Alzheimer's disease is characterized by plaques of amyloid-beta peptide, cleaved from amyloid-beta protein precursor . Our hypothesis is that lifespan profiles of AD-associated mRNA and protein levels in monkeys would differ from mice and that differential lifespan expression profiles would be useful to understand human AD pathogenesis. We compared profiles of AbetaPP mRNA, AbetaPP protein, and Abeta levels in rodents and primates. We also tracked a transcriptional regulator of the AbetaPP gene, specificity protein 1 , and the beta amyloid precursor (...) cleaving enzyme . In mice, AbetaPP and SP1 mRNA and their protein products were elevated late in life; Abeta levels declined in old age. In monkeys, SP1, AbetaPP, and BACE1 mRNA declined in old age, while protein products and Abeta levels rose. Proteolytic processing in both species did not match production of Abeta. In primates, AbetaPP and SP1 mRNA levels coordinate, but an inverse relationship exists with corresponding protein products as well as Abeta levels. Comparison of human DNA and mRNA sequences to monkey and mouse counterparts revealed structural features that may explain differences in transcriptional and translational processing. These findings are important for selecting appropriate models for AD and other age-related diseases. (shrink)

Although activated spinal cord glia contribute importantly to neuropathic pain, how nerve injury activates glia remains controversial. It has recently been proposed, on the basis of genetic approaches, that toll-like receptor 4 may be a key receptor for initiating microglial activation following L5 spinal nerve injury. The present studies extend this idea pharmacologically by showing that TLR4 is key for maintaining neuropathic pain following sciatic nerve chronic constriction injury. Established neuropathic pain was reversed by intrathecally delivered TLR4 receptor antagonists derived (...) from lipopolysaccharide. Additionally, -naltrexone, -naloxone, and -naloxone, which we show here to be TLR4 antagonists in vitro on both stably transfected HEK293-TLR4 and microglial cell lines, suppressed neuropathic pain with complete reversal upon chronic infusion. Immunohistochemical analyses of spinal cords following chronic infusion revealed suppression of CCI-induced microglial activation by -naloxone and -naloxone, paralleling reversal of neuropathic pain. Together, these CCI data support the conclusion that neuron-to-glia signaling through TLR4 is important not only for initiating neuropathic pain, as suggested previously, but also for maintaining established neuropathic pain. Furthermore, these studies suggest that the novel TLR4 antagonists -naloxone and -naloxone can each fully reverse established neuropathic pain upon multi-day administration. This finding with -naloxone is of potential clinical relevance. This is because -naloxone is an antagonist that is inactive at the -opioid selective receptors on neurons that produce analgesia. Thus, these data suggest that -opioid antagonists such as -naloxone may be useful clinically to suppress glial activation, yet -opioid agonists suppress pain. (shrink)

Der lebende Organismus stellt einen bestimmten, individuellen Teil des Universums dar, indem er seine Selbständigkeit abgetrennt von dem übrigen Universum erhält, durch den Teilungseffekt, welcher durch die Anordnung seiner Teile bestimmt wird. Es ist anerkannt, dass die Teilung nicht vollständig ist, jedoch eine beschränkte gegenseitige Beziehung zulässt. Es ist auch anerkannt, dass der Grad der Organisation in einer verwandten Reihe sich ändert von den tiefen Verwickelungen der einfachen Zelle zu den mannigfachen Abwandlungen wie sie beim Menschen auftreten. Die Auffassung von (...) effektiver Teilung ist ausserdem auch fest und substantiell auf der Tatsache begründet, die durch das Vorhandensein der Plasmamembran und Grenzflächen kolloidaler Aggregaten gegeben ist. Betont ist die dynamische Natur der charakteristischen Gleichgewichtszustände und es wird aufmerksam gemacht auf die kontinuierliche Bildung von effektiven Teilungen bei verschiedenen Gleichgewichtszuständen. Weitere Untersuchung der Bedeutung dieser Teilungen ergibt viele interessante Folgerungen. Schwierigkeiten finden sich, wenn man eine derartige Beschreibung auf geistige Phänomena ausdehnt. Zwar bestehen grundlegende Übereinstimmungen, aber es ist schwer sie genau zu definieren. Es ist klar, dass eine Synthese dieser Art notwendigerweise unvollständig ist, aber es schien wertvoll den Versuch zu machen, L'organisme vivant est présenté ici comme une partie définie et individualisée de l'univers maintenant son individualité propre au moyen de „l'effet de partition” déterminé par l'arrangement de ses parties. Il est entendu que la partition n'est pas complète mais permet encore des relations réciproques mais limitées. Il est reconnu aussi que le degré d'organisation varie dans le cours d'une série, des complexités profondes de la cellule aux innombrables modifications exhibées par l'organisme humain. Le concept de la partition effective est basé solidement sur l'évidence présentée par la membrane plasmatique et les limites de phases dans les aggrégations colloidales. De plus il est important de noter spécialement la nature dynamique des équilibres caractéristiques et l'on ne saurait manquer d'attirer l'attention sur la formation continue de partitions effectives aux différents niveaux d'équilibre. L'étude ultérieure de la signification de ces partitions présente un grand nombre d'implications intéressantes. Il est à noter que des difficultés sont rencontrées quand on essaie d'inclure en une description de ce genre les phénomènes mentaux et psychiques. Des stabilités fondamentales existent, mais elles sont difficiles à définir avec précision. Il est évident du reste au lecteur qu'une synthèse telle que celle-ci est nécessairement incomplète mais néanmoins intéressante à faire. (shrink)

