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Biomedical subjects

G A Jacobs

Publications and source records attributed to G A Jacobs.

At least 19 recordsLinked to original sources
PubMed2000

Extraction of sensory parameters from a neural map by primary sensory interneurons.

We examine the anatomical basis for the representation of stimulus parameters within a neural map and examine the extraction of these parameters by sensory interneurons (INs) in the cricket cercal sensory system. The extraction of air current direction by these sensory interneurons can be understood largely in terms of the anatomy of the system. There are two critical anatomical constraints. (1) The arborizations of afferents with similar directional tuning properties are located near each other within the neural map. Therefore, a continuous variation in stimulus direction causes a continuous variation in the spatial pattern of activation. (2) The restriction of the synaptic connections of an interneuron to a unique set of afferents results from the unique anatomy of that interneuron: its dendritic arbors are located within restricted regions of the afferent map containing afferents with a limited subset of directional sensitivities. The functional organization of the set of four interneurons studied here is equivalent to a Cartesian coordinate system for computing the stimulus direction vector. For any air current stimulus direction, the firing rates of the active interneurons could be decoded as Cartesian coordinates by neurons at successive processing stages. The implications of this Cartesian coordinate system are discussed with respect to optimal coding strategies and developmental constraints on the cellular implementation of this coding scheme.

Afferent Pathways↗
PubMed1999

Neural mapping of direction and frequency in the cricket cercal sensory system.

Primary mechanosensory receptors and interneurons in the cricket cercal sensory system are sensitive to the direction and frequency of air current stimuli. Receptors innervating long mechanoreceptor hairs (>1000 microm) are most sensitive to low-frequency air currents (<150 Hz); receptors innervating medium-length hairs (900-500 microm) are most sensitive to higher frequency ranges (150-400 Hz). Previous studies demonstrated that the projection pattern of the synaptic arborizations of long hair receptor afferents form a continuous map of air current direction within the terminal abdominal ganglion (). We demonstrate here that the projection pattern of the medium-length hair afferents also forms a continuous map of stimulus direction. However, the afferents from the long and medium-length hair afferents show very little spatial segregation with respect to their frequency sensitivity. The possible functional significance of this small degree of spatial segregation was investigated, by calculating the relative overlap between the long and medium-length hair afferents with the dendrites of two interneurons that are known to have different frequency sensitivities. Both interneurons were shown to have nearly equal anatomical overlap with long and medium hair afferents. Thus, the differential overlap of these interneurons with the two different classes of afferents was not adequate to explain the observed frequency selectivity of the interneurons. Other mechanisms such as selective connectivity between subsets of afferents and interneurons and/or differences in interneuron biophysical properties must play a role in establishing the frequency selectivities of these interneurons.

Afferent Pathways↗
PubMed1997

Neural mechanisms of behavioral plasticity: metamorphosis and learning in Manduca sexta.

This review summarizes our current understanding of the neural circuit underlying the larval proleg withdrawal reflex (PWR) of Manduca sexta and describes how PWR function changes in two contexts: metamorphosis and learning. The first form of PWR plasticity occurs during the larval-pupal transformation, when the reflex is lost. One mechanism that contributes to this loss is the weakening of monosynaptic excitatory connection from proleg sensory neurons to proleg retractor motor neurons. This change is associated with the hormonally-mediated regression of proleg motor neuron dendrites, which may break synaptic contacts between the sensory and motor neurons. After pupation, some of the proleg motor neurons die in a segment-specific pattern that persists even after individual motor neurons are isolated from the nervous system and exposed to hormones in vitro. The second form of PWR plasticity involves short-term, activity-dependent changes in neural function during the larval stage. The nicotinic cholinergic connections from proleg sensory neurons to motor neurons exhibit several forms of plasticity including facilitation, depression, post-tetanic potentiation and two types of muscarinic modulation. Larval PWR behavior exhibits two simple forms of learning-habituation and dishabituation-which involve alterations in the central PWR circuit. These studies of a simple circuit illustrate neural mechanisms by which behaviors undergo both short- and long-term modifications.

Animals↗
PubMed1996

Aminodiol HIV protease inhibitors. Synthesis and structure-activity relationships of P1/P1' compounds: correlation between lipophilicity and cytotoxicity.

