Photonic chip-based low-noise microwave oscillator.

Numerous modern technologies are reliant on the low-phase noise and exquisite timing stability of microwave signals. Substantial progress has been made in the field of microwave photonics, whereby low-noise microwave signals are generated by the down-conversion of ultrastable optical references using a frequency comb1-3. Such systems, however, are constructed with bulk or fibre optics and are difficult to further reduce in size and power consumption. In this work we address this challenge by leveraging advances in integrated photonics to demonstrate low-noise microwave generation via two-point optical frequency division4,5. Narrow-linewidth self-injection-locked integrated lasers6,7 are stabilized to a miniature Fabry-Pérot cavity8, and the frequency gap between the lasers is divided with an efficient dark soliton frequency comb9. The stabilized output of the microcomb is photodetected to produce a microwave signal at 20 GHz with phase noise of -96 dBc Hz-1 at 100 Hz offset frequency that decreases to -135 dBc Hz-1 at 10 kHz offset-values that are unprecedented for an integrated photonic system. All photonic components can be heterogeneously integrated on a single chip, providing a significant advance for the application of photonics to high-precision navigation, communication and timing systems.

3D integration enables ultralow-noise isolator-free lasers in silicon photonics.

Photonic integrated circuits are widely used in applications such as telecommunications and data-centre interconnects1-5. However, in optical systems such as microwave synthesizers6, optical gyroscopes7 and atomic clocks8, photonic integrated circuits are still considered inferior solutions despite their advantages in size, weight, power consumption and cost. Such high-precision and highly coherent applications favour ultralow-noise laser sources to be integrated with other photonic components in a compact and robustly aligned format-that is, on a single chip-for photonic integrated circuits to replace bulk optics and fibres. There are two major issues preventing the realization of such envisioned photonic integrated circuits: the high phase noise of semiconductor lasers and the difficulty of integrating optical isolators directly on-chip. Here we challenge this convention by leveraging three-dimensional integration that results in ultralow-noise lasers with isolator-free operation for silicon photonics. Through multiple monolithic and heterogeneous processing sequences, direct on-chip integration of III-V gain medium and ultralow-loss silicon nitride waveguides with optical loss around 0.5 decibels per metre are demonstrated. Consequently, the demonstrated photonic integrated circuit enters a regime that gives rise to ultralow-noise lasers and microwave synthesizers without the need for optical isolators, owing to the ultrahigh-quality-factor cavity. Such photonic integrated circuits also offer superior scalability for complex functionalities and volume production, as well as improved stability and reliability over time. The three-dimensional integration on ultralow-loss photonic integrated circuits thus marks a critical step towards complex systems and networks on silicon.

Integrated turnkey soliton microcombs.

Optical frequency combs have a wide range of applications in science and technology1. An important development for miniature and integrated comb systems is the formation of dissipative Kerr solitons in coherently pumped high-quality-factor optical microresonators2-9. Such soliton microcombs10 have been applied to spectroscopy11-13, the search for exoplanets14,15, optical frequency synthesis16, time keeping17 and other areas10. In addition, the recent integration of microresonators with lasers has revealed the viability of fully chip-based soliton microcombs18,19. 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.

Coprocessed heterogeneous near-infrared lasers on thin-film lithium niobate.

Thin-film lithium niobate (TFLN) is an attractive platform for photonic applications on account of its wide bandgap, its large electro-optic coefficient, and its large nonlinearity. Since these characteristics are used in systems that require a coherent light source, size, weight, power, and cost can be reduced and reliability enhanced by combining TFLN processing and heterogeneous laser fabrication. Here, we report the fabrication of laser devices on a TFLN wafer and also the coprocessing of five different GaAs-based III-V epitaxial structures, including InGaAs quantum wells and InAs quantum dots. Lasing is observed at wavelengths near 930, 1030, and 1180 nm, which, if frequency-doubled using TFLN, would produce blue, green, and orange visible light. A single-sided power over 25 mW is measured with an integrating sphere.

IRF11 synergizes with STAT1 and STAT2 to promote type I IFN production.

