Gene expression and biological processes influenced by deletion of Stat3 in pulmonary type II epithelial cells

<p>Abstract</p> <p>Background</p> <p>The signal transducer and activator of transcription 3 (STAT3) mediates gene expression in response to numerous growth factors and cytokines, playing an important role in many cellular processes. To better understand the molecular mechanisms by which <it>Stat3 </it>influences gene expression in the lung, the effect of pulmonary epithelial cell specific deletion of <it>Stat3 </it>on genome wide mRNA expression profiling was assessed. Differentially expressed genes were identified from Affymetrix Murine GeneChips analysis and subjected to gene ontology classification, promoter analysis, pathway mapping and literature mining.</p> <p>Results</p> <p>Total of 791 mRNAs were significantly increased and 314 mRNAs were decreased in response to the deletion of <it>Stat3</it>^Δ/Δin the lung. STAT is the most enriched cis-elements in the promoter regions of those differentially expressed genes. Deletion of <it>Stat3 </it>induced genes influencing protein metabolism, transport, chemotaxis and apoptosis and decreased the expression of genes mediating lipid synthesis and metabolism. Expression of <it>Srebf1 </it>and <it>2</it>, genes encoding key regulators of fatty acid and steroid biosynthesis, was decreased in type II cells from the <it>Stat3</it>^Δ/Δmice, consistent with the observation that lung surfactant phospholipids content was decreased. <it>Stat3 </it>influenced both pro- and anti-apoptotic pathways that determine cell death or survival. <it>Akt</it>, a potential transcriptional target of <it>Stat3</it>, was identified as an important participant in <it>Stat3 </it>mediated pathways including Jak-Stat signaling, apoptosis, Mapk signaling, cholesterol and fatty acid biosynthesis.</p> <p>Conclusion</p> <p>Deletion of <it>Stat3 </it>from type II epithelial cells altered the expression of genes regulating diverse cellular processes, including cell growth, apoptosis and lipid metabolism. Pathway analysis indicates that STAT3 regulates cellular homeostasis through a complex regulatory network that likely enhances alveolar epithelial cell survival and surfactant/lipid synthesis, necessary for the protection of the lung during injury.</p

Key-updatable public-key encryption with keyword search (Or: How to realize PEKS with efficient key updates for IoT environments)

Security and privacy are the key issues for the Internet of Things (IoT) systems. Especially, secure search is an important functionality for cooperation among users\u27 devices and non-trusted servers. Public-key encryption with keyword search (PEKS) enables us to search encrypted data and is expected to be used between a cloud server and users\u27 mobile devices or IoT devices. However, those mobile devices might be lost or stolen. For IoT devices, it might be difficult to store keys in a tamper-proof manner due to prohibitive costs. In this paper, we deal with such a key-exposure problem on PEKS and introduce the concept of PEKS with key-updating functionality, which we call key-updatable PEKS (KU-PEKS). Specifically, we propose two models of KU-PEKS: the key-evolution model and the key-insulation model. In the key-evolution model, a pair of public and secret keys can be updated if needed (e.g., the secret key is exposed). In the key-insulation model, the public key remains fixed while the secret key can be updated if needed. The former model makes a construction simple and more efficient than the latter. On the other hand, the latter model is preferable for practical use since a user never updates their public key. We show constructions in each model in a black-box manner. We also give implementation results on Raspberry Pi 3, which can be regarded as a reasonable platform of IoT devices

Seismic Performance of Isolated Bridges Considering Long-term Deterioration of Isolators

Mechanical properties of natural rubber seismic isolators are varied due to aging deterioration. It is needed that seismic performance of isolated bridges are maintained considering aging deterioration of isolators over their lifetime. In this study, seismic failure modes and seismic safety of isolated bridges were evaluated considering uncertainties in the material and mechanical properties and aging deterioration of isolators. It was shown that seismic safety of the isolated bridges is mainly controlled by the rupture strain of the isolator if the ultimate capacity ratio between the isolator and the column is low and that adequate capacity ratio is needed to enhance seismic safety and reparability of isolated bridges

