The role of good form in young Infants' perception of partly occluded objects.

Young infants have been reported to perceive the unity of a center-occluded object when the visible ends of the object undergo common motion, but not on the basis of stationary information (e.g., P. J. Kellman & E. S. Spelke, 1983). We investigated the possibility that 4-month-old infants will attend to and utilize the global configuration (i.e., the "good form") of a partly occluded, moving object to perceive its unity and coherence behind the occluder. In the first experiment, infants viewed a partly occluded circle or cross that translated laterally. Infants who habituated in the minimum number of trials ("fast habituators") showed a reliable posthabituation preference for a broken object over a complete object, indicating perception of unity in the habituation display. Slow habituators exhibited no posthabituation preference. In the second experiment, infants were presented with small ring and cross displays, and the infants looked longer at the broken object. There were no reliable differences in performance between fast and slow habituators. A control group demonstrated no reliable posthabituation preference. In three additional conditions, infants viewed either a partly occluded half ring or a display in which two rod parts were either relatable and nonaligned or nonrelatable. The results indicated that curvature per se provided information in support of completion, in addition to global configuration and motion. Implications for theories of infants' visual development are discussed.

Identification of gender in domestic-cat faces with and without training: perceptual learning of a natural categorization task.

Three experiments were conducted to determine whether human observers could identify the gender of 40 domestic cats (20 female, 20 male) depicted in individual color photographs. In experiment 1a, observers performed at chance for photographs depicting whole cats, cat heads (bodies occluded), and cat bodies (heads occluded). Experiment 1b showed that chance performance was also obtained when the photographs were full-face close-ups of the cats. Experiment 2a revealed that even with gender-identification training on 30 (15 female, 15 male) of the 40 face close-ups, observers were unable to generalize their training to reliably identify the gender of the 10 remaining test faces (5 female, 5 male). However, experiment 2b showed that gender-identification training with the 14 most accurately identified faces from experiment 1b (7 female, 7 male) was successful in raising gender identification of the 10 test faces above chance. Experiments 3a and 3b extended this facilitative effect of gender-identification training to a population of animal-care workers. The findings indicate that, with appropriate training, human observers can identify the gender of cat faces at an above-chance level. A perceptual category learning account emphasizing the on-line formation of differentiated male versus female prototypes during training is offered as an explanation of the findings.

Visual deficits in children born at less than 32 weeks' gestation with and without major ocular pathology and cerebral damage.

AIMS: A study was carried out to compare the visual abilities of prematurely born children with those of matched full term controls. METHODS: The vision of 68 children born at less than 32 weeks' gestation and aged between 5 and 7 1/2 years at the time of testing was compared with that of a control group of children born at full term, and matched for sex and age from due date. RESULTS: The premature children had significantly poorer distance and near visual acuity, contrast sensitivity and stereopsis, and a high incidence of colour vision defects (predominantly tritan type). These differences were associated with the high incidence of ocular pathology experienced by 31 (45%) of the premature children compared with only nine (13%) of the controls. When excluding children with ocular and cerebral pathology, 32 matched pairs of premature and control children remained. The 32 premature children did not differ from their controls in terms of distance and near acuities or stereopsis, but they did have significantly poor contrast sensitivity in both their 'best' and 'worst' eyes. None of the 32 control children had colour vision defects, compared with seven of the matched premature children. CONCLUSION: This adds support to previous speculation that the preterm eye is at risk of subtle visual impairment independent of the occurrence of refractive error, manifest squint, disorders of the fundus and media, and cerebral damage.

Epidermal growth factor receptor tyrosine kinase. Investigation of catalytic mechanism, structure-based searching and discovery of a potent inhibitor.

Inhibition of tyrosine kinases is a possible approach for the treatment of cancer. We have investigated the catalytic mechanism of the epidermal growth factor receptor tyrosine kinase (EGF-RTK) in order to obtain information for use in structure-based searching for inhibitors. Initial rate studies imply that EGF-RTK forms a ternary complex together with ATP and peptide substrate. Investigation of pH and temperature dependence suggests that the kinase reaction requires the ionised form of a carboxylate (pK = 6.3) and the protonated form of another group (pK = 9.1). These characteristics are consistent with a mechanism where the carboxylate of Asp813(pK = 6.3) facilitates deprotonation of the tyrosyl hydroxyl of the peptide substrate, activating it as a nucleophile to attack the gamma-phosphorus of ATP which interacts with a protonated enzyme side-chain (pK = 9.1), possibly the guanidinium group of Arg817. This proposed catalytic mechanism was used to define a query when searching for inhibitors in a database of predicted three-dimensional structures. The procedure involved searching for compounds that mimic the ATP gamma-phosphate, tyrosyl hydroxyl and the tyrosyl aromatic ring, all of which seem to interact strongly with the enzyme during catalysis. This search allowed identification of inhibitors of EGF-RTK which were used to define queries for two-dimensional searching of a larger database, leading to the discovery of 4-(3-chloroanilino)quinazoline (CAQ) which is a potent inhibitor (Ki = 16 nM) of the enzyme. The compound is believed to be the first representative from a new structural class of anilinoquinazoline tyrosine kinase inhibitors. It follows competitive kinetics with respect to ATP and noncompetitive kinetics when the peptide is varied, implying that it functions as an analogue of ATP. CAQ is a novel and potent lead in the search for tyrosine kinase inhibitors as potential agents for the treatment of cancer.