Interferon regulatory factor 11 (IRF11), a fish specific member of IRF family, is a transcription factor known for its positive role in teleost antiviral defense by regulating IFN expression. Despite its recognized function, the precise mechanism of IRF11 in type I IFNs production remains largely unknown. In this study, we identified IRF11 in Japanese eel, Anguilla japonica, (AjIRF11) and determined its involvement in the later phase of fish IFN production. Our results demonstrate that IRF11-induced IFN production operates through ISRE binding. Mutations in each ISRE site within the promoter of AjIFN2 or AjIFN4 abolished IRF11-mediated activation of IFN promoters. In addition, the overexpression of AjIRF11 does not significantly impact the activation of AjIFN promoters induced by RLR-related signaling pathway proteins. Furthermore, IRF11-knockdown in ZFLs (zebrafish liver cells) has no effect on the RLRs-induced expression of zebrafish IFN-φ1 and IFN-φ3, indicating that IRF11 is not involved in the RLR-mediated IFN production. However, AjIRF11 can form transcription complexes with AjSTAT1 or AjSTAT2, or form homo- or heterodimers with AjIRF1 to stimulate the transcription of type I IFNs. Overall, it is shown in this study that IRF11 can act synergistically with STAT1 and/or STAT2 for the induction of IFN.

Not exclusively the activity, but the sweet spot: a dehydrogenase point mutation synergistically boosts activity, substrate tolerance, thermal stability and yield.

Catalytic activity is undoubtedly a key focus in enzyme engineering. The complicated reaction conditions hinder some enzymes from industrialization even though they have relatively promising activity. This has occurred to some dehydrogenases. Hydroxysteroid dehydrogenases (HSDHs) specifically catalyze the conversion between hydroxyl and keto groups, and hold immense potential in the synthesis of steroid medicines. We underscored the importance of 7α-HSDH activity, and analyzed the overall robustness and underlying mechanisms. Employing a high-throughput screening approach, we comprehensively assessed a mutation library, and obtained a mutant with enhanced enzymatic activity and overall stability/tolerance. The superior mutant (I201M) was identified to harbor improved thermal stability, substrate susceptibility, cofactor affinity, as well as the yield. This mutant displayed a 1.88-fold increase in enzymatic activity, a 1.37-fold improvement in substrate tolerance, and a 1.45-fold increase in thermal stability when compared with the wild type (WT) enzyme. The I201M mutant showed a 2.25-fold increase in the kcat/KM ratio (indicative of a stronger binding affinity for the cofactor). This mutant did not exhibit the highest enzyme activity compared with all the tested mutants, but these improved characteristics contributed synergistically to the highest yield. When a substrate at 100 mM was present, the 24 h yield by I201M reached 89.7%, significantly higher than the 61.2% yield elicited by the WT enzyme. This is the first report revealing enhancement of the catalytic efficiency, cofactor affinity, substrate tolerance, and thermal stability of NAD(H)-dependent 7α-HSDH through a single-point mutation. The mutated enzyme reached the highest enzymatic activity of 7α-HSDH ever reported. High enzymatic activity is undoubtedly crucial for enabling the industrialization of an enzyme. Our findings demonstrated that, when compared with other mutants boasting even higher enzymatic activity, mutants with excellent overall robustness were superior for industrial applications. This principle was exemplified by highly active enzymes such as 7α-HSDH.

Arenarialins A-F, Anti-inflammatory Meroterpenoids with Rearranged Skeletons from the Marine Sponge Dysidea arenaria.

Six new sesquiterpene quinone/hydroquinone meroterpenoids, arenarialins A-F (1-6), were isolated from the marine sponge Dysidea arenaria collected from the South China Sea. Their chemical structures and absolute configurations were determined by HRMS and NMR data analyses coupled with DP4+ and ECD calculations. Arenarialin A (1) features an unprecedented tetracyclic 6/6/5/6 carbon skeleton, whereas arenarialins B-D (2-4) possess two rare secomeroterpene scaffolds. Arenarialins A-F showed inhibitory activity on the production of inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 macrophages with arenarialin D regulating the NF-κB/MAPK signaling pathway.

Geochemical fractionation and potential release behaviour of heavy metals in lead‒zinc smelting soils.

The lack of understanding of heavy metal speciation and solubility control mechanisms in smelting soils limits the effective pollution control. In this study smelting soils were investigated by an advanced mineralogical analysis (AMICS), leaching tests and thermodynamic modelling. The aims were to identify the partitioning and release behaviour of Pb, Zn, Cd and As. The integration of multiple techniques was necessary and displayed coherent results. In addition to the residual fraction, Pb and Zn were predominantly associated with reducible fractions, and As primarily existed as the crystalline iron oxide-bound fractions. AMICS quantitative analysis further confirmed that Fe oxyhydroxides were the common dominant phase for As, Cd, Pb and Zn. In addition, a metal arsenate (paulmooreite) was an important mineral host for Pb and As. The pH-stat leaching indicted that the release of Pb, Zn and Cd increased towards low pH values while release of As increased towards high pH values. The separate leaching schemes were associated with the geochemical behaviour under the control of minerals and were confirmed by thermodynamic modelling. PHREEQC calculations suggested that the formation of arsenate minerals (schultenite, mimetite and koritnigite) and the binding to Fe oxyhydroxides synchronously controlled the release of Pb, Zn, Cd and As. Our results emphasized the governing role of Fe oxyhydroxides and secondary insoluble minerals in natural attenuation of heavy metals, which provides a novelty strategy for the stabilization of multi-metals in smelting sites.

