Neurotoxic Potential of Three Structural Analogs of β-N-oxalyl-α,β-Diaminopropanoic Acid (β-ODAP)

Lathyrism is a non-progressive motor neuron disease produced by consumption of the excitatory amino acid, 3-N-oxalyl-L-2,3-diaminopropanoic acid (-ODAP). To learn more about the mechanisms underlying Lathyrism three structural analogs of -ODAP were synthesized. Carboxymethyl-,-diaminopropanoic acid (CMDAP) evoked inward currents which were antagonized by APV (30 M), but not by CNQX (10 M). N-acetyl-,-diaminopropanoic acid (ADAP) evoked no detectable ionic currents but potentiated N-methyl-D-aspartate (NMDA)-activated currents. The potentiation of NMDA currents by ADAP was blocked by 7-chlorokynurenic acid. Carboxymethylcysteine (CMC) did not activate any detectable ionic currents. None of the three -ODAP analogs produced visible symptoms of toxicity in day old chicks when administered for 2–3 consecutive days. Ligand binding studies demonstrated that all the three compounds were effective to in displacing [³H]glutamate. The maximum inhibition was 92% for CMDAP, 61% for ADAP, 65% for CMC and 99% for -ODAP. These data indicate that analogs of -ODAP may interact with glutamate receptors without producing neurotoxicity.     

Bistability,switches and working memory in a two-neuron inhibitory-feedback model

It was reported earlier that an inhibitory-feedback network inspired by neostriatal circuitry may exhibit a bistable character and spontaneous switching phenomenon within the neuronal activity. In the presence of noise and external excitation, a few local neurons switch on and generate streams of impulses while other neurons remain quiescent. In time, the existing on neurons spontaneously switch off and other neurons switch on. In this paper we examine the nature of the bistability and switching phenomenon using a simple model consisting of two mutually inhibitory neurons. For nonspiking neuron model, described by a system of nonlinear differential equations, we present a simple bifurcation analysis, which follows the birth and annihilation of two stable fixed points when model parameters are varied. We show that both nonspiking and spiking models may have two stable states, but only spiking neurons exhibit switching. The mechanism of switching for model spiking neurons, described by an equivalent RC circuit with a number of currents, is analyzed using computer simulations. It is shown that switching can be described by a two-state Markov chain with one parameter, which depends on the set of model physiological parameters, such as duration of afterhyperpolarization (AHP), maximum and the time duration of inhibitory post-synaptic potentials (IPSP's) and amplitude of the neuron noise input. On and off states of the model can be rapidly changed by localized excitatory input and the network then sustains the pattern of on and off states. That is, such a network can be used as a programmable memory device. Our hypothesis is that biological neural networks exhibit switches in their evolution to low energy states and switches are essential for the load and readout of the temporary and long term memory.     

Effect of androgens on histochemical fibre type

Summary The temporal muscles of the guinea pig show a sexual differentiation reflected in their histochemical enzyme pattern. Using histochemical methods for mitochondrial (SDH, -GPDH), and glycolytic enzymes (phosphorylase, LDH) it could be shown, that in adult animals the male muscle is a white muscle with marked activity of glycolytic enzymes, the female muscle a red muscle displaying high activity of mitochondrial enzymes. This differential enzyme pattern can be converted by the application of testosterone to the female type during the postnatal development. The male sex hormone thus affects the histochemical enzyme pattern of the muscle, converting the red, female into a white, male muscle in the female guinea pig.     

Electrophoretic variation between class II molecules expressed on HLA-DRw8 homozygous typing cells reveals multiple distinct haplotypes

