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Exploration of the Activation Mechanism of the Epigenetic Regulator MLL3: A QM/MM Study

2021

The mixed lineage leukemia 3 or MLL3 is the enzyme in charge of the writing of an epigenetic mark through the methylation of lysine 4 from the N-terminal domain of histone 3 and its deregulation has been related to several cancer lines. An interesting feature of this enzyme comes from its regulation mechanism, which involves its binding to an activating dimer before it can be catalytically functional. Once the trimer is formed, the reaction mechanism proceeds through the deprotonation of the lysine followed by the methyl-transfer reaction. Here we present a detailed exploration of the activation mechanism through a QM/MM approach focusing on both steps of the reaction, aiming to provide new…

570StereochemistryLysineTrimerMolecular Dynamics Simulation01 natural sciencesBiochemistryMicrobiologyenzyme catalysisDFTArticleEpigenesis GeneticEnzyme catalysisQM/MM03 medical and health sciencesResidue (chemistry)Deprotonation0103 physical sciencesprotein regulationHumanscancerCàncerMolecular Biology030304 developmental biology0303 health sciencesBinding Sites010304 chemical physicsbiologyChemistryLysineNuclear ProteinsMethylation540QR1-502DNA-Binding ProteinsHistonebiology.proteinTyrosinemethyltransferaseProtein MultimerizationProtonsProteïnesTranscription Factors
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Thermomineral waters of Greece: geochemical characterization

2020

75 °C). In terms of pH most results vary from 5.5 to 823 °C) ii) warm (23 40 °C) iii) thermal (40 75 °C) and iv) hyperthermal (&gtfew springs show either very low pH (&lt10) proposing serpentinization processes. Regarding TDS concentrations collected waters can be subdivided into low salinity (up to 1.5 g/L) brackish (up to 20 g/L) and saline (up to 43 g/L). The medium high salinities can be justified by mixing with sea water and/or strong waterrock interaction processes. Isotope composition of O and H ranges from 12.7 to +2.7 ‰ SMOW and from 91 to +12 ‰ SMOW respectively and is generally comprised between the Global Meteoric Water Line and the East Mediterranean Meteoric Water Line. Only few water samples show a positive shift for δ18O possibly related to high temperature waterrock interaction processes. Carbon dioxide (18 997000 μmol/mol) or N2 (1100 989000 μmol/mol) or CH4 (&ltMany geothermal areas of Greece are located in regions affected by Miocene or Quaternary volcanism and in continental basins characterised by elevated heat flow. Moreover the majority of them is found along the coast as well as in islands of the Aegean Sea and thus thermal water is often brackish to saline due to marine intrusion into costal aquifer. In the present study almost 300 thermal and cold mineral water samples were collected along the Hellenic territory with their physicochemical parameters (temperature pH electrical conductivity and Eh) and the amount of bicarbonates (titration with 0.1N HCl) being determined in situ. Additionally gases found either in free or dissolved phase were sampled. Both water and gas samples were analysed at the INGVPa laboratories for major ions (Ion Chromatography) silica (Inductively Coupled Plasma Optical Emission Spectrometry) chemical composition of free and dissolved gases (Gas Chromatography) water isotopes (O and H) and carbon and helium isotopes of free and dissolved gases (Mass Spectrometry). The temperature of the investigated waters ranges from 6.5 to 98°C pH from 1.96 to 11.98 whilst Total Dissolved Solids (TDS) from 0.06 to 43 g/L. Based on the temperature parameter waters can be divided into four groups: i) cold (&lt0.5 913000 μmol/mol) are the prevailing gas species found in the studied sites. The δ13CCO2 values ranged from 20.1 to +8.5 ‰ whilst the isotope ratio of He from 0.21 to 6.71 R/RA.4) suggesting interaction with H2Srich gases or very high pH values (&gtSettore GEO/08 - Geochimica E Vulcanologia
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Central nervous system involvement at first relapse in patients with acute promyelocytic leukemia treated with all-trans retinoic acid and anthracycl…