AlGaAs soliton microcombs at room temperature.

Soliton mode locking in high-Q microcavities provides a way to integrate frequency comb systems. Among material platforms, AlGaAs has one of the largest optical nonlinearity coefficients, and is advantageous for low-pump-threshold comb generation. However, AlGaAs also has a very large thermo-optic effect that destabilizes soliton formation, and femtosecond soliton pulse generation has only been possible at cryogenic temperatures. Here, soliton generation in AlGaAs microresonators at room temperature is reported for the first time, to the best of our knowledge. The destabilizing thermo-optic effect is shown to instead provide stability in the high-repetition-rate soliton regime (corresponding to a large, normalized second-order dispersion parameter D2/κ). Single soliton and soliton crystal generation with sub-milliwatt optical pump power are demonstrated. The generality of this approach is verified in a high-Q silica microtoroid where manual tuning into the soliton regime is demonstrated. Besides the advantages of large optical nonlinearity, these AlGaAs devices are natural candidates for integration with semiconductor pump lasers. Furthermore, the approach should generalize to any high-Q resonator material platform.

Aspergetherins A-D, New Chlorinated Biphenyls with anti-MRSA Activity from the Marine Sponge Symbiotic Fungus Aspergillus terreus 164018.

Aspergetherins A-D (1-4), four new chlorinated biphenyls, were isolated from the rice fermentation of a marine sponge symbiotic fungus Aspergillus terreus 164018, along with seven known biphenyl derivatives (5-11). The structures of four new compounds were determined by a comprehensive analysis of the spectroscopic data, including HR-ESI-MS and 2D NMR data. All 11 isolates were evaluated for their anti-bacterial activity against two strains of methicillin-resistant Staphylococcus aureus (MRSA). Among them, compounds 1, 3, 8 and 10 showed anti-MRSA activity with MIC values of 1.0-128 µg/mL. Preliminary structure-activity relationship analysis unveiled that both chlorinated substitution and esterification of 2-carboxylic acid could impact the antibacterial activity of biphenyls.

Structure- and Data-Driven Protein Engineering of Transaminases for Improving Activity and Stereoselectivity.

Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. Machine learning provides a promising approach for protein engineering, but activity prediction models for ATAs remain elusive due to the difficulty of obtaining high-quality training data. Thus, we first created variants of the ATA from Ruegeria sp. (3FCR) with improved catalytic activity (up to 2000-fold) as well as reversed stereoselectivity by a structure-dependent rational design and collected a high-quality dataset in this process. Subsequently, we designed a modified one-hot code to describe steric and electronic effects of substrates and residues within ATAs. Finally, we built a gradient boosting regression tree predictor for catalytic activity and stereoselectivity, and applied this for the data-driven design of optimized variants which then showed improved activity (up to 3-fold compared to the best variants previously identified). We also demonstrated that the model can predict the catalytic activity for ATA variants of another origin by retraining with a small set of additional data.

Electrochemical Quantitation of the Glycosylation Level of Serum Neurofilament Light Chain for the Diagnosis of Neurodegeneration: An Interface-Solution Dual-Path Amplification Strategy.

Serum neurofilament light chain (NFL), a potential general biomarker for neurodegenerative diseases, is not specific enough to differentiate neurodegenerative diseases from other brain diseases such as cerebral thrombosis (CT). According to the importance of glycosylation in neurodegenerative pathogenesis, the NFL glycosylation level (oNFL/tNFL), defined as the ratio of glycosylated NFL (oNFL) to total NFL (tNFL), may be a more effective index. The major challenge in serum oNFL/tNFL detection is the ultra-low abundance of both NFL forms. In this paper, we achieved a convenient one-step electrochemical quantitation of oNFL/tNFL based on an interface-solution dual-path amplification strategy. Two amplified electrochemical signals─the reduction of Cu2+ from adsorbed porous nanoparticles on the sensor interface and the reduction of O2 from horseradish peroxidase-catalyzed H2O2 disproportionation in solution─were adopted to quantify tNFL and oNFL, respectively. The electrochemical sensor displayed good sensitivity, selectivity, and reproducibility. The dynamic range is 1-25 pg mL-1 for tNFL and 0.25-25 pg mL-1 for oNFL, respectively. By analyzing the clinic serum samples, for the first time, our work provided the abundance of oNFL in human serum and revealed that the oNFL/tNFL is effective not only in differentiating three kinds of brain damage patients from healthy people but also in differentiating neurodegeneration from non-neurodegeneration CT patients. As a general biomarker, the oNFL/tNFL is more specific than NFL, which is hoped to be a new and valid indicator for the diagnosis, progression, prediction, and treatment evaluation of neurodegenerative diseases.

