Biomedical subjects

S Binkley

Publications and source records attributed to S Binkley.

At least 19 recordsLinked to original sources

PubMed2000

The romantic sexology of John Addington Symonds.

This paper examines a radical text by the English Classicist and homosexual, John Addington Symonds (1840-1893). Through a close study of an unpublished and long concealed manuscript, "A Problem in Modern Ethics" (1891), Symonds's political vision and the odd form of writing it takes is revealed as romantic in character. Symonds polemicizes against the pathologization of homosexuals in the legal-medical discourses of the time and advocates on behalf of a latent homosexual ethics, shunned from modern Western society, but continuing to hold forth a promise for the civic and moral renewal of Western countries. Against the positions of Krafft-Ebing and others, Symonds argues for the acceptance of "manly love," in the spirit of the ancients, as a source of moral inspiration for a declining Europe. Where Symonds is often read by historians of homosexual radicalism as a precursor to the radical tradition of the 20th century, romantic acceptance of the untimeliness of his moral vision, indicates less a politically progressive than a romantically fatalistic enterprise.

England↗

PubMed2000

Three- and four-dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2C9 inhibitors.

The interaction of competitive type inhibitors with the active site of cytochrome P450 (CYP) 2C9 has been predicted using three- and four-dimensional quantitative structure activity relationship (3D-/4D-QSAR) models constructed using previously unreported and literature-derived data. 3D-QSAR pharmacophore models of the common structural features of CYP2C9 inhibitors were built using the program Catalyst and compared with 3D- and 4D-QSAR partial least-squares models, which use molecular surface-weighted holistic invariant molecular descriptors of the size and shape of inhibitors. The Catalyst models generated from multiple conformers of competitive inhibitors of CYP2C9 activities contained at least one hydrophobic and two hydrogen bond acceptor/donor regions. Catalyst model 1 was constructed with Ki(apparent) values for inhibitors of tolbutamide and diclofenac 4'-hydroxylation (n = 9). Catalyst model 2 was generated from literature Ki(apparent) values for (S)-warfarin 7-hydroxylation (n = 29), and Catalyst model 3 from literature IC50 values for tolbutamide 4-hydroxylation (n = 13). These three models illustrated correlation values of observed and predicted inhibition for CYP2C9 of r = 0.91, 0.89, and 0.71, respectively. Catalyst pharmacophores generated with Ki(apparent) values were validated by predicting the Ki(apparent) value of a test set of CYP2C9 inhibitors also derived from the literature (n = 14). Twelve of fourteen of these Ki(apparent) values were predicted to be within 1 log residual of the observed value using Catalyst model 1, whereas Catalyst model 2 predicted 10 of 14 Ki(apparent) values. The corresponding partial least-squares molecular surface-weighted holistic invariant molecular 3D- and 4D-QSAR models for all CYP2C9 data sets yielded predictable models as assessed using cross-validation. These 3D- and 4D-QSAR models of CYP inhibition will aid in future prediction of drug-drug interactions.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1999

Three- and four-dimensional quantitative structure activity relationship analyses of cytochrome P-450 3A4 inhibitors.

The program Catalyst was used to build three-dimensional quantitative structure activity relationship (3D-QSAR) pharmacophore models of the structural features common to competitive-type inhibitors of cytochrome P-450 (CYP) 3A4. These were compared with 3D- and four-dimensional (4D)-QSAR partial least-squares (PLS) models built using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors for size and shape of the inhibitor. The Catalyst pharmacophore model generated from multiple conformers of competitive inhibitors of CYP3A4-mediated midazolam 1'-hydroxylation (n = 14) yielded a high correlation of observed and predicted Ki values of r = 0.91. Similarly, PLS MS-WHIM was used to produce 3D- and 4D-QSARs for this data set and produced models that were statistically predictable after cross-validation. Two additional Catalyst pharmacophores were constructed from literature Ki values (n = 32) derived from the inhibition of CYP3A-mediated cyclosporin A metabolism and IC50 data (n = 22) from the inhibition of CYP3A4-mediated quinine 3-hydroxylation. These Catalyst pharmacophores illustrated correlations of observed and predicted inhibition for CYP3A4 of r = 0.77 and 0.92, respectively. The corresponding 4D-QSARs generated by PLS MS-WHIM for these data sets were of comparable quality as judged by cross-validation. Both Ki pharmacophores generated with Catalyst were also validated by predicting the Ki(apparent) values of a test set of eight CYP3A4 inhibitors not included in either model. In seven of eight cases, the residuals of the predicted Ki(apparent) values were within 1 log unit of the observed values. The 3D- and 4D-QSAR models produced in this study suggest the utility of future in silico prediction of CYP3A4-mediated drug-drug interactions.

