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)

The sporadic nature of Alzheimer's disease argues for an environmental link that may drive AD pathogenesis; however, the triggering factors and the period of their action are unknown. Recent studies in rodents have shown that exposure to lead during brain development predetermined the expression and regulation of the amyloid precursor protein and its amyloidogenic beta-amyloid product in old age. Here, we report that the expression of AD-related genes [APP, BACE1 ] as well as their transcriptional regulator were elevated in aged (...) monkeys exposed to Pb as infants. Furthermore, developmental exposure to Pb altered the levels, characteristics, and intracellular distribution of Abeta staining and amyloid plaques in the frontal association cortex. These latent effects were accompanied by a decrease in DNA methyltransferase activity and higher levels of oxidative damage to DNA, indicating that epigenetic imprinting in early life influenced the expression of AD-related genes and promoted DNA damage and pathogenesis. These data suggest that AD pathogenesis is influenced by early life exposures and argue for both an environmental trigger and a developmental origin of AD. (shrink)

Alzheimer's disease is characterized by amyloid-beta peptide -loaded plaques in the brain. Abeta is a cleavage fragment of amyloid-beta protein precursor and over production of APP may lead to amyloidogenesis. The regulatory region of the APP gene contains consensus sites recognized by the transcription factor, specificity protein 1 , which has been shown to be required for the regulation of APP and Abeta. To understand the role of SP1 in APP biogenesis, herein we have characterized the relative distribution and localization (...) of SP1, APP, and Abeta in various brain regions of rodent and primate models using immunohistochemistry. We observed that overall distribution and cellular localization of SP1, APP, and Abeta are similar and neuronal in origin. Their distribution is abundant in various layers of neocortex, but restricted to the Purkinje cell layer of the cerebellum, and the pyramidal cell layer of hippocampus. These findings suggest that overproduction of Abeta in vivo may be associated with transcriptional pathways involving SP1 and the APP gene. (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)

Spinoza semble adopter une position pleinement norninaliste 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 Ie système spinoziste est d’inspiration platoniste, et qu’il faut réinterpréter les passages d’apparence nominaliste pour les accorder avec Ie platonisme ou l’essentialisme. J’argurnente qu’un tel procédé n’est justifié ni par Ie texte ni par la structure du système de Spinoza. L’interprétation du spinozisme (...) que je propose Ie place dans Ie cadre logique du nominalisme contemporain, à I’instar du système de Nelson Goodman, par exemple. (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)

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)

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)

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)

Mencius, who lived in the 4th century B.C., is second only to Confucius in importance in the Confucian tradition. The _Mencius_ consists of sayings of Mencius and conversations he had with his contemporaries. When read side by side with the _Analects_, the _Mencius_ throws a great deal of light on the teachings of ConfuciusMencius developed many of the ideas of Confucius and at the same time discussed problems not touched upon by Confucius. He drew out the implications of Confucius' moral (...) principles and reinterpreted them for the conditions of his time. As the fullest of the four great Confucian texts, the _Mencius_ has been the required reading amongst Chinese scholars for two thousand years, and it still throws considerable light on the character of the Chinese people. (shrink)

A record of the words and teachings of Confucius, _The Analects_ is considered the most reliable expression of Confucian thought. However, the original meaning of Confucius's teachings have been filtered and interpreted by the commentaries of Confucianists of later ages, particularly the Neo-Confucianists of the Song dynasty, not altogether without distortion.In this monumental translation by Professor D. C. Lau, an attempt has been made to interpret the sayings as they stand. The corpus of the sayings is taken as an organic (...) whole and the final test of the interpretation rests on the internal consistency it exhibits. In other words, _The Analects_ is read in the light of _The Analects._This results in a truer understanding of Confucius' thought than the traditional interpretation and paves the way for a re-assessment of its importance in the history of Chinese thought and its relevance to the present day world.This volume also contains an introduction to the life and teachings of Confucius, and three appendices on the events in the life of Confucius, on his disciples, and on the composition of _The Analects._. (shrink)

This work provides an interesting, though sometimes rather sweeping, demonstration that the metaphysical problem of the same and the other is also the central problem of literature and literary criticism. The author defends the analogical imagination as the symbolic counterpart of participation in Platonic metaphysics.--D. C. B.

After an exceedingly short treatment of six theories of tragedy, the author concludes that while each has emphasized a necessary component of the tragic, none has really come to grips with its basic "paradox": the fact that while the art of tragedy attempts to explain the mystery of human suffering, such an attempt is doomed to failure.--D. C. B.