Design, synthesis, and biological evaluation of 5-(1H-indol-5-yl)isoxazole-3-carboxylic acids as novel xanthine oxidase inhibitors.

Xanthine oxidase (XO) is a key enzyme for the production of uric acid in the human body. XO inhibitors (XOIs) are clinically used for the treatment of hyperuricemia and gout, as they can effectively inhibit the production of uric acid. Previous studies indicated that both indole and isoxazole derivatives have good inhibitory effects against XO. Here, we designed and synthesized a novel series of N-5-(1H-indol-5-yl)isoxazole-3-carboxylic acids according to bioisosteric replacement and hybridization strategies. Among the obtained target compounds, compound 6c showed the best inhibitory activity against XO with an IC50 value of 0.13 µM, which was 22-fold higher than that of the classical antigout drug allopurinol (IC50 = 2.93 µM). Structure-activity relationship analysis indicated that the hydrophobic group on the nitrogen atom of the indole ring is essential for the inhibitory potencies of target compounds against XO. Enzyme kinetic studies proved that compound 6c acted as a mixed-type XOI. Molecular docking studies showed that the target compound 6c could not only retain the key interactions similar to febuxostat at the XO binding site but also generate some new interactions, such as two hydrogen bonds between the oxygen atom of the isoxazole ring and the amino acid residues Ser876 and Thr1010. These results indicated that 5-(1H-indol-5-yl)isoxazole-3-carboxylic acid might be an efficacious scaffold for designing novel XOIs and compound 6c has the potential to be used as a lead for further the development of novel anti-gout candidates.

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Long-term occupation of coal gangue dumping sites (CGDS) may destroy ecological environment of nearby area. However, how the CGDS affects the distribution pattern of soil seed banks and vegetation in the nearby area is not clear. In this study, we investigated soil seed bank and vegetation at different distances from the second CGDS of Yangchangwan in Ningdong mining area, Lingwu, Ningxia. The results showed that soil seed bank was mainly distributed in 0-10 cm layer and decreased with increasing soil depth. Species richness of soil seed bank and vegetation first increased and then tended to be stable with increasing distance to the CGDS. The influence range of CGDS on soil seed banks was 300-500 m and was 100-300 m on aboveground vegetation. The CGDS did not affect the vertical distribution pattern of soil seed bank, but significantly affected the horizontal distribution pattern of soil seed banks and aboveground vegetation. The key area of vegetation restoration around the CGDS was between 100 m and 300 m.

Shifts in the bacterial community caused by combined pollutant loads in the North Canal River, China.

A typical anthropogenically disturbed urban river polluted by a combination of conventional pollutants (nitrogen and phosphorus pollution) and heavy metals was investigated along a 238 km stretch. Changes in the bacterial community were evaluated using high-throughput sequencing, and the relationships between bacteria, heavy metals, and conventional pollutants were investigated. There was large spatial heterogeneity in the bacterial community along the river, and bacterial diversity in the upstream and midstream sections was much higher than in the downstream section. Heavy metals and conventional pollutants both exhibited close correlations with bacterial diversity and composition. For instance, potential fecal indicator bacteria, sewage indicator bacteria and pathogenic bacteria, such as Ruminococcus and Pseudomonas, were closely associated with Cu, Zn, and NH4+-N. Rather than conventional pollutants, heavy metals were the main driving factors of the microbial community characteristics. These results confirm that bacterial communities play a crucial role in biogeochemical cycles. Therefore, heavy metals could be used as biomarkers of complex pollution to indicate the pollution status of riverine ecosystems and contribute to the restoration of habitats in anthropogenically disturbed urban rivers.

How School Climate Affects the Development of the Social and Emotional Skills of Underprivileged-Background Students-An Empirical Study Based on the SSES2019 Data.

