Characterization of experimental phenylketonuria. Augmentation of hyperphenylalaninemia with alpha-methylphenylalanine and p-chlorophenylalanine

Phenylalanine in conjunction with p-chlorophenylalanine or alpha-methylphenylalanine was administered to suckling rats to induce hyperphenylalaninemia reminiscent of untreated phenylketonuria, and developmental parameters were monitored. The experimental model utilizing p-chlorophenylalanine was found to be unsatisfactory, in that the drug had general deleterious effects on growth, numerous side effects including increased mortality, and affected brain levels of biogenic monoamine neurotransmitters. The model utilizing alpha-methylphenylalanine was relatively free from nonspecific effects and thus, changes observed in the animals were attributable to experimental phenylketonuria. The latter animals had slightly decreased body and brain weights, and exhibited grossly elevated serum phenylalanine and urinary excretion of phenylketone metabolites. Hyperphenylalaninemia produced greatly disrupted brain amino acids at 10 days of age (prior to the formalization of the blood-brain barrier and specific transport systems) which was limited by 30 days of age to changes in glycine, gamma-aminobutyric acid and the aliphatic and aromatic amino acids which compete for uptake in the brain by a common carrier. These animals also exhibited a myelin deficit and changes in proteins from isolated nerve cell preparations. Mature animals which had daily treatment up to 60 days of age exhibited a long-term learning impairment. These observations are consistent with many aspects of the clinical picture of untreated phenylketonuric patients, and suggest that this animal model will be beneficial in studying the disease.     

Coping with complexity: lessons from the mathematical sciences

I suggest five research paradigms fundamental in the mathematical sciences that seem relevant to the hunt for explanations of genetic susceptibility to complex diseases. I discuss a few ways in which these paradigms are, or are not, currently being followed in complex disease genetics. This essay is intended to provoke discussion and not to resolve any problems. It represents a written version of remarks that I made as “Discussant’’ at a session at the 1997 National Institutes of Health Research Festival.     

Pheromone trail following in the ant Lasius niger: high accuracy and variability but no effect of task state

The use of pheromone trails in ant colony organization is an important model for understanding collective decision‐making and complex adaptive systems. The ant Lasius niger L. (Hymenoptera: Fomicidae) is one of the main model organisms used for such studies. Key to understanding pheromone trail use by ants is knowing how well trails are followed. The results of a previous study suggest that L. niger trail following is poor, with between 60% and 70% accuracy at a T bifurcation. It is hypothesized that the true trail following accuracy is higher, and that the low accuracy reported previously is the result of a methodological error. Specifically, it is hypothesized that ‘task state’ (i.e. what the ants ‘thought they were doing’) affected pheromone following accuracy. In the present study, the task state of the ants is set experimentally to one of three states: scouting (completely naive), recruited (having information that food has been found, but not where it is) and shuttling (having a strong memory of the location of a food source). Trail following accuracy is tested for each group. Trail following is found to be more accurate than previously reported: 83%, 82% and 74% correct decisions for scouts, recruits and shuttlers, respectively. However, the difference between the three groups is not significant. Importantly, very high inter‐trial variation is reported both in the present study and in experiments from other research groups. This variation is unexplainable by trail strengths or colony‐level differences, and is highlighted as an important factor when experimentally measuring trail following.     

The RNA synthesizing capacity of nuclei isolated from cultured mouse cells.

Nuclei isolated from rapidly proliferating mouse L cells synthesize considerably more RNA than nuclei prepared from resting cells.     

Characterization of experimental phenylketonuria augmentation of hyperphenylalaninemia with α-methylphenylalanine and p-chlorophenylalanine

Phenylalanine in conjuction with p-chlorophenylalanine or α-methylphenylalanine was administered to suckling rats to induce hyperphenylalaninemia reminiscent of untreated phenylketonuria, and developmental parameters were monitored. The experimental model utilizing p-chlorophenylalanine was found to be unsatisfactory, in that the drug had general deleterous effects on growth, numerous side effects including increased mortality, and affected brain levels of biogenic monoamine neurotransmitters. The model utilizing α-methylphenylalalanine was relatively free from nonspecific effects and thus, changes observed in the animals were attributable to expereimental phenylketonuria. The latter animals had slightly decreased body and brain weights, and exhibited grossly elevated serum phenylalanine and urinary excretion of phenylketone metabolites. Hyperphenylalaninemia produced greatly disrupted brain amino acids at 10 days of age (prior to the formalization of the blood-brain barrier and specific transport systems) which was limited by 30 days of age to changes in glycine, γ-aminobutyric acid and the aliphatic and aromatic amino acids which compete for uptake in t he brain by a common carrier. These animals also exhibited a myelin deficit and changes in proteins from isolated nerve cell preparations. Mature animals which had daily treatment up to 60 days of age results obtained with animal models and the clinical findings in untreated phenylketonuric patients.