The focus of this study was to analyze the content, distribution, and comparative genome relationships of 996 chromosome bin-mapped expressed sequence tags accounting for 2266 restriction fragments on the homoeologous group 3 chromosomes of hexaploid wheat. Of these loci, 634, 884, and 748 were mapped on chromosomes 3A, 3B, and 3D, respectively. The individual chromosome bin maps revealed bins with a high density of mapped ESTs in the distal region and bins of low density in the proximal region of the (...) chromosome arms, with the exception of 3DS and 3DL. These distributions were more localized on the higher-resolution group 3 consensus map with intermediate regions of high-mapped-EST density on both chromosome arms. Gene ontology classification of mapped ESTs was not significantly different for homoeologous group 3 chromosomes compared to the other groups. A combined analysis of the individual bin maps using 537 of the mapped ESTs revealed rearrangements between the group 3 chromosomes. Approximately 232 of the consensus mapped ESTs matched sequences on rice chromosome 1 and revealed large- and small-scale differences in gene order. Of the group 3 mapped EST unigenes ∼21 and 32% matched the Arabidopsis coding regions and proteins, respectively, but no chromosome-level gene order conservation was detected. (shrink)

The complex hexaploid wheat genome offers many challenges for genomics research. Expressed sequence tags facilitate the analysis of gene-coding regions and provide a rich source of molecular markers for mapping and comparison with model organisms. The objectives of this study were to construct a high-density EST chromosome bin map of wheat homoeologous group 2 chromosomes to determine the distribution of ESTs, construct a consensus map of group 2 ESTs, investigate synteny, examine patterns of duplication, and assess the colinearity with (...) class='Hi'>rice of ESTs assigned to the group 2 consensus bin map. A total of 2600 loci generated from 1110 ESTs were mapped to group 2 chromosomes by Southern hybridization onto wheat aneuploid chromosome and deletion stocks. A consensus map was constructed of 552 ESTs mapping to more than one group 2 chromosome. Regions of high gene density in distal bins and low gene density in proximal bins were found. Two interstitial gene-rich islands flanked by relatively gene-poor regions on both the short and long arms and having good synteny with rice were discovered. The map locations of two ESTs indicated the possible presence of a small pericentric inversion on chromosome 2B. Wheat chromosome group 2 was shown to share syntenous blocks with rice chromosomes 4 and 7. (shrink)

A total of 944 expressed sequence tags generated 2212 EST loci mapped to homoeologous group 1 chromosomes in hexaploid wheat. EST deletion maps and the consensus map of group 1 chromosomes were constructed to show EST distribution. EST loci were unevenly distributed among chromosomes 1A, 1B, and ID with 660, 826, and 726, respectively. The number of EST loci was greater on the long arms than on the short arms for all three chromosomes. The distribution of ESTs along chromosome arms (...) was nonrandom with EST clusters occurring in the distal regions of short arms and middle regions of long arms. Duplications of group 1 ESTs in other homoeologous groups occurred at a rate of 35.5%. Seventy-five percent of wheat chromosome 1 ESTs had significant matches with rice sequences, where large regions of conservation occurred between wheat consensus chromosome 1 and rice chromosome 5 and between the proximal portion of the long arm of wheat consensus chromosome 1 and rice chromosome 10. Only 9.5% of group 1 ESTs showed significant matches to Arabidopsis genome sequences. The results presented are useful for gene mapping and evolutionary and comparative genomics of grasses. (shrink)