Background: Promoting the development of the social and emotional skills of underprivileged-background students is an integral part of educational and social equity. To date, there has been a lack of relevant research in this field. Aims: This study investigated the impacts of cooperative school climate and competitive school climate on the development of the social and emotional skills of underprivileged-background students. Sample: This study used the data of Chinese underprivileged-background students (N = 1739) from the Study on Social and Emotional Skills conducted by the Organisation for Economic Cooperation and Development (OECD-SSES2019). Methods: This study selected the ordinary least squares (OLS) analysis method and the quantile regression (QR) analysis method. Results: The ordinary least squares (OLS) analysis results showed that cooperative school climates promoted the development of various dimensions of the social and emotional skills of underprivileged-background students, while competitive school climates had significant negative impacts on the collaboration and emotional regulation of underprivileged-background students and had no significant impact on the other three major domains, namely engagement with others, open-mindedness, and task performance. A quantile regression analysis further explored the heterogeneity in the impacts of cooperative school climate and competitive school climate on the development of the social and emotional skills of underprivileged-background students through quantile regression and found that the impacts of a competitive school climate on underprivileged-background students with different levels of social and emotional skills were homogeneous, while the impacts of a competitive school climate on underprivileged-background students with different levels of social and emotional skills were heterogeneous. Conclusions: These findings provide a greater insight into the roles of school cooperative climate and school competitive climate in the development process of the social and emotional skills of underprivileged-background students.

POViT: Vision Transformer for Multi-Objective Design and Characterization of Photonic Crystal Nanocavities.

We study a new technique for solving the fundamental challenge in nanophotonic design: fast and accurate characterization of nanoscale photonic devices with minimal human intervention. Much like the fusion between Artificial Intelligence and Electronic Design Automation (EDA), many efforts have been made to apply deep neural networks (DNN) such as convolutional neural networks to prototype and characterize next-gen optoelectronic devices commonly found in Photonic Integrated Circuits. However, state-of-the-art DNN models are still far from being directly applicable in the real world: e.g., DNN-produced correlation coefficients between target and predicted physical quantities are about 80%, which is much lower than what it takes to generate reliable and reproducible nanophotonic designs. Recently, attention-based transformer models have attracted extensive interests and been widely used in Computer Vision and Natural Language Processing. In this work, we for the first time propose a Transformer model (POViT) to efficiently design and simulate photonic crystal nanocavities with multiple objectives under consideration. Unlike the standard Vision Transformer, our model takes photonic crystals as input data and changes the activation layer from GELU to an absolute-value function. Extensive experiments show that POViT significantly improves results reported by previous models: correlation coefficients are increased by over 12% (i.e., to 92.0%) and prediction errors are reduced by an order of magnitude, among several key metric improvements. Our work has the potential to drive the expansion of EDA to fully automated photonic design (i.e., PDA). The complete dataset and code will be released to promote research in the interdisciplinary field of materials science/physics and computer science.

Sub-lineages of the SARS-CoV-2 Omicron variants: Characteristics and prevention.

Since the start of the coronavirus disease 2019 (COVID-19) pandemic, new variants of severe acute respiratory syndrome coronavirus 2 (SARS­CoV­2) have emerged, accelerating the spread of the virus. Omicron was defined by the World Health Organization in November 2021 as the fifth "variant of concern" after Alpha, Beta, Gamma, and Delta. In recent months, Omicron has become the main epidemic strain. Studies have shown that Omicron carries more mutations than Alpha, Beta, Gamma, Delta, and wild-type, facilitating immune escape and accelerating its transmission. This review focuses on the Omicron variant's origin, transmission, main biological features, subvariants, mutations, immune escape, vaccination, and detection methods. We also discuss the appropriate preventive and therapeutic measures that should be taken to address the new challenges posed by the Omicron variant. This review is valuable to guide the surveillance, prevention, and development of vaccines and other therapies for Omicron variants. It is desirable to develop a more efficient vaccine against the Omicron variant and take more effective measures to constrain the spread of the epidemic and promote public health.

Accumulation and potential ecological risks of Heavy Metals in sediments from Rivers in the Beijing-Tianjin Area.