Two-dimensional (2D) gel electrophoresis of immunoprecipitated HLA-DR antigens from eight homozygous typing cells (HTC) expressing the HLA-DRw8 specificity revealed a clustering of polymorphic chain patterns into distinct electrophoretic variants. The variant patterns correlate with three discrete HLA-D clusters that are defined in the mixed leukocyte culture reaction (MLR) using DRw8-positive HTC. These HLA-D clusters have been provisionally designated Dw8.1, detected primarily in Caucasoids, Dw8.2, detected primarily in American Indians, and Dw8.3, detected predominantly in Orientals. All three HLA-Dw8.1 cell lines express a single DR-locus product as defined by immunoprecipitation with a DR-specific monoclonal antibody, P4.1. This DR chain is identical among the Dw8.1 cell lines and different from the DR chains of the Dw8.2 and Dw8.3 cell lines. Two separate Dw8.2 HTC express a shared DR chain that is slightly more basic than the 8.1 DR molecule; interestingly, one of these lines also expresses an additional DR-like chain not found in the other cells. Thus, the two lines defining the Dw8.2 cluster share one distinct class 11 molecule, but differ in another and therefore are not biochemically HLA-identical. Cells from the Dw8.3 cluster are likewise distinct from all other Dw8 clusters. One additional DRw8-positive HTC has been analyzed and found to be distinct from the Dw8.1, 8.2 and 8.3 clusters by both MLR and 2D gels. lmmunoprecipitates using monoclonal antibody 1B5 [anti-DR and anti-DQ(DS)] identify additional polymorphic class II variants among the cell lines tested. These data indicate that HLA-DRw8 is a public serologic specificity present on class II molecules expressed on multiple distinct haplotypes. These haplotypes differ from each other in expression of polymorphic class II molecules encoded by at least two HLA loci. They also differ in HLA-D, even though they all type as HLA-DRw8 homozygous. In Dw8.2, variation in expressed chains is not reflected in variation in HLA-D, indicating that MLR, as well as serologic typing, does not detect the full degree of allelic polymorphism within HLA.     

Neither a mentalist nor a reductionist be!

There is basis for concern that applied psychophysiology, if not the field of biofeedback, is being coopted by, and merged into, a reborn inner model, with the return of cognition to preeminence in the psych and neuro disciplines. Despite currently fashionable views that such mentalistic inventions and neuro/psychological developments somehow illuminate behavior or offer simpler accounts of behavioral facts, there is little or no evidence that any such construction has ever told us anything new about behavior.Preparation of this article was supported in part by the following PHHS Grants: NHLBI HL 34034, NIDA DA 03476, NIDA DA 04130, NIDA DA 02490, NIDA DA 04133, NIDA DA 01147, NIDA DA 04731, and NIDA contract 271-86-8113.     

The singularly perturbed Hodgkin-Huxley equations as a tool for the analysis of repetitive nerve activity

A qualitative analysis of the Hodgkin-Huxley model (Hodgkin and Huxley 1952), which closely mimics the ionic processes at a real nerve membrane, is performed by means of a singular perturbation theory. This was achieved by introducing a perturbation parameter that, if decreased, speeds up the fast variables of the Hodgkin-Huxley equations (membrane potential and sodium activation), whereas it does not affect the slow variables (sodium inactivation and potassium activation). In the most extreme case, if the perturbation parameter is set to zero, the original four-dimensional system degenerates to a system with only two differential equations. This degenerate system is easier to analyze and much more intuitive than the original Hodgkin-Huxley equations. It shows, like the original model, an infinite train of action potentials if stimulated by an input current in a suitable range. Additionally, explanations for the increased sensitivity to depolarizing current steps that precedes an action potential can be found by analysis of the degenerate system. Using the theory of Mishchenko and Rozov (1980) it is shown that the degenerate system does not only represent a simplification of the original Hodgkin-Huxley equations but also gives a valid approximation of the original model at least for stimulating currents that are constant within a suitable range.     

