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Alberto Marzo Pankaj Singh Philippe Reymond Nikos Stergiopulos Umang Patel Rodney Hose 《Computer methods in biomechanics and biomedical engineering》2013,16(4):431-444
Haemodynamics is believed to play an important role in the initiation, growth and rupture of intracranial aneurysms. In this context, computational haemodynamics has been extensively used in an effort to establish correlations between flow variables and clinical outcome. It is common practice in the application of Dirichlet boundary conditions at domain inlets to specify transient velocities as either a flat (plug) profile or a spatially developed profile based on Womersley's analytical solution. This paper provides comparative haemodynamics measures for three typical cerebral aneurysms. Three dimentional rotational angiography images of aneurysms at three common locations, viz. basilar artery tip, internal carotid artery and middle cerebral artery were obtained. The computational tools being developed in the European project @neurIST were used to reconstruct the fluid domains and solve the unsteady Navier–Stokes equations, using in turn Womersley and plug-flow inlet velocity profiles. The effects of these assumptions were analysed and compared in terms of relevant haemodynamic variables within the aneurismal sac. For the aneurysm at the basilar tip geometries with different extensions of the afferent vasculature were considered to study the plausibility of a fully-developed axial flow at the inlet boundaries. The study shows that assumptions made on the velocity profile while specifying inlet boundary conditions have little influence on the local haemodynamics in the aneurysm, provided that a sufficient extension of the afferent vasculature is considered and that geometry is the primary determinant of the flow field within the aneurismal sac. For real geometries the Womersley profile is at best an unnecessary over-complication, and may even be worse than the plug profile in some anatomical locations (e.g. basilar confluence). 相似文献
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Emmanuel S. Buys Yu-Chieh Ko Clemens Alt Sarah R. Hayton Alexander Jones Laurel T. Tainsh Ruiyi Ren Andrea Giani Maeva Clerté Emma Abernathy Robert E. T. Tainsh Dong-Jin Oh Rajeev Malhotra Pankaj Arora Nadine de Waard Binglan Yu Raphael Turcotte Daniel Nathan Marielle Scherrer-Crosbie Stephanie J. Loomis Jae H. Kang Charles P. Lin Haiyan Gong Douglas J. Rhee Peter Brouckaert Janey L. Wiggs Meredith S. Gregory Louis R. Pasquale Kenneth D. Bloch Bruce R. Ksander 《PloS one》2013,8(3)
Primary open angle glaucoma (POAG) is a leading cause of blindness worldwide. The molecular signaling involved in the pathogenesis of POAG remains unknown. Here, we report that mice lacking the α1 subunit of the nitric oxide receptor soluble guanylate cyclase represent a novel and translatable animal model of POAG, characterized by thinning of the retinal nerve fiber layer and loss of optic nerve axons in the context of an open iridocorneal angle. The optic neuropathy associated with soluble guanylate cyclase α1–deficiency was accompanied by modestly increased intraocular pressure and retinal vascular dysfunction. Moreover, data from a candidate gene association study suggests that a variant in the locus containing the genes encoding for the α1 and β1 subunits of soluble guanylate cyclase is associated with POAG in patients presenting with initial paracentral vision loss, a disease subtype thought to be associated with vascular dysregulation. These findings provide new insights into the pathogenesis and genetics of POAG and suggest new therapeutic strategies for POAG. 相似文献
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Vivek Malhotra 《The EMBO journal》2013,32(12):1660-1664
The process by which proteins are secreted without entering the classical endoplasmic reticulum (ER)–Golgi complex pathway, in eukaryotic cells, is conveniently called unconventional protein secretion. Recent studies on one such protein called Acb1 have revealed a number of components involved in its secretion. Interestingly, conditions that promote the secretion of Acb1 trigger the biogenesis of a new compartment called CUPS (Compartment for Unconventional Protein Secretion). CUPS form near the ER exit site but lack ER‐specific proteins. Other proteins that share some of the features common with the secretion of Acb1 are interleukin‐1β and tissue transglutaminase. Here I will review recent advances made in the field and propose a new model for unconventional protein secretion. 相似文献
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Yogavel Manickam Nipun Malhotra Siddhartha Mishra Palak Babbar Abhishek Dusane Benoît Laleu Valeria Bellini Mohamed-Ali Hakimi Alexandre Bougdour Amit Sharma 《PLoS pathogens》2022,18(3)
Toxoplasmosis is caused by Toxoplasma gondii and in immunocompromised patients it may lead to seizures, encephalitis or death. The conserved enzyme prolyl-tRNA synthetase (PRS) is a validated druggable target in Toxoplasma gondii but the traditional ‘single target–single drug’ approach has its caveats. Here, we describe two potent inhibitors namely halofuginone (HFG) and a novel ATP mimetic (L95) that bind to Toxoplasma gondii PRS simultaneously at different neighbouring sites to cover all three of the enzyme substrate subsites. HFG and L95 act as one triple-site inhibitor in tandem and form an unusual ternary complex wherein HFG occupies the 3’-end of tRNA and the L-proline (L-pro) binding sites while L95 occupies the ATP pocket. These inhibitors exhibit nanomolar IC50 and EC50 values independently, and when given together reveal an additive mode of action in parasite inhibition assays. This work validates a novel approach and lays a structural framework for further drug development based on simultaneous targeting of multiple pockets to inhibit druggable proteins. 相似文献
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Golgi membranes remain segregated from the endoplasmic reticulum during mitosis in mammalian cells 总被引:8,自引:0,他引:8
What happens to organelles during mitosis, and how they are apportioned to each of the daughter cells, is not completely clear. We have devised a procedure to address whether Golgi membranes fuse with the Endoplasmic Reticulum (ER) during mitosis via the detection of interactions between ER and Golgi proteins. This procedure involves coexpressing an FKBP-tagged Golgi enzyme with an ER-retained protein fused to FRAP in COS cells. Since treatment with rapamycin induces a tight association between FKBP and FRAP, one would expect rapamycin to trap the FKBP-fused Golgi protein in the ER if it ever visits the ER during mitosis. However, after the doubly transfected cells progress through mitosis in the presence of rapamycin, we find the Golgi protein in the newly formed Golgi stacks and not in the ER. Based on these results, we conclude that Golgi membranes remain separate from the ER during mitosis in mammalian cells. 相似文献