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101.
102.
Hui Huang Michael P. Winters Sanath K. Meegalla Eric Arnoult S. Paul Lee Shuyuan Zhao Tonya Martin Brian Rady Jianying Liu Meghan Towers Monicah Otieno Fran Xu Heng Keang Lim Jose Silva Alessandro Pocai Mark R. Player 《Bioorganic & medicinal chemistry letters》2018,28(3):429-436
GPR40 partial agonism is a promising new mechanism for the treatment of type 2 diabetes mellitus with clinical proof of concept. Most of the GPR40 agonists in the literature have a carboxylic acid functional group, which may pose a risk for idiosyncratic drug toxicity. A novel series of GPR40 agonists containing a tetrazole as a carboxylic acid bioisostere was identified. This series of compounds features a benzo[b]thiophene as the center ring, which is prone to oxidation during phase 1 metabolism. Following SAR optimization targeting GPR40 agonist activity and intrinsic clearance in microsomes (human and rat), potent and metabolically stable compounds were selected for in vivo evaluation. The compounds are efficacious at lowering blood glucose in a SD rat oGTT model. 相似文献
103.
Takao Hikita Fatemeh Mirzapourshafiyi Pedro Barbacena Meghan Riddell Ayesha Pasha Mengnan Li Takuji Kawamura Ralf P Brandes Tomonori Hirose Shigeo Ohno Holger Gerhardt Michiyuki Matsuda Claudio A Franco Masanori Nakayama 《EMBO reports》2018,19(9)
Impaired cell polarity is a hallmark of diseased tissue. In the cardiovascular system, laminar blood flow induces endothelial planar cell polarity, represented by elongated cell shape and asymmetric distribution of intracellular organelles along the axis of blood flow. Disrupted endothelial planar polarity is considered to be pro‐inflammatory, suggesting that the establishment of endothelial polarity elicits an anti‐inflammatory response. However, a causative relationship between polarity and inflammatory responses has not been firmly established. Here, we find that a cell polarity protein, PAR‐3, is an essential gatekeeper of GSK3β activity in response to laminar blood flow. We show that flow‐induced spatial distribution of PAR‐3/aPKCλ and aPKCλ/GSK3β complexes controls local GSK3β activity and thereby regulates endothelial planar polarity. The spatial information for GSK3β activation is essential for flow‐dependent polarity to the flow axis, but is not necessary for flow‐induced anti‐inflammatory response. Our results shed light on a novel relationship between endothelial polarity and vascular homeostasis highlighting avenues for novel therapeutic strategies. 相似文献
104.
105.
Elisabet Bjanes Reyna Garcia Sillas Rina Matsuda Benjamin Demarco Timothe Fettrelet Alexandra A. DeLaney Opher S. Kornfeld Bettina L. Lee Eric M. Rodríguez Lpez Daniel Grubaugh Meghan A. Wynosky-Dolfi Naomi H. Philip Elise Krespan Dorothy Tovar Leonel Joannas Daniel P. Beiting Jorge Henao-Mejia Brian C. Schaefer Kaiwen W. Chen Petr Broz Igor E. Brodsky 《PLoS pathogens》2021,17(10)
Cell death plays a critical role in inflammatory responses. During pyroptosis, inflammatory caspases cleave Gasdermin D (GSDMD) to release an N-terminal fragment that generates plasma membrane pores that mediate cell lysis and IL-1 cytokine release. Terminal cell lysis and IL-1β release following caspase activation can be uncoupled in certain cell types or in response to particular stimuli, a state termed hyperactivation. However, the factors and mechanisms that regulate terminal cell lysis downstream of GSDMD cleavage remain poorly understood. In the course of studies to define regulation of pyroptosis during Yersinia infection, we identified a line of Card19-deficient mice (Card19lxcn) whose macrophages were protected from cell lysis and showed reduced apoptosis and pyroptosis, yet had wild-type levels of caspase activation, IL-1 secretion, and GSDMD cleavage. Unexpectedly, CARD19, a mitochondrial CARD-containing protein, was not directly responsible for this, as an independently-generated CRISPR/Cas9 Card19 knockout mouse line (Card19Null) showed no defect in macrophage cell lysis. Notably, Card19 is located on chromosome 13, immediately adjacent to Ninj1, which was recently found to regulate cell lysis downstream of GSDMD activation. RNA-seq and western blotting revealed that Card19lxcn BMDMs have significantly reduced NINJ1 expression, and reconstitution of Ninj1 in Card19lxcn immortalized BMDMs restored their ability to undergo cell lysis in response to caspase-dependent cell death stimuli. Card19lxcn mice exhibited increased susceptibility to Yersinia infection, whereas independently-generated Card19Null mice did not, demonstrating that cell lysis itself plays a key role in protection against bacterial infection, and that the increased infection susceptibility of Card19lxcn mice is attributable to loss of NINJ1. Our findings identify genetic targeting of Card19 being responsible for off-target effects on the adjacent gene Ninj1, disrupting the ability of macrophages to undergo plasma membrane rupture downstream of gasdermin cleavage and impacting host survival and bacterial control during Yersinia infection. 相似文献
106.