2009

Background The prevalence of and risk factors for central nervous system recurrence in patients with acute promyelocytic leukemia are not well established and remain a controversial matter. Design and Methods Between 1996 and 2005, 739 patients with newly diagnosed acute promyelocytic leukemia enrolled in two consecutive trials (PETHEMA LPA96 and LPA99) received induction therapy-with all-trans retinoic acid and idarubicin. Consolidation therapy comprised three courses of anthracycline monochemotherapy (LPA96), with all-trans retinoic acid and reinforced doses of idarubicin in patients with an intermediate or high risk of relapse (LPA99). Central nervous system prophylaxis was not given. Re…

:Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons Cyclic::Hydrocarbons Aromatic::Polycyclic Hydrocarbons Aromatic::Naphthacenes::Anthracyclines::Daunorubicin::Idarubicin [Medical Subject Headings]:Diseases::Pathological Conditions Signs and Symptoms::Pathologic Processes::Disease Attributes::Recurrence [Medical Subject Headings]Male:Named Groups::Persons::Age Groups::Adult::Middle Aged [Medical Subject Headings]idarubicinGastroenterology:Analytical Diagnostic and Therapeutic Techniques and Equipment::Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [Medical Subject Headings]:Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings]Central Nervous System NeoplasmsLeukemia Promyelocytic AcuteRecurrenceRisk FactorsCumulative incidenceAntibiotics AntineoplasticHematologyMiddle Agedall-trans retinoic acidLeukemiamedicine.anatomical_structure:Named Groups::Persons::Age Groups::Adolescent [Medical Subject Headings]Femalemedicine.drugAcute promyelocytic leukemiaAdultcentral nervous system relapsemedicine.medical_specialty:Diseases::Neoplasms::Neoplasms by Histologic Type::Leukemia::Leukemia Myeloid::Leukemia Myeloid Acute [Medical Subject Headings]AnthracyclineAdolescentCentral nervous system:Check Tags::Male [Medical Subject Headings]TretinoinNeoplasias del sistema nervioso centralCentral nervous system diseaseTretinoinInternal medicine:Named Groups::Persons::Age Groups::Adult [Medical Subject Headings]medicineIdarubicinHumans:Named Groups::Persons::Age Groups::Adult::Aged [Medical Subject Headings]Letters to the Editor:Chemicals and Drugs::Organic Chemicals::Hydrocarbons::Hydrocarbons Acyclic::Alkenes::Polyenes::Carotenoids::Retinoids [Medical Subject Headings]Leucemia promielocítica agudaAgedAntibióticos antineoplásicosbusiness.industryprognostic factors:Chemicals and Drugs::Chemical Actions and Uses::Pharmacologic Actions::Therapeutic Uses::Antineoplastic Agents::Antibiotics Antineoplastic [Medical Subject Headings]acute promyelocytic leukemiamedicine.diseaseSurgery:Diseases::Neoplasms::Neoplasms by Site::Nervous System Neoplasms::Central Nervous System Neoplasms [Medical Subject Headings]:Check Tags::Female [Medical Subject Headings]businessIdarubicin
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Constitutive and regulated α-secretase cleavage of Alzheimer’s amyloid precursor protein by a disintegrin metalloprotease

1999

Amyloid β peptide (Aβ), the principal proteinaceous component of amyloid plaques in brains of Alzheimer’s disease patients, is derived by proteolytic cleavage of the amyloid precursor protein (APP). Proteolytic cleavage of APP by a putative α-secretase within the Aβ sequence precludes the formation of the amyloidogenic peptides and leads to the release of soluble APPsα into the medium. By overexpression ofa disintegrinandmetalloprotease (ADAM), classified as ADAM 10, in HEK 293 cells, basal and protein kinase C-stimulated α-secretase activity was increased severalfold. The proteolytically activated form of ADAM 10 was localized by cell surface biotinylation in the plasma membrane, but the m…

