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To: tnsaf who wrote (1462)2/3/2002 4:47:45 PM
From: tnsaf  Read Replies (1) | Respond to of 7143
 
Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 2, 803-808, January 22, 2002

Mutation rates in mammalian genomes

Sudhir Kumar*, and Sankar Subramanian*
Department of Biology, Arizona State University, Tempe, AZ 85287-1501

Knowledge of the rate of point mutation is of fundamental importance, because mutations are a vital source of genetic novelty and a significant cause of human diseases. Currently, mutation rate is thought to vary many fold among genes within a genome and among lineages in mammals. We have conducted a computational analysis of 5,669 genes (17,208 sequences) from species representing major groups of placental mammals to characterize the extent of mutation rate differences among genes in a genome and among diverse mammalian lineages. We find that mutation rate is approximately constant per year and largely similar among genes. Similarity of mutation rates among lineages with vastly different generation lengths and physiological attributes points to a much greater contribution of replication-independent mutational processes to the overall mutation rate. Our results suggest that the average mammalian genome mutation rate is 2.2 × 109 per base pair per year, which provides further opportunities for estimating species and population divergence times by using molecular clocks.

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www.pnas.org/cgi/doi/10.1073/pnas.022629899



To: tnsaf who wrote (1462)2/10/2002 6:25:46 PM
From: tnsaf  Read Replies (1) | Respond to of 7143
 
Antigen-presenting dendritic cells provide the reducing extracellular microenvironment required for T lymphocyte activation

Proc. Natl. Acad. Sci. USA, Vol. 99, Issue 3, 1491-1496, February 5, 2002

Giovanna Angelini*,, Stefania Gardella*, Massimo Ardy*, Maria Rosa Ciriolo, Giuseppe Filomeni, Giovanna Di Trapani§, Frank Clarke§, Roberto Sitia¶, and Anna Rubartelli*
* Protein Biology Unit, National Cancer Research Institute, 16132 Genoa, Italy; Department of Biomedical Sciences, University of Chieti, 66100 Chieti, Italy; § School of Biomolecular and Biomedical Science, Griffith University, Brisbane 4111, Australia; and ¶ Università Vita-Salute San Raffaele, 20132 Milan, Italy

T lymphocytes are defective in cystine uptake and thus require exogenous thiols for activation and function. Here we show that monocyte-derived human dendritic cells (DCs) release cysteine in the extracellular space. Cysteine generation is increased by lipopolysaccharide and tumor necrosis factor , and by contact with T cells specifically recognizing soluble or alloantigens. These stimuli also induce thioredoxin (TRX) accumulation in DCs. However, only the contact with antigen-specific T cells triggers TRX secretion by the antigen-presenting cells. Fewer extracellular thiols are recovered after DC-T cell interactions when cystine uptake or TRX activity are inhibited. In addition, glutamate (Glu) and anti-TRX-inactivating antibodies inhibit antigen-dependent T lymphocyte proliferation. These findings indicate that, during antigen presentation, DCs uptake cystine and release cysteine and TRX, thus providing a reducing microenvironment that facilitates immune response.
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www.pnas.org/cgi/doi/10.1073/pnas.022630299