2-(3,4-Dichlorophenyl)-N-methyl-N-[2-(1-pyrrolidinyl)-1-substituted- ethyl]-acetamides: the use of conformational analysis in the development of a novel series of potent opioid kappa agonists.

This paper describes the synthesis of a series of N-[2-(1-pyrrolidinyl)ethyl]acetamides (1), methylated at C1 and/or C2 of the ethyl linking group, and their biological evaluation as opioid kappa agonists. Conformational analysis of corresponding desaryl analogues 2 suggested that only those compounds capable of occupying an energy minimum close to that of the known kappa agonist N-[2-(1-pyrrolidinyl)cyclohexyl] acetamide U-50488 might possess kappa agonist properties. Starting from chiral amino acids, other alkyl and aryl substituents were introduced at C1 of the ethyl-linking moiety, giving compounds capable of adopting the same conformation as U-50488. The most potent of these, 2-(3,4-dichlorophenyl)-N-methyl-N-[(1S)-1-phenyl-2-(1-pyrrolidinyl)ethyl] acetamide (8), was 146-fold more active than U-50488 in vitro in the mouse vas deferens model and exhibited potent naloxone-reversible analgesic effects (ED50 = 0.004 mg/kg sc) in an abdominal constriction model.

1,2,4-Triazolo[4,3-a]pyrazine derivatives with human renin inhibitory activity. 2. Synthesis, biological properties and molecular modeling of hydroxyethylene isostere derivatives.

A series of inhibitors of human renin have been synthesized, derived from combination of a 2-(8-propyl-6-pyridin-3-yl-1,2,4-triazolo[4,3-a]pyrazin-3-yl)- 3-pyridin- 3-ylpropionic acid moiety 6c with the hydroxyethylene isostere of the scissile amide bond (2S,4S,5S)-5-amino-6-cyclohexyl-4-hydroxy-2-isopropylhexanoic acid (ChaOH--Val). The more potent members of this series showed good inhibitory activity against partially purified human renin, 7d, for example, having an IC50 of 0.2 nM. Structure-activity relationships for these compounds were consistent with their binding to the S4-S2' sites of human renin. Analogues 7e and 7h-k with a variety of substituents at the C-terminus all had in vitro IC50S less than 1 nM. In contrast with the majority of previously reported inhibitors of similar potency, these compounds contain no natural amino acid fragments. When administered intravenously to anesthetized, sodium-depleted marmosets at doses of 0.3-3.0 mg/kg, compound 7d caused a marked reduction in mean arterial pressure. Following oral administration at 30 mg/kg in the same animal model, 7d again elicited a significant fall in mean arterial pressure, accompanied by suppression of plasma renin activity lasting up to 3 h after dosing.

Binding of platelet factor 4 to heparin oligosaccharides.

Heparin fractions of differing Mr (7800-18 800) prepared from commercial heparin by gel filtration and affinity chromatography on immobilized anti-thrombin III had specific activities when determined by anti-Factor Xa and anti-thrombin assays that ranged from 228 to 448 units/mg. The anti-Factor Xa activity of these fractions could be readily and totally neutralized by increasing concentrations of platelet factor 4 (PF4). That these fractions bound to immobilized PF4 was indicated by the complete binding under near physiological conditions of 3H-labelled unfractionated commercial heparin. An anti-thrombin III-binding oligosaccharide preparation (containing predominantly eight to ten saccharide units), prepared by degradation of heparin with HNO2 had high (800 units/mg) anti-Factor Xa, but negligible anti-thrombin, specific activity. The anti-Factor Xa activity of this material could not be readily neutralized by PF4, and the 3H-labelled oligosaccharides did not completely bind to immobilized PF4. A heterogeneous anti-thrombin III-binding preparation containing upwards of 16 saccharides had anti-thrombin specific activity of just less than one-half the anti-Factor Xa specific activity. This material was completely bound to immobilized PF4 and was eluted with similar concentrations of NaCl to those that were required to elute unfractionated heparins from these columns. Furthermore, increasing concentrations of PF4 neutralized the anti-Factor Xa activity of this material in a manner similar to that of unfractionated heparin. It is concluded that heparin oligosaccharides require saccharide units in addition to the anti-thrombin III-binding sequence in order to fully interact with PF4.

Erythrophagocytosis by acute lymphoblastic leukaemic cells.

Phagocytosis of erthyrocytes and platelets by bone marrow blast cells has been noted in 4 patients in the late relapse of acute lymphoblastic leukaemia (ALL). The underlying mechanism is unclear but prolonged course of the disease seems to be a major factor in the emergence of cells with phagocytic properties.