Inhibition of Neuronal Degenerin/Epithelial Na+ Channels by the Multiple Sclerosis Drug 4-Aminopyridine

The voltage-gated K⁺ (Kv) channel blocker 4-aminopyridine (4-AP) is used to target symptoms of the neuroinflammatory disease multiple sclerosis (MS). By blocking Kv channels, 4-AP facilitates action potential conduction and neurotransmitter release in presynaptic neurons, lessening the effects of demyelination. Because they conduct inward Na⁺ and Ca²⁺ currents that contribute to axonal degeneration in response to inflammatory conditions, acid-sensing ion channels (ASICs) contribute to the pathology of MS. Consequently, ASICs are emerging as disease-modifying targets in MS. Surprisingly, as first demonstrated here, 4-AP inhibits neuronal degenerin/epithelial Na⁺ (Deg/ENaC) channels, including ASIC and BLINaC. This effect is specific for 4-AP compared with its heterocyclic base, pyridine, and the related derivative, 4-methylpyridine; and akin to the actions of 4-AP on the structurally unrelated Kv channels, dose- and voltage-dependent. 4-AP has differential actions on distinct ASICs, strongly inhibiting ASIC1a channels expressed in central neurons but being without effect on ASIC3, which is enriched in peripheral sensory neurons. The voltage dependence of the 4-AP block and the single binding site for this inhibitor are consistent with 4-AP binding in the pore of Deg/ENaC channels as it does Kv channels, suggesting a similar mechanism of inhibition in these two classes of channels. These findings argue that effects on both Kv and Deg/ENaC channels should be considered when evaluating the actions of 4-AP. Importantly, the current results are consistent with 4-AP influencing the symptoms of MS as well as the course of the disease because of inhibitory actions on Kv and ASIC channels, respectively.     

Biological rhythms in birds — development, insights and perspectives

The aim of this review is to show that probably the internal clock of precocial birds is imprinted in the prenatal period by exogenous factors (zeitgeber). The activity of organ functions occurs early during embryonic development, before this function is ultimately necessary to ensure the survival of the embryo. Prenatal activation of some functional systems may have a training effect on the postnatal efficiency.The development of physiological control systems is influenced by endogenous and exogenous factors during the late prenatal and early postnatal period: epigenetic adaptation processes play an important role in the development of animals; they have acquired characteristics which are innated but not genetically fixed. As a rule, the actual value during the determination period has a very strong influence on the set-point of the system. This will be explained using the example of thermoregulation.It is shown in detail that it seems to be possible to imprint the prenatal development of circadian rhythms by periodic changes of the light-dark cycle but not by rhythmic influence of acoustic signals.Altogether, there are more questions open than solved concerning the perinatal genesis of circadian rhythms in birds. Topics are given for the future research.     

VARIABLE SELECTION ON EUROSTA'S GALL SIZE,I: THE EXTENT AND NATURE OF VARIATION IN PHENOTYPIC SELECTION

Natural fluctuations in environmental conditions are likely to induce variation in the intensity or direction of natural selection. A long-term study of the insect, Eurosta solidaginins Fitch (Diptera; Tephritidae), which induces stem galls on the perennial herb Solidago altissima (Asteraceae) was performed to explore the patterns of variation in phenotypic selection. The intensity of selection imposed by parasitoids and predators on gallmaking larvae, for gall size, was measured across 16 populations over the course of 4 generations, for a total of 64 population-generations. Directional selection was quantified by i, the selection intensity, and variance selection by j‘, a measure of the intensity of selection on phenotypic variance. Size-dependent attack by parasitoids caused upward directional selection (mean i_p = 0.42; SE = 0.023), while size-dependent bird attack favored larvae that induced smaller galls (mean i_b = -0.07; SE = 0.013. The mean net directional selection intensity was 0.35 (SE = 0.030), which indicates that insects inducing larger galls are generally favored by selection. The opposing patterns of size-dependent attack resulted in stabilizing selection in half the population generations, with an overall average. j‘ of -0.11 (SE = 0.078). The magnitude of directional selection was strongly influenced by the population mean gall size and weakly by the optimal gall size. The intensity of variance selection was strongly influenced by the shape of the fitness function, with sigmoidal and Gaussian-like shapes causing greater depletion of phenotypic variance.     

Killing of Escherichia coli cells modulated by components of the stability system ParD of plasmid R1

Summary The proteins P10 and P12 have been shown to be gene products of a new stability system, ParD, of plasmid R1. It is now shown that an R1 miniplasmid, pAB112, carrying a trans-complementable amber mutation in the gene of the P10 protein, is lethal for the host in the absence of suppression. This lethal effect is suppressed in a supF background and also by deletions in pAB112 that affect the gene of the P12 protein. These data indicate that the P12 protein has a lethal effect on the host and that this effect is neutralized by the P10 protein. The possibility that the stabilization conferred by the ParD system could be due to a counterselection, mediated by P12, of cells that lose the plasmid at cell division, is discussed.     

