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Biomedical subjects

P J Hancock

Publications and source records attributed to P J Hancock.

12 recordsLinked to original sources
PubMed2001

The crystal structure of human protein farnesyltransferase reveals the basis for inhibition by CaaX tetrapeptides and their mimetics.

Protein farnesyltransferase (FTase) catalyzes the attachment of a farnesyl lipid group to the cysteine residue located in the C-terminal tetrapeptide of many essential signal transduction proteins, including members of the Ras superfamily. Farnesylation is essential both for normal functioning of these proteins, and for the transforming activity of oncogenic mutants. Consequently FTase is an important target for anti-cancer therapeutics. Several FTase inhibitors are currently undergoing clinical trials for cancer treatment. Here, we present the crystal structure of human FTase, as well as ternary complexes with the TKCVFM hexapeptide substrate, CVFM non-substrate tetrapeptide, and L-739,750 peptidomimetic with either farnesyl diphosphate (FPP), or a nonreactive analogue. These structures reveal the structural mechanism of FTase inhibition. Some CaaX tetrapeptide inhibitors are not farnesylated, and are more effective inhibitors than farnesylated CaaX tetrapeptides. CVFM and L-739,750 are not farnesylated, because these inhibitors bind in a conformation that is distinct from the TKCVFM hexapeptide substrate. This non-substrate binding mode is stabilized by an ion pair between the peptide N terminus and the alpha-phosphate of the FPP substrate. Conformational mapping calculations reveal the basis for the sequence specificity in the third position of the CaaX motif that determines whether a tetrapeptide is a substrate or non-substrate. The presence of beta-branched amino acids in this position prevents formation of the non-substrate conformation; all other aliphatic amino acids in this position are predicted to form the non-substrate conformation, provided their N terminus is available to bind to the FPP alpha-phosphate. These results may facilitate further development of FTase inhibitors.

Alkyl and Aryl Transferases↗
PubMed2001

Human and automatic face recognition: a comparison across image formats.

Human subjects perform poorly at matching different images of unfamiliar faces. When images are taken by different capture devices (cameras), matching is difficult for human perceivers and also for automatic systems. We test an automatic face recognition system based on principal components analysis (PCA) and compare its performance with that of human subjects tested on the same set of images. A number of variants of the PCA system are compared, using different matching metrics and different numbers of components. PCA performance critically depends on the choice of distance metric, with a Mahalanobis metric consistently outperforming a Euclidean metric. Under optimal conditions, the automatic PCA system exceeds human performance on the same images. We hypothesise that unfamiliar face recognition may be mediated by processes corresponding to rather simple functions of the inputs.

Face↗
PubMed2000

Effects of dizocilpine (MK 801) on noradrenaline, serotonin and dopamine release and uptake.

In the present study, we examined the actions of the NMDA antagonist dizocilpine (MK801) on electrically evoked release and uptake of noradrenaline (NA) in the locus coeruleus (LC), serotonin (5-HT) in the dorsal raphe nucleus (DRN) and dopamine (DA) in the nucleus accumbens (NAc), measured by fast cyclic voltammetry (FCV) in rat brain slices. Dizocilpine (10 microM) significantly increased NA (to 248 +/- 15%) and 5-HT release (to 184 +/- 29%) and slowed monoamine uptake in the LC (t1/2 = 853 +/- 129%) and the DRN (t1/2 = 387 +/- 70%), respectively. However, dizocilpine had no effect on DA release or uptake in NAc. Actions on monoamines are thus likely and should be considered in the interpretation of data regarding dizocilpine.

Animals↗
PubMed2000

Evolving faces from principal components.

A system that uses an underlying genetic algorithm to evolve faces in response to user selection is described. The descriptions of faces used by the system are derived from a statistical analysis of a set of faces. The faces used for generation are transformed to an average shape by defining locations around each face and morphing. The shape-free images and shape vectors are then separately subjected to principal components analysis. Novel faces are generated by recombining the image components (eigenfaces) and then morphing their shape according to the principal components of the shape vectors (eigenshapes). The prototype system indicates that such a statistical analysis of a set of faces can produce plausible, randomly generated photographic images.

Biological Evolution↗
PubMed1999

Stereospecific effects of ketamine on dopamine efflux and uptake in the rat nucleus accumbens.

In addition to being a general anaesthetic, ketamine is a recognized drug of abuse. Many, if not all, drugs of abuse have been shown to increase dopamine efflux in the nucleus accumbens (NAc). As ketamine is optically active, we examined if its actions on dopamine efflux in the NAc were stereoselective. Slices of rat NAc were superfused with artificial CSF at 32 degrees C. Dopamine efflux was evoked by electrical stimulation (1 or 20 pulses, 100 Hz) and measured using fast cyclic voltammetry. (+/-)-Ketamine 100 mumol litre-1 increased dopamine efflux (to mean 174 (SEM 17)% of control, P < 0.05) and slowed dopamine uptake half-time (T1/2) to 164 (17)% of control, as did (+)-ketamine 100 mumol litre-1 (efflux 236 (16)% (P < 0.001); uptake T1/2 177 (25)% (P < 0.05)). The (-)-isomer was inactive. The effect of (+)-ketamine on dopamine efflux did not correlate with its action on dopamine uptake. (+)-Ketamine increased dopamine efflux on single pulse stimulation but to a lesser extent than on 20 pulse trains (P < 0.05). (+)-Ketamine was unable to block the inhibitory effect of quinpirole on single pulse dopamine efflux. Neither MK 801 10 mumol litre-1 nor metoclopramide 1 mumol litre-1 had any effect on dopamine release after short train stimuli (20 pulses, 100 Hz). We conclude that the (+)-isomer is the active form of ketamine and increases NAc dopamine efflux not by block of dopamine uptake; autoreceptors or NMDA receptors, but by mobilization of the dopamine storage pool to releasable sites.

