoptosis in GBM cells and long-term growth delay and morphological changes in glioma stem cells (GSCs). Transcriptomic analyses revealed that ELF4 controls two interlinked pathways: 1) Receptor tyrosine kinase signaling and 2) Lipid dynamics. ELF4 modulation directly affected receptor tyrosine kinase (RTK) signaling, as mitogen-activated protein kinase (MAPK) activity was dependent upon ELF4 levels. Furthermore, shotgun lipidomics revealed that ELF4 depletion disrupted several phospholipid classes, highlighting ELF4's importance in lipid homeostasis. CONCLUSIONS: We found that ELF4 is critical for the GBM cell identity by controlling genes of two dependent pathways: RTK signaling (SRC, PTK2B, and TNK2) and lipid dynamics (LRP1, APOE, ABCA7, PLA2G6, and PITPNM2). Our data suggest that targeting these two pathways simultaneously may be therapeutically beneficial to GBM patients.

Fourier Synthesis Dispersion Engineering of Photonic Crystal Microrings for Broadband Frequency Combs.

Dispersion engineering of microring resonators is crucial for optical frequency comb applications, to achieve targeted bandwidths and powers of individual comb teeth. However, conventional microrings only present two geometric degrees of freedom - width and thickness - which limits the degree to which dispersion can be controlled. We present a technique where we tune individual resonance frequencies for arbitrary dispersion tailoring. Using a photonic crystal microring resonator that induces coupling to both directions of propagation within the ring, we investigate an intuitive design based on Fourier synthesis. Here, the desired photonic crystal spatial profile is obtained through a Fourier relationship with the targeted modal frequency shifts, where each modal shift is determined based on the corresponding effective index modulation of the ring. Experimentally, we demonstrate several distinct dispersion profiles over dozens of modes in transverse magnetic polarization. In contrast, we find that the transverse electric polarization requires a more advanced model that accounts for the discontinuity of the field at the modulated interface. Finally, we present simulations showing arbitrary frequency comb spectral envelope tailoring using our Frequency synthesis approach.

Fractional Optical Angular Momentum and Multi-Defect-Mediated Mode Renormalization and Orientation Control in Photonic Crystal Microring Resonators.

Whispering gallery modes (WGMs) in circularly symmetric optical microresonators exhibit integer quantized angular momentum numbers due to the boundary condition imposed by the geometry. Here, we show that incorporating a photonic crystal pattern in an integrated microring can result in WGMs with fractional optical angular momentum. By choosing the photonic crystal periodicity to open a photonic band gap with a band-edge momentum lying between that of two WGMs of the unperturbed ring, we observe hybridized WGMs with half-integer quantized angular momentum numbers (m∈Z+1/2). Moreover, we show that these modes with fractional angular momenta exhibit high optical quality factors with good cavity-waveguide coupling and an order of magnitude reduced group velocity. Additionally, by introducing multiple artificial defects, multiple modes can be localized to small volumes within the ring, while the relative orientation of the delocalized band-edge states can be well controlled. Our Letter unveils the renormalization of WGMs by the photonic crystal, demonstrating novel fractional angular momentum states and nontrivial multimode orientation control arising from continuous rotational symmetry breaking. The findings are expected to be useful for sensing and metrology, nonlinear optics, and cavity quantum electrodynamics.

Prenatal hypothyroidism diminished exogenous NO-mediated diastolic effects in fetal rat thoracic aorta smooth muscle via increased oxidative stress.

Maternal hypothyroidism is an important problem of modern healthcare and is reported to increase the risk of cardiovascular diseases in the offspring later in life. However, it is unclear whether hypothyroidism during pregnancy causes vascular damage in the fetal period. We established the prenatal hypothyroidism rat model and collected the fetuses at the 21th day of gestation (GD21). Thyroid hormone concentrations in maternal and offspring blood serum were assessed by enzyme-linked immunosorbent assay (ELISA). The thoracic aortas of the fetuses were isolated for microvessel functional testing and histochemical stainings. qPCR and Western blot were performed to access mRNA and protein expression. We found that the concentrations of thyroid hormones in the serum of pregnant rats and fetuses were significantly suppressed at GD21. The responses of the fetal thoracic aortas to SNP were significantly attenuated in the PTU group. However, no statistical difference was found between the two groups when treated with either inhibitor (ODQ) or activator (BAY58-2667) of sGC. The production of O2-• in the arterial wall was significantly increased in hypothyroid fetuses. Moreover, the level of NADPH oxidase (NOX) was increased, while superoxide dismutase 2 (SOD2) was down-regulated in the PTU group, ultimately contributing to the increased production of superoxide. Additionally, decreased SNP-mediated vasodilation found in fetal vessels was improved by either NOX inhibitor (Apocynin) or SOD mimic (Tempol). These results indicate that increased oxidative stress is probably the cause of the diminished diastolic effect of exogenous NO in the thoracic artery of prenatal hypothyroidism exposed fetuses.

