Antitumor activity of Z15-0-2, a bispecific nanobody targeting PD-1 and CTLA-4.

The combination of programmed cell death protein 1 (PD-1) and cytotoxic T lymphocyte antigen 4 (CTLA-4) antibodies has potential for enhancing clinical efficacy. We described the development and antitumor activity of Z15-0, a bispecific nanobody targeting both the PD-1 and CTLA-4 pathways simultaneously. We designed and optimized the mRNA sequence encoding Z15-0, referred to as Z15-0-2 and through a series of in vitro and in vivo experiments, we established that the optimized Z15-0-2 mRNA sequence significantly increased the expression of the bispecific nanobody. Administration of Z15-0-2 mRNA to tumor-bearing mice led to greater inhibition of tumor growth compared to controls. In aggregate, we introduced a novel bispecific nanobody and have re-engineered it to boost expression of mRNA, representing a new drug development paradigm.

Fully connected-convolutional (FC-CNN) neural network based on hyperspectral images for rapid identification of P. ginseng growth years.

P. ginseng is a precious traditional Chinese functional food, which is used for both medicinal and food purposes, and has various effects such as immunomodulation, anti-tumor and anti-oxidation. The growth year of P. ginseng has an important impact on its medicinal and economic values. Fast and nondestructive identification of the growth year of P. ginseng is crucial for its quality evaluation. In this paper, we propose a FC-CNN network that incorporates spectral and spatial features of hyperspectral images to characterize P. ginseng from different growth years. The importance ranking of the spectra was obtained using the random forest method for optimal band selection. Based on the hyperspectral reflectance data of P. ginseng after radiometric calibration and the images of the best five VNIR bands and five SWIR bands selected, the year-by-year identification of P. ginseng age and its identification experiments for food and medicinal purposes were conducted, and the FC-CNN network and its FCNN and CNN branch networks were tested and compared in terms of their effectiveness in the identification of P. ginseng growth years. It has been experimentally verified that the best year-by-year recognition was achieved by utilizing images from five visible and near-infrared important bands and all spectral curves, and the recognition accuracy of food and medicinal use reached 100%. The FC-CNN network is significantly better than its branching model in the effect of edible and medicinal identification. The results show that for P. ginseng growth year identification, VNIR images have much more useful information than SWIR images. Meanwhile, the FC-CNN network utilizing the spectral and spatial features of hyperspectral images is an effective method for the identification of P. ginseng growth year.

Spatio-Temporal Changes in Ecosystem Quality across the Belt and Road Region.

The Silk Road Economic Belt and the 21st Century Maritime Silk Road Initiative (BRI) proposed in 2013 by China has greatly accelerated the social and economic development of the countries along the Belt and Road (B&R) region. However, the international community has questioned its impact on the ecological environment and a comprehensive assessment of ecosystem quality changes is lacking. Therefore, this study proposes an objective and automatic method to assess ecosystem quality and analyzes the spatiotemporal changes in the B&R region. First, an ecosystem quality index (EQI) is established by integrating the vegetation status derived from three remote sensing ecological parameters including the leaf area index, fractional vegetation cover and gross primary productivity. Then, the EQI values are automatically categorized into five ecosystem quality levels including excellent, good, moderate, low and poor to illustrate their spatiotemporal changes from the years 2016 to 2020. The results indicate that the spatial distributions of the EQIs across the B&R region exhibited similar patterns in the years 2016 and 2020. The regions with excellent levels accounted for the lowest proportion of less than 12%, while regions with moderate, low and poor levels accounted for more than 68% of the study area. Moreover, based on the EQI pattern analysis between the years 2016 and 2020, the regions with no significant EQI change accounted for up to 99.33% and approximately 0.45% experienced a significantly decreased EQI. Therefore, this study indicates that the ecosystem quality of the B&R region was relatively poor and experienced no significant change in the five years after the implementation of the "Vision and Action to Promote the Joint Construction of the Silk Road Economic Belt and the 21st Century Maritime Silk Road". This study can provide useful information for decision support on the future ecological environment management and sustainable development of the B&R region.

Fast Positioning Model and Systematic Error Calibration of Chang'E-3 Obstacle Avoidance Lidar for Soft Landing.

