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S Ray, A Ghosh, S Sinha
We study the quantum dynamics of the kicked Dicke model (KDM) in terms of the Floquet operator, and we analyze the connection between chaos and thermalization in this context. The Hamiltonian map is constructed by suitably taking the classical limit of the Heisenberg equation of motion to study the corresponding phase-space dynamics, which shows a crossover from regular to chaotic motion by tuning the kicking strength. The fixed-point analysis and calculation of the Lyapunov exponent (LE) provide us with a complete picture of the onset of chaos in phase-space dynamics...
September 2016: Physical Review. E
Yoichi Munehira, Ze Yang, Or Gozani
Histone methylation dynamics play a critical role in cellular programming during development. For example, specific lysine methyltransferases (KMTs) and demethylases (KDMs) have been implicated in the differentiation of mesenchymal stem cells into various cell lineages. However, a systematic functional analysis for an entire family of KMT or KDM enzymes has not been performed. Here we test the function of all the known and candidate KDMs in myoblast and osteoblast differentiation using the C2C12 cell differentiation model system...
October 9, 2016: Journal of Molecular Biology
J Bethke, M Poblete-Morales, R Irgang, A Yáñez, R Avendaño-Herrera
Renibacterium salmoninarum is the causative agent of bacterial kidney disease, which significantly affects salmonid farming worldwide. Despite this impact, there is scarce data on its iron uptake ability, a factor of pathogenesis. This study investigated the iron acquisition mechanisms of R. salmoninarum and its capacity to uptake iron from different sources. Thirty-two Chilean isolates and the DSM20767(T) type strain grew in the presence of 2,2'-Dipyridyl at varying concentrations (250-330 μm), and all isolates positively reacted on chrome azurol S agar...
November 2016: Journal of Fish Diseases
Laura Brugnara, Serafín Murillo, Anna Novials, Gemma Rojo-Martínez, Federico Soriguer, Albert Goday, Alfonso Calle-Pascual, Luis Castaño, Sonia Gaztambide, Sergio Valdés, Josep Franch, Conxa Castell, Joan Vendrell, Roser Casamitjana, Anna Bosch-Comas, Elena Bordiú, Rafael Carmena, Miguel Catalá, Elias Delgado, Juan Girbés, Alfonso López-Alba, Maria Teresa Martínez-Larrad, Edelmiro Menéndez, Inmaculada Mora-Peces, Gemma Pascual-Manich, Manuel Serrano-Ríos, Ramon Gomis, Emilio Ortega
Low physical activity (PA), or sedentary lifestyle, is associated with the development of several chronic diseases. We aimed to investigate current prevalence of sedentariness and its association with diabetes and other cardiovascular risk factors. PA was evaluated in a population-based, cross-sectional, randomly sampled study conducted in 2009-2010 in Spain. International Physical Activity Questionnaire (SF-IPAQ) was used to assess PA. 4991 individuals (median age 50 years, 57% women) were studied. Prevalence of sedentariness was 32...
2016: PloS One
M K Kang, S Mehrazarin, N-H Park, C-Y Wang
Histone N-terminal tails of nucleosomes are the sites of complex regulation of gene expression through post-translational modifications. Among these modifications, histone methylation had long been associated with permanent gene inactivation until the discovery of Lys-specific demethylase (LSD1), which is responsible for dynamic gene regulation. There are more than 30 members of the Lys demethylase (KDM) family, and with exception of LSD1 and LSD2, all other KDMs possess the Jumonji C (JmjC) domain exhibiting demethylase activity and require unique cofactors, for example, Fe(II) and α-ketoglutarate...
August 11, 2016: Oral Diseases
Jian Cao, Lizhen Wu, Shang-Min Zhang, Min Lu, William K C Cheung, Wesley Cai, Molly Gale, Qi Xu, Qin Yan
The CRISPR/Cas9 system is a powerful genome editing tool and has been widely used for biomedical research. However, many challenges, such as off-target effects and lack of easy solutions for multiplex targeting, are still limiting its applications. To overcome these challenges, we first developed a highly efficient doxycycline-inducible Cas9-EGFP vector. This vector allowed us to track the cells for uniform temporal control and efficient gene disruption, even in a polyclonal setting. Furthermore, the inducible CRISPR/Cas9 system dramatically decreased off-target effects with a pulse exposure of the genome to the Cas9/sgRNA complex...
