KDM6A Regulates Cell Plasticity and Pancreatic Cancer Progression by Non-Canonical Activin Pathway

BACKGROUND & AIMS: Inactivating mutations of KDM6A, a histone demethylase, were frequently found in pancreatic ductal adenocarcinoma (PDAC). We investigated the role of KDM6A in PDAC development. METHODS: We performed a pancreatic tissue microarray analysis of KDM6A protein levels. We used human PDAC cell lines for KDM6A knockout and knockdown experiments. We performed Bru-seq analysis to elucidate the effects of KDM6A loss on global transcription. We performed studies with Ptf1a(Cre); LSL-Kras(G12D); Trp53(R172H/+); Kdm6a(fl/fl or fl/Y), Ptf1a(Cre); Kdm6a(fl/fl or fl/Y), and orthotopic xenograft mice to investigate the impacts of Kdm6a deficiency on pancreatic tumorigenesis and pancreatitis. RESULTS: Loss of KDM6A was associated with metastasis in PDAC patients. Bru-seq analysis revealed upregulation of the epithelial-mesenchymal transition pathway in PDAC cells deficient of KDM6A. Loss of KDM6A promoted mesenchymal morphology, migration, and invasion in PDAC cells in vitro. Mechanistically, activin A and subsequent p38 activation likely mediated the role of KDM6A loss. Inhibiting either activin A or p38 reversed the effect. Pancreas-specific Kdm6a-knockout mice pancreata demonstrated accelerated PDAC progression, developed a more aggressive undifferentiated type PDAC, and increased metastases in the background of Kras and p53 mutations. Kdm6a-deficient pancreata in a pancreatitis model had a delayed recovery with increased PDAC precursor lesions compared to wild-type pancreata. CONCLUSIONS: Loss of KDM6A accelerates PDAC progression and metastasis, most likely by a non-canonical p38-dependant activin A pathway. KDM6A also promotes pancreatic tissue recovery from pancreatitis. Activin A might be utilized as a therapeutic target for KDM6A-deficient PDACs

Hopf Bifurcation in Models for Pertussis Epidemiology

Pertussis (whooping cough) incidence in the United States has oscillated with a period of about four years since data was first collected in 1922. An infection with pertussis confers immunity for several years, but then the immunity wanes, so that reinfection is possible. A pertussis reinfection is mild after partial loss of immunity, but the reinfection can be severe after complete loss of immunity. Three pertussis transmission models with waning of immunity are examined for periodic solutions. Equilibria and their stability are determined. Hopf bifurcation of periodic solutions around the endemic equilibrium can occur for some parameter values in two of the models. Periods of about four years are found for epidemiologically reasonable parameter values in two of these models

Isolation and Expression of Glucosinolate Synthesis Genes <em>CYP83A1</em> and <em>CYP83B1</em> in Pak Choi (<em>Brassica </em><em>rapa</em> L. ssp. <em>c</em><em>hinensis</em> var. <em>c</em><em>ommunis</em> (N. Tsen & S.H. Lee) Hanelt)

<em>CYP83A1</em> and <em>CYP83B1</em> are two key synthesis genes in the glucosinolate biosynthesis pathway. <em>CYP83A1</em> mainly metabolizes the aliphatic oximes to form aliphatic glucosinolate and <em>CYP83B1</em> mostly catalyzes aromatic oximes to synthesis corresponding substrates for aromatic and indolic glucosinolates. In this study, two <em>CYP83A1</em> genes named <em>BcCYP83A1-1</em> (JQ289997), <em>BcCYP83A1-2</em> (JQ289996) respectively and one <em>CYP83B1</em> (<em>BcCYP83B1</em>, HM347235) gene were cloned from the leaves of pak choi (<em>Brassica rapa</em> L. ssp. <em>chinensis </em>var. <em>communis </em>(N. Tsen & S.H. Lee) Hanelt) “Hangzhou You Dong Er” cultivar. Their ORFs were 1506, 1509 and 1500 bp in length, encoding 501, 502 and 499 amino acids, respectively. The predicted amino acid sequences of <em>CYP83A1-1</em>, <em>CYP83A1-2 </em>and <em>CYP83B1</em> shared high sequence identity of 87.65, 86.48 and 95.59% to the corresponding ones in <em>Arabidopsis</em>, and 98.80, 98.61 and 98.80% to the corresponding ones in <em>Brassica pekinensis </em>(Chinese cabbage), respectively. Quantitative real-time PCR analysis indicated that both <em>CYP83A1</em> and <em>CYP83B1</em> expressed in roots, leaves and petioles of pak choi, while the transcript abundances of <em>CYP83A1 </em>were higher in leaves than in petioles and roots, whereas <em>CYP83B1 </em>showed higher abundances in roots. The expression levels of glucosinolate biosynthetic genes were consistent with the glucosinolate profile accumulation in shoots of seven cultivars and three organs. The isolation and characterization of the glucosinolate synthesis genes in pak choi would promote the way for further development of agronomic traits via genetic engineering

Identification and evaluation of the inhibitory effect of Prunella vulgaris extract on SARS-coronavirus 2 virus entry.

Until now, antiviral therapeutic agents are still urgently required for treatment or prevention of SARS-coronavirus 2 (SCoV-2) virus infection. In this study, we established a sensitive SCoV-2 Spike glycoprotein (SP), including an SP mutant D614G, pseudotyped HIV-1-based vector system and tested their ability to infect ACE2-expressing cells. Based on this system, we have demonstrated that an aqueous extract from the Natural herb Prunella vulgaris (NhPV) displayed potent inhibitory effects on SCoV-2 SP (including SPG614 mutant) pseudotyped virus (SCoV-2-SP-PVs) mediated infections. Moreover, we have compared NhPV with another compound, Suramin, for their anti-SARS-CoV-2 activities and the mode of their actions, and found that both NhPV and Suramin are able to directly interrupt SCoV-2-SP binding to its receptor ACE2 and block the viral entry step. Importantly, the inhibitory effects of NhPV and Suramin were confirmed by the wild type SARS-CoV-2 (hCoV-19/Canada/ON-VIDO-01/2020) virus infection in Vero cells. Furthermore, our results also demonstrated that the combination of NhPV/Suramin with an anti-SARS-CoV-2 neutralizing antibody mediated a more potent blocking effect against SCoV2-SP-PVs. Overall, by using SARS-CoV-2 SP-pseudotyped HIV-1-based entry system, we provide strong evidence that NhPV and Suramin have anti-SARS-CoV-2 activity and may be developed as a novel antiviral approach against SARS-CoV-2 infection