Telomere and ribosomal DNA repeats are chromosomal targets of the bloom syndrome DNA helicase

BACKGROUND: Bloom syndrome is one of the most cancer-predisposing disorders and is characterized by genomic instability and a high frequency of sister chromatid exchange. The disorder is caused by loss of function of a 3' to 5' RecQ DNA helicase, BLM. The exact role of BLM in maintaining genomic integrity is not known but the helicase has been found to associate with several DNA repair complexes and some DNA replication foci. RESULTS: Chromatin immunoprecipitation of BLM complexes recovered telomere and ribosomal DNA repeats. The N-terminus of BLM, required for NB localization, is the same as the telomere association domain of BLM. The C-terminus is required for ribosomal DNA localization. BLM localizes primarily to the non-transcribed spacer region of the ribosomal DNA repeat where replication forks initiate. Bloom syndrome cells expressing the deletion alleles lacking the ribosomal DNA and telomere association domains have altered cell cycle populations with increased S or G2/M cells relative to normal. CONCLUSION: These results identify telomere and ribosomal DNA repeated sequence elements as chromosomal targets for the BLM DNA helicase during the S/G2 phase of the cell cycle. BLM is localized in nuclear bodies when it associates with telomeric repeats in both telomerase positive and negative cells. The BLM DNA helicase participates in genomic stability at ribosomal DNA repeats and telomeres

Local dynamics and global attractivity of a certain second-order quadratic fractional difference equation

We investigate the local and global character of the equilibrium and the local stability of the period-two solution of the difference equation [Mathematical equations cannot be displayed here, refer to PDF] where the parameters β, γ, δ, B, C, D are nonnegative numbers which satisfy B + C + D \u3e 0 and the initial conditions x-1 and x0 are arbitrary nonnegative numbers such that Bxnxn-1 + Cx2n-1 + Dxn \u3e 0 for all n ≥ 0

Motivasi kerja guru sekolah dasar ditinjau dari karakteristik demografi

Penelitian ini bertujuan untuk mengetahui perbedaan motivasi kerja guru sekolah dasar di tinjau dari karakteristik demografi. Penelitian ini merupakan penelitian kuantitatif. Subjek penelitian seluruh guru GT dan GTT di sekolah dasar negeri dan yayasan di Kecamatan Jiwan Madiun sebanyak 90 guru, terdiri dari 39 Guru GTT dan 51 Guru GT Yayasan dan Negeri. Metode pengumpulan data menggunakan angket. Uji validitas instrumen menggunakan Confirmatory Factor Analysis (CFA) menunjukkan sebanyak 65 butir valid. Uji reabilitas menggunakan Alpha Cronbach sebesar 0,968 lebih besar dari 0,50 sehingga reliable. Hasil penelitian menunjukkan bahwa ada perbedaan motivasi kerja guru GT dan GTT di sekolah dasar negeri dan yayasan. Guru GT di sekolah dasar negeri memiliki motivasi kerja yang lebih tinggi. Ditinjau dari karakteristik demografi ada perbedaan motivasi kerja guru. Dari karakteristik demografi guru GT di sekolah dasar negeri memiliki motivasi kerja yang tinggi. Sehingga dengan ditingkatkan motivasi kerja guru GT dan GTT di sekolah dasar negeri dan yayasan di tinjau dari karakteristik demografi akan meningkatnya kinerja guru dan rasa tanggung jawab atas pekerjaannya

Motivasi Kerja Guru Tetap dan Tidak Tetap Di Sekolah Yayasan Dan Sekolah Negeri Di Kota Madiun Ditinjau Dari Karakteristik Demografi Guru Sekolah dasar.

