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  • 1
    ISSN: 1432-0770
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract The discharge rates of premotor, brain-stem neurons that create eye movements modulate in relation to eye velocity yet firing rates of extraocular motoneurons contain both eye-position and eyevelocity signals. The eye-position signal is derived from the eye-velocity command by means of a neural network which functioins as a temporal integrator. We have previously proposed a network of lateral-inhibitory neurons that is capable of performing the required integration. That analysis centered on the temporal aspects of the signal processing for a limited class of idealized inputs. All of its cells were identical and carried only the integrated signal. Recordings in the brain stem, however, show that neurons in the region of the neural integrator have a variety of background firing rates, all carry some eye-velocity signal as well as the eye-position signal, and carry the former with different strengths depending on the type of eye movement being made. It was necessary to see if the proposed model could be modified to make its neurons more realistic. By modifying the spatial distribution of afferents to the network, we demonstrate that the same basic model functions properly in spite of afferents with nonuniform background firing rates. To introduce the eye-velocity signal a double-layer network, consisting of inhibitory and excitatory cells, was necessary. By presenting the velocity input to only local regions of this network it was shown that all cells in the network still carried the integrated signal and that its cells could carry different eye-velocity signals for different types of eye movements. Thus, this model stimulates quantitatively and qualitatively, the behavior of neurons seen in the region of the neural integrator.
    Type of Medium: Electronic Resource
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  • 2
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 656 (1992), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 3
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 656 (1992), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 4
    Electronic Resource
    Electronic Resource
    s.l. : American Chemical Society
    Industrial & engineering chemistry 41 (1949), S. 2221-2224 
    ISSN: 1520-5045
    Source: ACS Legacy Archives
    Topics: Chemistry and Pharmacology , Process Engineering, Biotechnology, Nutrition Technology
    Type of Medium: Electronic Resource
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  • 5
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 374 (1981), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 6
    Electronic Resource
    Electronic Resource
    Oxford, UK : Blackwell Publishing Ltd
    Annals of the New York Academy of Sciences 374 (1981), S. 0 
    ISSN: 1749-6632
    Source: Blackwell Publishing Journal Backfiles 1879-2005
    Topics: Natural Sciences in General
    Type of Medium: Electronic Resource
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  • 7
    Electronic Resource
    Electronic Resource
    Springer
    Biological cybernetics 14 (1973), S. 71-83 
    ISSN: 1432-0770
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Description / Table of Contents: Zusammenfassung 1. Es wird eine Folge von vier Modellen für das System der sakkadischen Augenbewegungen vorgeschlagen. Die Modelle werden von Stufe zu Stufe komplexer und bilden die experimentell gefundenen Antworten auf zunehmend kompliziertere Zielbewegungen nach. Bei der Konzeption der Modelle wird der Akzent auf Vereinbarkeit mit den strukturellen und funktioneilen Gegebenheiten der Neurologie gelegt. In jeder Stufe werden die Elemente dieser Modelle so gewählt, daß sie möglichst genau neuro-anatomischen Strukturen antsprechen und daß ihr Verhalten sich mit dem neurophysiologisch nachgewiesenen oder wahrscheinlich gemachten deckt. 2. Durch Ableitung von oculomotorischen Neuronen beim wachen Affen wurde die Dynamik des mechanischen Systems, bestehend aus den äußeren Augenmuskeln und dem Bindegewebe, in dem der Augapfel gelagert ist, erfaßt. Die Übergangsfunktion dieses Systems ist in die Modelle eingearbeitet. 3. Neuere Untersuchungen an den Strukturen des Hirnstamms, die für sakkadische Augenbewegungen verantwortlich sind, lassen im prämotorischen Apparat eine Anordnung vermuten, die im wesentlichen zwei neuronale Netzwerke enthält: einen Integrator und einen Pulsgenerator. Diese Schaltungen werden in den Modellen verwandt. 4. Nach Einarbeitung der obengenannten Änderungen in bestehende Modelle des sakkadischen Systems wird die Annahme, daß die visuelle Information durch das Nervensystem diskontinuierlich abgetastet wird, überflüssig. Die Modelle enthalten keine Abtastung, obwohl in Folge des sakkadischen Pulsgenerators ihr Verhalten als Ganzes noch immer das einer getasteten Regelung ist. 5. Das Grundmodell wird so modifiziert, daß sein Verhalten mit den Augenbewegungen übereinstimmt, die experimentell als Antwort auf kombinierte Sprung- und Rampenbewegungen des Ziels gefunden werden. Dies geschieht, indem der nach einer Reaktionszeit zu erwartende Fehler aufgrund des Momentanfehlers und seines Differentialquotienten geschätzt wird. 6. Parallele Datenverarbeitung ist eine allgemein bekannte Eigenschaft des Nervensystems. Durch Kombination dieser Eigenschaft mit einer zufälligen Entscheidungsschwelle wird das Modell so erweitert, daß es sich mit den experimentellen Befunden auch bei solchen Doppelsprüngen des Ziels deckt, bei denen der Sprungabstand kleiner als 0.2 sec ist. 7. Abschließend wird ein Modell vorgestellt, das ein Kontinuum von parallelen Datenverarbeitungskanälen einschließt und damit die retinotope räumliche Organisation des visuellen Systems sowie die tecto-bulbären motorischen Signale nachbildet. Es handelt sich hierbei um ein Denkmodell, das weder realisiert noch geprüft wurde. Es wird vielmehr dazu verwendet, komplexere Formen von Augenbewegungen zu diskutieren, wie sie z. B. aufzutreten scheinen, wenn der Entscheidungsprozeß zwischen den Hemisphären wechseln muß. Ebenso wird erörtert, wie das System schnelle Korrektursakkaden auslösen kann, deren Latenzen bis zu 85 msec kurz sind.