A series of novel aminodiol inhibitors of HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce the cytotoxicity of 1. We have observed a high degree of correlation between the lipophilicity and cytotoxicity of this series of inhibitors. It was found that appropriate substitution at the para position of the P1' phenyl group of 1 resulted in the identification of equipotent (both against the enzyme and in cell culture) compounds (10l, 10m, 10n, and 15c) which possess significantly decreased cytotoxicity.

Amines↗
PubMed1996

Functional organization of a neural map in the cricket cercal sensory system.

Directionally selective mechanosensory afferents in the cricket cercal sensory system form a map of air current direction in the terminal abdominal ganglion. The global organization of this map was revealed by studying the anatomical relationships between an ensemble of sensory afferents that represented the entire range of receptor hair directional sensitivities on the sensory epithelium. The shapes and three-dimensional positions of the terminal arborizations of these cells were highly conserved across animals. Afferents with similar directional sensitivities arborized near each other within the map, and their terminal arborizations showed significant anatomical overlap. There was a clear global organization pattern of afferents within the map: they were organized into a spiral shape, with stimulus direction mapped continuously around the spiral. These results demonstrate that this map is not formed via a direct point-to-point topographic projection from the sensory epithelium to the CNS. Rather, the continuous representation of air current direction is synthesized within the CNS via an anatomical reorganization of the afferent terminal arbors. The arbors are reorganized according to a functional property that is independent of the location of the mechanoreceptor in the epithelium. The ensemble data were used to derive predictions of the patterns of steady-state excitation throughout the map for different directional stimuli. These images represent quantitative and testable predictions of functional characteristics of the entire neural map.

Afferent Pathways↗
PubMed1996

Information theoretic analysis of dynamical encoding by filiform mechanoreceptors in the cricket cercal system.

1. The stimulus/response properties of 20 mechanosensory receptors in the cricket cercal sensory system were studied using electrophysiological techniques. These receptors innervated filiform hairs of various lengths and directional selectivities. Previous studies have characterized the sensitivity of such cells to the direction of air currents and to the amplitude of sinusoidal stimuli. In the experiments reported here, the quantity and quality of information encoded in the receptors' elicited responses about the dynamics of more complex air current waveforms were characterized. 2. Based on a white analysis of receptor response properties, the median frequency of each receptor's frequency tuning curve was found to be strongly correlated with the length of its associated mechanosensory hair. The receptors connected to hairs > 900 microns encoded frequencies below approximately 150 Hz very accurately and the receptors connected to shorter hairs encoded progressively higher bands of frequencies. These results were interpreted within the constraints imposed by the biomechanics of the air current-to-cercus boundary. 3. The encoding accuracy was expressed in the information theoretic units of bits/second, which characterizes the information transmission rate of a receptor. The information rates of the neuronal spike trains ranged from 75 to 220 bits/s. The information transmission rate was not correlated with the length of the mechanosensory hair. The average amount of information transmitted per action potential was negatively correlated with receptor hair length and ranged between 0.6 and 3.1 bits/spike. Decoding of the receptor responses was restricted to linear transformations of the spike trains. 4. The stimulus/response latencies of the different receptors ranged between 5 and 11 ms, and the integration time of the receptors ranged between 8 and 30 ms. The latency of a receptor was only weakly correlated with the length of its associated hair, and a receptor's integration time was correlated with hair length. 5. The stimulus/response phase difference for receptor cells that innervated hairs longer than approximately 800 microns increased with frequency > 50 Hz. The phase responses for receptor cells connected to hairs < 800 microns did not vary for frequencies > 50 Hz.

Action Potentials↗
PubMed1994

Construction and analysis of a database representing a neural map.

We describe the development and analysis of a quantitative database representing the global structural and functional organization of an entire sensory map. The database was derived from measurements of anatomical characteristics of a statistical sample of typical mechanosensory afferents in the cricket cercal sensory system. Anatomical characteristics of the neurons were measured quantitatively in three dimensions using a computer reconstruction system. The reconstructions of all neurons were aligned and scaled to a common standard set of dimensions, according to a highly reproducible set of intrinsic fiducial marks. The database therefore preserves accurate information about spatial relationships between the neurons within the ensemble. Algorithms were implemented to allow the integration of electrophysiological data about the stimulus/response characteristics of the reconstructed neurons into the database. The algorithms essentially map a physiological function onto a "field" representing the continuous distribution of synaptic terminals throughout the neural structure. Subsequent analysis allowed quantitative predictions of several important functional characteristics of the sensory map that emerge from its global organization. First, quantitative and testable predictions were made about ensemble response patterns within the map. The predicted patterns are presented as graphical images, similar to images that might be observed with activity-dependent dyes in the real neural system. Second, the synaptic innervation patterns from the sensory afferent map onto the dendrites of a postsynaptic target interneuron were predicted by calculating the overlap between the interneuron's dendrites with the afferent map. By doing so, several aspects of the stimulus/response properties of the interneuron were accurately predicted.

