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Natural product libraries with a remarkable range of biological activities play pivotal roles in drug discoveries due to their extraordinary structural complexity and immense diversity. l-Kynurenine (l-Kyn)-based derivatives are privileged pharmacophores that exhibit diverse therapeutic implications in neurological disorders. However, the difficulty in obtaining l-Kyn analogues with different skeletal structures has recently led to a decline in its medicinal research. Herein, we report a two-step, one-pot protocol for diversity-oriented biosynthesis of a collection of previously intractable l-Kyn-like compounds. The success of these challenging transformations mainly depends on unlocking the new catalytic scope of tryptophan 2,3-dioxygenases, followed by rational site-directed mutagenesis to modify the substrate domains further. As a result, 18 kynurenine analogues with diverse molecular scaffolds can be rapidly assembled in a predictable manner with 20-83% isolated yields, which not only fill the voids of the catalytic profile of tryptophan 2,3-dioxygenases with an array of substituent groups (e.g., F, Cl, Br, I, CH3, OCH3, and NO2) but also update the current understanding of its substrate spectrum. Our work highlights the great potential of existing enzymes in addressing long-standing synthetic challenges for facilitating the development or discovery of new drug candidates. Furthermore, our approach enables translating the reaction parameters from Eppendorf tubes to 1 L scale, affording l-4-Cl-Kyn and l-5-Cl-Kyn both on a gram scale with more than 80% isolated yields, and provides a promising alternative to further industrial applications.

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Stratospheric aerosols play an important role in the atmospheric chemical and radiative balance. To detect the stratospheric aerosol layer, a 1064 nm lidar with high resolution and large dynamic range is developed using a superconducting nanowire single-photon detector (SNSPD). Measurements are typically performed at 1064 nm for its sensitivity to aerosol, whereas detectors are limited by low efficiency and high dark count rate (DCR). SNSPDs are characterized by high efficiency in the infrared wavelength domain, as well as low noise and dead time, which can significantly enhance the signal quality. However, it is still challenging to build an SNSPD with both large active area and high count rate. To improve the maximal count rate (MCR) so as to avoid saturation in the near range, a 16-pixel interleaved SNSPD array and a multichannel data acquisition system are developed. As a reference, a synchronous system working at 532 nm is applied. In a continuous comparison experiment, backscatter ratio profiles are retrieved with resolutions of 90 m/3 min, and the 1064 nm system shows better performance, which is sensitive to aerosols and immune to the contamination of the ozone absorption and density of molecule change in the lower stratosphere.

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Coding technology provides new ideas for spatial resolution enhancement of coherent Doppler wind lidar (CDWL). To improve the performance of coding CDWL for ultra-fine-wind field detection, the crosstalk between neighboring laser pulses is analyzed in theory. The strong backscattered signal from aerosols in near field region will interfere with the weak atmospheric signal, making the accuracy of Doppler shift estimation deteriorate seriously. Considering the formation mechanism of crosstalk, a solution based on adaptive field of view (FOV) modulation is proposed to suppress the crosstalk which is validated by numerical simulation and experiment. Dynamic range of the backscatter intensity is controlled from 10 dB to 2 dB within the distance of 50 m to 300 m, thus the crosstalk is accordingly suppressed.

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A high spatial resolution coherent Doppler wind lidar (CDWL) incorporating the differential correlation pair (DCP) technique is proposed and demonstrated. By employing pulse pair with appropriate window functions, the spatial resolution can be enhanced, as the common parts of the correlation pair can be eliminated in the differential data processing. The performance of the new method is validated in the comparison experiment with the CDWLs adopting conventional schemes. Under a given peak power, the DCP technique provides higher wind velocity accuracy compared with a conventional pulsed CDWL where the laser spectral broadening caused by short pulses can be avoided and the carrier-to-noise ratio is improved. At a laser peak power of 250 W, with a spatial and temporal resolution of 3.3 m and 1 s, continuous radial wind profiling over 700 m is realized with a maximum error of 0.1 m/s.

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The coherent Doppler wind lidar (CDL) shows capability in precipitation detection. Retrieval of the raindrop size distribution (DSD) using CDL is still challenging work, as both accurate backscattering cross section at the working wavelength and reflectivity spectrum of raindrop are required. Firstly, the Mie theory and the vectorial complex ray model (VCRM) are applied to calculate backscattering cross section for small spheric raindrops and large oblate raindrops, respectively. Secondly, an iterative deconvolution method is proposed to separate the reflectivity spectrum of raindrop from the lidar power spectrum, which is a superposition of rain and aerosol components. An accompanying aerosol signal model considering the effect of temporal window, from the same height and time, is used to improve the accuracy and robustness of the iteration. In experiment, a co-located micro rain radar (MRR) is used for comparison. Good agreements are obtained despite tremendous differences in wavelength and scattering characteristics. As an example, at 600 m height, the R2 of linear fitting to the mean rain velocity and mean raindrop diameter between CDL and MRR are 0.96 and 0.93, respectively.

