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  • 1
    Language: English
    In: Experimental Parasitology, 2006, Vol.114(4), pp.289-296
    Description: Previously, tubulin has been purified from and used to identify novel molecules with selective antimitotic activity. However, is pathogenic and requires a relatively expensive medium for large-scale cultivation. Herein, the purification and characterization of tubulin from the non-pathogenic is reported, together with the sequence of α- and β-tubulin from this organism. This protein was purified by sonication, diethylaminoethyl–Sepharose chromatography, and one assembly disassembly cycle in 1% overall recovery based on total cellular protein. tubulin was indistinguishable from the corresponding protein in terms of binding affinity for dinitroaniline sulfanilamides and sensitivity to assembly inhibition by these compounds. The amino acid sequences derived from the α- and β-tubulin genes were 99.6 and 99.4% identical to the corresponding amino acid sequences from the Friedlin strain. These results indicate that tubulin from is suitable for use in drug screening.
    Keywords: Leishmania ; Tubulin ; Dinitroaniline ; Drug Discovery ; Deae ; Diethylaminoethyl ; Dmso ; Dimethyl Sulfoxide ; Egta ; Ethyleneglycol-Bis(Β-Aminoethyl Ether) ; GB-II-5 ; N1-Phenyl-3,5-Dinitro- N4, N4-Di- N-Propylsulfanilamide ; GB-II-150 ; N1-Phenyl-3,5-Dinitro- N4, N4-Di- N-Butylsulfanilamide ; PBS ; Phosphate-Buffered Saline ; Pme ; Buffer Consisting of 0.1 M Pipes (Ph 6.9), 1 Mm Mgcl 2, and 1 Mm Egta ; Biology ; Zoology
    ISSN: 0014-4894
    E-ISSN: 1090-2449
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 08 May 2007, Vol.104(19), pp.7821-6
    Description: Adenosine-to-inosine editing in the anticodon of tRNAs is essential for viability. Enzymes mediating tRNA adenosine deamination in bacteria and yeast contain cytidine deaminase-conserved motifs, suggesting an evolutionary link between the two reactions. In trypanosomatids, tRNAs undergo both cytidine-to-uridine and adenosine-to-inosine editing, but the relationship between the two reactions is unclear. Here we show that down-regulation of the Trypanosoma brucei tRNA-editing enzyme by RNAi leads to a reduction in both C-to-U and A-to-I editing of tRNA in vivo. Surprisingly, in vitro, this enzyme can mediate A-to-I editing of tRNA and C-to-U deamination of ssDNA but not both in either substrate. The ability to use both DNA and RNA provides a model for a multispecificity editing enzyme. Notably, the ability of a single enzyme to perform two different deamination reactions also suggests that this enzyme still maintains specificities that would have been found in the ancestor deaminase, providing a first line of evidence for the evolution of editing deaminases.
    Keywords: RNA Editing ; Adenosine Deaminase -- Physiology ; Cytidine Deaminase -- Physiology
    ISSN: 0027-8424
    E-ISSN: 10916490
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  • 3
    Language: English
    In: RNA (New York, N.Y.), July 2011, Vol.17(7), pp.1296-306
    Description: Adenosine to inosine editing at the wobble position allows decoding of multiple codons by a single tRNA. This reaction is catalyzed by adenosine deaminases acting on tRNA (ADATs) and is essential for viability. In bacteria, the anticodon-specific enzyme is a homodimer that recognizes a single tRNA substrate (tRNA(Arg)(ACG)) and can efficiently deaminate short anticodon stem-loop mimics of this tRNA in vitro. The eukaryal enzyme is composed of two nonidentical subunits, ADAT2 and ADAT3, which upon heterodimerization, recognize seven to eight different tRNAs as substrates, depending on the organism, and require a full-length tRNA for activity. Although crystallographic data have provided clues to why the bacterial deaminase can utilize short substrates, residues that provide substrate binding and recognition with the eukaryotic enzymes are not currently known. In the present study, we have used a combination of mutagenesis, binding studies, and kinetic analysis to explore the contribution of individual residues in Trypanosoma brucei ADAT2 (TbADAT2) to tRNA recognition. We show that deletion of the last 10 amino acids at the C terminus of TbADAT2 abolishes tRNA binding. In addition, single alanine replacements of a string of positively charged amino acids (KRKRK) lead to binding defects that correlate with losses in enzyme activity. This region, which we have termed the KR-domain, provides a first glance at key residues involved in tRNA binding by eukaryotic tRNA editing deaminases.
