Transdifferentiation of lung adenocarcinoma in mice with Lkb1 deficiency to squamous cell carcinoma

Lineage transition in adenocarcinoma (ADC) and squamous cell carcinoma (SCC) of non-small cell lung cancer, as implicated by clinical observation of mixed ADC and SCC pathologies in adenosquamous cell carcinoma, remains a fundamental yet unsolved question. Here we provide in vivo evidence showing the transdifferentiation of lung cancer from ADC to SCC in mice: Lkb1-deficient lung ADC progressively transdifferentiates into SCC, via a pathologically mixed mAd-SCC intermediate. We find that reduction of lysyl oxidase (Lox) in Lkb1-deficient lung ADC decreases collagen disposition and triggers extracellular matrix remodelling and upregulates p63 expression, a SCC lineage survival oncogene. Pharmacological Lox inhibition promotes the transdifferentiation, whereas ectopic Lox expression significantly inhibits this process. Notably, ADC and SCC show differential responses to Lox inhibition. Collectively, our findings demonstrate the de novo transdifferentiation of lung ADC to SCC in mice and provide mechanistic insight that may have important implications for lung cancer treatment

Check on the features of potted 20-inch PMTs with 1F3 electronics prototype at Pan-Asia

The Jiangmen underground neutrino observatory (JUNO) is a neutrino project with a 20-kton liquid scintillator detector located at 700-m underground. The large 20-inch PMTs are one of the crucial components of the JUNO experiment aiming to precision neutrino measurements with better than 3% energy resolution at 1 MeV. The excellent energy resolution and a large fiducial volume provide many exciting opportunities for addressing important topics in neutrino and astro-particle physics. With the container #D at JUNO Pan-Asia PMT testing and potting station, the features of waterproof potted 20-inch PMTs were measured with JUNO 1F3 electronics prototype in waveform and charge, which are valuable for better understanding on the performance of the waterproof potted PMTs and the JUNO 1F3 electronics. In this paper, basic features of JUNO 1F3 electronics prototype run at Pan-Asia will be introduced, followed by an analysis of the waterproof potted 20-inch PMTs and a comparison with the results from commercial electronics used by the container #A and #B

Real-time Monitoring for the Next Core-Collapse Supernova in JUNO

Core-collapse supernova (CCSN) is one of the most energetic astrophysical events in the Universe. The early and prompt detection of neutrinos before (pre-SN) and during the SN burst is a unique opportunity to realize the multi-messenger observation of the CCSN events. In this work, we describe the monitoring concept and present the sensitivity of the system to the pre-SN and SN neutrinos at the Jiangmen Underground Neutrino Observatory (JUNO), which is a 20 kton liquid scintillator detector under construction in South China. The real-time monitoring system is designed with both the prompt monitors on the electronic board and online monitors at the data acquisition stage, in order to ensure both the alert speed and alert coverage of progenitor stars. By assuming a false alert rate of 1 per year, this monitoring system can be sensitive to the pre-SN neutrinos up to the distance of about 1.6 (0.9) kpc and SN neutrinos up to about 370 (360) kpc for a progenitor mass of 30$M_{\odot}$ for the case of normal (inverted) mass ordering. The pointing ability of the CCSN is evaluated by using the accumulated event anisotropy of the inverse beta decay interactions from pre-SN or SN neutrinos, which, along with the early alert, can play important roles for the followup multi-messenger observations of the next Galactic or nearby extragalactic CCSN.Comment: 24 pages, 9 figure

Glucocorticoid modulatory element-binding protein 1 (GMEB1) interacts with the de-ubiquitinase USP40 to stabilize CFLARL and inhibit apoptosis in human non-small cell lung cancer cells

Abstract Background GMEB1 was originally identified via its interaction with GMEB2, which binds to the promoter region of the tyrosine aminotransferase (TAT) gene and modulates transactivation of the glucocorticoid receptor gene. In the cytosol, GMEB1 interacts with and inhibits CASP8, but the molecular mechanism is currently unknown. Methods Human non-small cell lung cancer cells and 293FT cells were used to investigate the function of GMEB1/USP40/CFLARL complex by WB, GST Pull-Down Assay, Immunoprecipitation, Immunofluorescence and Flow cytometry analysis. A549 cells overexpressing green fluorescent protein and GMEB1 shRNA were used for tumor xenograft using female athymic nu/nu 4-week-old mice. Results We found GMEB1 interacted with CFLARL (also known as c-FLIPL) in the cytosol and promoted its stability. USP40 targeted CFLARL for K48-linked de-ubiquitination. GMEB1 promoted the binding of USP40 to CFLARL. USP40 knockdown did not increase CFLARL protein level despite GMEB1 overexpression, suggesting GMEB1 promotes CFLARL stability via USP40. Additionally, GMEB1 inhibited the activation of pro-caspase 8 and apoptosis in non-small cell lung cancer (NSCLC) cell via CFLARL stabilization. Also, GMEB1 inhibited the formation of DISC upon TRAIL activation. CFLARL enhanced the binding of GMEB1 and CASP8. Downregulation of GMEB1 inhibited A549 xenograft tumor growth in vivo. Conclusions Our findings show the de-ubiquitinase USP40 regulates the ubiquitination and degradation of CFLARL; and GMEB1 acts as a bridge protein for USP40 and CFLARL. Mechanistically, we found GMEB1 inhibits the activation of CASP8 by modulating ubiquitination and degradation of CFLARL. These findings suggest a novel strategy to induce apoptosis through CFLARL targeting in human NSCLC cells

The Moisture Diffusion Equation for Moisture Absorption of Multiphase Symmetrical Sandwich Structures