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Researches on the atmospheric boundary layer (ABL) need accurate measurements with high temporal and spatial resolutions from a series of different instruments. Here, a method for identifying cloud, precipitation, windshear, and turbulence in the ABL using a single coherent Doppler wind lidar (CDWL) is proposed and demonstrated. Based on deep analysis of the power spectrum of the backscattering signal, multiple lidar products, such as carrier-to-noise (CNR), spectrum width, spectrum skewness, turbulent kinetic energy dissipation rate (TKEDR), and shear intensity are derived for weather identification. Firstly, the cloud is extracted by Haar wavelet covariance transform (HWCT) algorithm based on the CNR after range correction. Secondly, since the spectrum broadening may be due to turbulence, windshear or precipitation, the spectrum skewness is introduced to distinguish the precipitation from two other conditions. Whereas wind velocity is obtained by single peak fitting in clear weather condition, the double-peak fitting is used to retrieve wind and rainfall velocities simultaneously in the precipitation condition. Thirdly, judging from shear intensity and TKEDR, turbulence and windshear are classified. As a double check, the temporal continuity is used. Stable wind variances conditions such as low-level jets are identified as windshear, while arbitrary wind variances conditions are categorized as turbulence. In the field experiment, the method is implemented on a micro-pulse CDWL to provide meteorological services for the 70th anniversary of the China's National Day, in Inner Mongolia, China (43°54'N, 115°58'E). All weather conditions are successfully classified. By comparing lidar results to that of microwave radiometer (MWR), the spectrum skewness is found be more accurate to indicate precipitation than spectrum width or vertical speed. Finally, the parameter relationships and distributions are analyzed statistically in different weather conditions.

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Accurate power spectrum analysis of weak backscattered signals are the primary constraint in long-distance coherent Doppler wind lidar (CDWL) applications. To study the atmospheric boundary layer, an all-fiber CDWL with 300µJ pulse energy is developed. In principle, the coherent detection method can approach the quantum limit sensitivity if the noise in the photodetector output is dominated by the shot noise of the local oscillator. In practice, however, abnormal power spectra occur randomly, resulting in error estimation and low inversion probability. This phenomenon is theoretically analyzed and shown to be due to the leakage of a time-varying DC noise of the balanced detector. Thus, a correction algorithm with accurate noise modeling is proposed and demonstrated. The accuracy of radial velocity, carrier-to-noise ratio (CNR), and spectral width are improved. In wind profiling process, a robust sine-wave fitting algorithm with data quality control is adopted in the velocity-azimuth display (VAD) scanning detection. Finally, in 5-day continuous wind detection, the inversion probability is tremendously enhanced. As an example, it is increased from 8.6% to 52.1% at the height of 4 km.

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OBJECTIVE: MicroRNAs (miRNAs) are associated with hepatocellular carcinoma (HCC) progression and metastasis. However, it is unclear whether they could act as biomarkers for HCC diagnosis and prognosis. METHODS: In this study, the miR-122 and miR-199a expression levels were determined by quantitative real-time PCR (qRT-PCR). The function and molecular mechanism of miR-122 and miR-199a target genes were analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Correlation between miRNA expression levels and the overall survival (OS) of HCC patients was assessed by Kaplan-Meier analysis. RESULTS: Serum miR-122 expression had no significant difference between patients with HCC (HCC patients) and healthy controls (HCs), whereas serum miR-199a expression was significantly lower in HCC patients than the HCs (p<0.05). Receiver-operator characteristic (ROC) curve analysis revealed that miR-199a could be an effective diagnostic biomarker for HCC, which was confirmed by obvious expression polarization patterns of miR-199a target genes. Kaplan-Meier analysis revealed that miR-122 expression level was associated with the OS of HCC patients (p<0.001), suggesting that miR-122 could be a prognostic biomarker for HCC. CONCLUSIONS: Collectively, our results showed that circulating miR-199a and miR-122 levels could serve as novel, non-invasive biomarkers for HCC diagnosis and prognosis, respectively.

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Generally, the pulse duration of a coherent Doppler wind lidar (CDWL) is shortened to minimize the spatial resolution at the sacrifice of carrier-to-noise ratio, since the peak power of a laser source is limited by the stimulated Brillouin scattering or other nonlinear optical phenomena. To solve this problem, an all-fiber CDWL incorporating Golay coding is proposed and demonstrated. Given the peak power of the laser pulse, the Golay coding method can improve the measuring precision by improving the pulse repetition frequency of the outgoing laser. In the experiment, the Golay coding implementation is optimized by normalizing the intensity of every single pulse of the outgoing laser with a closed-loop feedback, achieving a spatial resolution of 6 m and a temporal resolution of 2 s with a maximum detection range of 552 m. The wind profile in line of sight and the result derived from another noncoding CDWL show good agreement.

