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https://www.readbyqxmd.com/read/28211871/expression-level-is-a-key-determinant-of-e2f1-mediated-cell-fate
#1
Igor Shats, Michael Deng, Adam Davidovich, Carolyn Zhang, Jungeun S Kwon, Dinesh Manandhar, Raluca Gordân, Guang Yao, Lingchong You
The Rb/E2F network has a critical role in regulating cell cycle progression and cell fate decisions. It is dysfunctional in virtually all human cancers, because of genetic lesions that cause overexpression of activators, inactivation of repressors, or both. Paradoxically, the downstream target of this network, E2F1, is rarely strongly overexpressed in cancer. E2F1 can induce both proliferation and apoptosis but the factors governing these critical cell fate decisions remain unclear. Previous studies have focused on qualitative mechanisms such as differential cofactors, posttranslational modification or state of other signaling pathways as modifiers of the cell fate decisions downstream of E2F1 activation...
February 17, 2017: Cell Death and Differentiation
https://www.readbyqxmd.com/read/28207964/impaired-nephrogenesis-in-neonatal-rats-with-oxygen-induced-retinopathy
#2
Mayu Nakagawa, Naoto Nishizaki, Amane Endo, Tomonosuke Someya, Yuta Saito, Akira Mizutani, Taichi Hara, Yayoi Murano, Koji Sakuraya, Satoshi Hara, Daisuke Umino, Daishi Hirano, Shuichiro Fujinaga, Yoshiyuki Ohtomo, Toshiaki Shimizu
OBJECTIVES: Preterm neonates are born while nephrogenesis is ongoing and are commonly exposed to factors in a hyperoxic environment that can impair renal development. Oxidative stress has also been implicated in the development of retinopathy of prematurity (ROP). The rat model of oxygen-induced retinopathy (OIR) is the most clinically relevant model of ROP because its biologic features closely resemble those of ROP in preterm infants. We investigated impaired renal development in a rat model of OIR...
February 16, 2017: Pediatrics International: Official Journal of the Japan Pediatric Society
https://www.readbyqxmd.com/read/28193005/mapping-the-energetic-epitope-of-an-antibody-interleukin-23-interaction-with-hydrogen-deuterium-exchange-fast-photochemical-oxidation-of-proteins-mass-spectrometry-and-alanine-shave-mutagenesis
#3
Jing Li, Hui Wei, Stanley R Krystek, Derek Bond, Ty M Brender, Daniel Cohen, Jena Feiner, Nels Hamacher, Johanna Harshman, Richard Y-C Huang, Susan H Julien, Zheng Lin, Kristina Moore, Luciano Mueller, Claire Noriega, Preeti Sejwal, Paul Sheppard, Brenda Stevens, Guodong Chen, Adrienne A Tymiak, Michael L Gross, Lumelle A Schneeweis
Epitope mapping the specific residues of an antibody/antigen interaction can be used to support mechanistic interpretation, antibody optimization, and epitope novelty assessment. Thus, there is a strong need for mapping methods, particularly integrative ones. Here, we report the identification of an energetic epitope by determining the interfacial hot-spot that dominates the binding affinity for an anti-interleukin-23 (anti-IL-23) antibody by using the complementary approaches of hydrogen/deuterium exchange mass spectrometry (HDX-MS), fast photochemical oxidation of proteins (FPOP), alanine shave mutagenesis, and binding analytics...
February 9, 2017: Analytical Chemistry
https://www.readbyqxmd.com/read/28179426/erk-kinases-phosphorylate-lin28a-to-modulate-p19-cell-proliferation-and-differentiation
#4
Xiangyuan Liu, Min Chen, Long Li, Liyan Gong, Hu Zhou, Daming Gao
Lin28a, originally discovered in the nematode Caenorhabditis elegans and highly conserved across species, is a well characterized regulator of let-7 miRNAs and is implicated in cell proliferation and pluripotency control. However, little is known about how Lin28a function is modulated at post-translational level and thereby responds to major signaling pathways. Here we show that Lin28a is directly phosphorylated by ERK1/2 kinases at Ser200. By editing lin28a gene with Crispr/Cas9 based method, we generated P19 mouse embryonic carcinoma (EC) stem cells expressing Lin28a-S200A (phospho-deficient) and Lin28a-S200D (phospho-mimetic) mutants respectively to study the functional impact of S200 phosphorylation...
