Design of novel broad-spectrum antiviral nucleoside analogues using natural bases ring-opening strategy.

The global prevalence of RNA virus infections has presented significant challenges to public health in recent years, necessitating the expansion of its alternative therapeutic library. Due to its evolutional conservation, RNA-dependent RNA polymerase (RdRp) has emerged as a potential target for broad-spectrum antiviral nucleoside analogues. However, after over half a century of structural modification, exploring unclaimed chemical space using frequently-used structural substitution methods to design new nucleoside analogues is challenging. In this study, we explore the use of the "ring-opening" strategy to design new base mimics, thereby using these base mimics to design new nucleoside analogues with broad-spectrum antiviral activities. A total of 29 compounds were synthesized. Their activity against viral RdRp was initially screened using an influenza A virus RdRp high-throughput screening model. Then, the antiviral activity of 38a was verified against influenza virus strain A/PR/8/34 (H1N1), demonstrating a 50% inhibitory concentration (IC50) value of 9.95 µM, which was superior to that of ribavirin (the positive control, IC50 = 11.43 µM). Moreover, 38a also has inhibitory activity against coronavirus 229E with an IC50 of 30.82 µM. In addition, compounds 42 and 46f exhibit an 82% inhibition rate against vesicular stomatitis virus at a concentration of 20 µM and hardly induce cytotoxicity in host cells. This work demonstrates the feasibility of designing nucleoside analogues with "ring-opening" bases and suggests the "ring-opening" nucleosides may have greater polarity, and designing prodrugs is an important aspect of optimizing their antiviral activity. Future research should focus on enhancing the conformational restriction of open-loop bases to mimic Watson-Crick base pairing better and improve antiviral activity.

Divergent Synthesis of Quinolines: Exploiting the Duality of Free Radicals.

Herein, we present a green scheme for the divergent synthesis of two polysubstituted quinolines from a singular substrate via exploiting free-radical duality. Photocatalytically generated imine radicals produce 3,4-disubstituted quinolines via a novel rearrangement in the presence of an inorganic base. Alternatively, they react in the presence of an organic base to furnish 2,3-disubstituted quinolines. Mechanism studies support the hypothesis that the electrophilic/nucleophilic bias of free radicals can be adjusted by altering the reaction conditions.

PCDH1, a poor prognostic biomarker and potential target for pancreatic adenocarcinoma metastatic therapy.

BACKGROUND: Pancreatic adenocarcinoma (PAAD) is an aggressive solid tumour characterised by few early symptoms, high mortality, and lack of effective treatment. Therefore, it is important to identify new potential therapeutic targets and prognostic biomarkers of PAAD. METHODS: The Cancer Genome Atlas and Genotype-Tissue Expression databases were used to identify the expression and prognostic model of protocadherin 1 (PCDH1). The prognostic performance of risk factors and diagnosis of patients with PAAD were evaluated by regression analysis, nomogram, and receiver operating characteristic curve. Paraffin sections were collected from patients for immunohistochemistry (IHC) analysis. The expression of PCDH1 in cells obtained from primary tumours or metastatic biopsies was identified using single-cell RNA sequencing (scRNA-seq). Real-time quantitative polymerase chain reaction (qPCR) and western blotting were used to verify PCDH1 expression levels and the inhibitory effects of the compounds. RESULTS: The RNA and protein levels of PCDH1 were significantly higher in PAAD cells than in normal pancreatic ductal cells, similar to those observed in tissue sections from patients with PAAD. Aberrant methylation of the CpG site cg19767205 and micro-RNA (miRNA) hsa-miR-124-1 may be important reasons for the high PCDH1 expression in PAAD. Up-regulated PCDH1 promotes pancreatic cancer cell metastasis. The RNA levels of PCDH1 were significantly down-regulated following flutamide treatment. Flutamide reduced the percentage of PCDH1 RNA level in PAAD cells Panc-0813 to < 50%. In addition, the PCDH1 protein was significantly down-regulated after Panc-0813 cells were incubated with 20 µM flutamide and proves to be a potential therapeutic intervention for PAAD. CONCLUSION: PCDH1 is a key prognostic biomarker and promoter of PAAD metastasis. Additionally, flutamide may serve as a novel compound that down-regulates PCDH1 expression as a potential treatment for combating PAAD progression and metastasis.

Design of Photosensitive Cobalt Complex Intermediates and Their Application in the Green Syntheses of Molecules Containing the Quinazolin-4(3H)-imine Scaffold.

Cobalt/photoredox cooperative catalysis is a well-explored technology for visible-light photoredox catalysis. Recently, the photosensitivity of Co(II) complexes in homogeneous catalysis has aroused the interest of scientists. In this study, photosensitive Co(II) complex intermediates were designed to develop new synthetic methods. These intermediates, consisting of Co(II) and two substrate molecules, bind to O2 and absorb visible light over a wide spectral range, triggering in situ oxidative decarboxylation to produce molecules containing the quinazolin-4(3H)-imine scaffold. These reactions employed glyoxylic acid and ketoacids as new building blocks, and good to excellent yields of the corresponding products were obtained under mild reaction conditions using green and inexpensive reagents and solvents. These results are of importance since the design of Co-based photosensitive intermediates will aid in establishing novel methods for harnessing visible light and hence lead to innovation in organic syntheses.