Penelitian ini bertujuan untuk mengetahui: 1) Perbedaan motivasi kerja Guru Tetap (GT) dan Guru Tidak Tetap (GTT) Sekolah Dasar Negeri dan sekolah yayasan di Kota Madiun, 2) Motivasi kerja guru Guru Tetap (GT) dan Guru Tidak Tetap (GTT) Sekolah Dasar Negeri dan sekolah yayasan di Kota Madiun ditinjau dari karakteristik demografi guru. Penelitian ini merupakan penelitian kuantitatif. Populasi penelitian adalah seluruh guru tetap dan tidak tetap di sekolah dasar yayasan maupun negeri di Kecamatan Jiwan Kabupaten Madiun sebanyak 83 guru yang terdiri dari 39 Guru Tidak Tetap dan 51 Guru Tetap Yayasan dan Negeri di Kota Madiun. Metode pengumpulan data menggunakan angket. Uji validitas instrumen menggunakan menggunakan Confirmatory Factor Analysis (CFA) yang menunjukkan sebanyak 65 butir pernytaan valid. Uji reabilitas menggunakan Alpha Cronbach sebesar sebesar 0,968 lebih besar dari 0,50 sehingga reliable. Analisis data dalam penelitian ini menggunakan perangkat program SPSS Hasil penelitian menunjukkan bahwa ada perbedaan motivasi kerja guru GT dan GTT di sekolah dasar negeri dan yayasan. Guru GT di sekolah dasar negeri memiliki motivasi kerja yang lebih tinggi disbanding dengan guru GT dan GTT di sekolah yayasan. Ditinjau dari karakteristik demografi ada perbedaan motivasi kerja yaitu: a) Ditinjau dari jenis kelamin guru GT perempuan di sekolah dasar negeri memiliki motivasi tinggi disbanding guru perempuan GT dan GTT di sekolah yayasan. b) Dari uisa guru GT di sekolah dasar negeri yang berusia lebih dari 30 tahun memiliki motivasi kerja tinggi disanding dengan gutu GT dan GTT yang berusia lebih dari 30 tahun di sekolah yayasan. c) Dari tingkat pendidikan guru GT di sekolah dasar negeri yang lulusan sarjana memiliki motivasi kerja tinggi disbanding dengan guru GT dan GTT lulusan sarjana di sekolah yayasan. d) Dari pengalaman kerja guru GT di sekolah dasar negeri yang pengalaman kerja lebih dari 10 tahun memiliki motivasi kerja tinggi dibanding dengan guru GT dan GTT yang memiliki pengalaman kerja lebih dari 10 tahun di sekolah yayasan. Sehingga dengan ditingkatkan motivasi kerja guru GT dan GTT di sekolah dasar negeri dan yayasan di tinjau dari karakteristik demografi akan meningkatnya kinerja guru dan rasa tanggung jawab atas pekerjaannya

Cezanne regulates E2F1-dependent HIF2α expression

Mechanisms regulating protein degradation ensure the correct and timely expression of transcription factors such as hypoxia inducible factor (HIF). Under normal O2 tension, HIFα subunits are targeted for proteasomal degradation, mainly through vHL-dependent ubiquitylation. Deubiquitylases are responsible for reversing this process. Although the mechanism and regulation of HIFα by ubiquitin-dependent proteasomal degradation has been the object of many studies, little is known about the role of deubiquitylases. Here, we show that expression of HIF2α (encoded by EPAS1) is regulated by the deubiquitylase Cezanne (also known as OTUD7B) in an E2F1-dependent manner. Knockdown of Cezanne downregulates HIF2α mRNA, protein and activity independently of hypoxia and proteasomal degradation. Mechanistically, expression of the HIF2α gene is controlled directly by E2F1, and Cezanne regulates the stability of E2F1. Exogenous E2F1 can rescue HIF2α transcript and protein expression when Cezanne is depleted. Taken together, these data reveal a novel mechanism for the regulation of the expression of HIF2α, demonstrating that the HIF2α promoter is regulated by E2F1 directly and that Cezanne regulates HIF2α expression through control of E2F1 levels. Our results thus suggest that HIF2α is controlled transcriptionally in a cell-cycle-dependent manner and in response to oncogenic signalling

DEAF1 is a Pellino1-interacting protein required for interferon production by Sendai virus and double-stranded RNA

Double-stranded (ds) RNA of viral origin, a ligand for Melanoma Differentiation-associated gene 5 (MDA5) and Toll-Like Receptor 3 (TLR3), induces the TANK-Binding Kinase 1 (TBK1)-dependent phosphorylation and activation of Interferon Regulatory Factor 3 (IRF3) and the E3 ubiquitin ligase Pellino1, which are required for interferon β (IFNβ) gene transcription. Here, we report that Pellino1 interacts with the transcription factor Deformed Epidermal Autoregulatory Factor 1 (DEAF1). The interaction is independent of the E3 ligase activity of Pellino1, but weakened by the phosphorylation of Pellino1. We show that DEAF1 binds to the IFNβ promoter and to IRF3 and IRF7, that it is required for the transcription of the IFNβ gene and IFNβ secretion in MEFs infected with Sendai virus or transfected with poly(I:C). DEAF1 is also needed for TLR3-dependent IFNβ production. Taken together, our results identify DEAF1 as a novel component of the signal transduction network by which dsRNA of viral origin stimulates IFNβ production