Human activities can introduce heavy metals to water bodies, where they are then deposited in sediments. The risks, spatial distributions, and toxicities of heavy metals in sediment were investigated along the North Canal in the densely Beijing-Tianjin area. The average geoaccumulation index ranged from 0.2 to 2.91 and the highest value was obtained for Cd. All the pollution load indexes were greater than one, indicating that the heavy metals originated from anthropogenic sources. The risk indexes at three sampling points were greater than 300, indicating high potential ecological risk. Two probable effect concentration quotient values greater than 0.5, suggesting potential toxicity to certain sediment-dwelling organisms. Identification and evalution heavy metals could assist in improvement of the water quality, and support management strategies to restore the environment.

Risk assessment of heavy metals in suspended particulate matter in a typical urban river.

Suspended particulate matter (SPM) is a major source of contamination in urban rivers as it serves as a carrier for pollutants, such as heavy metals. In this study, the Beiyun River, northern China, was used as a case study to determine the characteristics of SPM-associated heavy metal spatial distribution, to evaluate the potential ecological risks and identify heavy metal sources. The concentrations of seven heavy metals and other associated indicators (TC, TN, TP, and OM) were measured at 12 sites and analyzed by Pearson correlation (PC) and principal component analyses (PCA). The average concentrations of Cr, Ni, Cu, Zn, As, Cd, and Pb were 70.72, 27.88, 31.35, 115.70, 27.77, 0.23, and 29.62 mg/kg, respectively, with significant spatial differences occurring between some elements. Igeo values established the ranked order of heavy metal pollutant concentrations in SPM as As > Cd > Zn > Cu > Pb > Cr > Ni. [Formula: see text] analysis demonstrated that the ranked order of potential ecological risk from the seven metals was Cd > As > Cu > Pb > Ni > Cr > Zn. Potential ecological risk index (RI) results confirmed the high potential ecological risk in the study area. Among the measured heavy metals, Cd represented the highest pollution risk, as shown by its highest [Formula: see text] value. Correlation analysis (CA) showed that Zn had a strong correlation with Cu and Pb. Significant positive correlations were found between TC, TN, TP, and Cu. Three element pairs, Zn-Cd, Cr-Cu, and Cr-Ni, were also found to have strong correlations. Zn, Cu, and Ni were mainly introduced by human activities including urban industrial sewage discharge (such as metallurgy and electroplating industrial wastewater), agricultural drainage, and landfill wastewater, while Cr mainly originated from natural processes like mineral weathering and atmospheric precipitation. This information on the concentration, risk, and sources of SPM in Beiyun River provides an important reference for the reduction of heavy metal pollution in SPM in a typical river in the Haihe River Basin (China).

Inhibitory effects of human lactoferrin on U14 cervical carcinoma through upregulation of the immune response.

Human lactoferrin (hLF) is a multifunctional glycoprotein that inhibits cancer growth. However, the inhibitory effect of this glycoprotein in cervical cancer remains inconclusive. This study investigated the efficacy of hLF on the inhibition of U14 cervical cancer in vivo. Recombinant adenovirus carrying hLF (Ad-hLF) were constructed. Mice inoculated with U14 cells were randomly allocated to four treatments: i) Phosphate-buffered saline (negative control), ii) Ad-green fluorescent protein (negative control), iii) Ad-hLF (studied) or iv) cyclophosphamide (CTX; positive control). Tumor growth, as well as levels of natural killer (NK) cells, CD4+ and CD8+ peripheral blood T lymphocyte subpopulations, serum cytokines and vascular endothelial growth factor (VEGF) in tumor tissues were detected. Compared with the negative controls, tumor growth was inhibited by hLF and mice lifespans in the Ad-hLF-treated group were prolonged to reach the levels of the CTX-treated group. The activity of tumor-killing NK cells was upregulated by hLF. Moreover, the number of CD4+ and CD8+ peripheral blood T lymphocyte subpopulations increased following treatment with Ad-hLF. Treatment with Ad-hLF increased the levels of serum interferon-γ, serum interleukin-2 (IL-2) and tumor necrosis factor-α, and decreased the levels of serum IL-4 in tumor-bearing mice. The expression of VEGF in tumor tissues was downregulated by hLF. In conclusion, hLF inhibits the growth of U14 solid tumors by modulating the immune response of tumor-bearing mice.

