A proportion of glioblastoma stemlike cells (GSCs) expressing endothelial cell marker CDH5 (vascular-endothelial–cadherin or CD144) can transdifferentiate into endothelial cells and form blood vessels. However, the implications of CDH5 expression in gliomas and how it is regulated in GSCs remain to be clarified. The mRNA and protein levels of CDH5 were detected in glioma samples and cultured cell lines, and the prognostic value of the CDH5 expression level for GBM patients was evaluated. Bioinformatics analysis was performed to reveal the potential functional roles of CDH5 in glioblastoma multiforme. Gene knockdown induced by short hairpin RNA, chromatin immunoprecipitation analysis, and a vasculogenic tube formation assay were performed to investigate the relationships among hypoxia, CDH5 expression level, and angiogenesis. CDH5 was overexpressed in gliomas, correlated with tumor grades, and was an independent adverse prognostic predictor for glioblastoma multiforme patients. CDH5 was specifically activated in GSCs but not in non-GSCs or neural stem cells, and CDH5+ cells could produce xenografts in immunocompromised mice. Bioinformatics analysis demonstrated that CDH5 might interact directly with hypoxia-inducible factor (HIF)2α. CDH5 expression was significantly upregulated in GSCs, but not in non-GSCs or normal neural stem cells, under a 1% O2 condition. Both HIF1α and HIF2α positively regulated CDH5 level in GSCs and could bind to the promoter of CDH5. Furthermore, CDH5 contributed to the vasculogenic mimicry of GSCs, especially under hypoxic conditions. The specific expression of CDH5 in GSCs may contribute to GSC-derived neovasculogenesis in glioblastoma multiforme, especially under hypoxic conditions, revealing novel tumorigenic mechanisms contributed by GSCs.
General hypergeometric distribution (GHGD) definition: from a finite space $N$ containing $n$ elements, randomly select totally $T$ subsets $M_i$ (each contains $m_i$ elements, $1 \geq i \geq T$), what is the probability that exactly $x$ elements are overlapped exactly $t$ times or at least $t$ times ($x_t$ or $x_{\geq t}$)? The GHGD described the distribution of random variables $x_t$ and $x_{\geq t}$. In our previous results, we obtained the formulas of mathematical expectation and variance for special situations ($T \leq 7$), and not provided proofs. Here, we completed the exact formulas of mean and variance for $x_t$ and $x_{\geq t}$ for any situation, and provided strict mathematical proofs. In addition, we give the asymptotic property of the variables. When the mean approaches to 0, the variance fast approaches to the value of mean, and actually, their difference is a higher order infinitesimal of mean. Therefore, when the mean is small enough ($<1$), it can be used as a fairly accurate approximation of variance.
Abstract Hypoxia-inducible factors (HIFs) play a key role in regulating cellular responses to low-oxygen conditions, particularly in promoting angiogenesis in tumor microenvironments. Aberrant HIF signaling enhances tumor growth and contributes to resistance against chemotherapy and radiotherapy. Targeting the HIF pathway has emerged as a promising strategy for cancer therapy. This study aimed to identify novel inhibitors of HIF signaling and evaluate their potential against the HIF–vascular endothelial growth factor (VEGF) axis for antiangiogenic therapy. In screening our in-house drug library using hypoxia response element dual-luciferase assay, HST3782, a novel 3-hydroxy-8-azabicyclo[3.2.1]octane-bridged compound, was identified as a promising HIF inhibitor, with IC50 of 1.028 μmol/L. In this work, the inhibitory effect of HST3782 on HIF signaling was confirmed in triple-negative breast cancer cells (SUM159) under hypoxic conditions (1% O2). Quantitative real-time polymerase chain reaction suggested the inhibitory effect of HST3782 on the expression of angiogenic genes, including VEGFa, VEGFR-1, BNIP3, and SERPINE1 in 786-O cells. Zebrafish model testing revealed that HST3782 inhibited intersegmental and subintestinal vessel development by up to 56% without marked toxicity. HST3782 was synthesized through a two-step 1,2,4 triazole cyclization reaction, followed by amide formation and ketone reduction steps. The last step of hydrogenation with sodium borohydride yielded a pair of endo-exo isomers. 2D-NOESY (Nuclear Overhauser effect spectroscopy) analysis confirmed that the compound's endo isomer (HST3782) had superior inhibitory effects relative to its exo form (8b). Given the above, HST3782 is a novel HIF inhibitor, with strong antiangiogenic effects and presents a valuable scaffold for future development of antiangiogenic drugs targeting the HIF–VEGF axis. Further studies are warranted to optimize HST3782's pharmacokinetics and therapeutic efficacy for antiangiogenic therapy in hypoxia-related malignancies.