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An efficient olefination protocol for the oxidative dehydrogenation of phenols and acrylates has been achieved using a palladium catalyst and O2 as the sole oxidant. This reaction exhibits high regio- and stereo-selectivity (E-isomers) with moderate to excellent isolated yields and a wide substrate scope (32 examples) including ethyl vinyl ketone and endofolliculina.

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Atmospheric depolarization ratio and wind velocity are measured simultaneously by a single versatile coherent Doppler lidar (CDL). Backscattering components at parallel and perpendicular polarization states are obtained by using a single balanced detector, adopting time-division multiplexing technique. Thus systematic error induced by the non-uniform response of different detectors in traditional lidars is avoided. The operation mode of the instrument can be switched from polarization CDL to traditional CDL by the user depending on atmospheric conditions and desired performance. As demonstrated, the perpendicular component of the backscattering, usually wasted, not only can be used to retrieve the ADR, but also can be used to improve the carrier to noise ratio in wind detection. In the traditional mode, given a tolerance of 0.5 m/s precision, a detection range of 6 km is achieved by using a 300 ns laser pulse with energy of 100 µJ, where the temporal and spatial resolution of 2 s and 60 m, respectively. Continuous wind detection of the atmospheric boundary layer over 26 hours is presented to demonstrate the robustness and stability of the system. Dynamic evolution and wind structure are recorded.

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AIM: To explore the effects of endothelin-1(ET-1) on hepatic stellate cells (HSCs) DNA uptake, DNA synthesis, collagen synthesis and secretion, inward whole-cell calcium concentration ([Ca2+]i) as well as the blocking effect of verapamil on ET-1-stimulated release of inward calcium (Ca2+) of HSC in vitro. METHODS: Rat hepatic stellate cells (HSCs) were isolated and cultivated. 3H-TdR and 3H-proline incorporation used for testing DNA uptake and synthesis, collagen synthesis and secretion of HSCs cultured in vitro; Fluorescent calcium indicator Fura-2/AM was used to measure [Ca2+]i inward HSCs. RESULTS: ET-1 at the concentration of 5X10(-8) mol/L, caused significant increase both in HSC DNA synthesis (2,247+/-344 cpm, P<0.05) and DNA uptake (P<0.05) when compared with the control group. ET-1 could also increase collagen synthesis (P<0.05 vs control group) and collagen secretion (P<0.05 vs control group). Besides, inward HSC [Ca2+]i reached a peak concentration (422+/-98 mol/L, P<0.001) at 2 min and then went down slowly to 165+/-51 mol/L (P<0.01) at 25 min from resting state (39+/-4 mol/L) after treated with ET-1. Verapamil (5 mol/L) blocked ET-1-activated [Ca2+]i inward HSCs compared with control group (P<0.05). Fura-2/AM loaded HSC was suspended in no Ca2+ buffer containing 1 mol/L EGTA, 5 min later, 10(-8) mol/L of ET-1 was added, [Ca2+]i inward HSCs rose from resting state to peak 399+/-123 mol/L, then began to come down by the time of 20 min. It could also raise [Ca2+]i inward HSCs even without Ca2+ in extracellular fluid, and had a remarkable dose-effect relationship(P<0.05). Meanwhile, verapamil could restrain the action of ET-1(P<0.05). CONCLUSION: Actions of ET-1 on collagen metabolism of HSCs may depend on the transportation of inward whole-cell calcium.

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AIM: To evaluate clinical efficacy of four one-week triple therapies in eradicating Helicobacter pylori infection. METHODS: In this clinical trial, 132 patients with duodenal ulcer and chronic gastritis were randomly divided into four groups, and received treatment with OAC (omeprazole 20 mg + amoxicillin 1 000 mg + clarithromycin 250 mg), OFC (omeprazole 20 mg + furazolidone 100 mg + clarithromycin 250 mg), OFA (omeprazole 20 mg + furazolidone 100 mg + amoxicillin 1 000 mg) and OMC (omeprazole 20 mg + metronidazole 200 mg + clarithromycin 250 mg), respectively. Each drug was taken twice daily for one week. The (13)C urea breath test was carried out 4-8 weeks after treatment to determine the success of H pylori eradication. RESULTS: A total of 127 patients completed the treatment. The eradication rate for H pylori infection was 90.3%, 90.9%, 70.9% and 65.6%, respectively in OAC, OFC OMC and OFA groups. CONCLUSION: A high eradication rate can be achieved with one-week OAC or OFC triple therapy. Thus, one-week triple therapies with OAC and OFC are recommended for Chinese patients with duodenal ulcers and chronic gastritis.

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