Functional analysis of HOXD9 in human gliomas and glioma cancer stem cells

<p>Abstract</p> <p>Background</p> <p><it>HOX </it>genes encode a family of homeodomain-containing transcription factors involved in the determination of cell fate and identity during embryonic development. They also behave as oncogenes in some malignancies.</p> <p>Results</p> <p>In this study, we found high expression of the <it>HOXD9 </it>gene transcript in glioma cell lines and human glioma tissues by quantitative real-time PCR. Using immunohistochemistry, we observed HOXD9 protein expression in human brain tumor tissues, including astrocytomas and glioblastomas. To investigate the role of <it>HOXD9 </it>in gliomas, we silenced its expression in the glioma cell line U87 using <it>HOXD9</it>-specific siRNA, and observed decreased cell proliferation, cell cycle arrest, and induction of apoptosis. It was suggested that <it>HOXD9 </it>contributes to both cell proliferation and/or cell survival. The <it>HOXD9 </it>gene was highly expressed in a side population (SP) of SK-MG-1 cells that was previously identified as an enriched-cell fraction of glioma cancer stem-like cells. <it>HOXD9 </it>siRNA treatment of SK-MG-1 SP cells resulted in reduced cell proliferation. Finally, we cultured human glioma cancer stem cells (GCSCs) from patient specimens found with high expression of <it>HOXD9 </it>in GCSCs compared with normal astrocyte cells and neural stem/progenitor cells (NSPCs).</p> <p>Conclusions</p> <p>Our results suggest that <it>HOXD9 </it>may be a novel marker of GCSCs and cell proliferation and/or survival factor in gliomas and glioma cancer stem-like cells, and a potential therapeutic target.</p

A low-frequency IL4R locus variant in Japanese patients with intravenous immunoglobulin therapy-unresponsive Kawasaki disease

Background: Kawasaki disease (KD) is a systemic vasculitis which may be associated with coronary artery aneurysms. A notable risk factor for the development of coronary artery aneurysms is resistance to intravenous immunoglobulin (IVIG) therapy, which comprises standard treatment for the acute phase of KD. The cause of IVIG resistance in KD is largely unknown; however, the contribution of genetic factors, especially variants in immune-related genes, has been suspected. Methods: To explore genetic variants related to IVIG-unresponsiveness, we designated KD patients who did not respond to both first and second courses of IVIG therapy as IVIG-unresponsive patients. Using genomic DNA from 30 IVIG-unresponsive KD patients, we performed pooled genome sequencing targeting 39 immune-related cytokine receptor genes. Results: The single nucleotide variant (SNV), rs563535954 (located in the IL4R locus), was concentrated in IVIG-unresponsive KD patients. Individual genotyping showed that the minor allele of rs563535954 was present in 4/33 patients with IVIG-unresponsive KD, compared with 20/1063 individuals in the Japanese genome variation database (odds ratio = 7.19, 95% confidence interval 2.43-21.47). Furthermore, the minor allele of rs563535954 was absent in 42 KD patients who responded to IVIG treatment (P = 0.0337), indicating that a low-frequency variant, rs563535954, is associated with IVIG-unresponsiveness in KD patients. Although rs563535954 is located in the 3'-untranslated region of IL4R, there was no alternation in IL4R expression associated with the mior allele of rs563535954. However, IVIG-unresponsive patients that exhibited the minor allele of rs563535954 tended to be classified into the low-risk group (based on previously reported risk scores) for prediction of IVIG-resistance. Therefore, IVIG-unresponsiveness associated with the minor allele of rs563535954 might differ from IVIG-unresponsiveness associated with previous risk factors used to evaluate IVIG-unresponsiveness in KD. Conclusion: These findings suggest that the SNV rs563535954 could serve as a predictive indicator of IVIG-unresponsiveness, thereby improving the sensitivity of risk scoring systems, and may aid in prevention of coronary artery lesions in KD patients.ArticlePEDIATRIC RHEUMATOLOGY.17:34(2019)journal articl

Tumour resistance in induced pluripotent stem cells derived from naked mole-rats

The naked mole-rat (NMR, Heterocephalus glaber), which is the longest-lived rodent species, exhibits extraordinary resistance to cancer. Here we report that NMR somatic cells exhibit a unique tumour-suppressor response to reprogramming induction. In this study, we generate NMR-induced pluripotent stem cells (NMR-iPSCs) and find that NMR-iPSCs do not exhibit teratoma-forming tumorigenicity due to the species-specific activation of tumour-suppressor alternative reading frame (ARF) and a disruption mutation of the oncogene ES cell-expressed Ras (ERAS). The forced expression of Arf in mouse iPSCs markedly reduces tumorigenicity. Furthermore, we identify an NMR-specific tumour-suppression phenotype—ARF suppression-induced senescence (ASIS)—that may protect iPSCs and somatic cells from ARF suppression and, as a consequence, tumorigenicity. Thus, NMR-specific ARF regulation and the disruption of ERAS regulate tumour resistance in NMR-iPSCs. Our findings obtained from studies of NMR-iPSCs provide new insight into the mechanisms of tumorigenicity in iPSCs and cancer resistance in the NMR

Isotope production in proton-, deuteron-, and carbon-induced reactions on Nb 93 at 113 MeV/nucleon