Animals↗
PubMed1993

Synthesis and antiviral activity of novel isonucleoside analogs.

A series of branched-chain sugar isonucleosides was synthesized and evaluated for antiviral activity against herpesviruses. The preparation of homochiral [3S-(3 alpha, 4 beta, 5 alpha)]-2-amino-1, 9-dihydro-9-[tetrahydro-4,5-bis(hydroxymethyl)-3-furanyl]-6H-purin-6-one (7, BMS-181,164) and related compounds was stereospecifically achieved starting from 1,2-isopropylidene-D-xylofuranose (10). An efficient two-step reduction of the anomeric center of bis-acetate 18 involved formation of the chloride intermediate 19, followed by diisobutylaluminum hydride reduction. Tosylation of the resulting alcohol 20 provided the key intermediate 21, which was coupled with a variety of nucleobase anions. Several members of this new class of compounds possess activity against herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella-zoster virus (VZV), and human cytomegalovirus (HCMV). Compound 7 exhibits potent and selective activity against thymidine kinase encoding herpesviruses, in particular, HSV-1 and HSV-2. Evaluation of compound 7 for inhibition of WI-38 cell growth indicated an ID50 of > 700 microM. Although the antiherpetic activity in vitro of 7 is less than that of acyclovir (1), compound 7 displays superior efficacy in mouse model infections. The (bromovinyl)uridine analog 8 (BMS-181,165) also exhibits selective activity against HSV-1 and VZV, with no cytostatic effect on WI-38 cell growth at > 800 microM. Compound 8 is active against simian varicella virus and is efficacious in the corresponding monkey model.

Animals↗
PubMed1992

Synthesis and antiviral activity of 1-cyclobutyl-5-(2-bromovinyl)uracil nucleoside analogues and related compounds.

A series of racemic (1 alpha (E), 2 beta, 3 alpha)-1-[2,3-bis(hydroxymethyl)cyclobutyl]-5-(2-halovinyl)uracils was synthesized and evaluated in cell culture. The bromovinyl, iodovinyl, and chlorovinyl analogues, 13, 15, and 16, respectively, are all potent inhibitors of varicella zoster virus (VZV), but are less inhibitory to the replication of human cytomegalovirus (HCMV) and herpes simplex viruses 1 and 2 (HSV-1, HSV-2). The excellent anti-VZV activities of 13, 15, and 16 coupled with their virtual inability to inhibit WI-38 cell growth indicate high in vitro therapeutic indices. VZV thymidine kinase readily converts these compounds to their respective monophosphates but not to their corresponding diphosphates. Compound 13a, the (1'R) enantiomer of the bromovinyl analogue 13, was also synthesized, and its potency is comparable to that of the racemate. A lower homologue 14, (1 alpha (E),2 beta, 3 alpha)-1-[2-hydroxy-3-(hydroxymethyl)cyclobutyl]-5- (2-bromovinyl)uracil, was found to be inactive against VZV, HCMV, HSV-1, and HSV-2.

Antiviral Agents↗
PubMed1991

Anatomical relationships between sensory afferent arborizations in the cricket cercal system.

The anatomical relationships between sensory afferents within a topographic map in the cricket cercal sensory system were studied using a computer-based reconstruction system developed in our laboratory. Individual identified mechanosensory afferents were characterized physiologically, stained with cobalt, silver intensified, and reconstructed in three dimensions. All reconstructions were scaled to a common standard. The results indicate that there is very little variability in the position or extent of the terminal arborization of identified mechanosensory afferents. The topographic map was divided relatively equally into four regions representing each of the four classes of afferents studied. These regions were discrete but not completely segregated. Approximately 30% of the topographic map contained regions of overlap between two or more classes or afferents.

Abdomen↗
PubMed1991

Anatomy and physiology of identified wind-sensitive local interneurons in the cricket cercal sensory system.

