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Search Results: 1 - 10 of 461978 matches for " Nael A. McCarty "
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Functional Consequences of GPCR Heterodimerization: GPCRs as Allosteric Modulators
Karla K.V. Haack,Nael A. McCarty
Pharmaceuticals , 2011, DOI: 10.3390/ph4030509
Abstract: G Protein Coupled Receptors (GPCRs) represent the largest family of membrane proteins in the human genome, are the targets of approximately 25% of all marketed pharmaceuticals, and the focus of intensive research worldwide given that this superfamily of receptors is as varied in function as it is ubiquitously expressed among all cell types. Increasing evidence has shown that the classical two part model of GPCR signaling (one GPCR, one type of heterotrimeric G protein) is grossly oversimplified as many GPCRs can couple to more than one type of G protein, each subunit of the heterotrimeric G protein can activate different downstream effectors, and, surprisingly, other GPCRs can affect receptor behavior in G protein-independent ways. The concept of GPCR heterodimerization, or the physical association of two different types of GPCRs, presents an unexpected mechanism for GPCR regulation and function, and provides a novel target for pharmaceuticals. Here we present a synopsis of the functional consequences of GPCR heterodimerization in both in vitro and in vivo studies, focusing on the concept of GPCRs as allosteric modulators. Typically, an allosteric modulator is a ligand or molecule that alters a receptor’s innate functional properties, but here we propose that in the case of GPCR heterodimers, it is the physical coupling of two receptors that leads to changes in cognate receptor signaling.
Differential role of beta-arrestin ubiquitination in agonist-promoted down-regulation of M1 vs M2 muscarinic acetylcholine receptors
Valerie A Mosser, Kymry T Jones, Katie M Hoffman, Nael A McCarty, Darrell A Jackson
Journal of Molecular Signaling , 2008, DOI: 10.1186/1750-2187-3-20
Abstract: Herein we report that agonist activation of M1 mAChRs produces a sustained β-arrestin ubiquitination but no stable co-localization with β-arrestin. In contrast, sustained ubiquitination of β-arrestin by activation of M2 mAChRs does result in stable co-localization between the M2 mAChR and β-arrestin. Internalization of receptors was unaffected by proteasome inhibitors, but down-regulation was significantly reduced, suggesting a role for the ubiquitination machinery in promoting down-regulation of the receptors. Given the ubiquitination status of β-arrestin following agonist treatment, we sought to determine the effects of β-arrestin ubiquitination on M1 and M2 mAChR down-regulation. A constitutively ubiquitinated β-arrestin 2 chimera in which ubiquitin is fused to the C-terminus of β-arrestin 2 (YFP-β-arrestin 2-Ub) significantly increased agonist-promoted down-regulation of both M1 and M2 mAChRs, with the effect substantially higher on the M2 mAChR. Based on this observation, we were interested in examining the effects of disruption of potential ubiquitination sites in the β-arrestin sequence on receptor down-regulation. Agonist-promoted internalization of the M2 mAChR was not affected by expression of β-arrestin lysine mutants lacking putative ubiquitination sites, β-arrestin 2K18R, K107R, K108R, K207R, K296R, while down-regulation and stable co-localiztion of the receptor with this β-arrestin lysine mutant were significantly reduced. Interestingly, expression of β-arrestin 2K18R, K107R, K108R, K207R, K296R increased the agonist-promoted down-regulation of the M1 mAChR but did not result in a stable co-localiztion of the receptor with this β-arrestin lysine mutant.These findings indicate that ubiquitination of β-arrestin has a distinct role in the differential trafficking and degradation of M1 and M2 mAChRs.There are five subtypes of muscarinic acetylcholine receptors (M1 – M5 mAChR) with distinct yet overlapping tissue distributions. Muscarinic receptors regulate
Pyoverdine, the Major Siderophore in Pseudomonas aeruginosa, Evades NGAL Recognition
Mary E. Peek,Abhinav Bhatnagar,Nael A. McCarty,Susu M. Zughaier
Interdisciplinary Perspectives on Infectious Diseases , 2012, DOI: 10.1155/2012/843509
Abstract: Pseudomonas aeruginosa is the most common pathogen that persists in the cystic fibrosis lungs. Bacteria such as P. aeruginosa secrete siderophores (iron-chelating molecules) and the host limits bacterial growth by producing neutrophil-gelatinase-associated lipocalin (NGAL) that specifically scavenges bacterial siderophores, therefore preventing bacteria from establishing infection. P. aeruginosa produces a major siderophore known as pyoverdine, found to be important for bacterial virulence and biofilm development. We report that pyoverdine did not bind to NGAL, as measured by tryptophan fluorescence quenching, while enterobactin bound to NGAL effectively causing a strong response. The experimental data indicate that pyoverdine evades NGAL recognition. We then employed a molecular modeling approach to simulate the binding of pyoverdine to human NGAL using NGAL’s published crystal structures. The docking of pyoverdine to NGAL predicted nine different docking positions; however, neither apo- nor ferric forms of pyoverdine docked into the ligand-binding site in the calyx of NGAL where siderophores are known to bind. The molecular modeling results offer structural support that pyoverdine does not bind to NGAL, confirming the results obtained in the tryptophan quenching assay. The data suggest that pyoverdine is a stealth siderophore that evades NGAL recognition allowing P. aeruginosa to establish chronic infections in CF lungs. 