Chang'E-3 is China's first soft landing mission on an extraterrestrial celestial body. The laser Three-Dimensional Imaging (TDI) sensor is one of the key payloads of the Chang'E-3 lander. Its main task is to provide accurate 3D lunar surface information of the target landing area in real time for the selection of safe landing sites. Here, a simplified positioning model was constructed, to meet the accuracy and processing timeline requirements of the TDI sensor of Chang'E-3. By analyzing the influence of TDI intrinsic parameters, a permanent outdoor calibration field based on flat plates was specially designed and constructed, and a robust solution of the geometric calibration adjustment was realized by introducing virtual observation equations for unknowns. The geometric calibration and its absolute and relative positioning accuracy verification were carried out using multi-measurement and multi-angle imaging data. The results show that the error of TDI intrinsic parameters will produce a false obstacle with a maximum height of about 1.4 m on the plane, which will cause the obstacle avoidance system of Chang'E-3 to fail to find a suitable landing area or find a false flat area. Furthermore, the intrinsic parameters of the TDI have good stability and the accuracy of the reconstructed three-dimensional surface can reach about 4 cm after error calibration, which provides a reliable terrain guarantee for the autonomous obstacle avoidance of the Chang'E-3 lander.

QUantitative and Automatic Atmospheric Correction (QUAAC): Application and Validation.

The difficulty of atmospheric correction based on a radiative transfer model lies in the acquisition of synchronized atmospheric parameters, especially the aerosol optical depth (AOD). At the moment, there is no fully automatic and high-efficiency atmospheric correction method to make full use of the advantages of geostationary meteorological satellites in large-scale and efficient atmospheric monitoring. Therefore, a QUantitative and Automatic Atmospheric Correction (QUAAC) method is proposed which can efficiently correct high-spatial-resolution (HSR) satellite images. QUAAC uses the atmospheric aerosol products of geostationary satellites to match the synchronized AOD according to the temporal and spatial information of HSR satellite images. This method solves the problem that the AOD is difficult to obtain or the accuracy is not high enough to meet the demand of atmospheric correction. By using the obtained atmospheric parameters, atmospheric correction is performed to obtain the surface reflectance (SR). The whole process can achieve fully automatic operation without manual intervention. After QUAAC applied to Gaofen-2 (GF-2) HSR satellite and Himawari-8 (H-8) geostationary satellite, the results show that the effect of QUAAC correction is slightly better than that of the Fast Line-of-sight Atmospheric Analysis of Spectral Hypercubes (FLAASH) correction, and the QUAAC-corrected surface spectral curves have good coherence to that of the synchronously measured by field experiments.

Coupling with high-resolution remote sensing data to evaluate urban non-point source pollution in Tongzhou, China.

Urban non-point source (NPS) pollution has gradually become one of the important factors affecting the urban water environment. The quantitative evaluation of urban NPS pollution is the priority to identify key control area of urban NPS pollution. Current model applied in China is mainly focused on small-scale area, large-scale spatial continuous simulation is lacking. In this study A spatial continuous evaluation method coupled with high-resolution remote sensing data has been established and the method was applied to Tongzhou, China. With the spatial distribution of land-use type and built-up area which were been obtained by remote sensing technology, the accumulative and wash-off load of urban NPS nitrogen and phosphorus were estimated for the prominent problems of nitrogen and phosphorus nutrient pollution in the rivers in the study area. The main sources of urban NPS Nitrogen and phosphorus pollution are roof and road rainfall runoff respectively. Compared to other urban NPS pollution models, the method developed in this study can quickly realize spatial visualization assessment of urban NPS pollution and provide a means to estimate urban NPS loads in entire city or urban agglomeration, it is applicable for common urban NPS pollutants and also has advantages in areas without data.

Development of bifunctional anti-PD-L1 antibody MMAE conjugate with cytotoxicity and immunostimulation.

In recent years, tumor immunotherapy, especially the combination of PD1/PD-L1 inhibitors and chemotherapy, has developed rapidly. However, the systemic side effects induced by chemotherapy remain a crucial problem that needs to be addressed. Antibody drug conjugates (ADCs) are exceptional target-specific prodrugs that greatly improve the therapeutic window of chemotherapy drugs. Therefore, designing PD-L1-targeting ADCs is an interesting research project. In this study, we confirmed for the first time that the commercial anti-PD-L1 antibody Atezolizumab has better endocytosis efficiencies than Avelumab, and was more suitable for ADC design. Then, the most popular cytotoxic payload MMAE was conjugated to Atezolizumab via a classical dipeptide (valine-alanine) linker to generate a bifunctional PD-L1 ADC (ADC 3). An in vitro cytotoxicity test indicated the potent tumor cell inhibitory activity of ADC 3, with EC50 values of 9.75 nM to 11.94 nM. In addition, a co-culture of PBMCs in vitro proved that ADC 3 retained the immune activation effect of the Atezolizumab antibody. Moreover, ADC 3 exhibited a higher tumor inhibition rate and tumor regression rate in humanized immune system mice. To the best of our knowledge, this is the most active PD-L1-ADC reported thus far, which may promote the development of immunotherapy and novel ADCs.