General hypergeometric distribution (GHGD) describes the following distribution: from a finite space containing N elements, select T subsets with each subset contains M[i] (T-1 >= i >= 0) elements, what is the probability that exactly x elements are overlapped exactly t times or at least t times (XLO=t or XLO>=t, T >= t >= 0, here LO is level of overlap)? The classical hypergeometric distribution (HGD) describes the situation of two subsets, while the general situation has not been resolved, despite the overlapped elements has been visualized with the Venn diagram method for about 140 years. GHGD described not only the distribution of XLO=t or XLO>=t that are overlapped in all of the subsets (XLO=T), but also the XLO=t or XLO>=t that are overlapped in a portion of the subsets (LO = t or LO >= t, T >= t >= 0). Here, we developed algorithms to calculate the GHGD and discovered graceful formulas of the essential statistics for the GHGD, including mathematical expectation, variance, and high order moments. In addition, statistical theory to infer a statistically reliable gene set from multiple datasets based on these formulas was established by applying Chebyshev's inequalities.
Abstract Background: In recent years, the prevalence of fowl adenovirus serotype 4 (FAdV-4) has caused huge economic losses to the Chinese poultry industry. The objective of this study was to determine the occurrence of FAdV-4 in Yunnan Province through an epidemiological investigation of poultry and wild birds from 2017 to 2021 and phylogenetic analysis of the isolated fiber genes. Results: The results showed that the FAdV-4 positive rate in poultry and migratory birds was 11.34% and 0.3%, respectively. The infection rate of the poultry tissue samples was high in central and west-ern Yunnan Province, and the infected hosts were mainly local chickens. Via the detection of common poultry infectious diseases prone to co-infection, it was found that the birds were mainly co-infected with pathogens such as infectious laryngotracheitis, chicken infectious anemia virus, and avian influenza virus. Five poultry-source strains and one wild bird-source strain were isolated, and phylogenetic analysis of these strains using the fiber gene showed that they all had high homology with the early Chinese highly pathogenic strains and clustered with the same genetic and evolutionary clade as the Chinese reference strain. The fiber protein is characterized by loci that indicate highly pathogenic strains (G 219 D, P 307 A, V 319 I, and A 308 T). Conclusions: The results of our study demonstrate that FAdV-4 continues to exhibit a high prevalence rate among poultry populations in Yunnan Province, China. Notably, we report the first detection of FAdV-4 in the feces of black-necked cranes. Our statistical analysis reveals that central Yunnan and western Yunnan experience a high incidence rate of FAdV-4, often accompanying co-infections with ILT, CIAV, and AIV.
Leaves are essential vegetative organs of plants. Studying the variations in leaf nutrient content and microbial communities of male and female plants at reproductive stages helps us understand allocation and adaptation strategies. This study aimed to determine the nutrient characteristics and microbial differences in the leaves of male and female Idesia polycarpa at reproductive stages. Seven-year-old female and male plants were used as test materials in this experiment. The samples were collected at three stages: flowering (May), fruit matter accumulation (July), and fruit ripening (October). The nitrogen (TN), phosphorus (TP), potassium (TK), carbon (TC), and the pH of the female and male leaves were analyzed. In addition, the leaf microbial diversity and differential metabolites were determined using the Illumina high-throughput sequencing method and the ultra-high performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) method at the reproductive developmental stages. This study found that male and female plant leaves had different TN and TK contents over time but no difference in TC and TP content. The significant differences in bacterial diversity between male and female plants and the richness of the fungi of male plants at the flowering and fruit maturity stages were observed. Proteobacteria, Pseudomonadaceae, Ascomycota, and Aspergillus were the dominant bacteria and fungi in the Idesia polycarpa leaves. The presence of microorganisms differed in the two sexes in different periods. Alphaproteobacteria and Sordariomycetes were the indicator groups for male leaves, and Pseudomonas and Sordariomycetes were the indicator groups for female leaves. Significant differences in phenolic acid were found between male and female leaves. A KEGG enrichment analysis revealed that differential metabolites were enriched in metabolic pathways, amino acid biosynthesis, and the nucleotide metabolism. According to a correlation analysis, leaf TK and TP were strongly correlated with endophytic bacteria abundance and differential metabolite composition. This study revealed the changes in substances and microorganisms in the leaves of male and female plants in their reproductive stages. It provides a theoretical basis for developing and utilizing the leaves of Idesia polycarpa and for field management.
The method on the determination of the chlorine content in solid biofuel by oxygen bomb is studies in this paper and the optimal conditions for incineration are suggested.The method is simple,quick and practical,and it needs little quantity reagents.Analytical result obtained by this method is accurate and precise,and it could be used for routine testing work.
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