February 8, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28165883/the-role-of-il-23-in-the-treatment-of-psoriasis
#5
Lluís Puig
The IL-23/IL-17 axis is currently considered to be crucial in the pathogenesis of psoriasis. Human IL-23 is primarily produced by antigen-presenting cells and induces and maintains differentiation of Th17 cells and Th22 cells, a primary cellular source of proinflammatory cytokines such as IL-17 and IL-22, which mediate the epidermal hyperplasia, keratinocyte immune activation and tissue inflammation inherent in psoriasis. Agents that target the p40 subunit common to both IL-12 and IL-23 have shown robust clinical activity, but selectivity for IL-23p19 could offer advantages in efficacy and safety with respect to anti-p40 blockade...
February 6, 2017: Expert Review of Clinical Immunology
https://www.readbyqxmd.com/read/28164768/protective-effect-of-aspirin-against-oligomeric-a%C3%AE-42-induced-mitochondrial-alterations-and-neurotoxicity-in-differentiated-ec-p19-neuronal-cells
#6
Hamendra Singh Parmar, Zbynek Houdek, Martin Pesta, Vaclava Cerna, Pavel Dvorak, Jiri Hatina
Amyloid-beta (Aβ) induced mitochondrial dysfunction is one of the major causes of neuronal toxicity in Alzheimer's disease. Many recent reports suggest involvement of mitochondrial alterations through intracellular accumulation of oligomeric Aβ. These mitochondrial alterations include increased reactive oxygen species (ROS), mt-DNA depletion, decreased oxidative phosphorylation and ATP production, membrane depolarization, reduced number of mitochondria etc. These all defects cumulatively caused neural toxicity and alterations in cellular energy homeostasis...
February 2, 2017: Current Alzheimer Research
https://www.readbyqxmd.com/read/28157724/orchestration-of-late-events-in-erythropoiesis-by-klf1-eklf
#7
Merlin Nithya Gnanapragasam, James J Bieker
PURPOSE OF REVIEW: Transcriptional regulators provide the molecular and biochemical basis for the cell specific properties and characteristics that follow from their central role in establishing tissue-restricted expression. Precise and sequential control of terminal cell divisions, nuclear condensation, and enucleation are defining characteristics within erythropoietic differentiation. This review is focused on KLF1, a central global regulator of this process. RECENT FINDINGS: Studies in the past year have brought a number of proteins that are targets of KLF1 regulation into focus with respect to their roles in terminal erythroid differentiation...
February 2, 2017: Current Opinion in Hematology
https://www.readbyqxmd.com/read/28153853/epigenetic-activation-of-mu-opioid-receptor-mor-gene-via-increased-expression-and-function-of-mitogen-and-stress-activated-protein-kinase-1-msk1
#8
Yadav Wagley, Ping-Yee Law, Li-Na Wei, Horace H Loh
Since the discovery of mu opioid receptor (MOR) gene two decades ago, various regulatory factors have been shown to interact with the MOR promoter and modulate transcript levels. However, the majority of early transcriptional studies on MOR gene have not addressed how intracellular signaling pathways mediate extracellular modulators. In this study, we demonstrate that MOR epigenetic regulation requires multiple co-ordinated signals converged at the MOR promoter, involving mitogen-activated protein kinase (MAPK) activation and mitogen-and stress-activated protein kinase (MSK1) - similar ranges of intracellular signaling pathways that are activated by opioid agonists...