When hydrophilic materials (such as natural fiber, epoxy resin or concrete) compose sandwich structures, the moisture absorption from hydrothermal environments may significantly affect their mechanical properties. Although some experimental works were carried out, few mathematical efforts have been made to describe the moisture diffusion of multiphase symmetrical sandwich structures thus far. In this paper, the moisture diffusion equation was developed to effectively predict the moisture diffusion behavior of multiphase symmetrical sandwich structures as the function of aging time. Both finite element analysis (FEA) and experimental works were carried out to validate the accuracy of the analytical method, and the analytical results show a good agreement with FEA and experimental data. The effect of the interface condition on the concentration at the interfaces was discussed; the difference between concentration and normalized concentration was illustrated; the correct interface condition, which is a continuous normalized concentration condition, was explained for the moisture diffusion behavior of sandwich structures

The Moisture Diffusion Equation for Moisture Absorption of Multiphase Symmetrical Sandwich Structures

When hydrophilic materials (such as natural fiber, epoxy resin or concrete) compose sandwich structures, the moisture absorption from hydrothermal environments may significantly affect their mechanical properties. Although some experimental works were carried out, few mathematical efforts have been made to describe the moisture diffusion of multiphase symmetrical sandwich structures thus far. In this paper, the moisture diffusion equation was developed to effectively predict the moisture diffusion behavior of multiphase symmetrical sandwich structures as the function of aging time. Both finite element analysis (FEA) and experimental works were carried out to validate the accuracy of the analytical method, and the analytical results show a good agreement with FEA and experimental data. The effect of the interface condition on the concentration at the interfaces was discussed; the difference between concentration and normalized concentration was illustrated; the correct interface condition, which is a continuous normalized concentration condition, was explained for the moisture diffusion behavior of sandwich structures

Isolation and characterization of MbWRKY1, a WRKY transcription factor gene from Malus baccata (L.) Borkh involved in drought tolerance

WRKY transcription factors are involved in stress responses in plants. However, their roles in abiotic stresses are still not well known in Malus plants. In the present study, a WRKY gene was isolated from Malus baccata (L.) Borkh and designated as MbWRKY1. Subcellular localization revealed that MbWRKY1 was localized in nucleus. The expression levels of MbWRKY1 were up-regulated by dehydration, salinity, and ABA treatments in M. baccata seedlings. When MbWRKY1 was introduced into tobacco, it improved drought stress tolerance in transgenic plants. When dealt with drought treatment, the transgenic plants had the higher contents of chlorophyll, proline, relative water content, AsA and GSH than WT. Compared to WT plants, the over-expression of MbWRKY1 in transgenic tobacco also led to decreased levels of H2O2, MDA, and elecrolyte leakage when dealt with drought stress. There were increased activities of POD, CAT, SOD and APX in transgenic tobaccos, especially when dealt with drought treatment. Moreover, the MbWRKY1 transgenic plants enhanced the expressions of oxidative stress response (NtPOD, NtCAT, NtSOD and NtAPX) and stress-related genes (NtP5CS and NtLEA5) when dealt with drought stress. These results suggest that MbWRKY1 gene plays a positive regulatory role in drought stress response.The accepted manuscript in pdf format is listed with the files at the bottom of this page. The presentation of the authors' names and (or) special characters in the title of the manuscript may differ slightly between what is listed on this page and what is listed in the pdf file of the accepted manuscript; that in the pdf file of the accepted manuscript is what was submitted by the author

Isolation and functional analysis of MdNAS1, with functions in improved iron stress tolerance and abnormal flower in transgenic tobacco

Metal elements are essential micronutrients required by all plants for natural physiological activities. Nicotianamine is considered as the chelate substance in the transport of metal ions. In the present study, a new gene encoding NA synthase was isolated from Malus domestica (L.) Borkh and designated as MdNAS1. The expression levels of MdNAS1 were enriched in leaf, and phloem which were highly affected by Fe stress, indoleacetic acid (IAA) and abscisic acid (ABA) treatments in M. domestica seedlings. Subcellular localization research revealed that MdNAS1 was localized in cytoplasmic membrane. Overexpression of MdNAS1 in transgenic tobaccos increased the tolerance to Fe stress, but also contributes to higher chlorophyll, NA, Fe, Mn, Cu and Zn contents and abnormal flowers. Moreover, the MdNAS1-OE tobaccos had the increased expression levels of Fe uptake and transport related genes (NtFRO, NtIRT1, NtVIT, NtNRAMP1, and NtYSL)

14-3-3 Binding Sites in the Snail Protein Are Essential for Snail-Mediated Transcriptional Repression and Epithelial-Mesenchymal Differentiation

The Snail transcription factor is a repressor and a master regulator of epithelial-mesenchymal transition (EMT) events in normal embryonic development and during tumor metastases. Snail directly regulates genes affecting cell adhesion, motility, and polarity. Invasive tumor cells express high levels of Snail, which is a marker for aggressive disease and poor prognosis. Transcriptional repression and EMT induction by Snail requires binding to its obligate corepressor, the LIM protein Ajuba. It is unclear how this complex is assembled and maintained on Snail target genes. Here we define functional 14-3-3 binding motifs in Snail and Ajuba, which selectively bind 14-3-3 protein isoforms. In Snail, an NH2-terminal motif in the repression domain cooperates with a COOH-terminal, high-affinity motif for binding to 14-3-3 proteins. Coordinate mutation of both motifs abolishes 14-3-3 binding and inhibits Snail-mediated gene repression and EMT differentiation. Snail, 14-3-3 proteins, and Ajuba form a ternary complex that is readily detected through chromatin immunoprecipitation at the endogenous E-cadherin promoter. Collectively, these data show that 14-3-3 proteins are new components of the Snail transcriptional repression machinery and mediate its important biological functions.</p