Catalysis↗

PubMed1999

Three and four dimensional-quantitative structure activity relationship (3D/4D-QSAR) analyses of CYP2D6 inhibitors.

Three- and four-dimensional quantitative structure activity relationship (3D/4D-QSAR) pharmacophore models of competitive inhibitors of CYP2D6 were constructed using data from our laboratory or the literature. The 3D-QSAR pharmacophore models of the common structural features of CYP2D6 inhibitors were built using the program Catalyst (Molecular Simulations, San Diego, CA, USA). These 3D-QSAR models were compared with 3D and 4D-QSAR partial least squares (PLS) models which were constructed using molecular surface-weighted holistic invariant molecular (MS-WHIM) descriptors of size and shape of inhibitors. The first Catalyst model was generated from multiple conformers of competitive inhibitors (n = 20) of CYP2D6 mediated bufurolol 1'-hydroxylation. This model demonstrated a correlation of observed and predicted Ki (apparent) values of r = 0.75. A second Catalyst model was constructed from literature derived Ki (apparent) values (n = 31) for the inhibition of CYP2D6. This model provided a correlation of observed and predicted inhibition for CYP2D6 of r = 0.91. Both Catalyst Ki pharmacophores were then validated by predicting the Ki (apparent) of a test set of known CYP2D6 inhibitors (n = 15). Ten out of 15 of these Ki (apparent) values were predicted to be within one log residual of the observed value using our CYP2D6 inhibitor model, while the literature model predicted nine out of 15 values. Similarly, 3D- and 4D-QSARs derived from PLS MS-WHIM for our dataset yielded predictable models as assessed using cross-validation. The corresponding cross-validated PLS MS-WHIM model for the literature dataset yielded a comparable 3D-QSAR and improved 4D-QSAR value. Such computational models will aid in future prediction of drug-drug interactions.

Cytochrome P-450 CYP2D6 Inhibitors↗

PubMed1996

Field observations of yawning and activity in humans.

Rates of wrist activity and yawning were recorded continuously for 7-15 days in adult human male and female subjects. In the 15 min following 747 yawns wrist motion increased reliably in all subject records. The data were consistent with an hypothesis that yawning is predictive of an increase in activity level. In a second study, data from daily logs kept by 45 subjects confirmed previous findings that yawning frequency is unrelated to prior amount of sleep, or to times of awaking or retiring. More yawning occurred during the week than during weekends.

Adolescent↗

PubMed1994

Wrist motion rhythm phase shifts in travelers may differ from changes in time zones.

Wrist motions (223-471)/5 min were measured during 17-32 days of continuous recordings made from human passengers as they traveled across zero to five time zones for business and pleasure. The travelers all exhibited daily cycles of activity and rest. The duration of daily activity, alpha, was 1.1 h less at the destination; the mean was 63 wrist motions/5 min less at the destination. Phase shifts of the daily rhythm (e.g., acrophases, 0.0 to 5.3 h) advanced or delayed in the direction expected from time zone changes. However, the magnitude of the phase shifts differed (e.g., as much as 2.3 h) from the expected changes because of transmeridian travel and there were phase shifts even when there was no change in time zone. Differences were observed in phase shifts assessed by different methodologies of determining phase (waveforms, onsets, offsets, acrophases).

Adult↗

PubMed1993

Structures and molecules involved in generation and regulation of biological rhythms in vertebrates and invertebrates.

Melatonin from the retina and the pineal gland functions in neuroendocrine hierarchies. Photoreceptors--eyes and extraretinal--detect light. Oscillators--pineal and suprachiasmatic nuclei--act as pacemakers. Driven neuroendocrine rhythms carry temporal hormone signals throughout the body. Light controls melatonin: light sets the phase of the melatonin rhythm and determines the duration of melatonin synthesis. By these means, circadian rhythms (e.g., in locomotor activity and body temperature) and seasonal rhythms (e.g., in reproduction) are controlled.

Animals↗

PubMed1993

98.6 degrees.

Explore the source record for details and available documents.

Body Temperature↗

PubMed1993

Individual, phase, and weekly variations in daily cycles of wrist activity in freeliving humans.

Wrist activity was monitored in 17 college students for 11-15 days each. Records of individuals had distinctive patterns, like fingerprints. The subjects all exhibited daily cycles in their activity with activity during the daytime and with period lengths close to 24 h. There was individual variation in average phase (onset 5.3 h, offset 4.5 h, acrophase 6.1 h). Individual subjects all showed 7-day oscillations in their activity patterns associated with the weekly work-leisure schedules. During the leisure weekends, the subjects as a group had a 2.1-h delay in onset, a 1.5-h delay in acrophase, and a 0.8-h shortening in alpha.