    Keywords: RNA Editing ; Adenosine Deaminase -- Chemistry ; Protein Interaction Domains and Motifs -- Physiology ; RNA, Transfer -- Metabolism ; Trypanosoma Brucei Brucei -- Enzymology
    ISSN: 13558382
    E-ISSN: 1469-9001
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  • 4
    Language: English
    In: The Journal of biological chemistry, 06 January 2006, Vol.281(1), pp.115-20
    Description: Editing of tRNAs is widespread in nature and either changes the decoding properties or restores the folding of a tRNA. Unlike the phylogenetically disperse adenosine (A) to inosine (I) editing, cytosine (C) to uridine (U) editing has only been previously described in organellar tRNAs. We have shown that cytoplasmic tRNA(Thr)(AGU) undergoes two distinct editing events in the anticodon loop: C to U and A to I. In vivo, every inosine-containing tRNA(Thr) is also C to U edited at position 32. In vitro, C to U editing stimulates conversion of A to I at the wobble base. Although the in vivo and in vitro requirements differ, in both cases, the C to U change plays a key role in A to I editing. Due to an unusual abundance of A34-containing tRNAs, our results also suggest that the unedited and edited tRNAs are functional, each dedicated to decoding a specific threonine codon. C to U editing of cytoplasmic tRNA expands the editing repertoire in eukaryotic cells, and when coupled to A to I changes, leads to an interrelation between editing sites.
    Keywords: RNA Editing ; RNA, Transfer, Amino Acyl -- Chemistry ; Trypanosoma Brucei Brucei -- Genetics
    ISSN: 0021-9258
    E-ISSN: 1083351X
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  • 5
    Language: English
    In: The Journal of pharmacology and experimental therapeutics, July 2012, Vol.342(1), pp.150-62
    Description: Antisense oligonucleotides (ASO) containing 2'-O-methoxyethyl ribose (2'-MOE) modifications have been shown to possess both excellent pharmacokinetic properties and robust pharmacological activity in several animal models of human disease. 2'-MOE ASOs are generally well tolerated, displaying minimal to mild proinflammatory effect at doses far exceeding therapeutic doses. Although the vast majority of 2'-MOE ASOs are safe and well tolerated, a small subset of ASOs inducing acute inflammation in mice has been identified. The mechanism for these findings is not clear at this point, but the effects are clearly sequence-specific. One of those ASOs, ISIS 147420, causes a severe inflammatory response atypical of this class of oligonucleotides characterized by induction in interferon-β (IFN-β) at 48 h followed by acute transaminitis and extensive hepatocyte apoptosis and necrosis at 72 h. A large number of interferon-stimulated genes were significantly up-regulated in liver as early as 24 h. We speculated that a specific sequence motif might cause ISIS 147420 to be mistaken for viral RNA or DNA, thus triggering an acute innate immune response. ISIS 147420 toxicity was independent of Toll-like receptors, because there was no decrease in IFN-β in Toll/interleukin-1 receptor-domain-containing adapter-inducing IFN-β or Myd88-deficient mice. The involvement of cytosolic retinoic acid-inducible gene (RIG)-I-like pattern recognition receptors was also investigated. Pretreatment of mice with melanoma differentiation-associated gene 5 (MDA5) and IFN-β promoter stimulator-1 ASOs, but not RIG-I or laboratory of genetics and physiology 2 (LGP2) ASOs, prevented the increase in IFN-β and alanine aminotransferase induced by ISIS 147420. These results revealed a novel mechanism of oligonucleotide-mediated toxicity requiring both MDA5 and IPS-1 and resulting in the activation of the innate immune response.
