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Summary The concentrations of testosterone (T) and 5-dihydrotestosterone were measured in fluid collected from the rete testis of immature and adult rats. The results indicate that adult levels of T are attained in the seminiferous tubules much earlier than in the peripheral circulation.This work was performed at the Worcester Foundation for Experimental Biology, Shrewsbury, Massachusetts, USA and supported by the National Institutes of Health through grants HD12641 and HD12642. We thank Dr B.V. Caldwell for antiserum to testosterone. 相似文献
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Stomata consist of a pair of guard cells that mediate gas and water-vapour exchange between plants and the atmosphere. Stomatal precursor cells-meristemoids-possess a transient stem-cell-like property and undergo several rounds of asymmetric divisions before further differentiation. Here we report that the Arabidopsis thaliana basic helix-loop-helix (bHLH) protein MUTE is a key switch for meristemoid fate transition. In the absence of MUTE, meristemoids abort after excessive asymmetric divisions and fail to differentiate stomata. Constitutive overexpression of MUTE directs the entire epidermis to adopt guard cell identity. MUTE has two paralogues: FAMA, a regulator of guard cell morphogenesis, and SPEECHLESS (SPCH). We show that SPCH directs the first asymmetric division that initiates stomatal lineage. Together, SPCH, MUTE and FAMA bHLH proteins control stomatal development at three consecutive steps: initiation, meristemoid differentiation and guard cell morphogenesis. Our findings highlight the roles of closely related bHLHs in cell type differentiation in plants and animals. 相似文献
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A second generation human haplotype map of over 3.1 million SNPs 总被引:2,自引:0,他引:2
International HapMap Consortium Frazer KA Ballinger DG Cox DR Hinds DA Stuve LL Gibbs RA Belmont JW Boudreau A Hardenbol P Leal SM Pasternak S Wheeler DA Willis TD Yu F Yang H Zeng C Gao Y Hu H Hu W Li C Lin W Liu S Pan H Tang X Wang J Wang W Yu J Zhang B Zhang Q Zhao H Zhao H Zhou J Gabriel SB Barry R Blumenstiel B Camargo A Defelice M Faggart M Goyette M Gupta S Moore J Nguyen H Onofrio RC Parkin M Roy J Stahl E Winchester E Ziaugra L Altshuler D Shen Y Yao Z Huang W Chu X He Y Jin L Liu Y 《Nature》2007,449(7164):851-861
We describe the Phase II HapMap, which characterizes over 3.1 million human single nucleotide polymorphisms (SNPs) genotyped in 270 individuals from four geographically diverse populations and includes 25-35% of common SNP variation in the populations surveyed. The map is estimated to capture untyped common variation with an average maximum r2 of between 0.9 and 0.96 depending on population. We demonstrate that the current generation of commercial genome-wide genotyping products captures common Phase II SNPs with an average maximum r2 of up to 0.8 in African and up to 0.95 in non-African populations, and that potential gains in power in association studies can be obtained through imputation. These data also reveal novel aspects of the structure of linkage disequilibrium. We show that 10-30% of pairs of individuals within a population share at least one region of extended genetic identity arising from recent ancestry and that up to 1% of all common variants are untaggable, primarily because they lie within recombination hotspots. We show that recombination rates vary systematically around genes and between genes of different function. Finally, we demonstrate increased differentiation at non-synonymous, compared to synonymous, SNPs, resulting from systematic differences in the strength or efficacy of natural selection between populations. 相似文献
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Mullighan CG Goorha S Radtke I Miller CB Coustan-Smith E Dalton JD Girtman K Mathew S Ma J Pounds SB Su X Pui CH Relling MV Evans WE Shurtleff SA Downing JR 《Nature》2007,446(7137):758-764
Chromosomal aberrations are a hallmark of acute lymphoblastic leukaemia (ALL) but alone fail to induce leukaemia. To identify cooperating oncogenic lesions, we performed a genome-wide analysis of leukaemic cells from 242 paediatric ALL patients using high-resolution, single-nucleotide polymorphism arrays and genomic DNA sequencing. Our analyses revealed deletion, amplification, point mutation and structural rearrangement in genes encoding principal regulators of B lymphocyte development and differentiation in 40% of B-progenitor ALL cases. The PAX5 gene was the most frequent target of somatic mutation, being altered in 31.7% of cases. The identified PAX5 mutations resulted in reduced levels of PAX5 protein or the generation of hypomorphic alleles. Deletions were also detected in TCF3 (also known as E2A), EBF1, LEF1, IKZF1 (IKAROS) and IKZF3 (AIOLOS). These findings suggest that direct disruption of pathways controlling B-cell development and differentiation contributes to B-progenitor ALL pathogenesis. Moreover, these data demonstrate the power of high-resolution, genome-wide approaches to identify new molecular lesions in cancer. 相似文献
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Oxysterols direct immune cell migration via EBI2 总被引:1,自引:0,他引:1
Hannedouche S Zhang J Yi T Shen W Nguyen D Pereira JP Guerini D Baumgarten BU Roggo S Wen B Knochenmuss R Noël S Gessier F Kelly LM Vanek M Laurent S Preuss I Miault C Christen I Karuna R Li W Koo DI Suply T Schmedt C Peters EC Falchetto R Katopodis A Spanka C Roy MO Detheux M Chen YA Schultz PG Cho CY Seuwen K Cyster JG Sailer AW 《Nature》2011,475(7357):524-527
Epstein-Barr virus-induced gene 2 (EBI2, also known as GPR183) is a G-protein-coupled receptor that is required for humoral immune responses; polymorphisms in the receptor have been associated with inflammatory autoimmune diseases. The natural ligand for EBI2 has been unknown. Here we describe the identification of 7α,25-dihydroxycholesterol (also called 7α,25-OHC or 5-cholesten-3β,7α,25-triol) as a potent and selective agonist of EBI2. Functional activation of human EBI2 by 7α,25-OHC and closely related oxysterols was verified by monitoring second messenger readouts and saturable, high-affinity radioligand binding. Furthermore, we find that 7α,25-OHC and closely related oxysterols act as chemoattractants for immune cells expressing EBI2 by directing cell migration in vitro and in vivo. A critical enzyme required for the generation of 7α,25-OHC is cholesterol 25-hydroxylase (CH25H). Similar to EBI2 receptor knockout mice, mice deficient in CH25H fail to position activated B cells within the spleen to the outer follicle and mount a reduced plasma cell response after an immune challenge. This demonstrates that CH25H generates EBI2 biological activity in vivo and indicates that the EBI2-oxysterol signalling pathway has an important role in the adaptive immune response. 相似文献
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Wertz IE Kusam S Lam C Okamoto T Sandoval W Anderson DJ Helgason E Ernst JA Eby M Liu J Belmont LD Kaminker JS O'Rourke KM Pujara K Kohli PB Johnson AR Chiu ML Lill JR Jackson PK Fairbrother WJ Seshagiri S Ludlam MJ Leong KG Dueber EC Maecker H Huang DC Dixit VM 《Nature》2011,471(7336):110-114
Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics. 相似文献