Non-Markovian Configurational Diffusion and Reaction Coordinates for Protein Folding

The non-Markovian nature of polymer motions is accounted for in folding kinetics, using frequency-dependent friction. Folding, like many other problems in the physics of disordered systems, involves barrier crossing on a correlated energy landscape. A variational transition state theory (VTST) that reduces to the usual Bryngelson-Wolynes Kramers approach when the non-Markovian aspects are neglected is used to obtain the rate, without making any assumptions regarding the size of the barrier, or the memory time of the friction. The transformation to collective variables dependent on the dynamics of the system allows the theory to address the controversial issue of what are ``good'' reaction coordinates for folding.Comment: 9 pages RevTeX, 3 eps-figures included, submitted to PR

Ultrasound-evoked immediate early gene expression in the brainstem of the Chinese torrent frog, Odorrana tormota

The concave-eared torrent frog, Odorrana tormota, has evolved the extraordinary ability to communicate ultrasonically (i.e., using frequencies > 20 kHz), and electrophysiological experiments have demonstrated that neurons in the frog’s midbrain (torus semicircularis) respond to frequencies up to 34 kHz. However, at this time, it is unclear which region(s) of the torus and what other brainstem nuclei are involved in the detection of ultrasound. To gain insight into the anatomical substrate of ultrasound detection, we mapped expression of the activity-dependent gene, egr-1, in the brain in response to a full-spectrum mating call, a filtered, ultrasound-only call, and no sound. We found that the ultrasound-only call elicited egr-1 expression in the superior olivary and principal nucleus of the torus semicircularis. In sampled areas of the principal nucleus, the ultrasound-only call tended to evoke higher egr-1 expression than the full-spectrum call and, in the center of the nucleus, induced significantly higher egr-1 levels than the no-sound control. In the superior olivary nucleus, the full-spectrum and ultrasound-only calls evoked similar levels of expression that were significantly greater than the control, and egr-1 induction in the laminar nucleus showed no evidence of acoustic modulation. These data suggest that the sampled areas of the principal nucleus are among the regions sensitive to ultrasound in this species

Genomewide meta-analysis identifies loci associated with IGF-I and IGFBP-3 levels with impact on age-related traits

The growth hormone/insulin-like growth factor (IGF) axis can be manipulated in animal models to promote longevity, and IGF-related proteins including IGF-I and IGF-binding protein-3 (IGFBP-3) have also been implicated in risk of human diseases including cardiovascular diseases, diabetes, and cancer. Throug

Probing the Interstellar Medium in Early type galaxies with ISO observations

Four IRAS-detected early type galaxies were observed with ISO. With the exception of the 15 micron image of NGC1052, the mid-IR emission from NGC1052, NGC1155, NGC5866 and NGC6958 at 4.5, 7 and 15 microns show extended emission. Mid-IR emission from NGC1052, NGC1155, and NGC6958 follows a de Vaucouleurs profile. The ratio of 15/7 micron flux decreases with radius in these galaxies, approaching the values empirically observed for purely stellar systems. In NGC5866, the 7 and 15 micron emission is concentrated in the edge-on dust lane. All the galaxies are detected in the [CII] line, and the S0s NGC1155 and NGC5866 are detected in the [OI] line as well. The ISO-LWS observations of the [CII] line are more sensitive measures of cool, neutral ISM than HI and CO by about a factor of 10-100. Three of four early type galaxies, namely NGC1052, NGC6958 and NGC5866, have low ratio FIR/Blue and show a lower [CII]/FIR, which is due to a softer radiation field from old stellar populations. The low [CII]/CO ratio in NGC5866 ([CII]/CO(1-0) < 570) confirms this scenario. We estimate the UV radiation expected from the old stellar populations in these galaxies and compare it to that needed to heat the gas to account for the cooling observed [CII] and [OI] lines. In three out of four galaxies, NGC1052, NGC5866 and NGC6958, the predicted UV radiation falls short by a factor of 2-3. In view of the observed intrinsic scatter in the "UV-upturn" in elliptical galaxies and its great sensitivity to age and metallicity effects, this is not significant. However, the much larger difference (about a factor of 20) between the UV radiation from old stars and that needed to produce the FIR lines for NGC 1155 is strong evidence for the presence of young stars, in NGC1155.Comment: To appear in the Astrophysical Journal. Figure 1 appears as a separate jpg figur

IGF-1, IGFBP-1, and IGFBP-3 Polymorphisms Predict Circulating IGF Levels but Not Breast Cancer Risk: Findings from the Breast and Prostate Cancer Cohort Consortium (BPC3)