Kerr optical parametric oscillation in a photonic crystal microring for accessing the infrared.

Continuous wave optical parametric oscillation (OPO) provides a flexible approach for accessing mid-infrared wavelengths between 2 µm and 5 µm, but operation at these wavelengths has not yet been integrated into silicon nanophotonics. Typically, a Kerr OPO uses a single transverse mode family for pump, signal, and idler modes, and relies on a delicate balance to achieve normal (but close-to-zero) dispersion near the pump and the requisite higher-order dispersion needed for phase- and frequency-matching. Within integrated photonics platforms, this approach results in two major problems. First, the dispersion is very sensitive to geometry, so that small fabrication errors can have a large impact. Second, the device is susceptible to competing nonlinear processes near the pump. In this Letter, we propose a flexible solution to infrared OPO that addresses these two problems by using a silicon nitride photonic crystal microring (PhCR). The frequency shifts created by the PhCR bandgap enable OPO that would otherwise be forbidden. We report an intrinsic optical quality factor up to (1.2 ± 0.1)×106 in the 2-µm band, and use a PhC ring to demonstrated an OPO with a threshold dropped power in the cavity of (90 ± 20) mW, with the pump wavelength at 1998 nm, and the signal and idler wavelengths at 1937 nm and 2063 nm, respectively. We further discuss how to extend the OPO spectral coverage in the mid-infrared. These results establish the PhCR OPO as a promising route for integrated laser sources in the infrared.

Disruption of Circadian Rhythms by Shift Work Exacerbates Reperfusion Injury in Myocardial Infarction.

BACKGROUND: Shift work is associated with increased risk of acute myocardial infarction (AMI) and worsened prognosis. However, the mechanisms linking shift work and worsened prognosis in AMI remain unclear. OBJECTIVES: This study sought to investigate the impact of shift work on reperfusion injury, a major determinant of clinical outcomes in AMI. METHODS: Study patient data were obtained from the database of the EARLY-MYO-CMR (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI) registry, which was a prospective, multicenter registry of patients with ST-segment elevation myocardial infarction (STEMI) undergoing cardiac magnetic resonance (CMR) imaging after reperfusion therapy. The primary endpoint was CMR-defined post-reperfusion infarct size. A secondary clinical endpoint was the composite of major adverse cardiac events (MACE) during follow-up. Potential mechanisms were explored with the use of preclinical animal AMI models. RESULTS: Of 706 patients enrolled in the EARLY-MYO-CMR registry, 412 patients with STEMI were ultimately included. Shift work was associated with increased CMR-defined infarct size (ß = 5.94%; 95% CI: 2.94-8.94; P < 0.0001). During a median follow-up of 5.0 years, shift work was associated with increased risks of MACE (adjusted HR: 1.92; 95% CI: 1.12-3.29; P = 0.017). Consistent with clinical findings, shift work simulation in mice and sheep significantly augmented reperfusion injury in AMI. Mechanism studies identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that played a crucial role in mediating the detrimental effects of shift work on myocardial injury. CONCLUSIONS: The current study provided novel findings that shift work increases myocardial infarction reperfusion injury. It identified a novel nuclear receptor subfamily 1 group D member 1/cardiotrophin-like cytokine factor 1 axis in the heart that might play a crucial role in mediating this process. (Early Assessment of Myocardial Tissue Characteristics by CMR in STEMI [EARLY-MYO-CMR] registry; NCT03768453).

Metabolomics-based phenotypic screens for evaluation of drug synergy via direct-infusion mass spectrometry.

Drugs used in combination can synergize to increase efficacy, decrease toxicity, and prevent drug resistance. While conventional high-throughput screens that rely on univariate data are incredibly valuable to identify promising drug candidates, phenotypic screening methodologies could be beneficial to provide deep insight into the molecular response of drug combination with a likelihood of improved clinical outcomes. We developed a high-content metabolomics drug screening platform using stable isotope-tracer direct-infusion mass spectrometry that informs an algorithm to determine synergy from multivariate phenomics data. Using a cancer drug library, we validated the drug screening, integrating isotope-enriched metabolomics data and computational data mining, on a panel of prostate cell lines and verified the synergy between CB-839 and docetaxel both in vitro (three-dimensional model) and in vivo. The proposed unbiased metabolomics screening platform can be used to rapidly generate phenotype-informed datasets and quantify synergy for combinatorial drug discovery.

Disruption of dNTP homeostasis by ribonucleotide reductase hyperactivation overcomes AML differentiation blockade.