107.
Honoree Fleming Rebekah Condon Genevieve Peterson Ilse Guck Elizabeth Prescott Kathryn Chatfield Meghan Duff 《Journal of cellular biochemistry》1998,71(3):400-415
Human Ishikawa endometrial cells form domes when confluent monolayers are stimulated with fresh fetal bovine serum. Extensive structural and biochemical changes have been detected during the approximately 30 h differentiation period. The earliest detectable change involves the formation of multinucleated structures and the appearance of “granules” that stain for biotin within those structures. Nuclei become associated with each other and are ultimately enclosed within a biotin-containing membrane. Aggregated membrane-sheathed nuclei and the cells containing them begin to elevate from the dish as biotin staining becomes apparent in apical membranes. The elevated structures are called predomes and consist of one or more very large cells containing the sheathed nuclei. Apical membranes of these unusual cells extend far out into the medium in structures that resemble endometrial pinopods. A lumen under the elevated cells fills with transcytosed fluid. As differentiation proceeds, highly concentrated chromatin material that was flattened against apical and lateral membranes of the predome cells begins to disperse. Small mononuclear cells evolve from larger predome cells. Apical membranes of predome and dome cells continue to stain for biotin. Gel electrophoresis of SDS-solubilized biotin-containing membranes, followed by Western blot analysis using avidin-linked peroxidase, resulted in three stained bands with molecular weights similar to those of the mitochondrial carboxylases: propionyl carboxylase, methylmalonyl carboxylase, and pyruvate carboxylase. J. Cell. Biochem. 71:400–415, 1998. © 1998 Wiley-Liss, Inc. 相似文献
108.
Nina Wale Rebecca C. Fuller Snke Johnsen McKenna L. Turrill Meghan. A. Duffy 《Ecology and evolution》2021,11(24):18591
Predators can strongly influence disease transmission and evolution, particularly when they prey selectively on infected hosts. Although selective predation has been observed in numerous systems, why predators select infected prey remains poorly understood. Here, we use a mathematical model of predator vision to test a long‐standing hypothesis about the mechanistic basis of selective predation in a Daphnia–microparasite system, which serves as a model for the ecology and evolution of infectious diseases. Bluegill sunfish feed selectively on Daphnia infected by a variety of parasites, particularly in water uncolored by dissolved organic carbon. The leading hypothesis for selective predation in this system is that infection‐induced changes in the transparency of Daphnia render them more visible to bluegill. Rigorously evaluating this hypothesis requires that we quantify the effect of infection on the visibility of prey from the predator''s perspective, rather than our own. Using a model of the bluegill visual system, we show that three common parasites, Metschnikowia bicuspidata, Pasteuria ramosa, and Spirobacillus cienkowskii, decrease the transparency of Daphnia, rendering infected Daphnia darker against a background of bright downwelling light. As a result of this increased brightness contrast, bluegill can see infected Daphnia at greater distances than uninfected Daphnia—between 19% and 33% further, depending on the parasite. Pasteuria and Spirobacillus also increase the chromatic contrast of Daphnia. These findings lend support to the hypothesis that selective predation by fish on infected Daphnia could result from the effects of infection on Daphnia''s visibility. However, contrary to expectations, the visibility of Daphnia was not strongly impacted by water color in our model. Our work demonstrates that models of animal visual systems can be useful in understanding ecological interactions that impact disease transmission. 相似文献
109.
Meghan E. Hall Nima Khadem Mohtaram Stephanie M. Willerth 《Journal of biological engineering》2017,11(1):38
Background
Human induced pluripotent stem cells (hiPSCs) can form any tissue found in the body, making them attractive for regenerative medicine applications. Seeding hiPSC aggregates into biomaterial scaffolds can control their differentiation into specific tissue types. Here we develop and analyze a mathematical model of hiPSC aggregate behavior when seeded on melt electrospun scaffolds with defined topography.Results
We used ordinary differential equations to model the different cellular populations (stem, progenitor, differentiated) present in our scaffolds based on experimental results and published literature. Our model successfully captures qualitative features of the cellular dynamics observed experimentally. We determined the optimal parameter sets to maximize specific cellular populations experimentally, showing that a physiologic oxygen level (~?5%) increases the number of neural progenitors and differentiated neurons compared to atmospheric oxygen levels (~?21%) and a scaffold porosity of ~?63% maximizes aggregate size.Conclusions
Our mathematical model determined the key factors controlling hiPSC behavior on melt electrospun scaffolds, enabling optimization of experimental parameters.110.