Isolation of a new monoterpenoid glycoside from Anhua dark tea based on an NMR-guided method and its cytotoxic activity against MDA-MB-231 and SH-SY5Y cell lines.

Based on an NMR-guided method, one new monoterpenoid glycoside (1) was isolated from Anhua dark tea, together with five known compounds (2-6). The structure of the new compound was determined as 3-(5,5-dimethyltetrahydrofuranyl)-1-buten-3-ol primeveroside, and trivially named anhuaterpenoside A (1), on the basis of detailed spectroscopic analyses, and acidic hydrolysis. Compound 1 exhibits cytotoxic activity against MDA-MB-231 and SH-SY5Y cell lines with IC50 value of 23.26 µM and 18.57 µM, respectively.

A new triterpenoid saponin from Pulsatilla cernua predicted by NMR-based mosaic method.

A saponin (1) with gypsogenin as aglycone was isolated from the roots of Pulsatilla cernua. The aglycone of compound 1 was considered as gypsogenin which was rarely found in this genus. Its structure was predicted by NMR-based "mosaic" method rapidly, and further confirmed on the basis of spectroscopic data, including 2D NMR spectra and chemical evidence. This work suggested that NMR-based mosaic method is suitable for most of saponins from common species of genus Pulsatilla.

Neuroprotective effect of catechins derivatives isolated from Anhua dark tea on NMDA-induced excitotoxicity in SH-SY5Y cells.

Anhua dark tea known as the earliest produced Chinese dark tea, has been commercially available and famous for its unique flavor and health care effect. NMDA receptors are glutamate-coupled ion channels that critically involved in survival of neuronal cells and neurodegenerative diseases. Thus, it is considered a promising target for the therapy of neurodegenerative disease. In this study, four catechins including two new catechins derivatives (1-2), together with thirteen known flavonoids were isolated from Anhua dark tea. The structures of compounds 1-2 [2S,3R-6-methoxycarbonylgallocatechin (1) and 2R,3R-6-methoxycarbonylgallocatechin (2)] were determined on the basis of their spectroscopic data. The preliminary bioassay indicated that compound 1 showed the best neuroprotective effects via N-methyl-d-aspartate (NMDA) receptors inhibition. Compound 1 protected SH-SY5Y cells against NMDA-induced injury and cell apoptosis via the modulation of NR2B expression, the activation of PI3K/Akt signaling and caspase-dependent pathway. The results suggested compound 1 would be a potent dietary therapy reagent for prevention of excitable brain injury.

Global mean estimation using a self-organizing dual-zoning method for preferential sampling.

Giving an appropriate weight to each sampling point is essential to global mean estimation. The objective of this paper was to develop a global mean estimation method with preferential samples. The procedure for this estimation method was to first zone the study area based on self-organizing dual-zoning method and then to estimate the mean according to stratified sampling method. In this method, spreading of points in both feature and geographical space is considered. The method is tested in a case study on the metal Mn concentrations in Jilin provinces of China. Six sample patterns are selected to estimate the global mean and compared with the global mean calculated by direct arithmetic mean method, polygon method, and cell method. The results show that the proposed method produces more accurate and stable mean estimates under different feature deviation index (FDI) values and sample sizes. The relative errors of the global mean calculated by the proposed method are from 0.14 to 1.47 % and they are the largest (4.83-8.84 %) by direct arithmetic mean method. At the same time, the mean results calculated by the other three methods are sensitive to the FDI values and sample sizes.

Design and synthesis of N-aryl isothioureas as a novel class of gastric H(+) /K(+) -ATPase inhibitors.

To find new H(+) /K(+) -ATPase inhibitors for the treatment of peptic ulcer disease, a series of novel N-aryl isothiourea derivatives were synthesized and their structures were identified by (1) H NMR and GC-MS. The effects of these compounds on inhibiting gastric acid secretion were evaluated by the guinea pig stomach mucous membrane study with pantoprazole magnesium as a positive control. The results showed that, of the 37 N-aryl isothiourea compounds synthesized, 20 compounds have comparable or stronger gastric acid inhibitory activities than that of pantoprazole magnesium. The quantitative structure-activity relationships (QSARs) of the N-aryl isothiourea compounds were also studied by comparative molecular field analysis (CoMFA) computation, and the model structure that was supposed to give more powerful bioactivities was finally predicted.

Improved Rotating Kernel Transformation Based Contourlet Domain Image Denoising Framework.