Enhanced expression of adenovirus encoding rhEPO assisted by BAPTA.

Infection efficiency is the key issue for gene delivery using adenovirus vector and usually unsatisfactory. In this study, recombinant adenoviruses encoding recombinant human EPO were prepared using the Adeasy system, and injected into the mammary gland of goats via the teat canal. BAPTA was used to treat the mammary gland to facilitate adenoviruses infection compared with EGTA. Milk serum was collected from the infected mammary gland and characterized by ELISAs and Western blotting. Expression level of rhEPO from the group treated by BAPTA was higher than that treated by EGTA.

Recombinant human antithrombin expressed in the milk of non-transgenic goats exhibits high efficiency on rat DIC model.

Plasma-derived antithrombin (pAT) is often used for the treatments of disseminated intravascular coagulation (DIC) patients. In this paper, the recombinant adenovirus vector encoding human antithrombin (AT) cDNA was constructed and directly infused into the mammary gland of two goats. The recombinant human antithrombin (rhAT) was purified by heparin affinity chromatography from the goat milk, and then used in the treatment of thirty lipopolysaccharide (LPS) induced DIC rats. A high expression level of rhAT up to 2.8 g/l was obtained in the milk of goats. After purification, the recovery rate and the purity of the rhAT were up to 54.7 +/- 3.2% and 96.2 +/- 2.7%, respectively. In blood of the DIC rat model treated with rhAT, the levels of antithrombin and thrombin-antithrombin (TAT) were augmented significantly; meanwhile the consumption of fibrinogen and platelet was reduced significantly, and the increase of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) concentration was restrained modest and non-significant. For the above DIC indexes, there were no differences between pAT and rhAT (P > 0.05). Our results demonstrated that the way we established is a pragmatic tool for large-scale production of rhAT, and the rhAT produced with this method has potential as a substitute for pAT in the therapy of DIC patients.

Effects of different extenders on DNA integrity of boar spermatozoa following freezing-thawing.

The sperm-rich fraction, collected from eight mature Yorkshire boars, was frozen in an extender containing 9% LDL (w/v), 100mM trehalose, or 20% yolk (v/v), respectively. Sperm DNA integrity was assessed using the single-cell gel electrophoresis (SCGE). Other sperm quality characteristics such as motility, acrosome and membrane integrity were also monitored. The results showed that freezing-thawing caused an increase in sperm DNA fragmentation, and extender containing 9% LDL could significantly protect sperm DNA integrity (P<0.05) from the damage caused by cryopreservation and decrease DNA damages compared with extender containing 100mM trehalose and 20% yolk (v/v). No significant difference in damaged DNA was detected between frozen and unfrozen semen samples for extender of 9% LDL and 100mM trehalose, but cryopreservation could increase the degree of DNA damage (P<0.05), the percentage of damaged DNA degree of grade 2 and 3 was significantly increased. The deterioration in post-thaw sperm DNA integrity was concurrent with reduced sperm characteristics. The data here demonstrated that the cryoprotectant played a fundamental role in reducing boar sperm DNA damage and protecting DNA integrity. It can be suggested that evaluation of sperm DNA integrity, coupled with correlative and basic characteristics such as motility, acrosome integrity and membrane integrity, may aid in determining the quality of frozen boar semen.

Effect of sugars on maturation rate of vitrified-thawed immature porcine oocytes.

