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41.
International Consortium for Blood Pressure Genome-Wide Association Studies Ehret GB Munroe PB Rice KM Bochud M Johnson AD Chasman DI Smith AV Tobin MD Verwoert GC Hwang SJ Pihur V Vollenweider P O'Reilly PF Amin N Bragg-Gresham JL Teumer A Glazer NL Launer L Zhao JH Aulchenko Y Heath S Sõber S Parsa A Luan J Arora P Dehghan A Zhang F Lucas G Hicks AA Jackson AU Peden JF Tanaka T Wild SH Rudan I Igl W Milaneschi Y Parker AN Fava C Chambers JC Fox ER Kumari M Go MJ van der Harst P Kao WH 《Nature》2011,478(7367):103-109
Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140?mm?Hg systolic blood pressure or ≥90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention. 相似文献
42.
Ospelkaus C Warring U Colombe Y Brown KR Amini JM Leibfried D Wineland DJ 《Nature》2011,476(7359):181-184
Control over physical systems at the quantum level is important in fields as diverse as metrology, information processing, simulation and chemistry. For trapped atomic ions, the quantized motional and internal degrees of freedom can be coherently manipulated with laser light. Similar control is difficult to achieve with radio-frequency or microwave radiation: the essential coupling between internal degrees of freedom and motion requires significant field changes over the extent of the atoms' motion, but such changes are negligible at these frequencies for freely propagating fields. An exception is in the near field of microwave currents in structures smaller than the free-space wavelength, where stronger gradients can be generated. Here we first manipulate coherently (on timescales of 20 nanoseconds) the internal quantum states of ions held in a microfabricated trap. The controlling magnetic fields are generated by microwave currents in electrodes that are integrated into the trap structure. We also generate entanglement between the internal degrees of freedom of two atoms with a gate operation suitable for general quantum computation; the entangled state has a fidelity of 0.76(3), where the uncertainty denotes standard error of the mean. Our approach, which involves integrating the quantum control mechanism into the trapping device in a scalable manner, could be applied to quantum information processing, simulation and spectroscopy. 相似文献
43.
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
44.
Epithelial integrity in metazoan organs is maintained through the regulated proliferation and differentiation of organ-specific stem and progenitor cells. Although the epithelia of organs such as the intestine regenerate constantly and thus remain continuously proliferative, other organs, such as the mammalian urinary bladder, shift from near-quiescence to a highly proliferative state in response to epithelial injury. The cellular and molecular mechanisms underlying this injury-induced mode of regenerative response are poorly defined. Here we show in mice that the proliferative response to bacterial infection or chemical injury within the bladder is regulated by signal feedback between basal cells of the urothelium and the stromal cells that underlie them. We demonstrate that these basal cells include stem cells capable of regenerating all cell types within the urothelium, and are marked by expression of the secreted protein signal Sonic hedgehog (Shh). On injury, Shh expression in these basal cells increases and elicits increased stromal expression of Wnt protein signals, which in turn stimulate the proliferation of both urothelial and stromal cells. The heightened activity of this signal feedback circuit and the associated increase in cell proliferation appear to be required for restoration of urothelial function and, in the case of bacterial injury, may help clear and prevent further spread of infection. Our findings provide a conceptual framework for injury-induced epithelial regeneration in endodermal organs, and may provide a basis for understanding the roles of signalling pathways in cancer growth and metastasis. 相似文献
45.
Lorch JM Meteyer CU Behr MJ Boyles JG Cryan PM Hicks AC Ballmann AE Coleman JT Redell DN Reeder DM Blehert DS 《Nature》2011,480(7377):376-378
White-nose syndrome (WNS) has caused recent catastrophic declines among multiple species of bats in eastern North America. The disease's name derives from a visually apparent white growth of the newly discovered fungus Geomyces destructans on the skin (including the muzzle) of hibernating bats. Colonization of skin by this fungus is associated with characteristic cutaneous lesions that are the only consistent pathological finding related to WNS. However, the role of G. destructans in WNS remains controversial because evidence to implicate the fungus as the primary cause of this disease is lacking. The debate is fuelled, in part, by the assumption that fungal infections in mammals are most commonly associated with immune system dysfunction. Additionally, the recent discovery that G. destructans commonly colonizes the skin of bats of Europe, where no unusual bat mortality events have been reported, has generated further speculation that the fungus is an opportunistic pathogen and that other unidentified factors are the primary cause of WNS. Here we demonstrate that exposure of healthy little brown bats (Myotis lucifugus) to pure cultures of G. destructans causes WNS. Live G. destructans was subsequently cultured from diseased bats, successfully fulfilling established criteria for the determination of G. destructans as a primary pathogen. We also confirmed that WNS can be transmitted from infected bats to healthy bats through direct contact. Our results provide the first direct evidence that G. destructans is the causal agent of WNS and that the recent emergence of WNS in North America may represent translocation of the fungus to a region with a naive population of animals. Demonstration of causality is an instrumental step in elucidating the pathogenesis and epidemiology of WNS and in guiding management actions to preserve bat populations against the novel threat posed by this devastating infectious disease. 相似文献
46.
