Genetic Structure of Qiangic Populations Residing in the Western Sichuan Corridor

<div><p>The Qiangic languages in western Sichuan (WSC) are believed to be the oldest branch of the Sino-Tibetan linguistic family, and therefore, all Sino-Tibetan populations might have originated in WSC. However, very few genetic investigations have been done on Qiangic populations and no genetic evidences for the origin of Sino-Tibetan populations have been provided. By using the informative Y chromosome and mitochondrial DNA (mtDNA) markers, we analyzed the genetic structure of Qiangic populations. Our results revealed a predominantly Northern Asian-specific component in Qiangic populations, especially in maternal lineages. The Qiangic populations are an admixture of the northward migrations of East Asian initial settlers with Y chromosome haplogroup D (D1-M15 and the later originated D3a-P47) in the late Paleolithic age, and the southward Di-Qiang people with dominant haplogroup O3a2c1*-M134 and O3a2c1a-M117 in the Neolithic Age.</p></div

Phylogenetic relationship between Qiangic and reference populations analyzed by PCA with the frequencies of haplogroups.

<p>(a). PCA plot based on Y chromosome haplogroup frequencies of 51 populations; (b). PCA plot based on mtDNA haplogroups frequencies of 72 populations.</p

Reduced Median-joining network based on the HVRI data of mtDNA.

<p>Reduced Median-joining network based on the HVRI data of mtDNA.</p

Geographic locations of Qiangic and other referenced East Asian populations in this study.

<p>(a). Geographic location of WSC and distributions of the East Asian populations used in data analysis; (b). Detailed geographic location of studied Qiangic speaking populations. The number of individual sampled in each population is enclosed in parentheses.</p

Molecular diversity indices and growth summary statistics for Qiangic populations.

<p>Abbreviations: N, number of sequences; h, number of haplotypes; S, number of polymorphic sites; MNPD, mean number of pairwise differences; SD, standard deviation; P, probability value.</p><p>*is a part of the parameter name.</p

Growth summary statistics and frequency spectrum tests for deviation from neutrality.

a<p>means P<0.01,</p>b<p>means P<0.05,</p>c<p>means 0.05</p><p>*is a part of the parameter name or haplogroup name.</p

Discovery of (<i>R</i>)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND006) and (<i>R</i>)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2<i>H</i>‑pyrazolo[4,3‑<i>c</i>]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch

Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds <b>30</b> (ELND006) and <b>34</b> (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between <b>30</b>, <b>34</b>, Semagacestat <b>41</b>, Begacestat <b>42</b>, and Avagacestat <b>43</b> in mice is made. <b>30</b> lowered Aβ in the CSF of healthy human volunteers