February 2, 2017: Molecular Pharmacology
https://www.readbyqxmd.com/read/28152559/t-cell-responses-to-peptides-of-goodpasture-autoantigen-in-patients-with-anti-glomerular-basement-membrane-disease
#9
Shui-Yi Hu, Xiao-Yu Jia, Qiu-Hua Gu, Chong-Yan Yu, Xu-Yang Cheng, Qi-Zhuang Jin, Fu-de Zhou, Zhao Cui, Ming-Hui Zhao
AIM: Cell-mediated autoimmunity, especially autoreactive T cells, is crucial in the initiation of anti-glomerular membrane (GBM) disease. Epitopes for T cells on Goodpasture autoantigen are not fully defined. This study investigated T cell epitopes in anti-GBM patients, aiming to identify the epitopes and their clinical significance. METHODS: Peripheral blood mononuclear cells (PBMC) were collected from 13 patients with anti-GBM disease. Twenty-four overlapping linear peptides were synthesized covering the whole sequence of human α3(IV)NC1...
February 2, 2017: Nephrology
https://www.readbyqxmd.com/read/28100093/p19-targeted-abd-derived-protein-variants-inhibit-il-23-binding-and-exert-suppressive-control-over-il-23-stimulated-expansion-of-primary-human-il-17-t-cells
#10
Lucie Křížová, Milan Kuchař, Hana Petroková, Radim Osička, Marie Hlavničková, Ondřej Pelák, Jiří Černý, Tomáš Kalina, Petr Malý
Interleukin-23 (IL-23), a heterodimeric cytokine of covalently bound p19 and p40 proteins, has recently been closely associated with development of several chronic autoimmune diseases such as psoriasis, psoriatic arthritis or inflammatory bowel disease. Released by activated dendritic cells, IL-23 interacts with IL-23 receptor (IL-23R) on Th17 cells, thus promoting intracellular signaling, a pivotal step in Th17-driven pro-inflammatory axis. Here, we aimed to block the binding of IL-23 cytokine to its cell-surface receptor by novel inhibitory protein binders targeted to the p19 subunit of human IL-23...
January 19, 2017: Autoimmunity
https://www.readbyqxmd.com/read/28093506/the-tyrosine-kinase-receptor-tyro3-enhances-lifespan-and-neuropeptide-y-npy-neuron-survival-in-the-mouse-anorexia-anx-mutation
#11
Dennis Y Kim, Joanna Yu, Ryan K Mui, Rieko Niibori, Hamza Bin Taufique, Rukhsana Aslam, John W Semple, Sabine P Cordes
Severe appetite and weight loss define the eating disorder anorexia nervosa, and can also accompany the progression of some neurodegenerative disorders, such as amyotrophic lateral scelerosis (ALS). While acute loss of hypothalamic neurons that produce appetite-stimulating neuropeptide Y (Npy) and agouti related peptide (AgRP) in adult mice or in mice homozygous for the anorexia (anx) mutation causes aphagia, our understanding of the factors that help maintain appetite regulatory circuitry is limited. Here we identify a mutation that converts an arginine to a tryptophan (R7W) in the Tyrosine receptor kinase 3 (Tyro3) gene, which resides within the anx critical interval, as contributing to the severity of anx phenotypes...
January 12, 2017: Disease Models & Mechanisms
https://www.readbyqxmd.com/read/28074012/reduced-abundance-of-the-e3-ubiquitin-ligase-e6ap-contributes-to-decreased-expression-of-the-ink4-arf-locus-in-non-small-cell-lung-cancer
#12
Cristina Gamell, Twishi Gulati, Yaara Levav-Cohen, Richard J Young, Hongdo Do, Pat Pilling, Elena Takano, Neil Watkins, Stephen B Fox, Prudence Russell, Doron Ginsberg, Brendon J Monahan, Gavin Wright, Alex Dobrovic, Sue Haupt, Ben Solomon, Ygal Haupt
The tumor suppressor p16(INK4a), one protein encoded by the INK4/ARF locus, is frequently absent in multiple cancers, including non-small cell lung cancer (NSCLC). Whereas increased methylation of the encoding gene (CDKN2A) accounts for its loss in a third of patients, no molecular explanation exists for the remainder. We unraveled an alternative mechanism for the silencing of the INK4/ARF locus involving the E3 ubiquitin ligase and transcriptional cofactor E6AP (also known as UBE3A). We found that the expression of three tumor suppressor genes encoded in the INK4/ARF locus (p15(INK4b), p16(INK4a), and p19(ARF)) was decreased in E6AP(-/-) mouse embryo fibroblasts...
