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1.
Cognition ; 208: 104547, 2021 03.
Article in English | MEDLINE | ID: mdl-33385610

ABSTRACT

Previous studies (Hyönä, Yan, & Vainio, 2018; Yan et al., 2014) have demonstrated that in morphologically rich languages a word's morphological status is processed parafoveally to be used in modulating saccadic programming in reading. In the present parafoveal preview study conducted in Finnish, we examined the exact nature of this effect by comparing reading of morphologically complex words (a stem + two suffixes) to that of monomorphemic words. In the preview-change condition, the final 3-4 letters were replaced with other letters making the target word a pseudoword; for suffixed words, the word stem remained intact but the suffix information was unavailable; for monomorphemic words, only part of the stem was parafoveally available. Three alternative predictions were put forth. According to the first alternative, the morphological effect in initial fixation location is due to parafoveally perceiving the suffix as a highly frequent letter cluster and then adjusting the saccade program to land closer to the word beginning for suffixed than monomorphemic words. The second alternative, the processing difficulty hypothesis, assumes a morphological complexity effect: suffixed words are more complex than monomorphemic words. Therefore, the attentional window is narrower and the saccade is shorter. The third alternative posits that the effect reflects parafoveal access to the word's stem. The results for the initial fixation location and fixation durations were consistent with the parafoveal stem-access view.


Subject(s)
Eye Movements , Reading , Attention , Fixation, Ocular , Humans , Saccades
2.
Cereb Cortex ; 31(5): 2549-2560, 2021 03 31.
Article in English | MEDLINE | ID: mdl-33367590

ABSTRACT

Music can induce strong subjective experience of emotions, but it is debated whether these responses engage the same neural circuits as emotions elicited by biologically significant events. We examined the functional neural basis of music-induced emotions in a large sample (n = 102) of subjects who listened to emotionally engaging (happy, sad, fearful, and tender) pieces of instrumental music while their hemodynamic brain activity was measured with functional magnetic resonance imaging (fMRI). Ratings of the four categorical emotions and liking were used to predict hemodynamic responses in general linear model (GLM) analysis of the fMRI data. Multivariate pattern analysis (MVPA) was used to reveal discrete neural signatures of the four categories of music-induced emotions. To map neural circuits governing non-musical emotions, the subjects were scanned while viewing short emotionally evocative film clips. The GLM revealed that most emotions were associated with activity in the auditory, somatosensory, and motor cortices, cingulate gyrus, insula, and precuneus. Fear and liking also engaged the amygdala. In contrast, the film clips strongly activated limbic and cortical regions implicated in emotional processing. MVPA revealed that activity in the auditory cortex and primary motor cortices reliably discriminated the emotion categories. Our results indicate that different music-induced basic emotions have distinct representations in regions supporting auditory processing, motor control, and interoception but do not strongly rely on limbic and medial prefrontal regions critical for emotions with survival value.


Subject(s)
Auditory Cortex/diagnostic imaging , Emotions/physiology , Motor Cortex/diagnostic imaging , Music/psychology , Adult , Amygdala/diagnostic imaging , Amygdala/physiology , Auditory Cortex/physiology , Brain/diagnostic imaging , Brain/physiology , Female , Functional Neuroimaging , Gyrus Cinguli/diagnostic imaging , Gyrus Cinguli/physiology , Humans , Insular Cortex/diagnostic imaging , Insular Cortex/physiology , Magnetic Resonance Imaging , Male , Middle Aged , Motor Cortex/physiology , Parietal Lobe/diagnostic imaging , Parietal Lobe/physiology , Somatosensory Cortex/diagnostic imaging , Somatosensory Cortex/physiology , Young Adult
3.
PLoS One ; 6(9): e24825, 2011.
Article in English | MEDLINE | ID: mdl-21949762

ABSTRACT

MRCKα and MRCKß (myotonic dystrophy kinase-related Cdc42-binding kinases) belong to a subfamily of Rho GTPase activated serine/threonine kinases within the AGC-family that regulate the actomyosin cytoskeleton. Reflecting their roles in myosin light chain (MLC) phosphorylation, MRCKα and MRCKß influence cell shape and motility. We report further evidence for MRCKα and MRCKß contributions to the invasion of cancer cells in 3-dimensional matrix invasion assays. In particular, our results indicate that the combined inhibition of MRCKα and MRCKß together with inhibition of ROCK kinases results in significantly greater effects on reducing cancer cell invasion than blocking either MRCK or ROCK kinases alone. To probe the kinase ligand pocket, we screened 159 kinase inhibitors in an in vitro MRCKß kinase assay and found 11 compounds that inhibited enzyme activity >80% at 3 µM. Further analysis of three hits, Y-27632, Fasudil and TPCA-1, revealed low micromolar IC(50) values for MRCKα and MRCKß. We also describe the crystal structure of MRCKß in complex with inhibitors Fasudil and TPCA-1 bound to the active site of the kinase. These high-resolution structures reveal a highly conserved AGC kinase fold in a typical dimeric arrangement. The kinase domain is in an active conformation with a fully-ordered and correctly positioned αC helix and catalytic residues in a conformation competent for catalysis. Together, these results provide further validation for MRCK involvement in regulation of cancer cell invasion and present a valuable starting point for future structure-based drug discovery efforts.


