Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications

The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.     

Slipped capital femoral epiphysis associated with radiation therapy

We reviewed 32 children with 41 radiation-therapy associated slipped capital femoral epiphyses (RTASCFE). Ten were from the authors' institutions and 22 from the literature. Gender distribution was equal. The age at diagnosis of the malignancy was 4.3 +/- 3.1 years; the amount of radiation was 4,240 +/- 1,445 rads. Children with RTASCFE presented younger (10.4 +/- 3.2 years) than a routine SCFE. The average symptom duration was 5 +/- 6 months. Children with RTASCFE are usually thin (median weight, 10th percentile) in contrast to children with typical SCFE, who are usually obese (<95th percentile). The majority (82%) of the slips were mild, compared to routine SCFEs (approximately 50%); 28% were bilateral. There was a positive linear relationship between the age at presentation of the SCFE and the age at diagnosis of the malignancy; there was a negative linear relationship between the age at presentation of the SCFE and the amount of radiation therapy.     

Properties of slips of zirconia stabilized by oxides of rare earth metals

Casting properties of concentrated aqueous dispersions of zirconia stabilized by Y₂O₃, Si₂O₃, or a mixture of them are investigated. Optimum values of the pH, temperature, and slip concentration for the production of thin-walled vacuum-tight articles are established. Translated from Ogneupory, No. 3, pp. 12–15, March, 1995.     

Geographic variations in the composition of ivory of the African elephant (Loxodonta africana)

OBJECTIVES: The purpose of the present study was to compare the inclination of the occlusal plane with occlusal guidance as a contributing factor to masticatory movement. METHODS: Masticatory movements of 41 young adults were measured using a 3-D mandibular movement analysing system. The inclination of the occlusal plane was measured in the sagittal plane using a 3-D digitizer. The contribution of the occlusal guidance and the inclination of the occlusal plane to the direction of the masticatory path of closure was evaluated at various closing levels. RESULTS: The masticatory path of closure outside the intercuspal range was influenced mainly by the inclination of the occlusal plane, and the masticatory path of closure near the intercuspal range was only influenced by occlusal guidance. The so-called gliding type masticatory pattern was observed predominantly in subjects with a posteriorly inclined occlusal plane. In contrast, a chopping type masticatory pattern was observed predominantly in subjects with an anteriorly inclined occlusal plane. CONCLUSIONS: The contribution of the inclination of the occlusal plane to masticatory movement was greater than that of occlusal guidance throughout the closing phase except near the intercuspal range.     

Mechanisms of insulin resistance in experimental hyperinsulinemic dogs

The aim of this work was to identify which proteins in horse dander extracts are allergens and to characterise them. Two-dimensional PAGE showed that horse dander preparations are composed of up to 50 proteins, all having acidic isoelectric points in the pH range 3-4.5. Immunoblots of two-dimensional PAGE were used to compare the reactivity of the proteins with IgE from 23 allergic patients. Patient sera were divided into two main groups recognising either allergens of 18.5 kDa or proteins of 27-29 and 31 kDa. The proteins of 27-29 kDa and 31 kDa were all N-glycosylated and their glycan chains seem to play a role in the binding of IgE from allergic patients. The sugar composition of their carbohydrate moiety was determined and lectin-binding experiments indicated presence of terminal sialic acid linked alpha-(2-->6) to galactose, galactose linked beta-(1-->4) to N-acetylglucosamine, and possibly presence of sialic acid linked alpha-(2-->3) to galactose. The 27-29-kDa glycoproteins had heterogeneous isoelectric points, most probably due to different degrees of sialylation in their oligosaccharide chains. The two 18.5-kDa allergens exhibited slightly different isoelectric points and their N-terminal sequences were identical, showing that they most likely were isoforms of the same protein. Sequence analyses revealed that their N-terminal sequences are similar to proteins belonging to the lipocalin family. We named the two 18.5-kDa proteins Equ c 2.0101 and Equ c 2.0102, according to International Allergen Nomenclature recommendations [King, T. P., Hoffman, D., Lowenstein, H., Marsh, D. G., Platts-Mills, T. A. E. & Thomas, W. (1995) J. Allergy Clin. Immunol. 96, 5-14]. The N-terminal of the allergens of 27-29 kDa were blocked and their sequences were not determined. Their amino acid compositions were determined and comparison with acidic mammalian proteins in the Swiss-Prot database revealed high scores with lipocalin proteins. This suggests that the glycosylated horse dander allergens belong to the lipocalin family, like Equ c 2.0101 and Equ c 2.0102.     

Hedgehog''s escape from Pandora''s box

The Hedgehog family of secreted glycoproteins proteins plays multifarious roles during vertebrate embryogenesis. In both the Drosophila and vertebrate embryo correct deployment of Hedgehog-like proteins is critical for the generation of pattern in many tissues and organs. New evidence now reveals that genes involved in hedgehog signalling are mutated in a number of common human genetic disorders, including skin cancer and craniofacial defects. The understanding of how cells generate, receive and transduce the Hedgehog signal during development has led to the establishment of molecular paradigms for the pathogenesis of these diseases. These studies clearly illustrate that knowledge of the normal role of a gene during development is critical for generating an understanding of the disease state in which it is mutated.     

