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251.
Susan M. White Elizabeth Bhoj Christoffer Nellåker Augusta M.A. Lachmeijer Aren E. Marshall Kym M. Boycott Dong Li Wendy Smith Taila Hartley Arran McBride Michelle E. Ernst Alison S. May Dagmar Wieczorek Rami Abou Jamra Margarete Koch-Hogrebe Katrin Õunap Sander Pajusalu K.L.I. van Gassen Kristin D. Kernohan 《American journal of human genetics》2021,108(4):749-756
252.
Rami A. Namas John Bartels Rosemary Hoffman Derek Barclay Timothy R. Billiar Ruben Zamora Yoram Vodovotz 《PloS one》2013,8(7)
We combined in silico, in vivo, and in vitro studies to gain insights into age-dependent changes in acute inflammation in response to bacterial endotoxin (LPS). Time-course cytokine, chemokine, and NO2
−/NO3
− data from “middle-aged” (6–8 months old) C57BL/6 mice were used to re-parameterize a mechanistic mathematical model of acute inflammation originally calibrated for “young” (2–3 months old) mice. These studies suggested that macrophages from middle-aged mice are more susceptible to cell death, as well as producing higher levels of pro-inflammatory cytokines, vs. macrophages from young mice. In support of the in silico-derived hypotheses, resident peritoneal cells from endotoxemic middle-aged mice exhibited reduced viability and produced elevated levels of TNF-α, IL-6, IL-10, and KC/CXCL1 as compared to cells from young mice. Our studies demonstrate the utility of a combined in silico, in vivo, and in vitro approach to the study of acute inflammation in shock states, and suggest hypotheses with regard to the changes in the cytokine milieu that accompany aging. 相似文献
253.
Lila Rami Patrick Auguste Noélie B. Thebaud Reine Bareille Richard Daculsi Jean Ripoche Laurence Bordenave 《PloS one》2013,8(11)
Shear stress is one of mechanical constraints which are exerted by blood flow on endothelial cells (ECs). To adapt to shear stress, ECs align in the direction of flow through adherens junction (AJ) remodeling. However, mechanisms regulating ECs alignment under shear stress are poorly understood. The scaffold protein IQ domain GTPase activating protein 1 (IQGAP1) is a scaffold protein which couples cell signaling to the actin and microtubule cytoskeletons and is involved in cell migration and adhesion. IQGAP1 also plays a role in AJ organization in epithelial cells. In this study, we investigated the potential IQGAP1 involvement in the endothelial cells alignment under shear stress. Progenitor-derived endothelial cells (PDECs), transfected (or not) with IQGAP1 small interfering RNA, were exposed to a laminar shear stress (1.2 N/m2) and AJ proteins (VE-cadherin and β-catenin) and IQGAP1 were labeled by immunofluorescence. We show that IQGAP1 is essential for ECs alignment under shear stress. We studied the role of IQGAP1 in AJs remodeling of PDECs exposed to shear stress by studying cell localization and IQGAP1 interactions with VE-cadherin and β-catenin by immunofluorescence and Proximity Ligation Assays. In static conditions, IQGAP1 interacts with VE-cadherin but not with β-catenin at the cell membrane. Under shear stress, IQGAP1 lost its interaction from VE-cadherin to β-catenin. This “switch” was concomitant with the loss of β-catenin/VE-cadherin interaction at the cell membrane. This work shows that IQGAP1 is essential to ECs alignment under shear stress and that AJ remodeling represents one of the mechanisms involved. These results provide a new approach to understand ECs alignment under to shear stress. 相似文献
254.
Convective respiratory flows in the pulmonary acinus and their influence on the fate of inhaled particles are typically studied using computational fluid dynamics (CFD) or scaled-up experimental models. However, experiments that replicate several generations of the acinar tree while featuring cyclic wall motion have not yet been realized. Moreover, current experiments generally capture only flow dynamics, without inhaled particle dynamics, due to difficulties in simultaneously matching flow and particle dynamics. In an effort to overcome these limitations, we introduce a novel microfluidic device mimicking acinar flow characteristics directly at the alveolar scale. The model features an anatomically-inspired geometry that expands and contracts periodically with five dichotomously branching airway generations lined with alveolar-like cavities. We use micro-particle image velocimetry with a glycerol solution as the carrying fluid to quantitatively characterize detailed flow patterns within the device and reveal experimentally for the first time a gradual transition of alveolar flow patterns along the acinar tree from recirculating to radial streamlines, in support of hypothesized predictions from past CFD simulations. The current measurements show that our microfluidic system captures the underlying characteristics of the acinar flow environment, including Reynolds and Womersley numbers as well as cyclic wall displacements and alveolar flow patterns at a realistic length scale. With the use of air as the carrying fluid, our miniaturized platform is anticipated to capture both particle and flow dynamics and serve in the near future as a promising in vitro tool for investigating the mechanisms of particle deposition deep in the lung. 相似文献
255.