IGF-1 has been shown to promote proliferation of normal epithelial breast cells, and the IGF pathway has also been linked to mammary carcinogenesis in animal models. We comprehensively examined the association between common genetic variation in the IGF1, IGFBP1, and IGFBP3 genes in relation to circulating IGF-I and IGFBP-3 levels and breast cancer risk within the NCI Breast and Prostate Cancer Cohort Consortium (BPC3). This analysis included 6,912 breast cancer cases and 8,891 matched controls (n = 6,410 for circulating IGF-I and 6,275 for circulating IGFBP-3 analyses) comprised primarily of Caucasian women drawn from six large cohorts. Linkage disequilibrium and haplotype patterns were characterized in the regions surrounding IGF1 and the genes coding for two of its binding proteins, IGFBP1 and IGFBP3. In total, thirty haplotype-tagging single nucleotide polymorphisms (htSNP) were selected to provide high coverage of common haplotypes; the haplotype structure was defined across four haplotype blocks for IGF1 and three for IGFBP1 and IGFBP3. Specific IGF1 SNPs individually accounted for up to 5% change in circulating IGF-I levels and individual IGFBP3 SNPs were associated up to 12% change in circulating IGFBP-3 levels, but no associations were observed between these polymorphisms and breast cancer risk. Logistic regression analyses found no associations between breast cancer and any htSNPs or haplotypes in IGF1, IGFBP1, or IGFBP3. No effect modification was observed in analyses stratified by menopausal status, family history of breast cancer, body mass index, or postmenopausal hormone therapy, or for analyses stratified by stage at diagnosis or hormone receptor status. In summary, the impact of genetic variation in IGF1 and IGFBP3 on circulating IGF levels does not appear to substantially influence breast cancer risk substantially among primarily Caucasian postmenopausal women

Common genetic variation in IGF1, IGFBP-1, and IGFBP-3 in relation to mammographic density: a cross-sectional study

INTRODUCTION: Mammographic density is one of the strongest risk factors for breast cancer and is believed to represent epithelial and stromal proliferation. Because of the high heritability of breast density, and the role of the insulin-like growth factor (IGF) pathway in cellular proliferation and breast development, we examined the association between common genetic variation in this pathway and mammographic density. METHODS: We conducted a cross-sectional analysis among controls (n = 1,121) who were between the ages of 42 and 78 years at mammography, from a breast cancer case-control study nested within the Nurses' Health Study cohort. At the time of mammography, 204 women were premenopausal and 917 were postmenopausal. We genotyped 29 haplotype-tagging SNPs demonstrated to capture common genetic variation in IGF1, IGF binding protein (IGFBP)-1, and IGFBP-3. RESULTS: Common haplotype patterns in three of the four haplotype blocks spanning the gene encoding IGF1 were associated with mammographic density. Haplotype patterns in block 1 (p = 0.03), block 3 (p = 0.009), and block 4 (p = 0.007) were associated with mammographic density, whereas those in block 2 were not. None of the common haplotypes in the three haplotype blocks spanning the genes encoding IGFBP-1/IGFBP-3 were significantly associated with mammographic density. Two haplotype-tagging SNPs in IGF1, rs1520220 and rs2946834, showed a strong association with mammographic density. Those with the homozygous variant genotype for rs1520220 had a mean percentage mammographic density of 19.6% compared with those with the homozygous wild-type genotype, who had a mean percentage mammographic density of 27.9% (p for trend < 0.0001). Those that were homozygous variant for rs2946834 had a mean percentage mammographic density of 23.2% compared with those who were homozygous wild-type with a mean percentage mammographic density of 28.2% (p for trend = 0.0004). Permutation testing demonstrated that results as strong as these are unlikely to occur by chance (p = 0.0005). CONCLUSION: Common genetic variation in IGF1 is strongly associated with percentage mammographic density

Genome-wide association study of Tourette Syndrome

Tourette Syndrome (TS) is a developmental disorder that has one of the highest familial recurrence rates among neuropsychiatric diseases with complex inheritance. However, the identification of definitive TS susceptibility genes remains elusive. Here, we report the first genome-wide association study (GWAS) of TS in 1285 cases and 4964 ancestry-matched controls of European ancestry, including two European-derived population isolates, Ashkenazi Jews from North America and Israel, and French Canadians from Quebec, Canada. In a primary meta-analysis of GWAS data from these European ancestry samples, no markers achieved a genome-wide threshold of significance (p<5 × 10−8); the top signal was found in rs7868992 on chromosome 9q32 within COL27A1 (p=1.85 × 10−6). A secondary analysis including an additional 211 cases and 285 controls from two closely-related Latin-American population isolates from the Central Valley of Costa Rica and Antioquia, Colombia also identified rs7868992 as the top signal (p=3.6 × 10−7 for the combined sample of 1496 cases and 5249 controls following imputation with 1000 Genomes data). This study lays the groundwork for the eventual identification of common TS susceptibility variants in larger cohorts and helps to provide a more complete understanding of the full genetic architecture of this disorder