1. A group of wind sensitive local interneurons (9DL Interneurons) in the terminal abdominal ganglion of the cricket Acheta domesticus were identified and studied using intracellular staining and recording techniques. 2. The 9DL interneurons had apparent resting potentials ranging from -38 mV to -45 mV. At this membrane potential, these cells produced graded responses to wind stimuli; action potentials were never observed at these resting potentials. However, when the 9DL interneurons were hyperpolarized to a membrane potential of approximately -60 mV, a single action potential at the leading edge of the wind stimulus response was sometimes observed. 3. The wind stimulus threshold of the 9DL interneurons to the types of stimuli used in these studies was approximately 0.01 cm/s. Above this threshold, the excitatory responses increased logarithmically with increasing peak wind velocity up to approximately 0.5 cm/s. 4. The 9DL interneurons were directionally sensitive; their response amplitudes varied with wind stimulus orientation. 9DL1 cells responded maximally when stimulated with wind directed at the front of the animal. The apparent peak in directional sensitivity of the 9DL2 interneurons varied between the side and the rear of the animal, depending upon the site of electrode penetration within the cell's dendritic arbor. 5. The locations of dendritic branches of the 9DL interneurons within the afferent map of wind direction were used to predict the excitatory receptive field of these interneurons.

Action Potentials↗
PubMed1991

Representation of sensory information in the cricket cercal sensory system. I. Response properties of the primary interneurons.

1. Six different types of primary wind-sensitive interneurons in the cricket cercal sensory system were tested for their sensitivity to the orientation and peak velocity of unidirectional airflow stimuli. 2. The cells could be grouped into two distinct classes on the basis of their thresholds and static sensitivities to airflow velocity. 3. Four interneurons (the right and left 10-2 cells and the right and left 10-3 cells) made up one of the two distinct velocity sensitivity classes. The mean firing frequencies of these interneurons were proportional to the logarithm of peak stimulus velocity over the range from 0.02 to 2.0 cm/s. 4. The other two interneurons studied (left and right 9-3) had a higher air-current velocity threshold, near the saturation level of the 10-2 and 10-3 interneurons. The slope of the velocity sensitivity curve for the 9-3 interneurons was slightly greater than that for the 10-2 and 10-3 interneurons, extending the sensitivity range of the system as a whole to at least 100 cm/s. 5. All of the interneurons had broad, symmetrical, single-lobed directional sensitivity tuning curves that could be accurately represented as truncated sine waves with 360 degree period. 6. The four low-threshold interneurons (i.e., left and right 10-2 and 10-3) had peak directional sensitivities that were evenly spaced around the horizontal plane, and their overlapping tuning curves covered all possible air-current stimulus orientations. The variance in the cells' responses to identical repeated stimuli varied between approximately 10% at the optimal stimulus orientations and approximately 30% at the zero-crossing orientations. 7. The two higher threshold interneurons (left and right 9-3) had broader directional sensitivity curves and wider spacing, resulting in reduced overlap with respect to the low-threshold class.

Animals↗
PubMed1990

Lessons from the aftermath of Flight 232. Practical considerations for the mental health profession's response to air disasters.

The fiery crash of a DC-10 at Sioux City, Iowa, on July 19, 1989, caused a crisis of major proportions, with attendant mental health needs. Various articles have described the need for psychological response teams in such crises. The present article provides practical guidelines for the preparation of a mental health disaster plan and for the coordination of a mental health team responding to a major air disaster. Such disasters can occur in any part of the country at any time. It is hoped that the suggestions in the present article will help teams that respond to future air disasters provide more rapid, effective, and efficient delivery of services to the survivors and their families, and the families of those who are killed.

Accidents, Aviation↗
PubMed1990

Postsynaptic changes at a sensory-to-motoneuron synapse contribute to the developmental loss of a reflex behavior during insect metamorphosis.