Anesthetics, Dissociative↗
PubMed1998

A comparison of two computer-based face identification systems with human perceptions of faces.

The performance of two different computer systems for representing faces was compared with human ratings of similarity and distinctiveness, and human memory performance, on a specific set of face images. The systems compared were a graph-matching system (Lades M, Vorbrüggen JC, Buhmann J, Lage J, von der Malsburg C, Würtz RP, Konen W. IEEE., Trans Comput 1993;42:300-311.) and coding based on principal components analysis (PCA) of image pixels (Turk M, Pentland A. J Cognitive Neurosci 1991;3:71-86.). Replicating other work, the PCA-based system produced very much better performance at recognising faces, and higher correlations with human performance with the same images, when the images were initially standardised using a morphing procedure and separate analysis of 'shape' and 'shape-free' components then combined. Both the graph-matching and (shape + shape-free) PCA systems were equally able to recognise faces shown with changed expressions, both provided reasonable correlations with human ratings and memory data, and there were also correlations between the facial similarities recorded by each of the computer models. However, comparisons with human similarity ratings of faces with and without the hair visible, and prediction of memory performance with and without alteration in face expressions, suggested that the graph-matching system was better at capturing aspects of the appearance of the face, while the PCA-based system seemed better at capturing aspects of the appearance of specific images of faces.

Adult↗
PubMed1996

Face processing: human perception and principal components analysis.

Principal components analysis (PCA) of face images is here related to subjects' performance on the same images. In two experiments subjects were shown a set of faces and asked to rate them for distinctiveness. They were subsequently shown a superset of faces and asked to identify those that had appeared originally. Replicating previous work, we found that hits and false positives (FPs) did not correlate: Those faces easy to identify as being "seen" were unrelated to those faces easy to reject as being "unseen." PCA was performed on three data sets: (1) face images with eye position standardized, (2) face images morphed to a standard template to remove shape information, and (3) the shape information from faces only. Analyses based on PCA of shape-free faces gave high predictions of FPs, whereas shape information itself contributed only to hits. Furthermore, whereas FPs were generally predictable from components early in the PCA, hits appeared to be accounted for by later components. We conclude that shape and "texture" (the image-based information remaining after morphing) may be used separately by the human face processing system, and that PCA of images offers a useful tool for understanding this system.

Adult↗
PubMed1991

A statistical analysis of natural images matches psychophysically derived orientation tuning curves.

A neural net method is used to extract principal components from real-world images. The initial components are a Gaussian followed by horizontal and vertical operators, starting with the first derivative and moving to successively higher orders. Two of the components are 'bar-detectors'. Their measured orientation selectivity is similar to that suggested by Foster & Ward (Proc. R. Soc. Lond. B 243, 75 (1991] to account for brief-exposure psychophysical data. In tests with noise images, the ratio of sensitivity between the two components is controlled by the degree of anisotropy in the image.

Humans↗
PubMed1985

Physiologic and biochemical effects of ritodrine therapy on the mother and perinate.

The materno-fetal and neonatal effects of ritodrine were studied in 37 women treated for premature labor with intravenous (i.v.) ritodrine. Marked cardiovascular, respiratory, and biochemical side effects of therapy were seen in the mothers and tachycardia was noted in the fetuses. The neonates of 18 women in whom ritodrine successfully postponed delivery were delivered with good Apgar scores and their admission vital signs and nursery courses were benign. Ritodrine failed to delay delivery more than a week in 19 mothers. There were no differences between their newborns and 20 control neonates in admission vital signs, blood gases, blood chemistries, complete blood counts, platelet counts, peak bilirubin, or duration of oxygen therapy. This study revealed no deleterious effects on neonates delivered after maternal ritodrine therapy despite significant maternal and fetal effects.

Birth Weight↗
PubMed1984

Gastric motility in premature infants fed two different formulas.

The effect of two different formulas on gastric contractions was investigated in 10 preterm infants, of mean birth weight 1,149 g and mean gestational age 30.5 weeks, who were being advanced from a 20 calorie per ounce formula (Enfamil) to a 24 calorie per ounce formula (Similac Special Care 24). The neonates were fed by gravity with a feeding tube on a 2-h schedule. The orogastric tube was connected between feedings to a pressure transducer and recorder system upon which pressure waves reflecting gastric contractions were recorded. In the 1st h after feeding there were significantly fewer gastric contractions with 24 calorie than 20 calorie formula. The mean intensity of the gastric contractions per minute of contraction time was significantly less in the 1st h after feeding with the 24 calorie compared with the 20 calorie formula. In the 2nd h after feeding these values were similar. Gastric contractions are decreased with 24 calorie formula compared with 20 calorie formula during the 1st h after feeding. This difference in contractions may influence tolerance to different formulas.

Energy Intake↗
PubMed1983

Limitation of pulsatility index as a diagnostic tool in the newborn.

Pulsatile flow in the anterior cerebral arteries was studied and pulsatility index (PI) calculated by 3 observers in 10 newborn infants in order to establish the reproducibility of a noninvasive Doppler technique. No significant differences were noted among the observers and the estimated error of observation was 0.073. Subsequently, 14 healthy preterm infants were studied daily by a single observer in an attempt to establish a normal range of PI for prematures in the first 5 days of life. The babies were concomitantly studied with serial ultrasound examinations to rule out intracranial hemorrhage. The study revealed good interobserver reliability but wide variation of PI in normal, healthy premature infants with values falling within abnormal ranges previously described in asphyxiated infants or those with intraventricular hemorrhage (IVH). Caution is advised in using the PI to predict outcome.

Cerebral Arteries↗