July 25, 2016: Nucleic Acids Research
Sunil Kumar, Prasad Venkata, Yonggyun Kim
Histone H4, a nucleosome subunit in eukaryotes, plays crucial roles in DNA package and regulation of gene expression through covalent modification. A viral histone H4 encoded in Cotesia plutellae bracovirus (CpBV), a polydnavirus, is called CpBV-H4. It is highly homologous to other histone H4 proteins except 38 extra amino acid residues in the N terminus. CpBV-H4 can form octamer with other histone subunits and alter host gene expression. In this study, CpBV-H4 was transiently expressed in a natural host (Plutella xylostella) and its suppressive activity on host gene expression was evaluated by suppressive subtractive hybridization (SSH) technique...
July 20, 2016: Journal of General Virology
S Krishnan, R C Trievel
Jumonji C (JmjC) lysine demethylases (KDMs) catalyze the site- and state-specific demethylation of lysine residues in histone and nonhistone protein substrates. These enzymes have been implicated in diverse genomic processes, including epigenetic gene regulation, DNA damage response, DNA replication, and regulation of heterochromatin structure. In addition, a number of JmjC KDMs contribute to the incidence of numerous cancers, rendering them targets for the development of novel chemotherapeutic drugs. Using the JMJD2 KDM subfamily as representative examples, this chapter outlines strategies for purifying highly active, recombinant JmjC KDMs lacking inhibitory transition metal ions, characterizing kinetic parameters of these enzymes using a coupled fluorescent assay, and determining crystal structures of the enzymes in complex with methylated histone peptides...
2016: Methods in Enzymology
Louise J Walport, Richard J Hopkinson, Rasheduzzaman Chowdhury, Rachel Schiller, Wei Ge, Akane Kawamura, Christopher J Schofield
While the oxygen-dependent reversal of lysine N(ɛ)-methylation is well established, the existence of bona fide N(ω)-methylarginine demethylases (RDMs) is controversial. Lysine demethylation, as catalysed by two families of lysine demethylases (the flavin-dependent KDM1 enzymes and the 2-oxoglutarate- and oxygen-dependent JmjC KDMs, respectively), proceeds via oxidation of the N-methyl group, resulting in the release of formaldehyde. Here we report detailed biochemical studies clearly demonstrating that, in purified form, a subset of JmjC KDMs can also act as RDMs, both on histone and non-histone fragments, resulting in formaldehyde release...
2016: Nature Communications
Simon D Nielsen, Ulrike Leurs, Magnus Bergner, Silvia A Barris, Kanchan Devkota, Kamilla Meyer, Daniella Iaria, Jack McCaughan, Brian Lohse, Jesper L Kristensen, Rasmus P Clausen
The design and synthesis of modified pentapeptides based on a truncated version of the substrate for KDM4C, a histone lysine demethylase (KDM), and investigation of their inhibitory activity at KDM4C is reported. By modifying the lysine residue corresponding to lysine 9 at histone 3 (H3K9), three different series of peptides were designed and synthesized. One series contained N-acylated H3K9 and two series introduced triazoles in this position via click chemistry to enable facile variation of headgroups. The click reaction is compatible with free amino acids and this was performed on an azido containing deprotected pentapeptide demonstrating a highly facile and convergent synthetic strategy for making substrate-based inhibitors...
2016: Protein and Peptide Letters
Antero Salminen, Kai Kaarniranta, Anu Kauppinen
Hypoxia is an environmental stress at high altitude and underground conditions but it is also present in many chronic age-related diseases, where blood flow into tissues is impaired. The oxygen-sensing system stimulates gene expression protecting tissues against hypoxic insults. Hypoxia stabilizes the expression of hypoxia-inducible transcription factor-1α (HIF-1α), which controls the expression of hundreds of survival genes related to e.g. enhanced energy metabolism and autophagy. Moreover, many stress-related signaling mechanisms, such as oxidative stress and energy metabolic disturbances, as well as the signaling cascades via ceramide, mTOR, NF-κB, and TGF-β pathways, can also induce the expression of HIF-1α protein to facilitate cell survival in normoxia...
