Role of a FMRFamide-like family of neuropeptides in the pharyngeal nervous system of Caenorhabditis elegans

The nervous system of C. elegans has a remarkable abundance of flp genes encoding FMRFamide-like (FLP) neuropeptides. To provide insight into the physiological relevance of this neuropeptide diversity, we have tested more than 30 FLPs (encoded by 23 flps) for bioactivity on C. elegans pharynx. Eleven flp genes encode peptides that inhibit pharyngeal activity, while eight flp genes encode peptides that are excitatory. Three potent peptides (inhibitory, FLP-13A, APEASPFIRFamide; excitatory, FLP-17A, KSAFVRFamide; excitatory, FLP-17B, KSQYIRFamide) are encoded by flp genes, which, according to reporter gene constructs, are expressed in pharyngeal motoneurons. Thus, they may act through receptors localized on the pharyngeal muscle. The two other potent peptides, FLP-8 (excitatory AF1, KNEFIRFamide,) and FLP-11A (inhibitory, AMRNALVRFamide), appear to be expressed in extrapharyngeal neurons and are therefore likely to act either indirectly or as neurohormones. Intriguingly, a single neuron can express peptides that have potent but opposing biological activity in the pharynx. Only five flp genes encode neuropeptides that have no observable effect on the pharynx, but none of these have shown reporter gene expression in the pharyngeal nervous system. To examine the roles of multiple peptides produced from single precursors, a comparison was made between the bioactivity of different neuropeptides for five flp genes (flp-3, flp-13, flp-14, flp-17, and flp-18). For all but one gene (flp-14), the effects of peptides encoded by the same gene were similar. Overall, this study demonstrates the impressive neurochemical complexity of the simple circuit that regulates feeding in the nematode, C. elegans.     

The effect of mutations surrounding and within the active site on the catalytic activity of ricin A chain.

Models for the binding of the sarcin-ricin loop (SRL) of 28S ribosomal RNA to ricin A chain (RTA) suggest that several surface exposed arginine residues surrounding the active site cleft make important interactions with the RNA substrate. The data presented in this study suggest differing roles for these arginyl residues. Substitution of Arg48 or Arg213 with Ala lowered the activity of RTA 10-fold. Furthermore, substitution of Arg213 with Asp lowered the activity of RTA 100-fold. The crystal structure of this RTA variant showed it to have an unaltered tertiary structure, suggesting that the positively charged state of Arg213 is crucial for activity. Substitution of Arg258 with Ala had no effect on activity, although substitution with Asp lowered activity 10-fold. Substitution of Arg134 prevented expression of folded protein, suggesting a structural role for this residue. Several models have been proposed for the binding of the SRL to the active site of RTA in which the principal difference lies in the conformation of the second 'G' in the target GAGA motif in the 28S rRNA substrate. In one model, the sidechain of Asn122 is proposed to make interactions with this G, whereas another model proposes interactions with Asp75 and Asn78. Site-directed mutagenesis of these residues of RTA favours the first of these models, as substitution of Asn78 with Ser yielded an RTA variant whose activity was essentially wild-type, whereas substitution of Asn122 reduced activity 37.5-fold. Substitution of Asp75 failed to yield significant folded protein, suggesting a structural role for this residue.     

Effect of maternal dietary exclusion on breast fed infants with eczema: two controlled studies.

Thirty seven breast fed infants with eczema were studied to see whether changes in their mothers'' diets affected their skin condition. Nineteen mothers and babies took part in a double blind crossover trial of exclusion of egg and cows'' milk, and 18 took part in open exclusion of 11 foods followed by double blind challenge to those mothers whose infants seemed to respond. Babies were examined at the beginning and end of each dietary period, and the extent and severity of the rash were given a numerical score. The eczema improved in six infants when their mothers avoided egg and cows'' milk and worsened again when these were reintroduced. Two infants suffered gastrointestinal reactions after maternal ingestion of egg and cows'' milk, one developing colitis. Maternal dietary exclusion seems to benefit some breast fed babies with eczema.     

Outcome of Investigation of Patients with Presenile Dementia

Of 106 patients admitted for investigation to a neurological hospital with a presumptive diagnosis of dementia, 84 were confirmed to have intellectual impairment or loss of learning and memory function or both. A possible aetiology for the dementia was found in 36 of these 84 patients; the commonest causes discovered were intracranial mass lesions, arterial disease, and alcoholism. Fifteen of the 106 patients were found not to be demented but to have some other illness, most commonly depression. Of the whole series some 15% of the patients suffered from conditions that were amenable to treatment.     

Myoclonus in guinea pigs is induced by indole-containing but not piperazine-containing 5HT agonists

L-5-Hydroxytryptophan (5HTP) induces in guinea pigs a myoclonic jerking which is dependent upon stimulation of brainstem 5-hydroxytryptamine (5HT) receptors. We have investigated the ability of 5HT precursors and a range of synthetic 5HT agonists to produce myoclonus. The 5HT precursors and 5HT agonists containing an indole nucleus induced dose-dependent jerking in guinea pigs. In contrast, 5HT agonists possessing a piperazine moiety induced occasional jerking only at toxic doses, but not at those doses normally associated with 5HT agonistsactivity. The difference in activity between the indole-containing compounds and piperazine-containing 5HT agonists suggests that myoclonus is due to activation of an indole-selective brainstem 5HT receptor and provides further evidence for multiple cerebral 5HT receptors.