Differentiation blockade is a hallmark of acute myeloid leukemia (AML). A strategy to overcome such a blockade is a promising approach against the disease. The lack of understanding of the underlying mechanisms hampers development of such strategies. Dysregulated ribonucleotide reductase (RNR) is considered a druggable target in proliferative cancers susceptible to deoxynucleoside triphosphate (dNTP) depletion. Herein, we report an unanticipated discovery that hyperactivating RNR enables differentiation and decreases leukemia cell growth. We integrate pharmacogenomics and metabolomics analyses to identify that pharmacologically (eg, nelarabine) or genetically upregulating RNR subunit M2 (RRM2) creates a dNTP pool imbalance and overcomes differentiation arrest. Moreover, R-loop-mediated DNA replication stress signaling is responsible for RRM2 activation by nelarabine treatment. Further aggravating dNTP imbalance by depleting the dNTP hydrolase SAM domain and HD domain-containing protein 1 (SAMHD1) enhances ablation of leukemia stem cells by RRM2 hyperactivation. Mechanistically, excessive activation of extracellular signal-regulated kinase (ERK) signaling downstream of the imbalance contributes to cellular outcomes of RNR hyperactivation. A CRISPR screen identifies a synthetic lethal interaction between loss of DUSP6, an ERK-negative regulator, and nelarabine treatment. These data demonstrate that dNTP homeostasis governs leukemia maintenance, and a combination of DUSP inhibition and nelarabine represents a therapeutic strategy.

Nutritional programming by maternal diet alters offspring lipid metabolism in a marine teleost.

Nutritional programming - the association between the early nutritional environment and long-term consequences for an animal - is an emerging area of research in fish biology. Previous studies reported correlations between maternal provisioning of essential fatty acids to eggs and the whole-body fatty acid composition of larvae reared under uniform conditions for red drum, Sciaenops ocellatus. This study aimed to further investigate the nutritional stimulus and the consequences of nutritional programming by feeding adult red drum several distinct diets and rearing larvae under uniform conditions until 21 days post-hatching when larval lipid and fatty acid compositions were assessed. Different maternal diets produced eggs with distinctive lipid and fatty acid compositions, and despite receiving the same larval diet for almost 3 weeks, larvae showed differences in total fatty acid accumulation and in retention of highly unsaturated fatty acids (HUFA). Specifically, larvae reared from a maternal diet of shrimp generally showed elevated levels of fatty acids in the initial steps of the n-3 and n-6 HUFA biosynthetic pathways and reduced levels of fatty acid products of the same pathways, especially in triglyceride. Furthermore, the variations in larval fatty acid accumulation induced by maternal diet varied among females. Lipid metabolism altered by parental diet may have consequences for larval physiological processes and behavioral performance, which may ultimately influence larval survival.

Circadian nuclear receptor Rev-erbα is expressed by platelets and potentiates platelet activation and thrombus formation.

AIMS: Adverse cardiovascular events have day/night patterns with peaks in the morning, potentially related to endogenous circadian clock control of platelet activation. Circadian nuclear receptor Rev-erbα is an essential and negative component of the circadian clock. To date, the expression profile and biological function of Rev-erbα in platelets have never been reported. METHODS AND RESULTS: Here, we report the presence and functions of circadian nuclear receptor Rev-erbα in human and mouse platelets. Both human and mouse platelet Rev-erbα showed a circadian rhythm that positively correlated with platelet aggregation. Global Rev-erbα knockout and platelet-specific Rev-erbα knockout mice exhibited defective in haemostasis as assessed by prolonged tail-bleeding times. Rev-erbα deletion also reduced ferric chloride-induced carotid arterial occlusive thrombosis, prevented collagen/epinephrine-induced pulmonary thromboembolism, and protected against microvascular microthrombi obstruction and infarct expansion in an acute myocardial infarction model. In vitro thrombus formation assessed by CD41-labelled platelet fluorescence intensity was significantly reduced in Rev-erbα knockout mouse blood. Platelets from Rev-erbα knockout mice exhibited impaired agonist-induced aggregation responses, integrin αIIbß3 activation, and α-granule release. Consistently, pharmacological inhibition of Rev-erbα by specific antagonists decreased platelet activation markers in both mouse and human platelets. Mechanistically, mass spectrometry and co-immunoprecipitation analyses revealed that Rev-erbα potentiated platelet activation via oligophrenin-1-mediated RhoA/ERM (ezrin/radixin/moesin) pathway. CONCLUSION: We provided the first evidence that circadian protein Rev-erbα is functionally expressed in platelets and potentiates platelet activation and thrombus formation. Rev-erbα may serve as a novel therapeutic target for managing thrombosis-based cardiovascular disease.

The Role of CD147 in Pathological Cardiac Hypertrophy Is Regulated by Glycosylation.