March 2016: Aging and Disease
Yi-Chao Zheng, Bin Yu, Zhe-Sheng Chen, Ying Liu, Hong-Min Liu
Since the first lysine-specific demethylase (KDM), lysine-specific demethylase 1 (LSD1), was characterized in 2004, several families of KDMs have been identified. LSD1 can specifically demethylate H3K4me1/2, H3K9me1/2 as well as some nonhistone substrates. It has been demonstrated to be an oncogene as well as a drug target. Hence, tens of small-molecule LSD1 inhibitors have been designed, synthesized and applied for cancer treatment. However, the two LSD1 inhibitors that have been advanced into early phase clinical trials are trans-2-phenylcyclopropylamine (TCP) derivatives, which indicate that TCP is a druggable scaffold for LSD1 inhibitor...
May 2016: Epigenomics
Nikhil Patkar, Kiran Ghodke, Swapnali Joshi, Shruti Chaudhary, Russel Mascerhenas, Sona Dusseja, Shashikant Mahadik, Sheetal Gaware, Prashant Tembhare, Sumeet Gujral, Sharayu Kabre, Pratibha Kadam-Amare, Hasmukh Jain, Uma Dangi, Bhausaheb Bagal, Navin Khattry, Manju Sengar, Brijesh Arora, Gaurav Narula, Shripad Banavali, Hari Menon, Papagudi Ganesan Subramanian
We document the characteristics of BCR-ABL kinase domain mutations (KDM) in the largest study from India comprising of 385 patients and demonstrate that more than half (51.9%) of these patients have detectable abnormalities in the KD both in adult and in pediatric chronic myelogenous leukemia (CML). These comprise singly occurring missense mutations (25.5%), polyclonal/compound point mutations (4.9%), and insertions/deletions (29.6%). Missense mutations were most commonly seen in the imatinib-binding region followed by the P-loop...
November 2016: Leukemia & Lymphoma
Giuseppe Seghieri, Laura Policardo, Francesco Profili, Paolo Francesconi, Roberto Anichini, Stefano Del Prato
AIMS: To identify incidental previously unrecognized diabetes (IPUD) among hospitalized patients and corresponding mortality risk in comparison with individuals with known diabetes (KDM). METHODS: Out of 214,991 individuals discharged in year 2011 from all hospitals of Tuscany, Italy we retrospectively identified IPUD as individuals with no known diabetes and/or previous antidiabetic medication, receiving at least two prescriptions of glucose-lowering-drugs over the next 6months after discharge...
April 2016: Journal of Diabetes and its Complications
Vassilios Bavetsias, Rachel M Lanigan, Gian Filippo Ruda, Butrus Atrash, Mark G McLaughlin, Anthony Tumber, N Yi Mok, Yann-Vaï Le Bihan, Sally Dempster, Katherine J Boxall, Fiona Jeganathan, Stephanie B Hatch, Pavel Savitsky, Srikannathasan Velupillai, Tobias Krojer, Katherine S England, Jimmy Sejberg, Ching Thai, Adam Donovan, Akos Pal, Giuseppe Scozzafava, James M Bennett, Akane Kawamura, Catrine Johansson, Aleksandra Szykowska, Carina Gileadi, Nicola A Burgess-Brown, Frank von Delft, Udo Oppermann, Zoe Walters, Janet Shipley, Florence I Raynaud, Susan M Westaway, Rab K Prinjha, Oleg Fedorov, Rosemary Burke, Christopher J Schofield, Isaac M Westwood, Chas Bountra, Susanne Müller, Rob L M van Montfort, Paul E Brennan, Julian Blagg
We report the discovery of N-substituted 4-(pyridin-2-yl)thiazole-2-amine derivatives and their subsequent optimization, guided by structure-based design, to give 8-(1H-pyrazol-3-yl)pyrido[3,4-d]pyrimidin-4(3H)-ones, a series of potent JmjC histone N-methyl lysine demethylase (KDM) inhibitors which bind to Fe(II) in the active site. Substitution from C4 of the pyrazole moiety allows access to the histone peptide substrate binding site; incorporation of a conformationally constrained 4-phenylpiperidine linker gives derivatives such as 54j and 54k which demonstrate equipotent activity versus the KDM4 (JMJD2) and KDM5 (JARID1) subfamily demethylases, selectivity over representative exemplars of the KDM2, KDM3, and KDM6 subfamilies, cellular permeability in the Caco-2 assay, and, for 54k, inhibition of H3K9Me3 and H3K4Me3 demethylation in a cell-based assay...