January 10, 2017: Science Signaling
https://www.readbyqxmd.com/read/28063798/evaluation-of-biological-properties-of-3-3-4-4-benzophenonetetracarboxylic-dianhydride-derivatives-and-their-ability-to-inhibit-hexokinase-activity
#13
Krzysztof Kochel, Mateusz D Tomczyk, Rui F Simões, Tomasz Frączek, Adrian Soboń, Paulo J Oliveira, Krzysztof Z Walczak, Aneta Koceva-Chyła
This investigation has explored the properties of 3,3',4,4'-benzophenonetetracarboxylic dianhydride (BDTA) derivatives with regard to their being prospective inhibitors of hexokinase II (HKII). A pluripotent embryonic carcinoma cell line P19 (ECC), was used as the biological target for newly generated potential inhibitors of HKII. The results obtained from Virtual High-Throughput Screening (VHTS), molecular modeling and biological activity studies showed BDTA to be a promising leading structure with a good binding score and simplest functionalization...
December 25, 2016: Bioorganic & Medicinal Chemistry Letters
https://www.readbyqxmd.com/read/28054967/expression-purification-and-biophysical-characterization-of-a-secreted-anthrax-decoy-fusion-protein-in-nicotiana-benthamiana
#14
Kalimuthu Karuppanan, Sifti Duhra-Gill, Muchena J Kailemia, My L Phu, Carlito B Lebrilla, Abhaya M Dandekar, Raymond L Rodriguez, Somen Nandi, Karen A McDonald
Anthrax toxin receptor-mediated drug development for blocking anthrax toxin action has received much attention in recent decades. In this study, we produced a secreted anthrax decoy fusion protein comprised of a portion of the human capillary morphogenesis gene-2 (CMG2) protein fused via a linker to the fragment crystallizable (Fc) domain of human immunoglobulin G1 in Nicotiana benthamiana plants using a transient expression system. Using the Cauliflower Mosaic Virus (CaMV) 35S promoter and co-expression with the p19 gene silencing suppressor, we were able to achieve a high level of recombinant CMG2-Fc-Apo (rCMG2-Fc-Apo) protein accumulation...
January 4, 2017: International Journal of Molecular Sciences
https://www.readbyqxmd.com/read/28049897/expression-and-regulation-of-tal2-during-neuronal-differentiation-in-p19-cells
#15
Takanobu Kobayashi
 T-cell acute lymphocytic leukemia 2 (Tal2) is a gene encoding a member of the basic helix-loop-helix transcription factor family, which is essential for the normal development of the mouse brain. We found that Tal2 was induced during neural differentiation in P19 cells, which are pluripotent mouse embryonal carcinoma cells that differentiate into the neural lineage upon both exposure to all-trans retinoic acid (atRA) and the formation of cell aggregation. Tal2 expression during neural differentiation in P19 cells was detected within 3 h after induction with atRA and retinoic acid receptor α (RARα)...
2017: Yakugaku Zasshi: Journal of the Pharmaceutical Society of Japan
https://www.readbyqxmd.com/read/28043778/neuritogenic-activity-of-bi-functional-bis-tryptoline-triazole
#16
Jutamas Jiaranaikulwanitch, Sarin Tadtong, Piyarat Govitrapong, Valery V Fokin, Opa Vajragupta
Alzheimer's disease (AD) is a common neurodegenerative disorder, one of the hallmarks of which is the deposition of aggregated β-amyloid peptides (Aβ40,42) as plaques in the brain. Oligomers of these peptides have been reported to be toxic and to inhibit neurite outgrowth, as evidenced by neurite dystrophy and significant loss of synaptic connectivity of neurons in the AD brain resulting in cognitive decline. These peptides also react with biological metal in the brain to generate free radicals, thereby aggravating neuronal cell injury and death...