    Keywords: Dead-Box RNA Helicases -- Immunology ; DNA -- Immunology ; Immunity, Innate -- Immunology ; Interferon Type I -- Immunology ; Oligonucleotides, Antisense -- Immunology ; Ribose -- Immunology
    E-ISSN: 1521-0103
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  • 6
    Language: English
    In: Stan. Tech. L. Rev., Vol.17 pp.595-809, 2014
    Description: ... Given the current implementation of Meaningful Use rules for health information technology and the Omnibus HIPAA Rule in health care generally, the stage is now set for a distinctive law of "health information" to emerge. ... The diffusion of electronic health records (EHRs) has now reached a critical mass, assuring that more healthcare entities are dealing with digitized records of protected health information (PHI). ... Provisions Allocating Responsibility and Liability to Business Associates HIPAA's Privacy Rule has long required CEs to have contracts or other arrangements with BAs "to ensure that the business associates safeguard protected health information, and use and disclose the information only as permitted or required by the Privacy Rule." ... First, it expressly includes " a Health Information Organization, E-prescribing Gateway, or other person that provides data transmission services with respect to protected health information to a covered entity and that requires access on a routine basis to such protected health information." ... The Omnibus HIPAA Rule also makes plain that " a person that offers a personal health record to one or more individuals on behalf of a covered entity" also is a business associate for purposes of HIPAA obligations and liability. ... HIPAA in the Cloud from a Patient's Perspective While patients anticipate that their healthcare provider will usually engage in due diligence before selecting a cloud service provider, they nevertheless appreciate (if sometimes on a visceral or intuitive level) the risks involved in cloud computing scenarios. ... While covered entities and cloud service providers seek legal guidance as they work together to safeguard health data, patients have an interest in assuring that their privacy is protected. ... For example, HHS could affirm the value of CEs and upstream BAs vetting potential vendors prior to contracting to evaluate their qualifications and compliance with HIPAA; using a BAA that includes all terms required by HHS; actively monitoring the agent's performance; providing appropriate and ongoing training and instruction to cloud service providers; and responding to signals of possible violations. ... Nor did Congress adequately appreciate, in HITECH, the degree to which big data companies' use of health-inflected data could eventually render HIPAA irrelevant by fueling the creation of medical reputations unmoored from covered medical records. ... In order to address these twenty-first century challenges to health privacy, policymakers should take two steps: rendering existing data about information practices more intelligible to consumers, and presenting in plain terms to Congress the types of privacy challenges enabled by the deployment of big data.
    Keywords: Inappropriately; Accountability; Centralization; Specialization; Inappropriate; Deduplication; Communication; Transmission; Reputational; Consolidated; Computer & Internet Law; Healthcare Law; Pensions & Benefits Law; Public Health & Welfare Law
    ISSN: 1098-4267
    Source: Academic Law Reviews (LexisNexis®)
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  • 7
    Language: English
    In: Quarterly Journal of the Royal Meteorological Society, January 2015, Vol.141(686), pp.37-51
    Description: We propose a strategy to couple a stochastic lattice gas model of a cloud system to a rather general class of convective parametrization schemes. As proposed in similar models recently presented in the literature, a cloud system in a grid box of a general circulation model (GCM) is modelled as a subgrid lattice of elements that can be in one of states, each corresponding to a different convective regime. The time evolution of each element of the lattice is represented as a Markov process characterized by transition rates dependent on large‐scale fields and/or local interactions. In order to make application to GCMs computationally feasible, we propose a reduction method leading to a system of − 1 stochastic differential equations with multiplicative noise. The accuracy of the reduction method is tested in a minimal version of the model. The coupling to a convective scheme is performed in such a way that, in the limit of space‐ and time‐scale separation, the modified stochastic parametrization converges to the original deterministic version of the host scheme. Experiments with a real GCM are then performed, coupling the minimal version of the stochastic model to the Betts–Miller scheme in an aquaplanet version of the Planet Simulator. In this configuration, the stochastic extension of the parametrization keeps the climatology of its deterministic limit but strongly impacts the statistics of the extremes of daily convective precipitation.