1. Introduction Cystic fibrosis (CF) is an inherited disease resulting in the formation of thick, sticky mucus in the lungs and digestive pathways [1]. CF lungs are breeding grounds for a variety of bacterial pathogens. Pseudomonas aeruginosa is the most common bacterial isolate that persists in CF lungs by evading host defenses and clearance mechanisms, contributing to declining lung function [1, 2]. In order to grow and thrive, bacteria need iron as a cofactor for many metabolic enzymes. However, in the case of infection, iron is not freely available in the host and is predominantly found in iron-binding proteins such as transferrin, lactoferrin, and ferritin [3]. Thus, due to the low bioavailability of free iron, bacteria produce iron-chelating small molecules known as siderophores that are secreted in apo-form and imported as ferric complexes [1, 4]. P. aeruginosa produces two siderophores, pyoverdine (Figures 1(a), and 1(b)) and pyochelin, that are found to be important for biofilm development and bacterial virulence [4]. Figure 1: Molecular structures of ferric bacterial siderophores used in this study. (a) Chemical structure of
Relating the Disease Mutation Spectrum to the Evolution of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR)
Lavanya Rishishwar, Neha Varghese, Eishita Tyagi, Stephen C. Harvey, I. King Jordan, Nael A. McCarty
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0042336
Abstract: Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons) show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%), along with the best set of paired sensitivity (58%) and specificity (60%) values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly defining the set of target residues, resulting in a potential savings of both time and money.
Modeling the Conformational Changes Underlying Channel Opening in CFTR
Kazi S. Rahman, Guiying Cui, Stephen C. Harvey, Nael A. McCarty
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0074574
Abstract: Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Changes in side-chain interactions are observed in all major domains of the protein, and experimental confirmation was obtained for a novel intra-protein salt bridge that breaks near the end of the transition. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.
The Effect of Parent Material and Soil Development on Geochemical Characteristics of Forest Soils in Fuman-Masule Region
M. Nael1,A. Jalalian,H. Khademi,M. Kalbasi
Journal of Science and Technology of Agriculture and Natural Resources , 2011,
Abstract: Geologic and pedologic controls are the main factors determining the distribution of elements in natural soil environments. In order to assess the role of these factors in the content and distribution of major elements of soil, six parent materials including phyllite (Ph), tonalite (To), periditite (Pe), dolerite (Do), shale (Sh) and limestone (Li) were selected in Fuman-Masule region. Soil genesis and development of representive residual pedons were studied for each parent material. Total content of Si, Al, Ca, Mg, Fe, Mn, K, Na, Ti and P of soil horizons were measured and compared to the geochemical and mineralogical composition of parent materials. Maximum concentrations of Fe2O3 and MgO were found in the soils derived from Pe and Do; however, these soils had low content of SiO2 and Al2O3, which is in conformity with the geochemical composition of the parent rocks. On the contrary, FeCBD content of these soils was lowest, indicating the low degree of soil development and, by the same fact, the importance of inheritance factor in soil Fe concentration. However, comparison of total Fe and FeCBD in Li1, Sh2 and To2 revealed that relative development of these pedons is higher than the others. Silicon depletion in Ph1, To2 and Sh2 pedons, relative to parent rocks, is higher than in Pe and Do pedons. However, this element is enriched in Li pedons. MnO content of Pe and Do pedons is governed by geogenic factors, while in Sh pedons, pedogenic factors, especially redox conditions, play the major role. Exchangeable forms of Ca and Na are determined by soil properties rather than by parent material type. Notwithstanding the redistribution of all major elements throughout pedons due to soil forming processes, the importance of inheritance factor in soil Si, Al, Mg, Fe, K, and Ti is higher than pedogenic factors.
