Hyperparametric Oscillation via Bound States in the Continuum.

Optical hyperparametric oscillation based on the third-order nonlinearity is one of the most significant mechanisms to generate coherent electromagnetic radiation and produce quantum states of light. Advances in dispersion-engineered high-Q microresonators allow for generating signal waves far from the pump and decrease the oscillation power threshold to submilliwatt levels. However, the pump-to-signal conversion efficiency and absolute signal power are low, fundamentally limited by parasitic mode competition and attainable cavity intrinsic Q to coupling Q ratio, i.e., Q_{i}/Q_{c}. Here, we use Friedrich-Wintgen bound states in the continuum (BICs) to overcome the physical challenges in an integrated microresonator-waveguide system. As a result, on-chip coherent hyperparametric oscillation is generated in BICs with unprecedented conversion efficiency and absolute signal power. This work not only opens a path to generate high-power and efficient continuous-wave electromagnetic radiation in Kerr nonlinear media but also enhances the understanding of a microresonator-waveguide system-an elementary unit of modern photonics.

Coherent supercontinuum generation in all-normal dispersion Si3N4 waveguides.

Spectral broadening of optical frequency combs with high repetition rate is of significant interest in optical communications, radio-frequency photonics and spectroscopy. Silicon nitride waveguides (Si3N4) in the anomalous dispersion region have shown efficient supercontinuum generation spanning an octave-bandwidth. However, the broadening mechanism in this regime is usually attained with femtosecond pulses in order to maintain the coherence. Supercontinuum generation in the normal dispersion regime is more prone to longer (ps) pulses, but the implementation in normal dispersion silicon nitride waveguides is challenging as it possesses strong requirements in propagation length and losses. Here, we experimentally demonstrate the use of a Si3N4 waveguide to perform coherent spectral broadening using pulses in the picosecond regime with high repetition rate. Moreover, our work explores the formation of optical wave breaking using a higher energy pulse which enables the generation of a coherent octave spanning spectrum. These results offer a new prospect for coherent broadening using long duration pulses and replacing bulky optical components.

Differential phase reconstruction of microcombs.

Measuring microcombs in amplitude and phase provides unique insight into the nonlinear cavity dynamics, but spectral phase measurements are experimentally challenging. Here, we report a linear heterodyne technique assisted by electro-optic downconversion that enables differential phase measurement of such spectra with unprecedented sensitivity (-50 dBm) and bandwidth coverage (>110 nm in the telecommunications range). We validate the technique with a series of measurements, including single-cavity and photonic molecule microcombs.

Frequency-comb-calibrated swept-wavelength interferometry.

Lasers are often used to characterize samples in a non-destructive manner and retrieve sensing information transduced in changes in amplitude and phase. In swept wavelength interferometry, a wavelength-tunable laser is used to measure the complex response (i.e. in amplitude and phase) of an optical sample. This technique leverages continuous advances in rapidly tunable lasers and is widely used for sensing, bioimaging and testing of photonic integrated components. However, the tunable laser requires an additional calibration step because, in practice, it does not tune at a constant rate. In this work, we use a self-referenced frequency comb as an optical ruler to calibrate the laser used in swept-wavelength interferometry and optical frequency domain reflectometry. This allows for realizing high-resolution complex spectroscopy over a bandwidth exceeding 10 THz. We apply the technique to the characterization of low-loss integrated photonic devices and demonstrate that the phase information can disentangle intrinsic from coupling losses in the characterization of high-Q microresonators. We also demonstrate the technique in reflection mode, where it can resolve attenuation and dispersion characteristics in integrated long spiral waveguides.

Prospects on the nano-plastic particles internalization and induction of cellular response in human keratinocytes.

BACKGROUND: Today, cosmetic products are very popular with both men and women to improve their appearance and increase their social acceptability. RESULTS: In this study, nano-sized (30-300 nm) plastic particles were isolated from the commercial face-scrubs and treated on the human keratinocytes. The observed adherence of polyethylene nano-plastics (PENPs), polystyrene NPs (PSNPs), and face-scrubs isolated nano-plastics (NPs) on the keratin layer reveals a significant attachment of NPs from the cosmetics that are applied on the skin for a short duration. This attachment property could facilitate further adherence of protein molecules on NPs and the protein-corona formation. The protein-corona mimics protein aggregates, thereby triggers macropinocytosis, followed by the macropinolysosomal process in the cell. These internalized NPs induced the concentration-dependent cytotoxic, cytostatic and cytoprotective activity in keratinocytes. Both single dose and chronic long-term exposure of lethal and sub-lethal concentrations of NPs resulted in oxidative stress-mediated down-regulation of cell growth and proliferation inhibition. Autophagic structures and premature aging were also observed using an electron microscopy and a senescence marker, respectively in the NPs internalized HaCaT cells incubated in a fresh, NPs-free medium. CONCLUSION: Though 2D culture models have many limitations, it produces significant conceptual advancements. This work provides an insight into the NPs concentration-dependent regulatory, cytoprotective, and cytotoxic effects in HaCaT cells. However, 3D model studies are required to identify the detailed mechanisms of NPs toxicity and cytoprotective events in cells at the molecular level.