Comparative residual toxicities of pesticides to the predator Agistemus industani (Acari: Stigmaeidae) on citrus in Florida

Residual toxicities of registered and selected experimental pesticides used on citrus against Agistemus industani Gonzalez (Acari: Stigmaeidae) were compared. Pesticides considered highly toxic to A. industani were: abamectin 0.15 EC at 731ml/ha+FC 435-66 petroleum oil at 46.8l/ha, pyridaben 75WP at 469g/ha, ethion 4EC at 7.01l/ha+FC 435-66 petroleum oil at 46.8l/ha, propargite 6.55 EC at 3.51l/ha, chlorfenapyr 2SC at 1.46l/ha applied alone or in combination with FC 435-66 petroleum oil at 46.8l/ha, sulphur 80DF at 16.81kg/ha, dicofol 4EC at 7.01l/ha, fenbutatin oxide 50WP at 2.24kg/ha, benomyl 50WP at 2.24kg/ha, benomyl 50WP at 1.68kg/ha+ferbam 76 GF at 5.60kg/ha, ferbam 76GF at 11.21kg/ha, neem oil 90EC at 46.8l/ha, and copper hydroxide DF (40% metallic copper) at 4.48kg metallic copper/ha+FC 435-66 petroleum oil at 46.8l/ha. Pesticides that were moderately to slightly toxic included: copper sulphate 98% at 4.48kg metallic copper/ha+FC 435-66 petroleum oil at 46.8l/ha, fenbuconazole 2F at 280ml/ha+FC 435-66 petroleum oil at 46.8l/ha, FC 435-66 petroleum oil applied alone at 46.8l/ha or 23.4l/ha, and diflubenzuron 25WP at 1.40kg/ha. Pesticides that were non-toxic included: fenbuconazole 2F at 585ml/ha, malathion 57EC at 5.85l/ha, FC 435-66 petroleum oil at 46.8l/ha, carbaryl 80S at 3.36kg/ha, chlorpyrifos 4EC at 4.68l/ha, and formetanate 92SP at 1.12kg/ha. Understanding the toxic effects of field weathered pesticides against key predacious mite species is important for effective IPM. The results of this study provide a comparison of direct and indirect toxic effects of various pesticides to A. industani under field conditions.     

Lethal genes on the sex chromosomes concealed in a population of the mosquito Aedes aegypti L.

A population has been examined in which an overall parity between the sexes hides considerable between-family variation in sex ratio. A proportion of families show highly distorted sex ratios, with either an excess of females or an excess of males. Distorted sex ratios are invariably associated with mortality in the immature stages at a level appropriate to the action of recessive lethal genes. It has been shown that 26% of M-bearing (Y) chromosomes and at least 24% of m-bearing (X) chromosomes carry a recessive lethal gene.Two such genes have been investigated. l kills males and, in a cross between two heterozygotes, gives rise to a sex ratio close to 2:1 (excess families). k kills females and, in a cross between two heterozygotes, gives rise to a sex ratio close to 1:2 (excess families). Selection for excess or excess did not increase the level of sex ratio distortion.No crossing over occurs between k and the M/m locus whereas l shows 5–10% recombination with M/m. A test for allelism confirmed that l and k are not allelic. The penetrance of k is complete whereas l shows somewhat less than full penetrance. The penetrance of l has been improved by selection.The high frequency of lethals remained in the population during the two year period of study. There was evidence for heterosis preserving this frequency, the heterozygotes living longer and producing more progeny. However lethals were no longer to be found after four further years of laboratory culture.     

Die Feinstruktur der Zirbeldrüse normaler,trächtiger und experimentell beeinflußter Meerschweinchen