Adult↗

PubMed1992

Wrist activity in a woman: daily, weekly, menstrual, lunar, annual cycles?

Wrist activity was monitored continuously for one year in a woman who went about her normal life. The year of data were analyzed for changes and rhythms--daily, weekly, menstrual, lunar, annual. For each day, average motions/5 minutes, activity onset, activity offset, alpha (duration of activity), and acrophase were measured. Periodograms and average daily wave forms were calculated. Well-defined, entrained, daily rest-activity cycles were observed throughout the year with periods close to 24 hours. There was weekend delay (0.7 hours) in onset, weekend decrease in alpha (1.0 hours), and weekend advance of acrophase (0.4 hours). Motions/5 minutes decreased 9%, onsets were 0.3 hours later, and alphas were 0.4 hours shorter on menstrual cycle days 8 through 18 which should have encompassed the time of ovulation. Lunar phase had no effect. Annual changes in onset (1.1 hours), offset (1.2 hours), and acrophase (1.1 hours) were attributed to the 1-hour change between standard and daylight savings time.

Circadian Rhythm↗

PubMed1990

Human daily rhythms measured for one year.

Four human subjects recorded their wake-up and to-sleep times for one year each. The data were plotted to display individual circadian rhythms and the data were analyzed statistically. First, individuals had characteristic patterns in which visible changes in the patterns were observed mainly when time zones were changed because of travel. Second, the months with the latest wake-up and latest to-sleep times concentrated around the winter solstice; the months with the earliest wake-up and earliest to-sleep times concentrated around the fall equinox. Third, new moon versus full moon days were not different. Fourth, one-hour changes between standard and daylight savings time in the USA were reflected by near one-hour changes in two subjects, but not in a third. Fifth, weekend delays in wake-up time (0.8-1.6 hours), weekend delays in to-sleep time (0.1-0.5 hours), and shorter weekend awake time (0.8-1.3 hours) were observed. Sixth, throughout the year, wake-up times were close to the time of sunrise, but to-sleep times were several hours past sunset.

Adult↗

PubMed1990

Day-night differences in the vesicle populations of nerve terminals in the rat and chick pineal gland.

Day-night differences in the ultrastructure of pineal neuronal elements were quantitated in the rat and the chick--two species that exhibit important differences in adrenergic control of melatonin synthesis. Area densities of small clear vesicles (40-60 nm) and small dense-cored vesicles (40-60 nm) in nerve terminals were significantly reduced during the night in the rat. In the chick, there were no day-night differences in the frequency of clear vesicles, but the number of small dense-cored vesicles tended to be greater at night. There was no effect of day-night sampling on area densities of large dense-cored vesicles (80-120 nm) in either species. These findings are consistent with biochemical evidence for day-night species differences in the adrenergic control of pineal function.

Animals↗

PubMed1989

Photoperiod modifies daily maps of light and dark sensitivity for N-acetyltransferase activity in pineal glands of 3-week old Gallus domesticus.

N-acetyltransferase (NAT) activity in pineal glands exhibits a circadian rhythm with peak activity occurring in the dark-time. We previously showed that in Gallus domesticus chicks pretreated with LD12:12, NAT activity was increased by dark exposure (peak dark sensitivity occurred during the expected dark-time) or decreased by light at night (peak light sensitivity occurred early in the night during the time of dark sensitivity). In this study we mapped dark sensitivity vs time (for NAT activity increase in response to 2 h dark pulses), and light sensitivity vs time (for NAT activity decrease in response to 10 min or 30 min light pulses) over a cycle for 3-week old chicks, Gallus domesticus, pretreated with long (LD16:8) or short photoperiod (LD8:16). Sensitivity to light was increased in the second 8 h after L/D by LD8:16. Sensitivity to dark was increased in the first 8 h after L/D by LD16:8.

Acetyltransferases↗

PubMed1989

Weekly phase shifts of rhythms self-reported by almost feral human students in the USA and Spain.