Novel antibody-drug conjugate with UV-controlled cleavage mechanism for cytotoxin release.

Antibody-drug conjugates (ADCs) are being developed worldwide with the potential to revolutionize current cancer treatment strategies. However, off-target toxicity caused by the instability of linkers remains one of the main issues to be resolved. Developing a novel photocontrol-ADC with good stability and photocontrolled release seemed to be an attractive and practical solution. In this study, we designed, for the first time, a novel ultraviolet (UV) light-controlled ADC by carefully integrating the UV-cleavable o-nitro-benzyl structure into the linker. Our preliminary work indicated that the ADC exhibited good stability and photocontrollability while maintaining a targeting effect similar to that of the naked antibody. Upon irradiation with UV light, the ADC rapidly released free cytotoxins and exerted significant cytotoxicity toward drug-resistant tumor cells. Compared to those of the unirradiated cells, the EC50 values of ADCs increased by up to 50-fold. Furthermore, our research confirmed that the degradation products of unirradiated ADC, Cys-1a, were relatively less toxic, thus potentially reducing the off-target toxicity caused by nonspecific uptake of ADCs. The novel design strategy of UV light-controlled ADCs may provide new perspectives for future research on ADCs and promote the development of photocontrol systems.

Design, Synthesis, and In Vitro Evaluation of the Photoactivatable Prodrug of the PARP Inhibitor Talazoparib.

In this article, we report the design, synthesis, photodynamic properties, and in vitro evaluation of photoactivatable prodrug for the poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor Talazoparib. In order to yield a photoactivatable, inactive prodrug, photoactivatable protecting groups (PPGs) were employed to mask the key pharmacophore of Talazoparib. Our study confirmed the good stability and photolytic effect of prodrugs. A PARP-1 enzyme inhibition assay and PARylation experiment showed that the inhibitory activity of the prodrug was reduced 380 times and more than 658 times, respectively, which proved that the prodrug's expected activity was lost after PPG protection. In BRCA1- and BRCA2-deficient cell lines, the inhibitory activity of the compound was significantly restored after ultraviolet (UV) irradiation. The results indicate that the photoactivatable prodrug strategy is an interesting approach for studying PARP inhibitors. Meanwhile, the described photoactivatable prodrug also provided a new biological tool for the mechanism research of PARP.

Molecular design and anticancer activities of small-molecule monopolar spindle 1 inhibitors: A Medicinal chemistry perspective.

As a dual-specificity protein kinase, monopolar spindle 1 (Mps1) is one of the main kinases involved in kinetochore localization and the spindle assembly checkpoint (SAC). Cancer cells often display chromosomal instability, which is a consequence of disfunction of cell cycle checkpoints partially. Mps1 is overexpressed in multiple cancer types to face the pressure from aberrant chromosomes and centrosomes. Therefore, Mps1 is a potential targeting approach to cancer treatment. Several compounds targeting Mps1 have been developed and approved to begin clinical trials for advanced nonhaematologic malignancies treatments, including but not limited to triple negative breast cancer (TNBC) treatment. In this review, we will highlight typical Mps1 inhibitors developed during the last decade and provide a reference for more potential Mps1 inhibitors exploration in the future.

Y08060: A Selective BET Inhibitor for Treatment of Prostate Cancer.

Prostate cancer is a commonly diagnosed cancer and a leading cause of cancer-related deaths. The bromodomain and extra terminal domain (BET) family proteins have emerged as potential therapeutic targets for the treatment of castration-resistant prostate cancer. A series of 2,2-dimethyl-2H-benzo[b][1,4]oxazin-3(4H)-one derivatives were designed and synthesized as selective bromodomain containing protein 4 (BRD4) inhibitors. The compounds potently inhibit BRD4(1) with nanomolar IC50 values and exhibit high selectivity over most non-BET subfamily members. One of the representative compounds 36 (Y08060) effectively suppresses cell growth, colony formation, and expression of androgen receptor (AR), AR regulated genes, and MYC in prostate cancer cell lines. In in vivo studies, 36 demonstrates a good PK profile with high oral bioavailability (61.54%) and is a promising lead compound for further prostate cancer drug development.