Zusammenfassung In der Meerschweinchenzirbeldrüse lassen sich elektronenmikroskopisch helle und dunkle Pinealzellen sowie einzelne Gliazellen nachweisen. In den bei weitem überwiegenden hellen Pinealzellen zeichnet sich ein Teil der vesicle-crowned rodlets (VCR) durch lokale Auftreibungen aus. Von VCR deutlich abzugrenzen sind die vesicle-crowned balls (VCB). Erstmalig beschrieben wird das Vorkommen von sog. Zylindern, die als Vorstufen von VCB aufgefaßt werden. In den relativ seltenen dunklen Pinealzellen, die sich durch chromatinreiche Kerne und elektronendichtes Zytoplasma auszeichnen, sind Vesikel, VCR, VCB und Zylinder seltener als in hellen Pinealzellen. Die reichlich vorhandenen marklosen Nervenfasern finden sich vor allem in perivasculären Räumen, seltener im Parenchym. Synapsen zwischen Nerven und Pinealzellen wurden nicht beobachtet. In den Zirbeldrüsen trächtiger Meerschweinchen zeichnen sich in der 2. Hälfte der Tragzeit die hellen Pinealzellen durch stärkere Lappung der Kerne, gehäuftes Auftreten von laktiven Zonen, Vermehrung von Mitochondrien, glattem ER, agranulären Vesikeln, VCR, VCB und Zylindern aus. Die dunklen Pinealzellen nehmen während der Tragzeit an Zahl zu. Post partum bilden sich diese Veränderungen innerhalb einer Woche zurück. Längerer Aufenthalt der Tiere in Dunkelheit führt zu einer Aktivierung der hellen Pinealzellen mit auffallender Vermehrung der VCR und zu einer Zunahme der dunklen Zellen. Unter Dauerbelichtung kommt es in den hellen Zellen zu einer Abnahme fast aller Zellorganellen und zu einer starken Vermehrung der VCR, die nach 70 Tagen auch Formveränderungen aufweisen. Nach Reserpinbehandlung beobachtet man eine Verminderung und degenerative Veränderungen der VCR. Es wird diskutiert, daß die VCR als prae- bzw. postsynaptische Strukturen der Erregungsübertragung von Nerven zu Pinealzellen bzw. von Pinealzellen untereinander dienen könnten.

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The fine structure of the pineal gland of normal, pregnant and experimentally affected guinea-pigs

Summary By means of electron microscopy light and dark pinealocytes can be distinguished in the guinea-pig pineal gland. Glial cells are rare. In the light pinealocyte. the most frequent cell type, some vesicle-crowned rodlets (VCR) show circumscribed thickenings. From these structures vesicle-crowned balls (VCB) have to be clearly distinguished. Furthermore cylinders occur, which, it is suggested, are precursors of VCB. Dark pinealocytes characterized by chromatin-rich nuclei and electron-dense cytoplasm are rare and contain fewer vesicles, VCR, VCB and cylinders than light pinealocytes. Numerous non-myelinated nerve fibres are situated within perivascular spaces, a few also in the parenchyma. Synapses between nerve fibres and pinealocytes were not observed. In the pineal gland of pregnant guinea-pigs the following changes can be observed in the second half of gestation. The light cells show many nuclear indentations and an increase of active zones, mitochondria, smooth ER, agranular vesicles, VCR, VCB, and cylinders respectively. The dark cells increase in number. After birth these changes reverse to normal within one week. Constant darkness leads to an activation of the light cells accompanied by an increase of the VCR and to an increase in number of the dark cells. Under constant illumination the light cells show a decrease of their organelles and a strong increase of the VCR. After 70 days the VCR also show a change in shape. Following reserpine treatment the VCR decrease in number and show signs of degeneration. It is discussed that the VCR function as pre- or postsynaptic structures and that they are involved either in transmitting impulses from nerve fibres to pinealocytes or from one pinealocyte to the other.

Untersuchung unter Leitung von Univ.-Doz. Dr. L. Vollrath.     

Meiotic studies ofElymus nutans andE. jacquemontii (Poaceae,Triticeae) and their hybrids withPseudoroegneria spicata and seventeenElymus species

Hybridizations ofElymus nutans andE. jacquemontii were carried out with one species ofPseudoroegneria (S genome), and 20Elymus species, each containing either of the SH, SY, SYH, or SYW genomes. Chromosome configurations were analysed at metaphase I of the two target taxa and their interspecific hybrids. It is concluded that (i)E. nutans is an allohexaploid containing the SYH genomes, andE. jacquemontii is an allotetraploid having the SY genomes; (ii) the genomic affinity is associated with the geographic distance between the species studied; (iii) minor genomic structural rearrangements have occurred within the hexaploid taxon ofE. nutans.     