CD147, also known as EMMPRIN or basigin, is a transmembrane glycoprotein receptor that activates matrix metalloproteinases and promotes inflammation. CD147 function is regulated by posttranslational modifications of which glycosylation has attracted the most attention. In this study, we demonstrated that glycosylated CD147 was the dominant form in heart tissue, and its levels were markedly elevated in response to transverse aortic constriction (TAC). Adeno-associated virus 9-mediated, cardiac-specific overexpression of wild-type CD147 in mice significantly promoted pressure overload-induced pathological cardiac remodeling accompanied by augmented oxidative stress and ferroptosis. By contrast, mutations of CD147 glycosylation sites notably weakened these detrimental effects of CD147. Mechanistically, CD147 exacerbated TAC-induced pathological cardiac remodeling via direct binding with the adaptor molecule TRAF2 and subsequent activation of TAK1 signalling, which was dependent on glycosylation of CD147. Collectively, our findings provide the first evidence that CD147 promoted pathological cardiac remodeling and dysfunction in a glycosylation-dependent manner through binding the adaptor protein TRAF2 and activating the downstream TRAF2-TAK1 signalling pathway. Thus, glycosylation of CD147 may be a potent interventional target for heart failure treatment.

Efficient chip-based optical parametric oscillators from 590 nm to 1150 nm.

Optical parametric oscillators are widely used to generate coherent light at frequencies not accessible by conventional laser gain. However, chip-based parametric oscillators operating in the visible spectrum have suffered from pump-to-signal conversion efficiencies typically less than 0.1 %. Here, we demonstrate efficient optical parametric oscillators based on silicon nitride photonics that address frequencies between 260 THz (1150 nm) and 510 THz (590 nm). Pumping silicon nitride microrings near 385 THz (780 nm) yields monochromatic signal and idler waves with unprecedented output powers in this wavelength range. We estimate on-chip output powers (separately for the signal and idler) between 1 mW and 5 mW and conversion efficiencies reaching ≈15 %. Underlying this improved performance is our development of pulley waveguides for broadband near-critical coupling, which exploits a fundamental connection between the waveguide-resonator coupling rate and conversion efficiency. Finally, we find that mode competition reduces conversion efficiency at high pump powers, thereby constraining the maximum realizable output power. Our work proves that optical parametric oscillators built with integrated photonics can produce useful amounts of visible laser light with high efficiency.

Conversion Efficiency in Kerr-Microresonator Optical Parametric Oscillators: From Three Modes to Many Modes.

Optical parametric oscillation in a Kerr nonlinear microresonator can generate coherent laser light with frequencies that are widely separated from the pump frequency, allowing, for example, visible light to be generated using a near-infrared pump. To be practically useful, the pump-to-signal conversion efficiency must be far higher than what has been demonstrated in microresonator-based oscillators with widely-separated output frequencies. To address this challenge, here we theoretically and numerically study parametric oscillations in Kerr nonlinear microresonators, revealing an intricate solution space that arises from an interplay of nonlinear processes. As a start, we use a three-mode approximation to derive an efficiency-maximizing relation between pump power and frequency mismatch. However, realistic devices, such as integrated microring resonators, support far more than three modes. Hence, a more accurate model that includes the entire modal landscape is necessary to determine potential inefficiencies arising from unwanted competing nonlinear processes. To this end, we numerically simulate the Lugiato-Lefever Equation that accounts for the full spectrum of nonlinearly-coupled resonator modes. We observe and characterize two nonlinear phenomena linked to parametric oscillations in multi-mode resonators: Mode competition and cross phase modulation-induced modulation instability. Both processes may impact conversion efficiency. Finally, we show how to increase the conversion efficiency to ≈ 25 % by tuning the microresonator loss rates. Our analysis will guide microresonator designs that aim for high conversion efficiency and output power.

Ultra-broadband Kerr microcomb through soliton spectral translation.

Broadband and low-noise microresonator frequency combs (microcombs) are critical for deployable optical frequency measurements. Here we expand the bandwidth of a microcomb far beyond its anomalous dispersion region on both sides of its spectrum through spectral translation mediated by mixing of a dissipative Kerr soliton and a secondary pump. We introduce the concept of synthetic dispersion to qualitatively capture the system's key physical behavior, in which the second pump enables spectral translation through four-wave mixing Bragg scattering. Experimentally, we pump a silicon nitride microring at 1063 nm and 1557 nm to enable soliton spectral translation, resulting in a total bandwidth of 1.6 octaves (137-407 THz). We examine the comb's low-noise characteristics, through heterodyne beat note measurements across its spectrum, measurements of the comb tooth spacing in its primary and spectrally translated portions, and their relative noise. These ultra-broadband microcombs provide new opportunities for optical frequency synthesis, optical atomic clocks, and reaching previously unattainable wavelengths.