Super absorbent polymer seed coatings promote seed germination and seedling growth of Caragana korshinskii in drought.

Coating seeds with water absorbent materials can improve their survival, especially for those planted in drought or barren areas. In this study, effects of five kinds of super absorbent polymers (SAPs) on seed germination and seedling growth of Caragana korshinskii under drought conditions were investigated. Our results showed that SAP coatings could significantly improve the percentage and energy of seed germination, as well as reduce the relative electrical conductivity (REC), proline, malondialdehyde (MDA), H2O2 content, and peroxidase (POD) activity during germination. These results implied that seeds could uptake moisture from SAP coatings to alleviate drought-induced oxidative stress and membrane damage, thus exhibiting a better vigor and germination performance. After coating C. korshinskii seeds with SAPs, more seedlings emerged and grew better. Under the combined influence of the water absorption capacity of SAP and other factors, the efficiencies of five SAP coatings are in the sequence D>E>B>A>C. The function of the SAP coating on promoting seedling survival was confirmed in Mu Us Sandy Land in Ordos, Inner Mongolia Autonomous Region, China. The average seedling number of SAP D-coated seeds increased twofold on that of naked seeds. Our results are expected to be helpful in understanding and utilizing SAP seed coatings in improving plant survival under drought conditions.

[Pre- and post-iodine nutritional status among the population related to the practice of new standard on edible iodized salt, in Yunnan province].

OBJECTIVE: In order to understand the iodine nutritional status, after the salt-iodine content was showed a reduction in 2012 and to evaluate the current situation after the new standards was brought into force to the general population in an experimental community of Yunnan province. METHODS: Randomly sampled urine and salt were collected, to test the iodine concentration in the study-site. Pre-and post-levels of the iodized salt under the provision of the new standards, were identified. RESULTS: of this study were gathered upon 3 weeks or 3 months, respectively. Results Data from the three randomly chosen study sites showed that the urine iodine concentration in the general populations was reducing gradually. In the general population, medians of Urine Iodine (MUI) were 279.71 µg/L, 239.64 µg/L and 226.26 µg/L, respectively. Proportion of the urine iodine value for 100-199 µg/L increased but ≥300 µg/L decreased, after the new standard was put into practice. Both homogeneity and stability of the new standard on iodized salt seemed to be good. CONCLUSION: Iodine nutrition in general population appeared reasonable under the use of newly set salt-iodine standards in general population living in Yunnan province.

Research on fast Fourier transforms algorithm of huge remote sensing image technology with GPU and partitioning technology.

Fast Fourier transforms (FFT) is a basic approach to remote sensing image processing. With the improvement of capacity of remote sensing image capture with the features of hyperspectrum, high spatial resolution and high temporal resolution, how to use FFT technology to efficiently process huge remote sensing image becomes the critical step and research hot spot of current image processing technology. FFT algorithm, one of the basic algorithms of image processing, can be used for stripe noise removal, image compression, image registration, etc. in processing remote sensing image. CUFFT function library is the FFT algorithm library based on CPU and FFTW. FFTW is a FFT algorithm developed based on CPU in PC platform, and is currently the fastest CPU based FFT algorithm function library. However there is a common problem that once the available memory or memory is less than the capacity of image, there will be out of memory or memory overflow when using the above two methods to realize image FFT arithmetic. To address this problem, a CPU and partitioning technology based Huge Remote Fast Fourier Transform (HRFFT) algorithm is proposed in this paper. By improving the FFT algorithm in CUFFT function library, the problem of out of memory and memory overflow is solved. Moreover, this method is proved rational by experiment combined with the CCD image of HJ-1A satellite. When applied to practical image processing, it improves effect of the image processing, speeds up the processing, which saves the time of computation and achieves sound result.

The fluxes of H2O2 and O2 can be used to evaluate seed germination and vigor of Caragana korshinskii.

