Rapid-time-course miniature and evoked excitatory currents at cerebellar synapses in situ.

Neurotransmission from mossy fibre terminals onto cerebellar granule cells is almost certainly mediated by L-glutamate. By taking advantage of the small soma size, limited number of processes and short dendrite length of granule cells, we have obtained high-resolution recordings of spontaneous miniature excitatory postsynaptic currents (m.e.p.s.cs) and evoked currents in thin cerebellar slices. Miniature currents have a similar time-course and pharmacology to evoked currents and consist of an exceptionally fast non-NMDA (N-methyl-D-aspartate) component (measured rise-time, 200 microseconds; estimated pre-filtered rise-time less than 100 microseconds; decay time constant, tau = 1.0 ms), followed by 50 pS NMDA channel openings that are directly resolvable. We could find no evidence for the recent proposal that miniature currents in granule cells are mediated solely by NMDA channels with a novel time course. The non-NMDA receptor component of m.e.p.s.cs has a skewed amplitude distribution, which suggests potential complications for quantal analysis. The difference in time course between the m.e.p.s.cs reported here and other synaptic currents in the brain could reflect differences in synaptic function or electrotonic filtering; the relative contribution of these possibilities has yet to be established.     

Preferential hydrophobic interactions are responsible for a preference of D-amino acids in the aminoacylation of 5'-AMP with hydrophobic amino acids.

We have studied the chemistry of aminoacyl AMP to model reactions at the 3' terminus of aminoacyl tRNA for the purpose of understanding the origin of protein synthesis. The present studies relate to the D, L preference in the esterification of 5'-AMP. All N-acetyl amino acids we studied showed faster reaction of the D-isomer, with a generally decreasing preference for D-isomer as the hydrophobicity of the amino acid decreased. The beta-branched amino acids, Ile and Val, showed an extreme preference for D-isomer. Ac-Leu, the gamma-branched amino acid, showed a slightly low D/L ratio relative to its hydrophobicity. The molecular basis for these preferences for D-isomer is understandable in the light of our previous studies and seems to be due to preferential hydrophobic interaction of the D-isomer with adenine. The preference for hydrophobic D-amino acids can be decreased by addition of an organic solvent to the reaction medium. Conversely, peptidylation with Ac-PhePhe shows a preference for the LL isomer over the DD isomer.     

Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome.

The inherited osteolyses or 'vanishing bone' syndromes are a group of rare disorders of unknown etiology characterized by destruction and resorption of affected bones. The multicentric osteolyses are notable for interphalangeal joint erosions that mimic severe juvenile rheumatoid arthritis (OMIMs 166300, 259600, 259610 and 277950). We recently described an autosomal recessive form of multicentric osteolysis with carpal and tarsal resorption, crippling arthritic changes, marked osteoporosis, palmar and plantar subcutaneous nodules and distinctive facies in a number of consanguineous Saudi Arabian families. We localized the disease gene to 16q12-21 by using members of these families for a genome-wide search for homozygous-by-descent microsatellite markers. Haplotype analysis narrowed the critical region to a 1.2-cM region that spans the gene encoding MMP-2 (gelatinase A, collagenase type IV; (ref. 3). We detected no MMP2 enzymatic activity in the serum or fibroblasts of affected family members. We identified two family-specific homoallelic MMP2 mutations: R101H and Y244X. The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains. Based on molecular modeling, the missense mutation disrupts hydrogen bond formation within the highly conserved prodomain adjacent to the catalytic zinc ion.     

Age distribution of circulatingα-interferon

Summary A sensitive radioimmunoassay showed that circulating -interferon in the plasma of healthy individuals was low in children and reached the highest level in the young adult, then declined gradually with age. Circulating -interferon was 0.201±0.059 ng/ml in males (n=19) and 0.184±0.076 ng/ml in females (n=14) at ages 30–39 years old. It was noted that circulating -interferon was maintained up to a certain level even in elderly individuals.     