ADAM10Molecular Sequence DataBiologyKidneyTransfectionCell LineSubstrate SpecificityADAM10 ProteinAmyloid beta-Protein PrecursorEndopeptidasesAmyloid precursor proteinAnimalsAspartic Acid EndopeptidasesHumansPoint MutationADAM17 ProteinAmino Acid SequenceCloning MolecularProtein kinase AProtein Kinase CSecretory pathwayBinding SitesMultidisciplinaryHEK 293 cellsP3 peptideMembrane ProteinsMetalloendopeptidasesBiological SciencesPeptide FragmentsRecombinant Proteinscarbohydrates (lipids)ADAM ProteinsKineticsZincAlpha secretaseBiochemistryMutagenesis Site-Directedbiology.proteinCattleAmyloid Precursor Protein SecretasesProceedings of the National Academy of Sciences
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An improvement of ComiR algorithm for microRNA target prediction by exploiting coding region sequences of mRNAs

2020

AbstractMicroRNA are small non-coding RNAs that post-transcriptionally regulate the expression levels of messenger RNAs. MicroRNA regulation activity depends on the recognition of binding sites located on mRNA molecules. ComiR is a web tool realized to predict the targets of a set of microRNAs, starting from their expression profile. ComiR was trained with the information regarding binding sites in the 3’utr region, by using a reliable dataset containing the targets of endogenously expressed microRNA in D. melanogaster S2 cells. This dataset was obtained by comparing the results from two different experimental approaches, i.e., inhibition, and immunoprecipitation of the AGO1 protein--a comp…

AGO1ImmunoprecipitationComputer sciencelcsh:Computer applications to medicine. Medical informaticsBiochemistryOpen Reading Frames03 medical and health sciences0302 clinical medicineStructural BiologymicroRNAMelanogasterAnimalsHumansCoding regionGene silencing3'UTRRNA MessengerBinding sitelcsh:QH301-705.5Molecular Biology030304 developmental biology0303 health sciencesMessenger RNAbiologyThree prime untranslated regionResearchApplied MathematicsmicroRNA target predictionbiology.organism_classificationComputer Science Applications3’UTRMicroRNAsDrosophila melanogasterlcsh:Biology (General)Coding regionlcsh:R858-859.7DNA microarrayDrosophila melanogasterAlgorithmAlgorithms030217 neurology & neurosurgeryBMC Bioinformatics
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A mathematical approach to model diffusion properties of sedimentary rocks relevant to Sicily cultural heritage

2007

Cultural heritage vestiges represent complex physical systems, able to interact with the environment through continuous exchanges of heat and fluids (water, air). In this wide context, particular relevance is assumed by transport phenomena and diffusion of pollutant, vehiculated inside the considered structure by water itself. Interaction mechanisms can be considered at various observation scales, depending on the material provenance and on its geometry and location. Involved materials are commonly constituted by porous rocks - more or less altered - belonging to geological sedimentary formations, as limestone, calcarenite and travertine. Their appreciable porosity affects significantly liq…

ARCHAEOLOGICAL SITE ENVIRONMENTAL RISK CAPILLARITY ABSORPTION MAGNETIC RESONANCE NUMERICAL MODELSettore FIS/07 - Fisica Applicata(Beni Culturali Ambientali Biol.e Medicin)
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Nitensidine A, a guanidine alkaloid from Pterogyne nitens, is a novel substrate for human ABC transporter ABCB1.

2014

The Pterogyne nitens (Fabaceae) tree, native to South America, has been found to produce guanidine alkaloids as well as bioactive flavonols such as kaempferol, quercetin, and rutin. In the present study, we examined the possibility of interaction between human ATP-binding cassette (ABC) transporter ABCB1 and four guanidine alkaloids isolated from P. nitens (i.e., galegine, nitensidine A, pterogynidine, and pterogynine) using human T cell lymphoblast-like leukemia cell line CCRF-CEM and its multi-drug resistant (MDR) counterpart CEM/ADR5000. In XTT assays, CEM/ADR5000 cells were resistant to the four guanidine alkaloids compared to CCRF-CEM cells, although the four guanidine alkaloids exhibi…

ATP Binding Cassette Transporter Subfamily BLeukemia T-CellStereochemistryATPasePharmaceutical ScienceATP-binding cassette transporterGuanidineschemistry.chemical_compoundStructure-Activity RelationshipCell Line TumorDrug DiscoveryHumansheterocyclic compoundsBinding siteGuanidineCytotoxicityP-glycoproteinPharmacologyAdenosine TriphosphatasesbiologyPlant ExtractsAlkaloidFabaceaeFluoresceinsAntineoplastic Agents PhytogenicDrug Resistance MultipleMolecular Docking SimulationComplementary and alternative medicinechemistryBiochemistryVerapamilDrug Resistance Neoplasmbiology.proteinMonoterpenesMolecular MedicineATP-Binding Cassette TransportersKaempferolPhytotherapyPhytomedicine : international journal of phytotherapy and phytopharmacology
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Binding mode analysis of ABCA7 for the prediction of novel Alzheimer's disease therapeutics