Effect of Geopedological Conditions on Content and Distribution of Selected Major and Trace Elements in Forest Soils of Fuman-Masule Region
M Nael,A Jalalian1,H Khademi,M Kalbasi
Journal of Science and Technology of Agriculture and Natural Resources , 2010,
Abstract: Geologic and pedologic controls are the main factors determining the behavior of elements in natural soil environments. In order to assess the role of these factors on content and distribution of selected major and trace elements in soil, six parent materials including: phyllite, tonalite, periditite, dolerite, shale and limestone were selected in Fuman-Masule region. Soil genesis and development of representive residual pedons were studied for each parent material and the total content of Si, Al, Ca, Mg, Fe, Ti, Mn, Ni, Co, Cr, Cu, Pb, V and Zn were compared among them. Enrichment/depletion patters of trace elements were assessed using Ti as reference element. Generally, Cr, Ni, Co and V are highest in soils derived from peridotite (984, 285, 53 and 204 mg/kg, respectively) and dolerite (1023, 176, 39 and 185 mg/kg, respectively). In the same way, Si and Al exhibit the features of parent materials in the sense that the lowest content was observed in soils developed on peridotite, dolerite and limestone. Zinc and Pb are highest in soils derived from shale (106 and 27 mg/kg, respectively). In a given pedon, different elements exhibited different enrichment/depletion patterns; moreover, a given element may behave differently not only in soils with different parent materials but also, in some cases, in soils developed on similar lithology. Lead, Zn, Cu and Mn have been generally enriched in most pedons, except in some acidic and strongly leached soils, whereas Co, Cr, Fe, Ni and V have been leached, especially from Dystrudepts and Eutrudepts. The latter elements, however, showed enrichment trend in Hapludalfs and Argiudolls parallel to the development of illuvial B horizons.
Engineering Ethics: A Critical Dimension of The Profession
Nael Barakat
International Journal of Engineering Pedagogy , 2011, DOI: 10.3991/ijep.v1i2.1639
Abstract: Engineering has always had a massive impact on human health and welfare. Unfortunately, the public only realizes the magnitude of this impact when very few engineering disasters occur, like huge oil spells in the sea or the failure of an aero-plane or a building. This is in spite of the plethora of engineering systems working perfectly around the clock to enhance every miniature aspect of public health and welfare. The ethical dimension of the engineering profession deals with the interaction with the public. However, engineering ethics are critical for reasons beyond keeping out of legal trouble and guarding the health and safety of humans. Ethics are necessary for the survival and continuity of the profession itself, amongst other reasons. Therefore, engineering codes of ethics have been set by professional societies and engineering ethics have been emphasized by accreditation organizations to be an integral part of the engineering curricula. In addition, ethics is the framework that allows the handling of evolving issues related to the profession of engineering. Examples of these issues include the globalization of the practice, continuous professional development (CPD) of the practitioners, and issues of emerging technologies (e.g. nanotechnology). In the midst of this huge dimension, the engineering instructor is challenged to incorporate engineering ethics in a packed curriculum. This paper will provide a quick overview of the basic concepts and definitions of engineering ethics as well as the importance of studying engineering ethics. Some recent engineering ethics challenges will be listed with focus on globalization, its influence on the professional and ethical side of the profession, and the perspective of the educator. Moreover, some suggested strategies and best practices to integrate engineering ethics in the curriculum will be discussed.
A Simple Exercise-to-Play Proposal that would Reduce Games Addiction and Keep Players Healthy
Nael Hirzallah
International Journal of Advanced Computer Sciences and Applications , 2013,
Abstract: Games players usually get addicted to video games in general and more specifically to those that are usually played over the internet. These players prefer to stay at home and play games rather than playing sports or outdoor games. This paper presents a proposal that aims to implement a simple way to let video games players exercise in order to play. The proposal targets games where players virtually live inside a certain area such as a forest, city or a war zone. Their aim is to explore the area, capture, kill and avoid being killed by something or someone. A costumed built treadmill acting as a movement capture device is proposed to capture players’ commands for movements. These movements include Running, walking, Stopping, and Turning. In that way, the players enjoy exercising as well as playing the game. However, sooner or later, the players get exhausted driving them to exit the game. That way, we believe that such a proposal would keep players healthy, and reduce the chance of addiction.
A Real-Time Method to Select and Prioritize Frames of a News Program
Nael Hirzallah
International Journal of ACM Jordan , 2010,
Abstract: This paper presents a system that willautomatically recognize the video frames during thebroadcast a typical news program. Such frames representusually images of anchorpersons, guest speakers,commercials and key news images. The system also workson prioritizing the news images per news story, in anattempt to generate an attractive and easy to read pictorialtranscript. The system focuses on selecting the proper keyframesfrom every news clip avoiding selecting imagesfrom commercials. It also works on recognizing theanchorperson image, and distinguishing it from imagesthat belong to guest speakers. The outcome of this systemis a pictorial transcript that is friendly and easy to read,index, and understand, especially when marking newsimages by their importance within each news story.
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