This study examined the effects of monosaccharide (glucose), disaccharide (sucrose) and polysaccharides (Ficoll and Lycium barbarum polysaccharide (LBP)) at different concentrations, using ethylene glycol (EG) as membrane-permeating cryoprotectant, on in vitro maturation of vitrified-thawed immature (GV) porcine oocytes. A total of 1145 oocytes were obtained by follicle aspiration from 496 ovaries of pigs slaughtered at a local abattoir and vitrified using a five-step method. After thawing and removal of cryoprotectant, oocytes were cultured for 44 h at 39 degrees C in a humidified atmosphere of 5% CO(2) in air. Oocytes were stained with DAPI and nuclear maturation was examined. The highest maturation rates were obtained in 1.5M glucose (8.62%), 0.75 M sucrose (20.0%), 3.0 g/ml Ficoll (13.79%) and 0.10 g/ml LBP (20.69%), respectively. The maturation rate using 0.75 M sucrose or 0.10 g/ml LBP was significantly higher compared to 1.5M glucose (P<0.05), but there was no significant difference from using 3.0 g/ml Ficoll (P>0.05). The percentage of oocytes reaching metaphase II (MII) stage in the cryopreserved groups was significantly lower than control (P<0.05). These results suggest that LBP is an effective non-permeating membrane cryoprotectant and 0.75 M sucrose or 0.10 g/ml LBP can be used as the vitrification solution for immature porcine oocytes.

Improvement of the quality of boar cryopreservation semen by supplementing with low density lipoprotein in diluents.

Low density lipoprotein was added at concentrations of 6%, 7%, 8%, 9% and 10% to the diluents used to freeze boar semen and its effect on the quality of cryopreservation was assessed The results indicated that 9% low density lipoprotein supplementation significantly improved the total motile sperm (p<0.05). The sperm straight-line velocity increased with the concentration of low density lipoprotein except at the concentration of 10%, at which concentration the sperm velocity declined (p<0.05). Supplementation at 8% and 9% low density lipoprotein significantly increased plasma membrane integrity (p<0.05). Compared with control, the low density lipoprotein supplementation significantly improved the percentage of acrosome integrity (p<0.05). With all parameters measured, the concentration of 9% low density lipoprotein showed a better effect on the quality of boar cryopreservation semen. The sperm DNA was more seriously damaged in the species of Yorkshire than in Duroc.

Phenyl-calix[4]arene-based fluorescent sensors: cooperative binding for carboxylates.

Tetrakis-(4-carbamoylphenyl)-substituted and tetrakis-(4-amidophenyl)-substituted calix[4]arenes as well as the monomeric biphenylcarbamate have been synthesized as fluorescent receptors for anion sensing. Their binding properties with various anions including F-, CH3COO-, Ph-COO-, and H2PO4- were investigated by fluorescence titrations, Job plot experiments, 1H NMR spectroscopies, and ESI-MS measurements. Importantly, we have found that calix[4]arene-based sensors exhibit greatly enhanced binding affinity and selectivity toward carboxylates. The binding associations of tetrakis-(4-carbamoylphenyl)-substituted calix[4]arene for carboxylates are 1-2 orders of magnitude greater than those of the monomeric biphenylcarbamate sensor. Such an enhancement in the binding affinity and selectivity is attributed to the cooperative binding of the multiple ligating groups as revealed from the ab inito DFT calculations. Although tetrakis-(4-amidophenyl)-substituted calix[4]arene exhibited relatively weaker binding affinity toward anions, its superior binding selectivity for acetate ion over fluoride ion is evident. Our results also suggest that carbamate functionality is a useful H-bond donor for hydrogen-bonding interactions in molecular recognition and supramolecular chemistry.

Effect of low density lipoprotein on DNA integrity of freezing-thawing boar sperm by neutral comet assay.

A modified protocol of neutral comet assay was utilized to assess the effect of low density lipoprotein (LDL) on the DNA integrity of boar freezing-thawing semen. The results demonstrated that the method was high sensitive and easier manipulation and LDL significantly protected sperm DNA integrity (p<0.05) from the damage caused by cryopreservation except TD at the concentration of 6%, 7% and TM at 6%, the optimal LDL concentration in diluents was 9%. Moreover, LDL showed better protection in 0.25 ml than in 0.5 ml types of straw (p<0.05) and no difference was observed in the same volume straw at the concentration of 9% and 10%. It was just the same for LDL effect on boar sperm DNA in cryopreservation 0 day and 30 days (p>0.05).