Seed deterioration is detrimental to plant germplasm conservation, and predicting seed germination and vigor with reliability and sensitivity means is urgently needed for practical problems. We investigated the link between hydrogen peroxide (H2O2) flux, oxygen influx and seed vigor of Caragana korshinskii by the non-invasive micro-test technique (NMT). Some related physiological and biochemical changes in seeds were also determined to further explain the changes in the molecular fluxes. The results showed that there was a good linear relationship between germination and H2O2 flux, and that O2 influx was more suitable for assessing seed vigor. H2O2 flux changed relatively little initially, mainly affected by antioxidants (APX, CAT and GSH) and H2O2 content; afterward, the efflux increased more and more rapidly due to high membrane permeability. With the damage of mitochondrial respiration and membrane integrity, O2 influx was gradually reduced. We propose that monitoring H2O2 and O2 fluxes by NMT may be a reliable and sensitive method to evaluate seed germination and vigor.

[Monitoring the thermal plume from coastal nuclear power plant using satellite remote sensing data: modeling, and validation].

Thermal plume from coastal nuclear power plant is a small-scale human activity, mornitoring of which requires high-frequency and high-spatial remote sensing data. The infrared scanner (IRS), on board of HJ-1B, has an infrared channel IRS4 with 300 m and 4-days as its spatial and temporal resolution. Remote sensing data aquired using IRS4 is an available source for mornitoring thermal plume. Retrieval pattern for coastal sea surface temperature (SST) was built to monitor the thermal plume from nuclear power plant. The research area is located near Guangdong Daya Bay Nuclear Power Station (GNPS), where synchronized validations were also implemented. The National Centers for Environmental Prediction (NCEP) data was interpolated spatially and temporally. The interpolated data as well as surface weather conditions were subsequently employed into radiative transfer model for the atmospheric correction of IRS4 thermal image. A look-up-table (LUT) was built for the inversion between IRS4 channel radiance and radiometric temperature, and a fitted function was also built from the LUT data for the same purpose. The SST was finally retrieved based on those preprocessing procedures mentioned above. The bulk temperature (BT) of 84 samples distributed near GNPS was shipboard collected synchronically using salinity-temperature-deepness (CTD) instruments. The discrete sample data was surface interpolated and compared with the satellite retrieved SST. Results show that the average BT over the study area is 0.47 degrees C higher than the retrieved skin temperature (ST). For areas far away from outfall, the ST is higher than BT, with differences less than 1.0 degrees C. The main driving force for temperature variations in these regions is solar radiation. For areas near outfall, on the contrary, the retrieved ST is lower than BT, and greater differences between the two (meaning > 1.0 degrees C) happen when it gets closer to the outfall. Unlike the former case, the convective heat transfer resulting from the thermal plume is the primary reason leading to the temperature variations. Temperature rising (TR) distributions obtained from remote sensing data and in-situ measurements are consistent, except that the interpolated BT shows more level details (> 5 levels) than that of the ST (up to 4 levels). The areas with higher TR levels (> 2) are larger on BT maps, while for lower TR levels (≤ 2), the two methods perform with no obvious differences. Minimal errors for satellite-derived SST occur regularly around local time 10 a. m. This makes the remote sensing results to be substitutes for in-situ measurements. Therefore, for operational applications of HJ-1B IRS4, remote sensing technique can be a practical approach to monitoring the nuclear plant thermal pollution around this time period.

[Research on calibration methods of ground-based thermal-infrared radiometer CE312].

The accuracy of the calibration coefficients of the ground-based thermal-infrared radiometer CE312 is one of the most important factors affecting the calibration of the thermal-infrared remote sensors. The theory of two calibration methods which calculate the bandpass radiance and spectral radiance respectively is introduced. The calibration of the CE312-1b is conducted with the blackbody in the laboratory, the accuracy and influence factors of the results are conducted by the MODIS data combined with in situ measurements data at Qinghai Lake in Aug 2010. The results show that calibration coefficients of thermal-infrared field radiometer CE312 calculated by the bandpass radiance method has better performance in the accuracy and applicability than the spectral radiance method.

[HJ1A/HSI radiometric calibration and spectrum response function sensitivity analysis].

Hyper spectrum imager (HSI) loaded on HJ-1A satellite is Chinese first spaceborne hyperspectrum sensor. Since the HSI has no spectrum response function of all channels, the usually used calibration method-reflectance based method has been modified, and a new calibration method is proposed, in which the spectrum response function is neglected. Based on the calibration experiment data of Dunhuang in Aug., 2009, the HSI sensor was calibrated on orbit. The different kinds of spectrum response were constructed based on the formula, and the errors of calibration results with different spectrum response function were analyzed. The results show, expecting for the channels of water vapor and oxygen absorption channel, the influence of spectrum response function in other channel is less than 3%, and the calibration result based on new calibration method can satisfy the application requirement.