Even sampling photonic-integrated interferometric array for synthetic aperture imaging.

To improve the effectiveness of spatial spectrum sampling for the photonic-integrated interferometric imaging, an array forming scheme is proposed with evenly distributed interferometric baselines, which is referred to as the even sampling photonic-integrated interferometric array (ESPIA). The subaperture array of ESPIA is configured as equi-spaced concentric rings. The subaperture beams are coupled and transmitted to the photonic integrated circuit through fiber optic channels and paired into baselines by the interferometric beam combination. The characteristics of ESPIA are analyzed with the discrete modulation transfer function (D-MTF) and multi-resolution mutual information (MR-MI). The simulation results show that it can realize the even sampling coverage of spatial spectrum effectively. With the same scale of synthetic aperture and subaperture array, it can also improve the capabilities of information acquisition for the interferometric array.

Wafer-scale high aspect-ratio sapphire periodic nanostructures fabricated by self-modulated femtosecond laser hybrid technology.

Sapphire nanostructures with a high aspect-ratio have broad applications in photoelectronic devices, which are difficult to be fabricated due to the properties of high transparency and hardness, remarkable thermal and chemical stability. Although the phenomenon of laser-induced periodic surface structures (LIPSS) provides an extraordinary idea for surface nanotexturing, it suffers from the limitation of the small depth of the nanostructures. Here, a high-efficiency self-modulated femtosecond laser hybrid technology was proposed to fabricate nanostructures with high aspect-ratios on the sapphire surface, which was combined backside laser modification and subsequent wet etching. Due to the refractive index mismatch, the focal length of the laser could be elongated when focused inside sapphire. Thus, periodic nanostructures with high-quality aspect ratios of more than 55 were prepared on the sapphire surface by using this hybrid fabrication method. As a proof-of-concept, wafer-scale (∼2 inches) periodic nanostripes with a high aspect-ratio were realized on a sapphire surface, which possesses unique diffractive properties compared to typical shallow gratings. The results indicate that the self-modulated femtosecond laser hybrid technology is an efficient and versatile technique for producing high aspect-ratio nanostructures on hard and transparent materials, which would propel the potential applications in optics and surface engineering, sensing, etc.

Smart Diffraction Gratings Based on the Shape Memory Effect.

The shape memory effect is the capability of a structure or a material that can be deformed into a certain temporary shape under external stimulus, and the shape will be fixed without the stimulus. The recovery process can be triggered by the same stimulus. The intelligent tunable device based on the shape memory effect has a wide range of applications in many fields. In the optical field, smart diffraction gratings can accomplish in situ optical diffractions according to requirements, meeting the high demand in the next generation of smart optical systems. However, it is essential to construct high-precision grating structures based on shape memory materials. Here, a smart diffraction grating based on UV-curable shape memory polymers (SMPs) via two-beam interference is reported, with nano-scale precision, excellent deformability and recovery ability, and adjustable spectroscopic performance. More importantly, based on the shape memory effect, grating structures that surpass the precision of the fabrication system can be obtained. The smart grating exhibits rapid deformation and recovery upon heating and long-term storage capability, which facilitates them to be applied in optics, electronics, and integrated sensing.

Shape memory of a polymer grating surface fabricated by two-beam interference lithography.

Switchable and reversible optical elements have potential applications in self-adaptive optics. Shape-memory polymer devices with adaptive properties could be easily switched under environment or field stimuli. Here, the laser beam interference technique was used to realize the periodic grating structures of the shape-memory polymer, and memory and recovery of the grating structures were performed. A one-dimensional grating structure was fabricated from dual-beam interference lithography of a nanosecond laser and underwent pressure in a condition of 195°C. The vertical height of the grating was reduced, and the diffraction light was weakened. When the sample was cooled down to room temperature, the morphology of the grating could be kept. After raising the ambient temperature of the sample to 120°C, the morphology of the grating was recovered to the original state, which realized the shape-memory function.