A contourlet domain image denoising framework based on a novel Improved Rotating Kernel Transformation is proposed, where the difference of subbands in contourlet domain is taken into account. In detail: (1). A novel Improved Rotating Kernel Transformation (IRKT) is proposed to calculate the direction statistic of the image; The validity of the IRKT is verified by the corresponding extracted edge information comparing with the state-of-the-art edge detection algorithm. (2). The direction statistic represents the difference between subbands and is introduced to the threshold function based contourlet domain denoising approaches in the form of weights to get the novel framework. The proposed framework is utilized to improve the contourlet soft-thresholding (CTSoft) and contourlet bivariate-thresholding (CTB) algorithms. The denoising results on the conventional testing images and the Optical Coherence Tomography (OCT) medical images show that the proposed methods improve the existing contourlet based thresholding denoising algorithm, especially for the medical images.

The depolymerization of sodium alginate by oxidative degradation.

Alginate has been extensively used as a carrier for macromolecules and as gene delivery vehicle. Both properties are molecular weight (Mw) dependent. Herein, we investigated factors affecting the oxidative depolymerization of alginate. The depolymerization process occurred mainly in the first 1 h. The Mw of the depolymerized alginate was influenced by the reaction temperature. At temperature 20 and 30°C, Mw of the alginate fragment kept constant and further Mw decrease was observed at 40°C. Along with the increase of hydrogen peroxide concentration, the Mw of the fragments decreased gradually. Influence of alginate initial concentration was marginal. A linear decrease of Mw was observed when the system pH was in the range of 5-7, whereas no further change was found when the system pH decreased from 7 to 8. Fourier transformed infrared spectroscopy spectra revealed that degradation undergoes by the breakage of the glycosidic bonds of polymers. No structural change was observed during the depolymerization process by UV spectroscopy. Cloud point pH increase was found for alginate 30 k. In summary, this method is an effective and convenient approach for preparing low Mw oligosaccharides from sodium alginate and may be potentially useful for the drug delivery system design with alginate.

5,7-Bis(benz-yloxy)-2-[4-(benz-yloxy)phen-yl]-4H-chromen-4-one.

In the title compound, C(36)H(28)O(5), the terminal benzene rings are twisted at dihedral angles of 6.75 (12), 70.86 (14) and 82.02 (12)° with the respect to the central plana r[maximum deviation = 0.070 (3) Å] chromen-4-one ring system. In the crystal structure, π-π stacking is observed between parallel benzene rings of adjacent mol-ecules [centroid-centroid distance = 3.7459 (16) Å].

[Study on the current situation and influential factors of child neglect among aged 3-6 year-olds in the urban areas of China].

OBJECTIVE: Children aged 3 - 6 years in the urban areas of China were surveyed for the first time to find out the state of child neglect (CN) as well as the major relevant risk factors so as to provide evidence for developing intervention measures. METHODS: 1163 children (of whom 49.6% were males and 4.5% were minority nationality) were randomly sampled under multistage stratification, from 25 cities which representing 15 provinces of China. Based on the Child Neglect Norms used by China, prevalence of CN was identified and SPSS-Windows 11.0 was employed for statistical analysis. Scores, frequency/degrees, age, sex and 5 types (physical, emotional, educational, medical and safety) of CN on every group of the regions, were calculated. Multifactorial analysis was conducted through Binary Logistic Regression and multiple linear regression to determine the relevant risk factors. RESULTS: (1) The average degree of CN for the 3 - 6 year-olds was 42.2, with its prevalence as 28.0%. Degrees of CN for the groups of 3, 4, 5, 6-year-olds were 41.7, 42.2, 42.1 and 43.1 (F = 0.988, P > 0.05), with frequencies of 25.0%, 25.3%, 27.9% and 35.4% (chi(2) = 4.798, P > 0.05), respectively. Degrees for CN in males and females were 42.7 and 41.8 (F = 2.502, P > 0.05) with the frequencies as 32.6% and 23.7% (chi(2) = 6.585, P < 0.05), respectively. Degrees of CN for the five types were 39.4-43.4 with the frequencies as 5.1%-12.9%, respectively. No significant difference was found in the frequency of the types (with an exception on 'physical neglect') between males and females (P > 0.05). The highest frequency (42.9%) of CN was seen in the single-parent families and the lowest in large family with three generations (25.5%). (2) According to monofactorial chi(2) test, the possible risk factors of CN would include: educational background, occupation and decrease of income of the parents during last year, etc. (3) Binary Logistic regression analysis showed that the influential factors to the occurrence of CN would include: father's educational background, sex of the child and mother's occupation, etc. (4) Multiple linear regression showed that the influential factors to the degree of CN were: family structure, number of supporting family members, relationship between parents and children, etc. CONCLUSION: The degree and frequency of CN among children aged 3 to 6 in the urban areas of China were high but similar among the four age groups. Male children had a higher frequency of neglect than females, but with similar degree. Children in single-parent families had the highest frequency. The major influential factors of CN would include: educational background, occupation, family structure, family income of the parents which were similar to the results reported from foreign literature.