The objectives of this study were to develop a high-density chromosome bin map of homoeologous group 7 in hexaploid wheat, to identify gene distribution in these chromosomes, and to perform comparative studies of wheat with rice and barley. We mapped 2148 loci from 919 EST clones onto group 7 chromosomes of wheat. In the majority of cases the numbers of loci were significantly lower in the centromeric regions and tended to increase in the distal regions. The level of duplicated (...) loci in this group was 24% with most of these loci being localized toward the distal regions. One hundred nineteen EST probes that hybridized to three fragments and mapped to the three group 7 chromosomes were designated landmark probes and were used to construct a consensus homoeologous group 7 map. An additional 49 probes that mapped to 7AS, 7DS, and the ancestral translocated segment involving 7BS also were designated landmarks. Landmark probe orders and comparative maps of wheat, rice, and barley were produced on the basis of corresponding rice BAC/PAC and genetic markers that mapped on chromosomes 6 and 8 of rice. Identification of landmark ESTs and development of consensus maps may provide a framework of conserved coding regions predating the evolution of wheat genomes. (shrink)

Spinoza semble adopter une position pleinement nominaliste lorsqu'il discue des notions universelles dans l'Ethique, mais on y trouve aussi plusieurs arguments où, semble-t-il, des universaux sont présupposés. La solution avancé par plusieurs commentateurs, y compris Haserot, est que le système spinoziste est d'inspiration platoniste, et qu'il faut réinterpréter les passages d'apparence nominaliste pour les accorder avec le platonisme ou l'essentialisme. J'argumente qu'un tel procédé n'est justifié ni par le texte ni par la structure du système de Spinoza. L'interprétation du spinozisme (...) que je propose le place dans le cadre logique du nominalisme contemporain, à l'instar du système de Nelson Goodman, par exemple. (shrink)

L’objectif de cet article est de proposer une analyse de deux conceptions distinctes de la causalité chez Spinoza. Selon la première la nature-dieu serait la cause directe de toute action qui a lieu au niveau des choses finies; tandis que, selon la seconde toute action finie ferait partie d’une chaîne infinie de causes qui est répandue dans la durée. Je montre que cette causalité-ci n’est ni illusoire ni simplement derivative, contre les suggestions de plusieurs travaux récents sur Spinoza. En deuxième (...) lieu nous proposons un modèle pour la causalité consécutive qui assure la possibilité que les êtres finis puissent fonctionner comme des causes adéquates au sens spinoziste dans le champ physique. Ici l’analyse s’oppose à plusieurs chercheurs qui soutiennent qu’il existe une rupture entre les attributs de la pensée et de l’étendue dans le système spinoziste.This study addresses the problem of analyzing two distinct conceptions of causality in Spinoza. According to the first god-nature is the direct cause of every action which occurs at the level of finite things; while, according to the second , every finite action would be part of an infinite chain of causes extended into duration. I show that sequential causality is neither illusory nor simply derivative, contrary to the suggestions made by several recent studies of Spinoza. Secondly, I offer a model for sequential causality which assures the possibility that finite beings may function as adequate causes within the physical field. Here my analysis is opposed to those commentators who argue for a rupture in Spinoza between the attributes of thought and extension. (shrink)

A total of 1918 loci, detected by the hybridization of 938 expressed sequence tag unigenes from 26 Triticeae cDNA libraries, were mapped to wheat homoeologous group 4 chromosomes using a set of deletion, ditelosomic, and nulli-tetrasomic lines. The 1918 EST loci were not distributed uniformly among the three group 4 chromosomes; 41, 28, and 31% mapped to chromosomes 4A, 4B, and 4D, respectively. This pattern is in contrast to the cumulative results of EST mapping in all homoeologous groups, as reported (...) elsewhere, that found the highest proportion of loci mapped to the B genome. Sixty-five percent of these 1918 loci mapped to the long arms of homoeologous group 4 chromosomes, while 35% mapped to the short arms. The distal regions of chromosome arms showed higher numbers of loci than the proximal regions, with the exception of 4DL. This study confirmed the complex structure of chromosome 4A that contains two reciprocal translocations and two inversions, previously identified. An additional inversion in the centromeric region of 4A was revealed. A consensus map for homoeologous group 4 was developed from 119 ESTs unique to group 4. Forty-nine percent of these ESTs were found to be homoologous to sequences on rice chromosome 3, 12% had matches with sequences on other rice chromosomes, and 39% had no matches with rice sequences at all. Limited homology was found between wheat ESTs on homoeologous group 4 and the Arabidopsis genome. Forty-two percent of the homoeologous group 4 ESTs could be classified into functional categories on the basis of blastX searches against all protein databases. (shrink)