Eleven students in the USA and fifteen students in Spain wrote their wake-up and to-sleep times on forms for a month. The subjects reported large day-to-day phase shifts of magnitude comparable to those of travelers and shiftworkers. All individuals exhibited some large phase shifts of their day-to-day wake-up and to-sleep times (largest shift average, 4.54 hours; range, -12.7 to +13.9 hours). The students had daily cycles and weekly cycles in their wake-up and to-sleep times. Synchrony (entrainment) with the 24-hour environment was achieved by large weekly phase advances (individual averages ranged 1.2-4.8 hours) rather than by small daily adjustments. There was considerable variation in awake time: there were 2-3 hour differences between individuals, and there were 3.2 hour differences depending on day of the week. Alarm use appeared to be the Zeitgeber, in contrast to laboratory studies which show light and social Zeitgebers for humans. There was a 4 hour difference between the Spanish and USA students which was attributed to the 5 hour difference in time zones. Wake-up time and prior to-sleep time were interdependent.

Adult↗

PubMed1989

Advancing schedules and constant light produce faster resynchronization of circadian rhythms.

House sparrows, Passer domesticus, were subjected to rotated light-dark (LD) cycles that consisted of repeated 8-hr advances or delays of 5 days of LD 8:16, with intervening 40-80 hr of constant dark or light. Sparrows reset the fastest (by the second cycle) when they were advanced with intervening constant light (LL). They reset the slowest (taking six cycles) when they were delayed with intervening constant dark (DD).

Animals↗

PubMed1988

Xenopus tadpole melanophores are controlled by dark and light and melatonin without influence of time of day.

Melanophores were studied in tadpoles of the South African clawed toad, Xenopus laevis, during the first week after hatching (stages 46-49) at 25 degrees C. The tadpoles had melanophores with dispersed melanosomes in the light and punctate melanophores in the dark in LD 12:12. The melanophores remained punctate in constant dark and the melanosomes remained dispersed in constant light. Lights-out (in the light-time of LD 12:12) caused the melanophores to become punctate, which occurred more quickly than the dispersion of melanosomes, which commenced when the lights were turned on (in the dark-time of LD 12:12). Melanophores with dispersed melanosomes in tadpoles (in constant light) became punctate in response to a series of melatonin concentrations (0.2-5 ng/ml) in their bathing water irrespective of the time of day melatonin was administered. An image-analysis technique for assessing melanophore responses was tested.

Animals↗

PubMed1987

Sparrow circadian rhythm responses to rotated light-dark schedules.

House sparrows, Passer domesticus, were individually subjected to light-dark regimens while their perching activity was continuously monitored. The sparrows resynchronized in 5 days when LD8:16 (8 hr of light alternating with 16 hr of dark) was advanced by 8 hr; however, the sparrows were 1.7 hr from resynchronization after 5 days when the schedule was delayed 8 hr. Sparrows subjected to two simultaneously presented light-dark schedules (rotated LD8:16 provided by one light source imposed together with LD12:12 provided by a second light source) did not ignore either cycle; instead the sparrows responded as to a sequence of photoperiods; they resynchronized the onsets of their activity with the first time of lights-on of the collective photoperiod provided by the two light sources.

Animals↗

PubMed1987

Circadian rhythm in pineal N-acetyltransferase activity: rapid phase reversal and response to shorter than 24-hour cycles (IV).

N-Acetyltransferase (NAT) is an enzyme whose rhythmic activity in the pineal gland and retina is responsible for circadian rhythms in melatonin. The NAT activity rhythm has circadian properties such as persistence in constant conditions and precise control by light and dark. Experiments are reported in which chicks (Gallus domesticus), raised for 3 weeks in 12 h of light alternating with 12 h of dark (LD12:12), were exposed to 1-3 days of light-dark treatments during which NAT activity was measured in their pineal glands. (a) In LD12:12, NAT activity rose from less than 4.5 nmol/pineal gland/h during the light-time to 25-50 nmol/pineal gland/h in the dark-time. Constant light (LL) attenuated the amplitude of the NAT activity rhythm to 26-45% of the NAT activity cycle in LD12:12 during the first 24 h. (b) The timing of the increase in NAT activity was reset by the first full LD12:12 cycle following a 12-h phase shift of the LD12:12 cycle (a procedure that reversed the times of light and dark by imposition of either 24 h of light or dark). This result satisfies one of the criteria for NAT to be considered part of a circadian driving oscillator. (c) In less than 24-h cycles [2 h of light in alternation with 2 h of dark (LD2:2), 4 h of light in alternation with 4 h of dark (LD4:4), and 6 h of light in alternation with 6 h of dark (LD6:6)], NAT activity rose in the dark during the chicks' previously scheduled dark-time but not the previously scheduled light-time of LD12:12. In a cycle where 8 h of light alternated with 8 h of dark (LD8:8), NAT activity rose in both 8-h dark periods, even though the second one fell in the light-time of the prior LD12:12 schedule.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetyltransferases↗