December 23, 2016: Bioorganic & Medicinal Chemistry
https://www.readbyqxmd.com/read/28042732/the-potential-utility-of-tildrakizumab-an-interleukin-23-inhibitor-for-the-treatment-of-psoriasis
#17
Zenas Z N Yiu, Richard B Warren
The approved biologic therapies are effective for the treatment of psoriasis, but have limitations. Tildrakizumab has a different mechanism of action and is a humanized immunoglobulin G1κ that binds to the p19 subunit of IL23. Areas covered: Phase I, II and III clinical trials investigated the pharmacokinetics, efficacy, safety and immunogenicity of tildrakizumab for patients with psoriasis. The mean half-life of tildrakizumab is between 20.2 to 28.2 days. Tildrakizumab achieved a PASI 75 of 66% and 74% at week 16 for the doses of 100 mg and 200 mg respectively in a phase IIb randomised clinical trial (RCT), and PASI 75 of 61%/64% and 62%/66% at week 12 for 100 mg and 200 mg respectively in two phase III RCTs...
January 1, 2017: Expert Opinion on Investigational Drugs
https://www.readbyqxmd.com/read/28039042/role-of-low-voltage-activated-calcium-current-and-extracellular-calcium-in-controlling-the-firing-pattern-of-developing-ca1-pyramidal-neurons
#18
Alberto Sánchez-Aguilera, José Luis Sánchez-Alonso, María Ángeles Vicente-Torres, Asunción Colino
The firing pattern of individual neurons is an important element for information processing and storing. During the first weeks of development, there is a transitional period during which CA1 pyramidal neurons display burst-spiking behavior in contrast to the adult regular-firing pattern. Spike after-depolarizations (ADPs) constitute a major factor underlying burst-spiking behavior. Using current-clamp recordings, we studied ADP waveforms and firing patterns in CA1 pyramidal neurons of Wistar rats from 9 to 19 postnatal days (P9-19)...
March 6, 2017: Neuroscience
https://www.readbyqxmd.com/read/28013042/production-of-stable-gfp-expressing-neural-cells-from-p19-embryonal-carcinoma-stem-cells
#19
Hedayatollah Shirzad, Fariba Esmaeili, Shabnam Bakhshalizadeh, Marzieh Ebrahimie, Esmaeil Ebrahimie
Murine P19 embryonal carcinoma (EC) cells are convenient to differentiate into all germ layer derivatives. One of the advantages of P19 cells is that the exogenous DNA can be easily inserted into them. Here, at the first part of this study, we generated stable GFP-expressing P19 cells (P19-GFP(+)). FACS and western-blot analysis confirmed stable expression of GFP in the cells. We previously demonstrated the efficient induction of neuronal differentiation from mouse ES and EC cells by application of a neuroprotective drug, selegiline In the second part of this study selegiline was used to induce differentiation of P19-GFP(+) into stable GFP-expressing neuron-like cells...
December 21, 2016: Molecular and Cellular Probes
https://www.readbyqxmd.com/read/27999597/construction-of-a-dual-fluorescence-reporter-system-to-monitor-the-dynamic-progression-of-pluripotent-cell-differentiation
#20
Wu-Sheng Sun, Ju-Lan Chun, Jeong-Tae Do, Dong-Hwan Kim, Jin-Seop Ahn, Min-Kyu Kim, In-Sul Hwang, Dae-Jin Kwon, Seong-Soo Hwang, Jeong-Woong Lee
Oct4 is a crucial germ line-specific transcription factor expressed in different pluripotent cells and downregulated in the process of differentiation. There are two conserved enhancers, called the distal enhancer (DE) and proximal enhancer (PE), in the 5' upstream regulatory sequences (URSs) of the mouse Oct4 gene, which were demonstrated to control Oct4 expression independently in embryonic stem cells (ESCs) and epiblast stem cells (EpiSCs). We analyzed the URSs of the pig Oct4 and identified two similar enhancers that were highly consistent with the mouse DE and PE...
2016: Stem Cells International
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