Structure,development and function of the branchial sieve of the common bream,Abramis brama,white bream,Blicca bjoerkna and roach,Rutilus rutilus

Synopsis The filter feeding organ of cyprinid fishes is the branchial sieve, which consists of a mesh formed by gill rakers and tiny channels on the gill arches. In order to establish its possible role during growth we measured the following morphological gill raker parameters over a range of sizes in three cyprinid fishes, bream, white bream and roach: inter raker distance, bony raker length, raker width, cushion length and channel width. At any given standard length common bream has the largest inter raker distance, roach the lowest and white bream is intermediate. In the comb model of filter feeding the inter raker distance is considered to be a direct measure of the mesh size and retention ability (= minimal size of prey that can be retained) of a filter. For the three species under study there is a conflict between the comb model and experimental data on particle retention. Lammens et al. (1987) found that common bream has a large retention ability whereas roach and white bream have a much smaller one. A new model, the channel model (Hoogenboezem et al. 1991) has been developed for common bream; in this model the lateral gill rakers can regulate the mesh size of the medial channels on the other side of the gill slit. The present data indicate that this model is not appropriate for white bream and roach. At any given standard length white bream and roach only reach 70% of the raker length of common bream, which means that in this model the gill slits should to be very narrow during filter feeding. The gill rakers consist of a bony raker and a fleshy cushion. The bony rakers have a rather long needle-like part outside the cushion in bream, but not in white bream and roach which have blunt gill rakers. Blunt gill rakers are not suited to reduce the diameter of the medial channels. The comb model seems more appropriate for white bream and roach, but doubts about the validity of this simple model remain. The sum of the areas of the medial channels is an approximation of the area through which water flows in the filter. This channel area therefore gives an impression of the capacity or flow rate of the filter. With this capacity estimation and an estimation of energy consumption we calculated an energy ratio of filter feeding. The energy ratio decreases with increasing standard length with an exponent close to the expected exponent of -0.40. The energy ratio is highest in bream, intermediate in white bream and lowest in roach.     

Expected utility maximization and selection of stable plant cultivars

Summary In most plant breeding programs, selection of the best commercially suitable cultivars for a target group of environments is based on information obtained from evaluation trials cultivated in a sample of environments. Information on the performance of cultivars collected in a sample of environments can only be approximate and, consequently, selection of the best cultivar involves choosing among cultivars that respond uncertainly in many environments. The agronomic and/or economic value of a cultivar across environments may be considered the general or overall utility of the cultivar. Data from a sample of environments therefore provides only an estimate of any cultivar's overall utility, with the overall goal of selection among all cultivars being the maximization of the expected utility. Within this frame-work, expected utility maximization, an approach to decision making that has been well developed in the disciplines of economics and statistics, can assist the plant breeder in making such decisions. This research was initiated (1) to determine how expected utility maximization might be used to develop indices that are useful for selecting broadly adapted plant cultivars, and (2) to determine how the breeder's preferences might affect choice of the best cultivar. The data used in this research were from USDA Regional Soybean Tests. The results indicated that expected utility maximization, which explicitly incorporates into the selection rule the plant breeder's preferences regarding stability, can be a useful aid in the selection of stable plant cultivars.     

A probabilistic approach to the construction of competing-risk life tables

"This paper aims to identify net and partial-crude probabilities in the competing-risk life table context, by using probabilistic approaches. Five types of lifelength random variables are defined to formulate these nonidentifiable probabilities. General expressions for net and partial-crude probabilities are first derived under independent risks assumptions. Two sets of explicit formulas for estimating the net and partial-crude probabilities are then derived in terms of the identifiable overall and crude probabilities by making the additional assumption of piecewise uniform distribution of the lifelength random variables. A study of the degree to which nonidentifiability can affect the net and partial-crude probabilities in a variety of situations is developed. An example from cross-sectional studies is employed to illustrate the methodology developed."     

Identification of a cationic channel in synaptosomal membranes

Synaptosomal membranes were fused with liposomes using the hydration technique to produce giant proteoliposomes amenable to patch clamp recordings. Single channel currents of a cationic channel with particular properties were detected. In a solution of 150 mM NaCl, the channel displayed a unit conductance of 136 pS and a mean open state lifetime of 1.1 ms. The gating of the channel was shown to be voltage as well as calcium dependent. Pharmacological studies revealed that the channel was insensitive to a variety of channel blockers, but was inactivated by ruthenium red. Presumably, this channel may play a role in regulating the evoked release of neurotransmitters. Offprint requests to: H. Breer     

Ion channel regulation by calmodulin binding

While many ion channels are modulated by phosphorylation, there is growing evidence that they can also be regulated by Ca²⁺-calmodulin, apparently through direct binding. In some cases, this binding activates channels; in others, it modulates channel activities. These phenomena have been documented in Paramecium, in Drosophila, in vertebrate photoreceptors and olfactory receptors, as well as in ryanodine receptor Ca²⁺-release channels. Furthermore, studies on calmodulin mutants in Paramecium have shown a clear bipartite distribution of two groups of mutations in the calmodulin gene that lead to opposite behavioral and electrophysiological phenotypes. These results indicate that the N-lobe of calmodulin specifically interacts with one class of ion-channel proteins and the C-lobe with another.