Design of potent and selective human cathepsin K inhibitors that span the active site

Potent and selective active-site-spanning inhibitors have been designed for cathepsin K, a cysteine protease unique to osteoclasts. They act by mechanisms that involve tight binding intermediates, potentially on a hydrolytic pathway. X-ray crystallographic, MS, NMR spectroscopic, and kinetic studies of the mechanisms of inhibition indicate that different intermediates or transition states are being represented that are dependent on the conditions of measurement and the specific groups flanking the carbonyl in the inhibitor. The species observed crystallographically are most consistent with tetrahedral intermediates that may be close approximations of those that occur during substrate hydrolysis. Initial kinetic studies suggest the possibility of irreversible and reversible active-site modification. Representative inhibitors have demonstrated antiresorptive activity both in vitro and in vivo and therefore are promising leads for therapeutic agents for the treatment of osteoporosis. Expansion of these inhibitor concepts can be envisioned for the many other cysteine proteases implicated for therapeutic intervention.

Modulation of Life-span by Histone Deacetylase Genes in Saccharomyces cerevisiae

The yeast Saccharomyces cerevisiae has a limited life-span, which is measured by the number of divisions that individual cells complete. Among the many changes that occur as yeasts age are alterations in chromatin-dependent transcriptional silencing. We have genetically manipulated histone deacetylases to modify chromatin, and we have examined the effect on yeast longevity. Deletion of the histone deacetylase gene RPD3 extended life-span. Its effects on chromatin functional state were evidenced by enhanced silencing at the three known heterochromatic regions of the genome, the silent mating type (HM), subtelomeric, and rDNA loci, which occurred even in the absence of SIR3. Similarly, the effect of the rpd3Δ on life-span did not depend on an intact Sir silencing complex. In fact, deletion of SIR3 itself had little effect on life-span, although it markedly accelerated the increase in cell generation time that is observed during yeast aging. Deletion of HDA1, another histone deacetylase gene, did not result in life-span extension, unless it was combined with deletion of SIR3. The hda1Δ sir3Δ resulted in an increase in silencing, but only at the rDNA locus. Deletion of RPD3 suppressed the loss of silencing in rDNA in a sir2 mutant; however, the silencing did not reach the level found in the rpd3Δ single mutant, and RPD3 deletion did not overcome the life-span shortening seen in the sir2 mutant. Deletion of both RPD3 and HDA1 caused a decrease in life-span, which resulted from a substantial increase in initial mortality of the population. The expression of both of these genes declines with age, providing one possible explanation for the increase in mortality during the life-span. Our results are consistent with the loss of rDNA silencing leading to aging in yeast. The functions of RPD3 and HDA1 do not overlap entirely. RPD3 exerts its effect on chromatin at additional sites in the genome, raising the possibility that events at loci other than rDNA play a role in the aging process.

Thermotolerance and extended life-span conferred by single-gene mutations and induced by thermal stress.

We have discovered that three longevity mutants of the nematode Caenorhabditis elegans also exhibit increased intrinsic thermotolerance (Itt) as young adults. Mutation of the age-1 gene causes not only 65% longer life expectancy but also Itt. The Itt phenotype cosegregates with age-1. Long-lived spe-26 and daf-2 mutants also exhibit Itt. We investigated the relationship between increased thermotolerance and increased life-span by developing conditions for environmental induction of thermotolerance. Such pretreatments at sublethal temperatures induce significant increases in thermotolerance and small but statistically highly significant increases in life expectancy, consistent with a causal connection between these two traits. Thus, when an animal's resistance to stress is increased, by either genetic or environmental manipulation, we also observe an increase in life expectancy. These results suggest that ability to respond to stress limits the life expectancy of C. elegans and might do so in other metazoa as well.

Life-span, T-cell responses, and incidence of lymphomas in congenic mice.

Survival, T-cell functions, and postmortem histopathology were studied in H-2 congenic strains of mice bearing H-2b, H-2k, and H-2d haplotypes. Males lived longer than females in all homozygous and heterozygous combinations except for H-2d homozygotes, which showed no differences between males and females. Association of heterozygosity with longer survival was observed only with H-2b/H-2b and H-2b/H-2d mice. Analysis using classification and regression trees (CART) showed that both males and females of H-2b homozygous and H-2k/H-2b mice had the shortest life-span of the strains studied. In histopathological analyses, lymphomas were noted to be more frequent in females, while hemangiosarcomas and hepatomas were more frequent in males. Lymphomas appeared earlier than hepatomas or hemangiosarcomas. The incidence of lymphomas was associated with the H-2 haplotype--e.g., H-2b homozygous mice had more lymphomas than did mice of the H-2d haplotype. More vigorous T-cell function was maintained with age (27 months) in H-2d, H-2b/H-2d, and H-2d/H-2k mice as compared with H-2b, H-2k, and H-2b/H-2k mice, which showed a decline of T-cell responses with age.

White and Negro spirituals, their life span and kinship, tracing 200 years of untrammeled song making and singing among our country folk, with 116 songs as sung by both races.

"The tune comparative list. One hundred and sixteen melodies of white people paired with same number of Negro-sung variants": p. [145]-227.

The span of life, as influenced by the heart, the kidneys and the blood vessels,

A summary of lectures given at the Santa Barbara cottage hospital. cf. Introd

Life-span services : a handbook of Illinois state government agencies serving persons with developmental disabilities.

"Life span brochure."--Introd.

Operator's, organizational, direct support, and general support maintenance manual : bridge, armored-vehicle-launched, scissoring type, aluminum, 60-ft. span, for use with M-48 and M-60 launcher (all makes and models), FSN 5420-522-9599).

"October 1972."

Extending the human life span : social policy and social ethics /

"NSF/RA 770123."

Global processing speed as a mediator of developmental changes in children's auditory memory span

This study examined the role of global processing speed in mediating age increases in auditory memory span in 5- to 13-year-olds. Children were tested on measures of memory span, processing speed, single-word speech rate, phonological sensitivity, and vocabulary. Structural equation modeling supported a model in which age-associated increases in processing speed predicted the availability of long-term memory phonological representations for redintegration processes. The availability of long-term phonological representations, in turn, explained variance in memory span. Maximum speech rate did not predict independent variance in memory span. (c) 2005 Elsevier Inc. All rights reserved.

Down Syndrome Across the Life Span

Beyond the myths: representing people with Down syndrome / Jan Gothard -- Learning in young children with Down syndrome: public perceptions, empirical evidence / Jennifer G. Wishart -- Self-regulation in children and young people with Down syndrome / Sheila Glenn and Cliff Cunningham -- What matters most? A reflection on a quarter century of early childhood intervention / Robin Treloar and Susan Cairns -- Making inclusion work: improving educational outcomes for students with Down syndrome in the regular classroom / Loretta R. Giorcelli -- Cognitive development and education: perspectives on Down syndrome from a twenty-year research programme / Susan Buckley and Gillian Bird -- Broadening approaches to literacy education for young adults with Down syndrome / Christina E. van Kraayenoord ... [et al.] -- Numeracy and money management skills in young adults with Down syndrome / Sandra Bochner ... [et al.] -- Life styles of adults with Down syndrome living at home / Anne Jobling and Monica Cuskelly -- Some studies involving individuals with Down syndrome and their relevance to a quality of life model / Verity Bottroff ... [et al.] -- From autonomy to work placement / Anna Contardi -- An appreciative inquiry about adults with Down syndrome / Susanne Muirhead -- Multiple perspectives of family life / Monica Cuskelly ... [et al.] -- Verbal-motor behaviour in persons with Down syndrome / Brian K.V. Maraj ... [et al.].