Thiel C Kessler K Giessl A Dimmler A Shalev SA von der Haar S Zenker M Zahnleiter D Stöss H Beinder E Abou Jamra R Ekici AB Schröder-Kress N Aigner T Kirchner T Reis A Brandstätter JH Rauch A 《American journal of human genetics》2011,(1):634-114
Defects of ciliogenesis have been implicated in a wide range of human phenotypes and play a crucial role in signal transduction and cell-cycle coordination. We used homozygosity mapping in two families with autosomal-recessive short-rib polydactyly syndrome Majewski type to identify mutations in NEK1 as an underlying cause of this lethal osteochondrodysplasia. NEK1 encodes a serine/threonine kinase with proposed function in DNA double-strand repair, neuronal development, and coordination of cell-cycle-associated ciliogenesis. We found that absence of functional full-length NEK1 severely reduces cilia number and alters ciliar morphology in vivo. We further substantiate a proposed digenic diallelic inheritance of ciliopathies by the identification of heterozygous mutations in NEK1 and DYNC2H1 in an additional family. Notably, these findings not only increase the broad spectrum of ciliar disorders, but suggest a correlation between the degree of defective microtubule or centriole elongation and organization and the severity of the resulting phenotype. 相似文献
256.
We recently proposed to conduct selective glycosylation reactions after in situ activation of a glycosyl donor promoted by a transition metal complex immobilized in a macromolecular matrix. In order to develop this catalytic entity, a feasible multi gram-scale synthesis for 2,3,4,6-tetra-O-benzyl-d-galactothionolactam, its transformation into galactonoamidines with aromatic aglycon, and subsequent debenzylation conditions were developed. The potential for epimerization reactions at C-2 of the glycosidic ring during the transformations from the 2,3,4,6-tetra-O-benzyl-d-galactonolactam into the N-benzyl-2,3,4,6-tetra-O-benzyl-d-galactonoamidines via the 2,3,4,6-tetra-O-benzyl-d-galactothionolactam are discussed and additionally characterized by using density functional theory calculations. 相似文献
257.
Proliferating cell nuclear antigen is a novel inhibitory ligand for the natural cytotoxicity receptor NKp44 总被引:1,自引:0,他引:1
Rosental B Brusilovsky M Hadad U Oz D Appel MY Afergan F Yossef R Rosenberg LA Aharoni A Cerwenka A Campbell KS Braiman A Porgador A 《Journal of immunology (Baltimore, Md. : 1950)》2011,187(11):5693-5702
NK cells play an important role in the early immune response to cancer. The NKp44 activating receptor is the only natural cytotoxicity receptor that is expressed exclusively by primate NK cells, yet its cellular ligands remain largely unknown. Proliferating cell nuclear Ag (PCNA) is overexpressed in cancer cells. In this study, we show that the NKp44 receptor recognizes PCNA. Their interaction inhibits NK cell function through NKp44/ITIM. The physical interaction of NKp44 and PCNA is enabled by recruitment of target cell PCNA to the NK immunological synapse. We demonstrate that PCNA promotes cancer survival by immune evasion through inhibition of NKp44-mediated NK cell attack. 相似文献
258.
Bourhis E Wang W Tam C Hwang J Zhang Y Spittler D Huang OW Gong Y Estevez A Zilberleyb I Rouge L Chiu C Wu Y Costa M Hannoush RN Franke Y Cochran AG 《Structure (London, England : 1993)》2011,19(10):1433-1442
The Wnt pathway inhibitors DKK1 and sclerostin (SOST) are important therapeutic targets in diseases involving bone loss or damage. It has been appreciated that Wnt coreceptors LRP5/6 are also important, as human missense mutations that result in bone overgrowth (bone mineral density, or BMD, mutations) cluster to the E1 propeller domain of LRP5. Here, we report a crystal structure of LRP6 E1 bound to an antibody, revealing that the E1 domain is a peptide recognition module. Remarkably, the consensus E1 binding sequence is a close match to a conserved tripeptide motif present in all Wnt inhibitors that bind LRP5/6. We show that this motif is important for DKK1 and SOST binding to LRP6 and for inhibitory function, providing a detailed structural explanation for the effect of the BMD mutations. 相似文献
259.
Eugenio Gaudio Francesco Paduano Riccardo Spizzo Apollinaire Ngankeu Nicola Zanesi Marco Gaspari Francesco Ortuso Francesca Lovat Jonathan Rock Grace A. Hill Mohamed Kaou Giovanni Cuda Rami I. Aqeilan Stefano Alcaro Carlo M. Croce Francesco Trapasso 《PloS one》2013,8(11)
Fhit protein is lost or reduced in a large fraction of human tumors, and its restoration triggers apoptosis and suppresses tumor formation or progression in preclinical models. Here, we describe the identification of candidate Fhit-interacting proteins with cytosolic and plasma membrane localization. Among these, Annexin 4 (ANXA4) was validated by co-immunoprecipitation and confocal microscopy as a partner of this novel Fhit protein complex. Here we report that overexpression of Fhit prevents Annexin A4 translocation from cytosol to plasma membrane in A549 lung cancer cells treated with paclitaxel. Moreover, paclitaxel administration in combination with AdFHIT acts synergistically to increase the apoptotic rate of tumor cells both in vitro and in vivo experiments. 相似文献
260.
Gilbert ER Cox CM Williams PM McElroy AP Dalloul RA Ray WK Barri A Emmerson DA Wong EA Webb KE 《PloS one》2011,6(1):e14636