Proliferation and germination of somatic embryos from embryogenic suspension cultures in <Emphasis Type="Italic">Phœnix dactylifera</Emphasis>

The present study demonstrates a procedure for the rapid development of a high number of somatic embryos from embryogenic suspension culture. This method might be efficient for mass propagation of Phnix dactylifera L. Embryogenic callus placed in liquid medium with 10^–5M ABA yielded an average 72 embryos per 100ml of culture medium within 2months, while those placed on solid medium yielded an average of 33, 20 and 16 embryos per 100ml of culture medium respectively for 10^–7, 10^–6 and 10^–5 M ABA after 4months. The combination of 2,4-DIchlorophenoxyacetic acid (2,4-D) (4.5×10^–7M), glutamine (6.7×10^–4M), and ABA (10^–5M) (L8 liquid medium) showed a beneficial effect on somatic embryos production compared to 2,4-D and glutamine alone, while this combination significantly (p<0.05) increased the accumulation of storage proteins (144 and 138mgg^–1 DW respectively for Jihel and Bousthami noir cultivars) in somatic embryos. The somatic embryos which underwent maturation on medium containing only 4.5×10^–7M 2,4-D and 10^–5M ABA (L6 liquid medium) accumulated more sugars (292 and 265mgg^–1 DW respectively for Jihel and Bousthami noir) than those matured on any other liquid medium. Histological studies revealed that somatic embryos (developed in L6 and L8 liquid media) accumulated less reserve compounds (proteins and sugars) than zygotic embryos. The addition of activated charcoal (0.25 and 0.5gl^–1) and phytagel^® (2.5gl^–1) to the germination medium may be useful for enhancing the germination of Phnix dactyliferasomatic embryos.     

Kinematic networks

Motor control in primates relates to a system which is highly redundant from the mechanical point of view — redundancy coming from an imbalance between the set of independently controllable variables and the set of system variables. The consequence is the manifestation of a broad class of ill-posed problems, problems for which it is difficult to identify unique solutions. For example (i) the problem of determining the coordinated patterns of rotation of the arm joints for a planned trajectory of the hand; (ii) the problem of determining the distribution of muscle forces for a desired set of joint torques. Ill-posed problems, in general, require regularization methods which allow to spell acceptable, if not unique, solutions. In the case of the motor system, we propose that the basic regularization mechanism is provided by the potential fields generated by the elastic properties of muscles, according to an organizational principle that we call Passive Motion Paradigm. The physiological basis of this hypothesis is reviewed and a Kinematic Network (K-net) model is proposed that expresses the kinematic transformations and the causal relations implied by elasticity. Moreover, it is shown how K-nets can be obtained from a kinematic Body Model, in the context of a specific task. Two particularly significant results are: (i) the uniform treatment of closed as well as open kinematic chains, and (ii) the development of a new method for the automatic generation of kinematic equations with arbitrary topology. Moreover, the model is akin to the concept of motor equivalence in the sense that it provides families of motor equivalent trajectories parametrized by tunable motor impedances.     

Characterization of Baboon (Papio hamadryas) Milk Proteins

The major proteins of baboon milk were identified as -lactoglobulin (LG), -lactalbumin (LA), lysozyme, lactoferrin, casein, and albumin by immobiline isoelectric focusing, SDS-PAGE, immunoblotting of gels with rabbit antisera to human LA, lysozyme, and albumin and bovine LG and casein, and N-terminal sequencing of proteins blotted from gels. The first 30 N-terminal residues of baboon LG are identical to those of macaque (Macaca fasicularis) LG except for a (D/N) polymorphism at residue 2. The complete cDNA sequence and derived amino acid composition of LG were elucidated using RT-PCR amplification of poly(A)⁺ mRNA purified from lactating mammary gland. Baboon LG consists of 168 amino acid residues (M_r 20,750) and is the longest LG identified to date. LG and LA polymorphisms with three (A, B, and C) and two (A and B) variants, respectively, were detected by immobiline IEF, pH 4–6, of individual baboon milk samples at varying stages of lactation.     