    Keywords: Stochastic Parametrization ; Atmospheric Convection ; Lattice Gas Models
    ISSN: 0035-9009
    E-ISSN: 1477-870X
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  • 8
    Language: English
    In: Climate Dynamics, 2016, Vol.46(5), pp.1459-1471
    Description: The sensitivity of climate models to increasing CO 2 concentration and the climate response at decadal time-scales are still major factors of uncertainty for the assessment of the long and short term effects of anthropogenic climate change. While the relative slow progress on these issues is partly due to the inherent inaccuracies of numerical climate models, this also hints at the need for stronger theoretical foundations to the problem of studying climate sensitivity and performing climate change predictions with numerical models. Here we demonstrate that it is possible to use Ruelle’s response theory to predict the impact of an arbitrary CO 2 forcing scenario on the global surface temperature of a general circulation model. Response theory puts the concept of climate sensitivity on firm theoretical grounds, and addresses rigorously the problem of predictability at different time-scales. Conceptually, these results show that performing climate change experiments with general circulation models is a well defined problem from a physical and mathematical point of view. Practically, these results show that considering one single CO 2 forcing scenario is enough to construct operators able to predict the response of climatic observables to any other CO 2 forcing scenario, without the need to perform additional numerical simulations. We also introduce a general relationship between climate sensitivity and climate response at different time scales, thus providing an explicit definition of the inertia of the system at different time scales. This technique allows also for studying systematically, for a large variety of forcing scenarios, the time horizon at which the climate change signal (in an ensemble sense) becomes statistically significant. While what we report here refers to the linear response, the general theory allows for treating nonlinear effects as well. These results pave the way for redesigning and interpreting climate change experiments from a radically new perspective.
    Keywords: Climate response ; Climate sensitivity ; Linear response theory ; IPCC climate change scenarios ; GCM ensemble simulations
    ISSN: 0930-7575
    E-ISSN: 1432-0894
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  • 9
    Language: English
    In: SSRN Electronic Journal, 2013
    ISSN: SSRN Electronic Journal
    E-ISSN: 1556-5068
    Source: CrossRef
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  • 10
    Language: English
    In: Journal of Statistical Physics, 2017, Vol.166(3), pp.1036-1064
    Description: The provision of accurate methods for predicting the climate response to anthropogenic and natural forcings is a key contemporary scientific challenge. Using a simplified and efficient open-source general circulation model of the atmosphere featuring O( $$10^5$$ 10 5 ) degrees of freedom, we show how it is possible to approach such a problem using nonequilibrium statistical mechanics. Response theory allows one to practically compute the time-dependent measure supported on the pullback attractor of the climate system, whose dynamics is non-autonomous as a result of time-dependent forcings. We propose a simple yet efficient method for predicting—at any lead time and in an ensemble sense—the change in climate properties resulting from increase in the concentration of CO $$_2$$ 2 using test perturbation model runs. We assess strengths and limitations of the response theory in predicting the changes in the globally averaged values of surface temperature and of the yearly total precipitation, as well as in their spatial patterns. The quality of the predictions obtained for the surface temperature fields is rather good, while in the case of precipitation a good skill is observed only for the global average. We also show how it is possible to define accurately concepts like the inertia of the climate system or to predict when climate change is detectable given a scenario of forcing. Our analysis can be extended for dealing with more complex portfolios of forcings and can be adapted to treat, in principle, any climate observable. Our conclusion is that climate change is indeed a problem that can be effectively seen through a statistical mechanical lens, and that there is great potential for optimizing the current coordinated modelling exercises run for the preparation of the subsequent reports of the Intergovernmental Panel for Climate Change.
    Keywords: Response theory ; Climate change ; Climate prediction ; General circulation model ; Pullback attractor ; Green function ; Climate projections
    ISSN: 0022-4715
    E-ISSN: 1572-9613
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