Oxidative stress-induced mitochondrial dysfunction drives inflammation and airway smooth muscle remodeling in patients with chronic obstructive pulmonary disease

BackgroundInflammation and oxidative stress play critical roles in patients with chronic obstructive pulmonary disease (COPD). Mitochondrial oxidative stress might be involved in driving the oxidative stress–induced pathology.ObjectiveWe sought to determine the effects of oxidative stress on mitochondrial function in the pathophysiology of airway inflammation in ozone-exposed mice and human airway smooth muscle (ASM) cells.MethodsMice were exposed to ozone, and lung inflammation, airway hyperresponsiveness (AHR), and mitochondrial function were determined. Human ASM cells were isolated from bronchial biopsy specimens from healthy subjects, smokers, and patients with COPD. Inflammation and mitochondrial function in mice and human ASM cells were measured with and without the presence of the mitochondria-targeted antioxidant MitoQ.ResultsMice exposed to ozone, a source of oxidative stress, had lung inflammation and AHR associated with mitochondrial dysfunction and reflected by decreased mitochondrial membrane potential (ΔΨm), increased mitochondrial oxidative stress, and reduced mitochondrial complex I, III, and V expression. Reversal of mitochondrial dysfunction by the mitochondria-targeted antioxidant MitoQ reduced inflammation and AHR. ASM cells from patients with COPD have reduced ΔΨm, adenosine triphosphate content, complex expression, basal and maximum respiration levels, and respiratory reserve capacity compared with those from healthy control subjects, whereas mitochondrial reactive oxygen species (ROS) levels were increased. Healthy smokers were intermediate between healthy nonsmokers and patients with COPD. Hydrogen peroxide induced mitochondrial dysfunction in ASM cells from healthy subjects. MitoQ and Tiron inhibited TGF-β–induced ASM cell proliferation and CXCL8 release.ConclusionsMitochondrial dysfunction in patients with COPD is associated with excessive mitochondrial ROS levels, which contribute to enhanced inflammation and cell hyperproliferation. Targeting mitochondrial ROS represents a promising therapeutic approach in patients with COPD

Identification of Common Differentially Expressed Genes in Urinary Bladder Cancer

BACKGROUND: Current diagnosis and treatment of urinary bladder cancer (BC) has shown great progress with the utilization of microarrays. PURPOSE: Our goal was to identify common differentially expressed (DE) genes among clinically relevant subclasses of BC using microarrays. METHODOLOGY/PRINCIPAL FINDINGS: BC samples and controls, both experimental and publicly available datasets, were analyzed by whole genome microarrays. We grouped the samples according to their histology and defined the DE genes in each sample individually, as well as in each tumor group. A dual analysis strategy was followed. First, experimental samples were analyzed and conclusions were formulated; and second, experimental sets were combined with publicly available microarray datasets and were further analyzed in search of common DE genes. The experimental dataset identified 831 genes that were DE in all tumor samples, simultaneously. Moreover, 33 genes were up-regulated and 85 genes were down-regulated in all 10 BC samples compared to the 5 normal tissues, simultaneously. Hierarchical clustering partitioned tumor groups in accordance to their histology. K-means clustering of all genes and all samples, as well as clustering of tumor groups, presented 49 clusters. K-means clustering of common DE genes in all samples revealed 24 clusters. Genes manifested various differential patterns of expression, based on PCA. YY1 and NFκB were among the most common transcription factors that regulated the expression of the identified DE genes. Chromosome 1 contained 32 DE genes, followed by chromosomes 2 and 11, which contained 25 and 23 DE genes, respectively. Chromosome 21 had the least number of DE genes. GO analysis revealed the prevalence of transport and binding genes in the common down-regulated DE genes; the prevalence of RNA metabolism and processing genes in the up-regulated DE genes; as well as the prevalence of genes responsible for cell communication and signal transduction in the DE genes that were down-regulated in T1-Grade III tumors and up-regulated in T2/T3-Grade III tumors. Combination of samples from all microarray platforms revealed 17 common DE genes, (BMP4, CRYGD, DBH, GJB1, KRT83, MPZ, NHLH1, TACR3, ACTC1, MFAP4, SPARCL1, TAGLN, TPM2, CDC20, LHCGR, TM9SF1 and HCCS) 4 of which participate in numerous pathways. CONCLUSIONS/SIGNIFICANCE: The identification of the common DE genes among BC samples of different histology can provide further insight into the discovery of new putative markers