Prolonged lipopolysaccharide exposure induces transient immunosuppression in BV2 microglia.

Continuous pre-exposure of immune cells to low level of inflammatory stimuli makes them hyporesponsive to subsequent exposure. This pathophysiological adaptation; known as endotoxin tolerance is a general paradigm behind several disease pathogenesis. Current study deals with this immunosuppression with respect to BV2 microglia. We attempted to investigate their immune response under prolonged endotoxin exposure and monitor the same upon withdrawal of the stimuli. BV2 microglia cells were maintained under continual exposure of lipopolysaccharide (LPS) for weeks with regular passage after 72 hr (prolonged LPS exposed cells [PLECs]). PLECs were found to be immunosuppressed with diminished expression of proinflammatory cytokines (IL6, IL1ß, TNF-α, and iNOS) and production of nitric oxide, as compared to once LPS exposed cells. Upon remaintenance of cells in normal media without LPS exposure (LPS withdrawal cells [LWCs]), the induced immunosuppression reversed and cells started responding to inflammatory stimuli; revealed by significant expression of proinflammatory cytokines. LWCs showed functional similarities to never LPS exposed cells (NLECs) in phagocytosis activity and their response to anti-inflammatory agents like dexamethasone. Despite their immunoresponsiveness, PLECs were inflamed and showed higher autophagy rate than NLECs. Additionally, we investigated the role of inhibitor of apoptotic proteins (IAPs) in PLECs to understand whether IAPs aids in the survival of microglial cells under stress conditions. Our results revealed that cIAP1 and cIAP2 are induced in PLECs which might play a role in retaining the viability. Furthermore, antagonism of IAPs has significantly induced cell death in PLECs suggesting the role of IAPs in microglial survival under stress condition. Conclusively, our data suggest that continuous exposure of BV2 microglia cells to LPS results in transient immunosuppression and indicates the involvement of IAPs in retaining their viability under inflammatory stress.

High-Q Si3N4 microresonators based on a subtractive processing for Kerr nonlinear optics.

Microresonator frequency combs (microcombs) are enabling new applications in frequency synthesis and metrology - from high-speed laser ranging to coherent optical communications. One critical parameter that dictates the performance of the microcomb is the optical quality factor (Q) of the microresonator. Microresonators fabricated in planar structures such as silicon nitride (Si3N4) allow for dispersion engineering and the possibility to monolithically integrate the microcomb with other photonic devices. However, the relatively large refractive index contrast and the tight optical confinement required for dispersion engineering make it challenging to attain Si3N4 microresonators with Qs > 107 using standard subtractive processing methods - i.e. photonic devices are patterned directly on the as-deposited Si3N4 film. In this work, we achieve ultra-smooth Si3N4 microresonators featuring mean intrinsic Qs around 11 million. The cross-section geometry can be precisely engineered in the telecommunications band to achieve either normal or anomalous dispersion, and we demonstrate the generation of mode-locked dark-pulse Kerr combs as well as soliton microcombs. Such high-Qs allow us to generate 100 GHz soliton microcombs, demonstrated here for the first time in Si3N4 microresonators fabricated using a subtractive processing method. These results enhance the possibilities for co-integration of microcombs with high-performance photonic devices, such as narrow-linewidth external-cavity diode lasers, ultra-narrow filters and demultiplexers.

Human inborn errors of long-chain fatty acid oxidation show impaired inflammatory responses to TLR4-ligand LPS.