Large conductance, Ca2+-activated potassium (BK) channels are widely expressed throughout the animal kingdom and play important roles in many physiological
processes, such as muscle contraction, neural transmission and hearing. These physiological roles derive from the ability
of BK channels to be synergistically activated by membrane voltage, intracellular Ca2+ and other ligands. Similar to voltage-gated K+ channels, BK channels possess a pore-gate domain (S5–S6 transmembrane segments) and a voltage-sensor domain (S1–S4). In addition,
BK channels contain a large cytoplasmic C-terminal domain that serves as the primary ligand sensor. The voltage sensor and
the ligand sensor allosterically control K+ flux through the pore-gate domain in response to various stimuli, thereby linking cellular metabolism and membrane excitability.
This review summarizes the current understanding of these structural domains and their mutual interactions in voltage-, Ca2+ - and Mg2+ -dependent activation of the channel.
Received 25 September 2008; received after revision 23 October 2008; accepted 24 October 2008 相似文献
47.
Dynamic protein methylation in chromatin biology 总被引:1,自引:1,他引:0
48.
Kramer J Böhrnsen F Lindner U Behrens P Schlenke P Rohwedel J 《Cellular and molecular life sciences : CMLS》2006,63(5):616-626
Microfracture of subchondral bone results in intrinsic repair of cartilage defects. Stem or progenitor cells from bone marrow
have been proposed to be involved in this regenerative process. Here, we demonstrate for the first time that mesenchymal stem
(MS) cells can in fact be recovered from matrix material saturated with cells from bone marrow after microfracture. This also
introduces a new technique for MS cell isolation during arthroscopic treatment. MS cells were phenotyped using specific cell
surface antibodies. Differentiation of the MS cells into the adipogenic, chondrogenic and osteogenic lineage could be demonstrated
by cultivation of MS cells as a monolayer, as micromass bodies or mesenchymal microspheres. This study demonstrates that MS
cells can be attracted to a cartilage defect by guidance of a collagenous matrix after perforating subchondral bone. Protocols
for application of MS cells in restoration of cartilage tissue include an initial invasive biopsy to obtain the MS cells and
time-wasting in vitro proliferation and possibly differentiation of the cells before implantation. The new technique already includes attraction
of MS cells to sites of cartilage defects and therefore may overcome the necessity of in vitro proliferation and differentiation of MS cells prior to transplantation.
Received 3 November 2005; received after revision 15 December 2005; accepted 4 January 2006 相似文献
49.
Foser S Redwanz I Ebeling M Heizmann CW Certa U 《Cellular and molecular life sciences : CMLS》2006,63(19-20):2387-2396
A hallmark of resistance to type I interferons (IFNs) is the lack of antiproliferative responses. We show here that costimulation with IFN-alpha and transforming growth factor beta-1 (TGF-beta) potentiates antiproliferative activity in a sensitive (ME15) and resistant (D10) human melanoma cell line. A DNA microarray-based search for proliferation control genes involved that are cooperatively activated by IFN-alpha and TGF-beta, yielded 28 genes. Among these are the insulin-like growth factor-binding protein 3 (IGFBP3) and the calcium-binding protein S100A2; we demonstrate, that recombinant IGFBP3 protein is a potent growth inhibitor requiring TGF-beta activity. The antiproliferative activity of S100A2 is significantly enhanced by IFN-alpha in stably transfected ME15 or D10 cell lines. We show for the first time that IFN-alpha is a potent inducer of intracellular calcium release required for activation of S100A2. Our study provides a functional link between IFN-alpha and TGF-beta signaling and extends the function of IFN signaling to calcium-sensitive processes. 相似文献
50.
Mangold U 《Cellular and molecular life sciences : CMLS》2006,63(18):2095-2101
In contrast to the considerable interest in the oncogene ornithine decarboxylase (ODC) and in the family of antizymes with
regard to cell proliferation and tumorigenesis, the endogenous antizyme inhibitor (AZI) has been less well studied. AZI is
highly homologous to the enzyme ODC but does not possess any decarboxylase activity. Elevated ODC activity is associated with
most forms of human malignancies. Antizymes bind ODC, inhibit ODC activity and promote the ubiquitin-independent degradation
of ODC. Consequently they are proposed as tumor suppressors. In particular, the most studied member of the antizyme family,
antizyme 1, has been demonstrated to play a role in tumor suppression. AZI inactivates all members of the antizyme family,
reactivates ODC and prevents the proteolytic degradation of ODC, which may suggest a role for AZI in tumor progression.
Received 9 December 2005; received after revision 13 April 2006; accepted 1 June 2006 相似文献