Isotope-production cross sections for p-, d-, and C-induced spallation reactions on Nb93 at 113 MeV/nucleon were measured using the inverse-kinematics method employing secondary targets of CH2, CD2, and C. The measured cross sections for Mo90, Nb90, Y86,88 produced by p-induced reactions were found to be consistent with those measured by the conventional activation method. We performed benchmark tests of the reaction models INCL-4.6, JQMD, and JQMD-2.0 implemented in the Particle and Heavy Ion Transport code System (PHITS) and of the nuclear data libraries JENDL-4.0/HE, TENDL-2017, and ENDF/B-VIII.0. The model calculations also showed generally good agreement with the measured isotope-production cross sections for p-, d-, and C-induced reactions. It also turns out that, among the three nuclear data libraries, JENDL-4.0/HE provides the best agreement with the measured data for the p-induced reactions. We compared the present Nb93 data with the Zr93 data, that were measured previously by the same inverse kinematics method (Kawase et al., Prog. Theor. Exp. Phys. 2017, 093D03 (2017)2050-391110.1093/ptep/ptx110), with particular attention to the effect of neutron-shell closure on isotope production in p- and d-induced spallation reactions. The isotopic distributions of the measured production cross sections in the Zr93 data showed noticeable jumps at neutron number N=50 in the isotopic chains of ΔZ=0 and -1, whereas no such jump appeared in isotopic chain of ΔZ=0 in the Nb93 data. From INCL-4.6 + GEM calculations, we found that the jump formed in the evaporation process is smeared out by the intranuclear cascade component in Nb91 produced by the Nb93(p,p2n) and (d,d2n) reactions on Nb93. Moreover, for Nb93, the distribution of the element-production cross sections as a function of the change in proton number ΔZ is shifted to smaller ΔZ than for Zr93, because the excited Nb prefragments generated by the cascade process are more likely to emit protons than the excited Zr prefragments, due to the smaller proton-separation energies of the Nb isotopes

Coulomb breakup reactions of 93,94 Zr in inverse kinematics

Coulomb breakup reactions of 93,94 Zr have been studied in inverse kinematics at incident beam energies of about 200 MeV/nucleon in order to evaluate neutron capture reaction methods. The 93 Zr(n,γ) 94 Zr reaction is particularly important as a candidate nuclear transmutation reaction for the long-lived fission product 93 Zr in nuclear power plants. One- and two-neutron removal cross sections on Pb and C targets were measured to deduce the inclusive Coulomb breakup cross sections, 375 ± 29 (stat.) ± 30 (syst.) and 403 ± 26 (stat.) ± 31 (syst.) mb for 93 Zr and 94 Zr, respectively. The results are compared with estimates using the standard Lorentzian model and microscopic calculations. The results reveal a possible contribution of the pygmy dipole resonance or giant quadrupole resonance in the Coulomb breakup reactions of 94 Zr

RNA-Binding Protein Musashi1 Modulates Glioma Cell Growth through the Post-Transcriptional Regulation of Notch and PI3 Kinase/Akt Signaling Pathways

Musashi1 (MSI1) is an RNA-binding protein that plays critical roles in nervous-system development and stem-cell self-renewal. Here, we examined its role in the progression of glioma. Short hairpin RNA (shRNA)-based MSI1-knock down (KD) in glioblastoma and medulloblastoma cells resulted in a significantly lower number of self renewing colony on day 30 (a 65% reduction), compared with non-silencing shRNA-treated control cells, indicative of an inhibitory effect of MSI1-KD on tumor cell growth and survival. Immunocytochemical staining of the MSI1-KD glioblastoma cells indicated that they ectopically expressed metaphase markers. In addition, a 2.2-fold increase in the number of MSI1-KD cells in the G2/M phase was observed. Thus, MSI1-KD caused the prolongation of mitosis and reduced the cell survival, although the expression of activated Caspase-3 was unaltered. We further showed that MSI1-KD glioblastoma cells xenografted into the brains of NOD/SCID mice formed tumors that were 96.6% smaller, as measured by a bioluminescence imaging system (BLI), than non-KD cells, and the host survival was longer (49.3±6.1 days vs. 33.6±3.6 days; P<0.01). These findings and other cell biological analyses suggested that the reduction of MSI1 in glioma cells prolonged the cell cycle by inducing the accumulation of Cyclin B1. Furthermore, MSI1-KD reduced the activities of the Notch and PI3 kinase-Akt signaling pathways, through the up-regulation of Numb and PTEN, respectively. Exposure of glioma cells to chemical inhibitors of these pathways reduced the number of spheres and living cells, as did MSI1-KD. These results suggest that MSI1 increases the growth and/or survival of certain types of glioma cells by promoting the activation of both Notch and PI3 kinase/Akt signaling

Cross sections for nuclide production in proton- and deuteron-induced reactions on 93

Isotopic production cross sections were measured for proton- and deuteron-induced reactions on 93Nb by means of the inverse kinematics method at RIKEN Radioactive Isotope Beam Factory. The measured production cross sections of residual nuclei in the reaction 93Nb + p at 113 MeV/u were compared with previous data measured by the conventional activation method in the proton energy range between 46 and 249 MeV. The present inverse kinematics data of four reaction products (90Mo, 90Nb, 88Y, and 86Y) were in good agreement with the data of activation measurement. Also, the model calculations with PHITS describing the intra-nuclear cascade and evaporation processes generally well reproduced the measured isotopic production cross sections