To localize wheat ESTs on chromosomes, 882 homoeologous group 6-specific ESTs were identified by physically mapping 7965 singletons from 37 cDNA libraries on 146 chromosome, arm, and sub-arm aneuploid and deletion stocks. The 882 ESTs were physically mapped to 25 regions flanked by 23 deletion breakpoints. Of the 5154 restriction fragments detected by 882 ESTs, 2043 were localized to group 6 chromosomes and 806 were mapped on other chromosome groups. The number of loci mapped was greatest on chromosome 6B and (...) least on 6D. The 264 ESTs that detected orthologous loci on all three homoeologs using one restriction enzyme were used to construct a consensus physical map. The physical distribution of ESTs was uneven on chromosomes with a tendency toward higher densities in the distal halves of chromosome arms. About 43% of the wheat group 6 ESTs identified rice homologs upon comparisons of genome sequences. Fifty-eight percent of these ESTs were present on rice chromosome 2 and the remaining were on other rice chromosomes. Even within the group 6 bins, rice chromosomal blocks identified by 1-6 wheat ESTs were homologous to up to 11 rice chromosomes. These rice-block contigs were used to resolve the order of wheat ESTs within each bin. (shrink)

So-called ‘distinctively mathematical explanations’ (DMEs) are said to explain physical phenomena, not in terms of contingent causal laws, but rather in terms of mathematical necessities that constrain the physical system in question. Lange argues that the existence of four or more equilibrium positions of any double pendulum has a DME. Here we refute both Lange’s claim itself and a strengthened and extended version of the claim that would pertain to any n-tuple pendulum system on the ground that such explanations are (...) actually causal explanations in disguise and their associated modal conditionals are not general enough to explain the said features of such dynamical systems. We argue and show that if circumscribing the antecedent for a necessarily true conditional in such explanations involves making a causal analysis of the problem, then the resulting explanation is not distinctively mathematical or non-causal. Our argument generalises to other dynamical systems that may have purported DMEs analogous to the one proposed by Lange, and even to some other counterfactual accounts of non-causal explanation given by Reutlinger and Rice. (shrink)

Study of the social determinants of consciousness is one of the more timely problems of contemporary philosophy. It requires a complex study of various factors determining the social nature of human consciousness and the cultural-historical mediation of humankind's reflection of the world. Esthetics, which studies the phenomenon of esthetic consciousness, has a place among these scientific disciplines.

The name Nikolai Fedorovich Fedorov has entered the ranks of the most outstanding thinkers who are worthy representatives of Russian philosophy. However, we shall not forget that this has become obvious only in recent years in the homeland of this unique philosopher. The scandal created by the publication in 1982 of Fedorov's works in the series Filosofskoe nasledie [Philosophical Heritage] is still remembered. On instructions from above, publication of the works was followed by dismissals, investigations, and allegations about the resurrection, (...) under conditions of "developed socialism," of the works of a "religious-conservative utopian"; there was also an anti-Fedorov campaign in the press. True, enthusiastic investigators—philosophers, literary figures, and artists—did not cease their efforts either before or after this ill-starred scandal to study and publish the works of this "strange" thinker. But it should be said—and this is pointed out in the book under review here—that under conditions of unfree development of philosophical thought, Fedorov's ideas were sometimes distorted to better accord with official attitudes, to make them "acceptable" for publication under the circumstances of that time, as well as for the sake of adapting them for the propaganda of various unofficial ideas, such as "native soil" ideas. Both Fedorov's person and his works have been surrounded by legend. Paradoxical though it may seem, foreign students of the works of the Russian philosopher have had more favorable conditions to study his legacy and have written many articles and books about him. Among them, the dissertation by Michael Hagemeister, Nikolai Fedorov. Studies of His Life, Works, and Influence, published as a book in the series Marburg Studies in the History and Culture of Eastern Europe in 1989, occupies a worthy place. (shrink)

In recent years the term "dialogue" has taken on a special nuance and, in the literature, usually refers to specially organized gatherings between Marxists and Christians. Intense arguments rage around the "dialogue." An extensive literature contains the most diverse explanations of its origins and content, objectives and possible outcomes. An attempt "on the run" to smash through this picket fence of judgments and single out some "rational core" is hardly promising in the final analysis. Another path is required, reconstructing the (...) very mechanism of the appearance of various evaluations out of some initial material, independent of the opinions of the theorists of the "dialogue." There appears to be no need for recourse to the history of the "dialogue," which is sufficiently known. Let us cite only certain factors. (shrink)

I do not feel I have the authority to evaluate the individual speeches, much less to venture any conclusion sans appel. Let me just limit myself to some cursory comments about the course of today's conversation and the prospects of a further discussion of this extremely complicated and serious topic.