2021

Graphical abstract

ATP Adenosine-triphosphateNBD nucleotide binding domainGSH reduced glutathionePolypharmacologyAlzheimer’s disease (AD)ATP-binding cassette transporterHTS high-throughput screeningBiochemistryABCA7Structural BiologyPLIF protein ligand interactionMSD membrane spanning domainPDB protein data bankTM transmembrane helixABC ATP-binding cassetteMultitarget modulation (PANABC)RMSD root mean square distanceABC transporter (ABCA1 ABCA4 ABCA7)Computer Science ApplicationsMOE Molecular Operating EnvironmentPharmacophoreSNP single-nucleotide polymorphismBiotechnologyResearch ArticleBBB blood-brain barrierBiophysicsDrug designComputational biologyBiologyAD Alzheimer’s diseasePET positron emission tomographyIC intracellular helixAPP amyloid precursor proteincryo-EM cryogenic-electron microscopyGeneticsHomology modelingBinding siteRational drug design and developmentComputingMethodologies_COMPUTERGRAPHICSNBD-cholesterol 7-nitro-2-13-benzoxadiazol-4-yl-cholesterolTransporterPSO particle swarm optimizationPET tracer (PETABC)ECD extracellular domainR-domain/region regulatory domain/regionABCA1biology.proteinEH extracellular helixTP248.13-248.65BODIPY-cholesterol 44-difluoro-4-bora-3a4a-diaza-s-indacene-cholesterolComputational and Structural Biotechnology Journal
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How and Where are Drugs Absorbed?

2007

A drug must interact with its receptors at their action sites or therapeutic target to exert its pharmacological or toxic effects. Therefore, the absorption of drug is an essential step which determines pharmacologic effects of drug. This article focuses on the biological barriers that the drug must cross in order to enter the body, drug absorption mechanisms, and influence of physiological characteristics of the administration route on absorption rate and extent. Keywords: drugs; absorption mechanisms; administration routes; passive diffusion; endocytosis

Absorption (pharmacology)DrugAbsorption rateChemistrymedia_common.quotation_subjectPharmacologic effectsReceptor-mediated endocytosisPharmacologyEndocytosisAction sitesmedia_common
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Protonation of the Biliverdin IXα Chromophore in the Red and Far-Red Photoactive States of a Bacteriophytochrome

2019

The tetrapyrrole chromophore biliverdin IXα (BV) in the bacteriophytochrome from Deinococcus radiodurans (DrBphP) is usually assumed to be fully protonated, but this assumption has not been systematically validated by experiments or extensive computations. Here, we use force field molecular dynamics simulations and quantum mechanics/molecular mechanics calculations with density functional theory and XMCQDPT2 methods to investigate the effect of the five most probable protonation forms of BV on structural stability, binding pocket interactions, and absorption spectra in the two photochromic states of DrBphP. While agreement with X-ray structural data and measured UV/vis spectra suggest that …

Absorption spectroscopyProtein ConformationPopulationProtonationMolecular Dynamics SimulationCrystallography X-Ray010402 general chemistryPhotochemistry01 natural sciencesArticlequantum chemistrychemistry.chemical_compoundMolecular dynamicsPhotochromismBacterial Proteins0103 physical scienceskvanttikemiaMaterials ChemistrymolekyylidynamiikkaPhysical and Theoretical Chemistryeducationta116excited statesphytochromeeducation.field_of_studyBinding SitesBiliverdin010304 chemical physicsChemistryBiliverdineta1182Chromophoremolecular dynamics3. Good health0104 chemical sciencesSurfaces Coatings and FilmsSpectrophotometry UltravioletDensity functional theoryDeinococcusvalokemiaproteiinitThe Journal of Physical Chemistry B
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