Analytical issues in the evaluation of food deprivation and sucrose concentration effects on the microstructure of licking behavior in the rat

A microstructural analysis of licking behavior in nondeprived and 23-hr food-deprived rats (n = 15) presented with various sucrose solutions (0.03-1.0 M) in daily single-bottle, 1-hr sessions was conducted. Food deprivation and concentration interacted to increase total licks. The effects of food deprivation and concentration on burst size (BS), burst number (BN), and other parameters varied as a function of the pause criterion (PC; 0.3-100 s) used to define licking bursts. A rationale for selecting a 1-s PC for further analysis is presented. Despite the lack of correlations between temporally contiguous burst and pause combinations, mean BS decreased and pause duration increased as meals progressed. At the 1-s PC, BS increased linearly with concentration, implying that this microstructural parameter is influenced in part by taste. Food deprivation did not affect BS but rather increased BN and proportionally extended the meal duration.     

Peripheral O2 diffusion does not affect V(O2)on-kinetics in isolated insitu canine muscle

To test the hypothesis that muscle O2 uptake (V(O2)) on-kinetics is limited, at least in part, by peripheral O2 diffusion, we determined the V(O2) on-kinetics in 1) normoxia (Control); 2) hyperoxic gas breathing (Hyperoxia); and 3) hyperoxia and the administration of a drug (RSR-13, Allos Therapeutics), which right-shifts the Hb-O2 dissociation curve (Hyperoxia+RSR-13). The study was conducted in isolated canine gastrocnemius muscles (n = 5) during transitions from rest to 3 min of electrically stimulated isometric tetanic contractions (200-ms trains, 50 Hz; 1 contraction/2 s; 60-70% peak V(O2)). In all conditions, before and during contractions, muscle was pump perfused with constantly elevated blood flow (Q), at a level measured at steady state during contractions in preliminary trials with spontaneous Q x Adenosine was infused intra-arterially to prevent inordinate pressure increases with the elevated Q x Q was measured continuously, arterial and popliteal venous O2 concentrations were determined at rest and at 5- to 7-s intervals during contractions, and V(O2) was calculated as Q x arteriovenous O2 content difference. PO2 at 50% HbO2 saturation (P50) was calculated. Mean capillary PO2 (Pc(O2)) was estimated by numerical integration. P50 was higher in Hyperoxia+RSR-13 [40 +/- 1 (SE) Torr] than in Control and in Hyperoxia (31 +/- 1 Torr). After 15 s of contractions, Pc(O2) was higher in Hyperoxia (97 +/- 9 Torr) vs. Control (53 +/- 3 Torr) and in Hyperoxia+RSR-13 (197 +/- 39 Torr) vs. Hyperoxia. The time to reach 63% of the difference between baseline and steady-state V(O2) during contractions was 24.7 +/- 2.7 s in Control, 26.3 +/- 0.8 s in Hyperoxia, and 24.7 +/- 1.1 s in Hyperoxia+RSR-13 (not significant). Enhancement of peripheral O2 diffusion (obtained by increased PcO2 at constant O2 delivery) during the rest-to-contraction (60-70% of peak V(O2)) transition did not affect muscle V(O2) on- kinetics.     

Active symbols and internal models: Towards a cognitive connectionism

In the first section of the article, we examine some recent criticisms of the connectionist enterprise: first, that connectionist models are fundamentally behaviorist in nature (and, therefore, non-cognitive), and second that connectionist models are fundamentally associationist in nature (and, therefore, cognitively weak). We argue that, for a limited class of connectionist models (feed-forward, pattern-associator models), the first criticism is unavoidable. With respect to the second criticism, we propose that connectionist modelsare fundamentally associationist but that this is appropriate for building models of human cognition. However, we do accept the point that there are cognitive capacities for which any purely associative model cannot provide a satisfactory account. The implication that we draw from is this is not that associationist models and mechanisms should be scrapped, but rather that they should be enhanced.In the next section of the article, we identify a set of connectionist approaches which are characterized by active symbols — recurrent circuits which are the basis of knowledge representation. We claim that such approaches avoid criticisms of behaviorism and are, in principle, capable of supporting full cognition. In the final section of the article, we speculate at some length about what we believe would be the characteristics of a fully realized active symbol system. This includes both potential problems and possible solutions (for example, mechanisms needed to control activity in a complex recurrent network) as well as the promise of such systems (in particular, the emergence of knowledge structures which would constitute genuine internal models).     

Synthesis of copolymers of tert‐butyl vinyl ether with maleic and citraconic anhydrides

In the present study, the effects of charge‐transfer complex formation and intramolecular fragmentation (side‐chain lactonization) in radical copolymerization of tert‐butyl vinyl ether (t‐BVE) with anhydrides of maleic (MA) and citraconic (CA) acids and the structure–thermal behavior relationships of the resulting copolymers were examined using the ¹H‐NMR, FTIR, DSC, and TGA analysis methods. It was shown that copolymerization under the chosen conditions proceeded through intramolecular fragmentation with the formation of γ‐lactone units. Side‐chain fragmentation of t‐BVE–MA and t‐BVE–CA copolymers also was confirmed by TGA and DSC analysis. © 2006 Wiley Periodicals, Inc. J Appl Polym Sci 100: 2455–2463, 2006 2006