Subject(s)
Neoplasm Invasiveness/pathology , Protein Kinase Inhibitors/chemistry , Protein-Tyrosine Kinases/antagonists & inhibitors , Protein-Tyrosine Kinases/chemistry , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/analogs & derivatives , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/chemistry , 1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine/pharmacology , Amides/chemistry , Amides/pharmacology , Catalytic Domain , Cell Line, Tumor , Collagen/metabolism , Crystallography, X-Ray , Drug Combinations , Extracellular Matrix/drug effects , Extracellular Matrix/metabolism , Humans , Inhibitory Concentration 50 , Laminin/metabolism , Models, Molecular , Myotonin-Protein Kinase , Protein Kinase Inhibitors/analysis , Protein Kinase Inhibitors/pharmacology , Protein Multimerization/drug effects , Proteoglycans/metabolism , Pyridines/chemistry , Pyridines/pharmacology , Thiophenes/chemistry , Thiophenes/pharmacology , rho-Associated Kinases/antagonists & inhibitors , rho-Associated Kinases/metabolism
4.
J Med Chem ; 52(9): 2683-93, 2009 May 14.
Article in English | MEDLINE | ID: mdl-19351152

ABSTRACT

Pyrimidine biosynthesis is an attractive drug target in a variety of organisms, including humans and the malaria parasite Plasmodium falciparum. Dihydroorotate dehydrogenase, an enzyme catalyzing the only redox reaction of the pyrimidine biosynthesis pathway, is a well-characterized target for chemotherapeutical intervention. In this study, we have applied SPROUT-LeadOpt, a software package for structure-based drug discovery and lead optimization, to improve the binding of the active metabolite of the anti-inflammatory drug leflunomide to the target cavities of the P. falciparum and human dihydroorotate dehydrogenases. Following synthesis of a library of compounds based upon the SPROUT-optimized molecular scaffolds, a series of inhibitors generally showing good inhibitory activity was obtained, in keeping with the SPROUT-LeadOpt predictions. Furthermore, cocrystal structures of five of these SPROUT-designed inhibitors bound in the ubiquinone binding cavity of the human dihydroorotate dehydrogenase are also analyzed.


Subject(s)
Drug Design , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/enzymology , Animals , Binding Sites , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/metabolism , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Conformation , Oxidoreductases Acting on CH-CH Group Donors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/metabolism
5.
J Med Chem ; 50(2): 186-91, 2007 Jan 25.
Article in English | MEDLINE | ID: mdl-17228860

ABSTRACT

Pyrimidine biosynthesis presents an attractive drug target in malaria parasites due to the absence of a pyrimidine salvage pathway. A set of compounds designed to inhibit the Plasmodium falciparum pyrimidine biosynthetic enzyme dihydroorotate dehydrogenase (PfDHODH) was synthesized. PfDHODH-specific inhibitors with low nanomolar binding affinities were identified that bind in the N-terminal hydrophobic channel of dihydroorotate dehydrogenase, the presumed site of ubiquinone binding during oxidation of dihydroorotate to orotate. These compounds also prevented growth of cultured parasites at low micromolar concentrations. Models that suggest the mode of inhibitor binding is based on shape complementarity, matching hydrophobic regions of inhibitor and enzyme, and interaction of inhibitors with amino acid residues F188, H185, and R265 are supported by mutagenesis data. These results further highlight PfDHODH as a promising new target for chemotherapeutic intervention in prevention of malaria and provide better understanding of the factors that determine specificity over human dihydroorotate dehydrogenase.


Subject(s)
Aminobiphenyl Compounds/chemical synthesis , Antimalarials/chemical synthesis , Carbazoles/chemical synthesis , Naphthalenes/chemical synthesis , Oxidoreductases Acting on CH-CH Group Donors/antagonists & inhibitors , Plasmodium falciparum/enzymology , Aminobiphenyl Compounds/chemistry , Aminobiphenyl Compounds/pharmacology , Animals , Antimalarials/chemistry , Antimalarials/pharmacology , Carbazoles/chemistry , Carbazoles/pharmacology , Dihydroorotate Dehydrogenase , Drug Design , Humans , Models, Molecular , Mutagenesis, Site-Directed , Naphthalenes/chemistry , Naphthalenes/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/chemistry , Oxidoreductases Acting on CH-CH Group Donors/genetics , Plasmodium falciparum/drug effects , Point Mutation , Protein Binding
6.
Bioorg Med Chem Lett ; 16(1): 88-92, 2006 Jan 01.
Article in English | MEDLINE | ID: mdl-16236496

ABSTRACT

The de novo molecular design program SPROUT has been applied to the X-ray crystal structures of Plasmodium and human dihydroorotate dehydrogenase, respectively. The resulting design templates were used to prepare a series of molecules which, in keeping with predictions, showed useful levels of species-selective enzyme inhibition.


Subject(s)
Antimalarials/chemical synthesis , Chemistry, Pharmaceutical/methods , Drug Design , Enzyme Inhibitors/pharmacology , Oxidoreductases Acting on CH-CH Group Donors/chemistry , Plasmodium falciparum/enzymology , Animals , Antimalarials/pharmacology , Catalysis , Computer Simulation , Crystallography, X-Ray , Dihydroorotate Dehydrogenase , Enzyme Inhibitors/chemistry , Humans , Inhibitory Concentration 50 , Kinetics , Models, Chemical , Models, Molecular , Molecular Conformation , Protein Conformation , Software , Substrate Specificity , Ubiquinone/chemistry
7.
Helsinki; Forestry Training Programme;Finland. National Board of Education; 1993. 239 p. ilus.(Forestry Training Programme, 21).
Monography in En | Desastres -Disasters- | ID: des-15628
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