Stimulation of mammalian cells with inflammatory inducers such as lipopolysaccharide (LPS) leads to alterations in activity of central cellular metabolic pathways. Interestingly, these metabolic changes seem to be important for subsequent release of pro-inflammatory cytokines. This has become particularly clear for enzymes of tricarboxylic acid (TCA) cycle such as succinate dehydrogenase (SDH). LPS leads to inhibition of SDH activity and accumulation of succinate to enhance the LPS-induced formation of IL-1ß. If enzymes involved in beta-oxidation of fatty acids are important for sufficient responses to LPS is currently not clear. Using cells from various patients with inborn long-chain fatty acid oxidation disorders (lcFAOD), we report that disease-causing deleterious variants of Electron Transfer Flavoprotein Dehydrogenase (ETFDH) and of Very Long Chain Acyl-CoA Dehydrogenase (ACADVL), both cause insufficient inflammatory responses to stimulation with LPS. The insufficiencies included reduced TLR4 expression levels, impaired TLR4 signaling, and reduced or absent induction of pro-inflammatory cytokines such as IL-6. The insufficient responses to LPS were reproduced in cells from healthy controls by targeted loss-of-function of either ETFDH or ACADVL, supporting that the deleterious ETFDH and ACADVL variants cause the attenuated responses to LPS. ETFDH and ACADVL encode two distinct enzymes both involved in fatty acid beta-oxidation, and patients with these deficiencies cannot sufficiently metabolize long-chain fatty acids. We report that genes important for beta-oxidation of long-chain fatty acids are also important for inflammatory responses to an acute immunogen trigger like LPS, which may have important implications for understanding infection and other metabolic stress induced disease pathology in lcFAODs.

Octyl itaconate enhances VSVΔ51 oncolytic virotherapy by multitarget inhibition of antiviral and inflammatory pathways.

The presence of heterogeneity in responses to oncolytic virotherapy poses a barrier to clinical effectiveness, as resistance to this treatment can occur through the inhibition of viral spread within the tumor, potentially leading to treatment failures. Here we show that 4-octyl itaconate (4-OI), a chemical derivative of the Krebs cycle-derived metabolite itaconate, enhances oncolytic virotherapy with VSVΔ51 in various models including human and murine resistant cancer cell lines, three-dimensional (3D) patient-derived colon tumoroids and organotypic brain tumor slices. Furthermore, 4-OI in combination with VSVΔ51 improves therapeutic outcomes in a resistant murine colon tumor model. Mechanistically, we find that 4-OI suppresses antiviral immunity in cancer cells through the modification of cysteine residues in MAVS and IKKß independently of the NRF2/KEAP1 axis. We propose that the combination of a metabolite-derived drug with an oncolytic virus agent can greatly improve anticancer therapeutic outcomes by direct interference with the type I IFN and NF-κB-mediated antiviral responses.

Spectral Interferometry with Frequency Combs.

In this review paper, we provide an overview of the state of the art in linear interferometric techniques using laser frequency comb sources. Diverse techniques including Fourier transform spectroscopy, linear spectral interferometry and swept-wavelength interferometry are covered in detail. The unique features brought by laser frequency comb sources are shown, and specific applications highlighted in molecular spectroscopy, optical coherence tomography and the characterization of photonic integrated devices and components. Finally, the possibilities enabled by advances in chip scale swept sources and frequency combs are discussed.

Overcoming the quantum limit of optical amplification in monolithic waveguides.

Optical amplifiers are essential in numerous photonic applications. Parametric amplifiers, relying on a nonlinear material to create amplification, are uniquely promising as they can amplify without generating excess noise. Here, we demonstrate amplification based on the third-order nonlinearity in a single chip while, in addition, reporting a noise figure significantly below the conventional quantum limit when operated in phase-sensitive mode. Our results show the potential of nanophotonics for realizing continuous-wave parametric amplification that can enable applications in optical communications, signal processing, and quantum optics across a wide range of frequencies.

Eukaryotic cell survival mechanisms: Disease relevance and therapeutic intervention.

Cell responds to stress by activating various modes of stress responses which aim for minimal damage to cells and speedy recovery from the insults. However, unresolved stresses exceeding the tolerance limit lead to cell death (apoptosis, autophagy etc.) that helps to get rid of damaged cells and protect cell integrity. Furthermore, aberrant stress responses are the hallmarks of several pathophysiologies (neurodegeneration, metabolic diseases, cancer etc.). The catastrophic remodulation of stress responses is observed in cancer cells in favor of their uncontrolled growth. Whereas pro-survival stress responses redirected to death signaling provokes excessive cell death in neurodegeneration. Clear understanding of such mechanistic link to disease progression is required in order to modulate these processes for new therapeutic targets. The current review explains this with respect to novel drug discoveries and other breakthroughs in therapeutics.