The adaptive significance of cultural behavior: Comments and reply

Summary Fundamentally, theoretically, there is only one process underlying genetic and cultural evolution: natural selection. Organism fitness-enhancement (adaptive significance) is one of its practical mechanisms; group formation and maintenance is another, often but not always through fitness-enhancement; and need-fulfillment is still another. If Durham can accept that formulation, and switch from organism-thinking to instruction-thinking (Cloak, 1975: 178), he will free himself from two handicaps: First, he can forget his worries about reductionism and determinism (1976a: 100, 101). Under this general theory of natural selection, cultural evolutionis biological evolution, continued by other (nongenetic) means. Second, he will spare himself the appearance of anthropomorphism, mentalism, and wishy-washiness attendant on his discussion of kinds of significance, other than adaptive significance, of cultural behaviors (1976a: 102–106, 115).     

The effect of intracapillary media feed protocols on hollow fiber cell culture

Summary Two intracapillary (IC) media feed protocols termed media rich and media lean were examined in an effort to understand the effect of this variable on hollow fiber cell cultures. The media rich protocol emphasized a high volume IC media per day (5 liters) containing no serum and a normal amount of extracapillary (EC) media serum (10% v/v). Alternatively, the media lean protocol used up to 1.0 liter of IC media per day containing 5% v/v serum and increased EC media serum (20% v/v). Both protocols produced substantial amounts of antibody in 25 days using HFN7.1 hybridoma cells (ATCC CRL 1606), however the media rich protocol produced twice as much antibody as the media lean protocol. The metabolism of the cells was dramatically different as measured by glucose uptake rate (GUR) with media lean cells having a six-fold lower GUR. Our results indicate that the media rich protocol is useful for producing larger amounts of antibody in a short time frame. The media lean protocol may be considered when the production costs of antibody, particularly media and serum, is the overriding concern.     

A Comment on La Vaque and Rossiter

The paper by La Vaque and Rossiter recommends that placebo-controlled trials only be conducted when best proven treatments are not available. In this comment, I review evidence suggesting that identifying best proven treatments is a complex task involving many variables and that making such a decision entails many real-world difficulties.     

Bacterial toxicity of cyclodextrins: Luminuous Escherichia coli as a model

The effect of various concentrations of natural and chemically modified cyclodextrins on the luminescence of an Escherichia coli suspension was investigated. All cyclodextrins were found to reduce, albeit to a varying degree, the luminescence level of the bacterial cells, thus suggesting a direct interaction between the cyclodextrins and cells. The inhibitory concentrations IC₂₀ and IC₅₀ of the various cyclodextrins were determined and taken to represent their toxicity effects upon the bacterial cells. Among the natural cyclodextrins, - and -CD interfered minimally with the bacterial luminescence and consequently were essentially non-toxic. The following descending order of toxicity was observed: -CD -CD > -CD. Among the chemically modified cyclodextrins, Dimeb was clearly toxic while Trimeb and the hydroxylated derivatives (hydroxypropyl-ga-CD, HPACD;--CD, HPBCD;--CD, HPGCD) were essentially non-toxic. The following descending order of toxicity was observed: Dimeb HPBCD > Trimeb > HPACD > HPGCD.     

Task Relevance Enhances Early Transient and Late Slow-Wave Activity of Distributed Cortical Sources

The primary purpose of these studies was to link together concepts related to attention/working memory and feedforward/feedback activity using MEG response profiles obtained in humans. Similar to recent studies of attention in monkeys, we show early spike-like activity (<200 ms poststimulus), most likely reflecting an early transient excitatory response mixed with feedback influences, followed by slow-wave activity (>200 ms poststimulus) in MEG cortical response profiles evoked by a visual working memory task. We experimentally dissociated the early transient activity from the later sustained activity (predominately feedback) by conducting an auditory size classification task. Words, representing common objects, evoked activity in occipital cortex (presumably due to imagery) even though visual stimuli were not present in this task. The initial spike was absent from the response profile obtained from occipital cortex, leaving only slow-wave activity, thereby allowing us to characterize or profile feedback activity in this situation. Attention or task relevance enhanced the initial spike and slow-wave activity in visually responsive areas. Prefrontal activity, along the superior frontal sulcus, evoked by the working memory task, was active later in time than initial activity in visual cortex and later than the earliest effect of attention modulation in visual cortex.