The larval-pupal transformation of the tobacco hornworm, Manduca sexta, involves the loss of many larval-specific behaviors, including a simple withdrawal reflex of the abdominal prolegs. This reflex is mediated by monosynaptic excitatory connections between afferents that innervate mechanosensory hairs on the proleg [the planta hairs (PHs)] and motoneurons that innervate proleg retractor muscles. In response to hormonal cues during the final days of larval life, the dendritic arbors of proleg retractor motoneurons regress extensively. Intracellular recordings indicate that the synaptic depolarization evoked in proleg motoneurons by electrical stimulation of PH afferents decreases by 78% during the larval-pupal transformation, over the same time course that the motoneuron dendrites regress. During the same period the number of PH afferents and the extent of their central projections may decrease slightly. To test the relative contributions of developmental changes in the presynaptic afferents and postsynaptic motoneurons to the weakening of the reflex pathway, we generated heterochronic mosaic pupae that retained one larval proleg. The PH afferents on the retained proleg retained their larval characteristics while their postsynaptic targets, the proleg motoneurons, appeared to regress normally. In the mosaic hemisegments, electrical stimulation of PH afferents evoked only a small synaptic depolarization of the proleg motoneurons, similar in amplitude to that recorded in normally developing pupae; thus, the developmental status of the afferents was irrelevant to the loss of the reflex. These findings suggest that postsynaptic changes, e.g., structural regression of motoneuron dendrites, may cause the weakening of the reflex pathway. This is the first demonstrated correlation between the hormonally mediated regression of motoneuron dendrites and the loss of a specific behavior during metamorphosis.

Animals↗
PubMed1989

An objective method for the evaluation of eye irritation in vivo.

It is generally agreed that intra- and interlaboratory variations in the evaluation of eye irritants are mainly due to the subjective judgement of eye lesions. The scoring of the palpebral conjunctivae is a typical example. To eliminate these difficulties in assessing eye irritants the relationship between corneal swelling, which can be determined using an objective technique, and the reading of other symptoms was investigated. The in vivo eye irritation assay was carried out on 34 substances according to the protocol laid down in Annex V, part B of Directive 79/831/EEC of the European Community on the classification, labelling and packaging of dangerous substances. Results were obtained for erythema, oedema, corneal opacity and corneal swelling. Erythema, oedema and opacity were evaluated according to the interpretation rules laid down in Annex VI, part IID of the EEC Directive 83/467/EEC. Corneal swelling was determined by the ultrasonic pachometer technique. Good correlations were found between the mean percentage corneal swelling after 24, 48 and 72 hr and the mean corneal opacity (r = 0.94) and erythema scores (r = 0.93) after the same observation times. The corneal swelling scores measured after 24 hr using the ultrasonic pachometer are comparable with those reported in the literature, which were obtained by optical pachometry. The good correlation with the other effects scored and the good repeatability of the results opens the possibility of introducing an objective and sensitive method into the ocular irritation assay and so reducing intra- and interlaboratory variations.

Animals↗
PubMed1989

Evaluation of a non-invasive human and an in vitro cytotoxicity method as alternatives to the skin irritation test on rabbits.

5 substances were investigated for their primary irritant effect by means of different protocols. The cutaneous blood flow values (CBFV) were measured in humans: in a 1st series of experiments 12 h after application of the pure substances for 48 h and in a 2nd series of experiments 1, 24, 48 and 72 h after application of the 10% diluted substances (subclinical concentration) for 3 h. Rabbit skin erythema scores were obtained 1, 24, 48 and 72 h after application of the undiluted substances for 4 h. The uridine uptake inhibition assay on KB cells was included as a cytotoxicity test. Results obtained for both protocols on humans are compared with each other and with the test data obtained on rabbits, and with the cytotoxicity data. Application of the undiluted substances for 48 h on human skin or for only 3 h at a 10% dilution resulted in the same ranking between the substances. The CBFV in the human correlated very well (r = 0.99) with erythema scores obtained on rabbits. A poor correlation was observed between the in vitro and the in vivo results. From this study, it can be concluded that CBFV measurement is a valid method for the detection of erythema at subclinical concentrations.

Animal Testing Alternatives↗
PubMed1988

Personality and smokeless tobacco use.

Smokeless tobacco use and personality factors associated with smokeless tobacco use were examined in a broad, representative sample of 8th and 10th graders from central and south-central Florida (n = 1413). Current, occasional, or ex-users of smokeless tobacco accounted for 51% of the males and 9% of the females. Smokeless tobacco users, as compared to non-users, had significantly higher Trait Anger, and Angry Temperament and Angry Reaction subscale scores on the State-Trait Personality Inventory, suggesting a possible role in the initiation of smokeless tobacco use. There were no differences in Trait Anger, Anxiety, or Curiosity scores between the three user groups, suggesting that trait personality does not play a role in the maintenance of smokeless tobacco use.

Adult↗