    Notes: Abstract 1. A sequence of four models is proposed for the saccadic eye movement control system. The models become increasingly complex as they are made to respond to increasingly more complicated target movements in accordance with experimental results. Compatibility with neurological structure and function is stressed in the formation of the models. In each case, the elements of the models are constructed to conform as closely as possible to neuroanatomical structures and behave in a way that has been established or suggested by neurophysiology. 2. The dynamic behavior of the mechanics of the extraocular muscles and eyeball suspensory tissues has been established by recording from oculomotoneurons in alert monkeys. The transfer function of this mechanical system is used in these models. 3. Recent experiments on the neural circuits in the brain stem that are responsible for saccadic eye movements suggest an arrangement of the premotor circuitry that contains two principal neural networks; an integrator and a pulse generator. This circuitry is used in the models. 4. When the above modifications are made to existing models of the saccadic system, they remove the necessity of supposing that the visual information is sampled by the nervous system. The models do not include a sampler although the saccadic pulse generator still makes the overall system behavior similar to that of a sampled-data system. 5. The basic model is modified to make its behavior agree with experimental eye movement responses to target ramps and step-ramps. This is done by using error and its rate of change to estimate the error that will exist one reaction time in the future. 6. Parallel processing of data is a well recognized property of the nervous system. By utilizing it in combination with a random decision threshold, the model is extended to produce results in agreement with experiments for double-step target movements in which the second step occurs less than 0.2 sec after the first. 7. Finally, a model is presented which incorporates a continuum of parallel processing to represent the retinotopic spatial organization of the visual system and the tecto-bulbar motor commands. The model is conceptual; it was not constructed or tested but is used to discuss more complex eye movement phenomena such as those that appear to occur when the decision process must shift between hemispheres and how the system might produce quick correcting saccades with latencies as short as 85 msec.
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  • 8
    Electronic Resource
    Electronic Resource
    Springer
    Biological cybernetics 49 (1983), S. 127-136 
    ISSN: 1432-0770
    Source: Springer Online Journal Archives 1860-2000
    Topics: Biology , Computer Science , Physics
    Notes: Abstract Single-unit recordings, stimulation studies, and eye movement measurements all indicate that the firing patterns of many oculomotor neurons in the brain stem encode eye-velocity commands in premotor circuits while the firing patterns of extraocular motoneurons contain both eye-velocity and eye-position components. It is necessary to propose that the eye-position component is generated from the eye-velocity signal by a leaky hold element or temporal integrator. Prior models of this integrator suffer from two important problems. Since cells appear to have a steady, background signal when eye position and velocity are zero, how does the integrator avoid integrating this background rate? Most models employ some form of lumped, oositive feedback the gain of which must be kept within totally unreasonable limits for proper operation. We propose a lateral inhibitory network of homogeneous neurons as a model for the neural integrator that solves both problems. Parameter sensitivity studies and lesion simulations are presented to demonstrate robustness of the model with respect to both the choice of parameter values and the consequences of pathological changes in a portion of the neural integrator pool.
    Type of Medium: Electronic Resource
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  • 9
    Publication Date: 2019-03-20
    Description: Malaria and cryptosporidiosis, caused by apicomplexan parasites, remain major drivers of global child mortality. New drugs for the treatment of malaria and cryptosporidiosis, in particular, are of high priority; however, there are few chemically validated targets. The natural product cladosporin is active against blood- and liver-stagePlasmodium falciparumandCryptosporidium parvumin cell-culture studies. Target deconvolution inP. falciparumhas shown that cladosporin inhibits lysyl-tRNA synthetase (PfKRS1). Here, we report the identification of a series of selective inhibitors of apicomplexan KRSs. Following a biochemical screen, a small-molecule hit was identified and then optimized by using a structure-based approach, supported by structures of bothPfKRS1 andC. parvumKRS (CpKRS). In vivo proof of concept was established in an SCID mouse model of malaria, after oral administration (ED90= 1.5 mg/kg, once a day for 4 d). Furthermore, we successfully identified an opportunity for pathogen hopping based on the structural homology betweenPfKRS1 andCpKRS. This series of compounds inhibitCpKRS andC. parvumandCryptosporidium hominisin culture, and our lead compound shows oral efficacy in two cryptosporidiosis mouse models. X-ray crystallography and molecular dynamics simulations have provided a model to rationalize the selectivity of our compounds forPfKRS1 andCpKRS vs. (human)HsKRS. Our work validates apicomplexan KRSs as promising targets for the development of drugs for malaria and cryptosporidiosis.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
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  • 10
    Publication Date: 2009-12-01
    Print ISSN: 0021-8979
    Electronic ISSN: 1089-7550
    Topics: Physics
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