February 25, 2016: Journal of Medicinal Chemistry
Ryan Lillico, Marina Gomez Sobral, Nicholas Stesco, Ted M Lakowski
Histone deacetylase (HDAC) inhibitors are cancer treatments that inhibit the removal of the epigenetic modification acetyllysine on histones, resulting in altered gene expression. Such changes in expression may influence other histone epigenetic modifications. We describe a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) method to quantify lysine acetylation and methylation and arginine methylation on histones extracted from cultured cells treated with HDAC inhibitors. The HDAC inhibitors vorinostat, mocetinostat and entinostat induced 400-600% hyperacetylation in HEK 293 and K562 cells...
February 5, 2016: Journal of Proteomics
Tom E McAllister, Katherine S England, Richard J Hopkinson, Paul E Brennan, Akane Kawamura, Christopher J Schofield
There is increasing interest in targeting histone N-methyl-lysine demethylases (KDMs) with small molecules both for the generation of probes for target exploration and for therapeutic purposes. Here we update on previous reviews on the inhibition of the lysine-specific demethylases (LSDs or KDM1s) and JmjC families of N-methyl-lysine demethylases (JmjC KDMs, KDM2-7), focusing on the academic and patent literature from 2014 to date. We also highlight recent biochemical, biological, and structural studies which are relevant to KDM inhibitor development...
February 25, 2016: Journal of Medicinal Chemistry
Song Hee Lee, Emily R Albright, Jeong-Hee Lee, Derek Jacobs, Robert F Kalejta
Intrinsic immune defenses mediated by restriction factors inhibit productive viral infections. Select viruses rapidly establish latent infections and, with gene expression profiles that imply cell-autonomous intrinsic defenses, may be the most effective immune control measure against latent reservoirs. We illustrate that lysine-specific demethylases (KDMs) are restriction factors that prevent human cytomegalovirus from establishing latency by removing repressive epigenetic modifications from histones associated with the viral major immediate early promoter (MIEP), stimulating the expression of a viral lytic phase target of cell-mediated adaptive immunity...
November 2015: Science Advances
Gareth W Langley, Anne Brinkø, Martin Münzel, Louise J Walport, Christopher J Schofield, Richard J Hopkinson
The dynamic post-translational modifications of histones play important roles in the regulation of transcription in animals. The demethylation of N(ε)-methyl lysine residues in the N-terminal tail of histone H3 is catalyzed by demethylases, of which the largest family is the ferrous iron and 2-oxoglutarate dependent demethylases (JmjC KDMs), which catalyze demethylation via initial hydroxylation of the N-methyl groups. We report studies on the conformational requirements of the JmjC KDM substrates using N-methylated lysine analogues prepared by metathesis reactions of suitably protected N-allylglycine...
March 18, 2016: ACS Chemical Biology
Hui Liu, Lanxin Liu, Andreana Holowatyj, Yuanyuan Jiang, Zeng-Quan Yang
Histone lysine demethylases (KDMs) comprise a large class of enzymes that catalyze site-specific demethylation of lysine residues on histones and other proteins. They play critical roles in controlling transcription, chromatin architecture, and cellular differentiation. However, the genomic landscape and clinical significance of KDMs in breast cancer remain poorly characterized. Here, we conducted a meta-analysis of 24 KDMs in breast cancer and identified associations among recurrent copy number alterations, gene expression, breast cancer subtypes, and clinical outcome...
May 2016: Molecular Carcinogenesis
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