New Spiro-Sesquiterpenoids from the Marine Sponge Myrmekioderma sp.

Three new spiro-sesquiterpenoids, myrmekiones A-C (1-3), were isolated from the marine sponge Myrmekioderma sp. collected from the South China Sea. The structures of 1-3 were experimentally illuminated though comprehensive NMR spectra, X-ray diffraction analysis and calculated ECD. These three compounds possessed a special spiro skeleton. Compound 1 was characterized by a chamigrane-type structure, it is the first time to obtain the single-crystal of this type of oil compounds. 2 and 3 were a pair of diastereoisomers that possessed an acorane skeleton. This study expands the chemical diversity of marine origin spiro-metabolites.

Shifting the pH Optima of (R)-Selective Transaminases by Protein Engineering.

Amine transaminases (ATAs) are powerful biocatalysts for the stereoselective synthesis of chiral amines. However, wild-type ATAs usually show pH optima at slightly alkaline values and exhibit low catalytic activity under physiological conditions. For efficient asymmetric synthesis ATAs are commonly used in combination with lactate dehydrogenase (LDH, optimal pH: 7.5) and glucose dehydrogenase (GDH, optimal pH: 7.75) to shift the equilibrium towards the synthesis of the target chiral amine and hence their pH optima should fit to each other. Based on a protein structure alignment, variants of (R)-selective transaminases were rationally designed, produced in E. coli, purified and subjected to biochemical characterization. This resulted in the discovery of the variant E49Q of the ATA from Aspergillus fumigatus, for which the pH optimum was successfully shifted from pH 8.5 to 7.5 and this variant furthermore had a two times higher specific activity than the wild-type protein at pH 7.5. A possible mechanism for this shift of the optimal pH is proposed. Asymmetric synthesis of (R)-1-phenylethylamine from acetophenone in combination with LDH and GDH confirmed that the variant E49Q shows superior performance at pH 7.5 compared to the wild-type enzyme.

Disease Resistance and Molecular Variations in Irradiation Induced Mutants of Two Pea Cultivars.

Induced mutation is useful for improving the disease resistance of various crops. Fusarium wilt and powdery mildew are two important diseases which severely influence pea production worldwide. In this study, we first evaluated Fusarium wilt and powdery mildew resistance of mutants derived from two elite vegetable pea cultivars, Shijiadacaiwan 1 (SJ1) and Chengwan 8 (CW8), respectively. Nine SJ1 and five CW8 M3 mutants showed resistant variations in Fusarium wilt, and the same five CW8 mutants in powdery mildew. These resistant variations were confirmed in M4 and M5 mutants as well. Then, we investigated the genetic variations and relationships of mutant lines using simple sequence repeat (SSR) markers. Among the nine effective SSR markers, the genetic diversity index and polymorphism information content (PIC) values were averaged at 0.55 and 0.46, which revealed considerable genetic variations in the mutants. The phylogenetic tree and population structure analyses divided the M3 mutants into two major groups at 0.62 genetic similarity (K = 2), which clearly separated the mutants of the two cultivars and indicated that a great genetic difference existed between the two mutant populations. Further, the two genetic groups were divided into five subgroups at 0.86 genetic similarity (K = 5) and each subgroup associated with resistant phenotypes of the mutants. Finally, the homologous PsMLO1 cDNA of five CW8 mutants that gained resistance to powdery mildew was amplified and cloned. A 129 bp fragment deletion was found in the PsMLO1 gene, which was in accord with er1-2. The findings provide important information on disease resistant and molecular variations of pea mutants, which is useful for pea production, new cultivar breeding, and the identification of resistance genes.

Directed evolution of an amine transaminase for the synthesis of an Apremilast intermediate via kinetic resolution.

Apremilast is an important active pharmaceutical ingredient that relies on a resolution to produce the key chiral amine intermediate. To provide a new catalytic and enzymatic process for Apremilast, we performed the directed evolution of the amine transaminase fromVibriofluvialis. Six rounds of evolution resulted in the VF-8M-E variant with > 400-fold increase specific activity over the wildtype enzyme. A homology model of VF-8M-E was built and a molecular docking study was performed to explain the increase in activity. The purified VF-8M-E was successfully applied to produce the key chiral amine intermediate in enantiopure form and 49% conversion via a kinetic resolution, representing a new enzymatic access towards Apremilast.