A new indolic antiauxin, α-(5,7-dichloroindole-3-)isobutyric acid: its chemical synthesis and biological activity

Summary A new potent antiauxin, -(5,7-dichloroindole-3-)isobutyric acid has been synthesized and shown to inhibit auxin-mediated elongation ofAvena coleoptiles and to stimulate root growth of rice seedlings. Its activity is stronger than -(p-chlorophenoxy)isobutyric acid and is comparable to that of 2,3,5-triiodobenzoic acid, which are typical antiauxins.     

Evolutionary and ecological implications of cardenolide sequestration in the monarch butterfly

Summary Monarch butterflies sequester cardenolides from their larval host plants in the milkweed genusAsclepias for use in defense against predation. Of 108Asclepias species in North America, monarchs are known to feed as larvae on 27. Research on 11 of these has shown that monarchs sequester cardenolides most effectively, to an asymptote of approximately 350 g/0.1 g dry butterfly, from plants with intermediate cardenolide contents rather than from those with very high or very low cardenolide contents. SinceAsclepias host plant species are distributed widely in space and time across the continent, monarchs exploit them by migration between breeding and overwintering areas. After overwintering in central Mexico, spring migrants east of the Rocky Mountains exploit three predominantAsclepias species in the southern USA that have moderately high cardenolide contents. Monarchs sequester cardenolides very effectively from these species. First generation butterflies are thus well protected against predators and continue the migration north. Across the northern USA and southern Canada most summer breeding occurs on a fourthAsclepias species and in autumn most of these monarchs migrate back to Mexican overwintering sites. The ecological implications of this cycle of cardenolide sequestration for the evolution of monarch migration are discussed.     

Failure of opioids to affect excitation and contraction in isolated ventricular heart muscle

Summary The opioid agonists morphine (selective for -receptors) and ethylketocyclazocine (selective for kappa-receptors), at concentrations evoking strong effects in neuronal structures, did not significantly affect the configuration of the intracellularly recorded action potential and the force of contraction in ventricular heart muscle isolated from guinea pigs, rabbits and man. These results suggest that any changes of heart functions in vivo in response to opioid-like drugs are probably not mediated postsynaptically at the myocardial cell membrane but rather presynaptically, influencing the release of noradrenaline and/or acetylcholine from the nerve terminals.     

Zinc antagonizes the effect of botulinum type A toxin at the mouse neuromuscular junction

Summary Zn²⁺ (10–100 M) elevated the frequency of miniature end-plate potentials (MEPPs) in the mouse diaphragm. The effect did not depend on external Ca²⁺. Botulinum type A toxin (BTX_A, 50 ng/ml) abolished MEPPs almost completely within 30 min. Zn²⁺ (100 M) restored MEPPs and increased their frequency after they had been abolished by BTX_A in Ca²⁺-free solutions. The antagonistic effect of Zn²⁺ in the Ca²⁺-free solution was reduced by exposing the diaphragm to the toxin in the Ca²⁺-free solutions containing high K⁺. Thus, the action of BTX_A is probably enhanced by depolarization of the motor nerve terminals.     

Submarine hot springs and the origin of life

The discovery of hydrothermal vents at oceanic ridge crests and the appreciation of their importance in the element balance of the oceans is one of the main recent advances in marine geochemistry. It is likely that vents were present in the oceans of the primitive Earth because the process of hydrothermal circulation probably began early in the Earth's history. Here we examine the popular hypothesis that life arose in these vents. This proposal, however, is based on a number of misunderstandings concerning the organic chemistry involved. An example is the suggestion that organic compounds were destroyed on the surface of the early Earth by the impact of asteroids and comets, but at the same time assuming that organic syntheses can occur in hydrothermal vents. The high temperatures in the vents would not allow synthesis of organic compounds, but would decompose them, unless the exposure time at vent temperatures was short. Even if the essential organic molecules were available in the hot hydrothermal waters, the subsequent steps of polymerization and the conversion of these polymers into the first organisms would not occur as the vent waters were quenched to the colder temperatures of the primitive oceans.