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Search Results: 1 - 10 of 406094 matches for " Douglas M. Cyr "
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The role of the UPS in cystic fibrosis
Turnbull Emma L,Rosser Meredith FN,Cyr Douglas M
BMC Biochemistry , 2007, DOI: 10.1186/1471-2091-8-s1-s11
Abstract: CF is an inherited autosomal recessive disease whose lethality arises from malfunction of CFTR, a single chloride (Cl-) ion channel protein. CF patients harbor mutations in the CFTR gene that lead to misfolding of the resulting CFTR protein, rendering it inactive and mislocalized. Hundreds of CF-related mutations have been identified, many of which abrogate CFTR folding in the endoplasmic reticulum (ER). More than 70% of patients harbor the ΔF508 CFTR mutation that causes misfolding of the CFTR proteins. Consequently, mutant CFTR is unable to reach the apical plasma membrane of epithelial cells that line the lungs and gut, and is instead targeted for degradation by the UPS. Proteins located in both the cytoplasm and ER membrane are believed to identify misfolded CFTR for UPS-mediated degradation. The aberrantly folded CFTR protein then undergoes polyubiquitylation, carried out by an E1-E2-E3 ubiquitin ligase system, leading to degradation by the 26S proteasome. This ubiquitin-dependent loss of misfolded CFTR protein can be inhibited by the application of ‘corrector’ drugs that aid CFTR folding, shielding it from the UPS machinery. Corrector molecules elevate cellular CFTR protein levels by protecting the protein from degradation and aiding folding, promoting its maturation and localization to the apical plasma membrane. Combinatory application of corrector drugs with activator molecules that enhance CFTR Cl- ion channel activity offers significant potential for treatment of CF patients. Publication history: Republished from Current BioData's Targeted Proteins database (TPdb; http://www.targetedproteinsdb.com).
Central domain deletions affect the SAXS solution structure and function of Yeast Hsp40 proteins Sis1 and Ydj1
Julio C Silva, Julio C Borges, Douglas M Cyr, Carlos HI Ramos, Iris L Torriani
BMC Structural Biology , 2011, DOI: 10.1186/1472-6807-11-40
Abstract: To investigate the relevance of central domains on the structure and function of Ydj1 and Sis1 we prepared Sis1 constructs deleting specific domains. The mutants had decreased affinity for heated luciferase but were equally capable of stimulating ATPase activity of Hsp70. Detailed low resolution structures were obtained and the overall flexibility of Hsp40 and its mutants were assessed using SAXS methods. Deletion of either the G/M or the G/M plus CTDI domains had little impact on the quaternary structure of Sis1 analyzed by the SAXS technique. However, deletion of the ZFLR-CTDI changed the relative position of the J-domains in Ydj1 in such a way that they ended up resembling that of Sis1. The results revealed that the G/F and G/M regions are not the only flexible domains. All model structures exhibit a common clamp-like conformation.Our results suggest that the central domains, previously appointed as important features for substrate binding, are also relevant keeping the J-domains in their specific relative positions. The clamp-like architecture observed seems also to be favorable to the interactions of Hsp40 with Hsp70.Molecular chaperones are proteins that are involved in assisting the folding and assembly of newly synthesized proteins recognizing non-native substrate proteins predominantly via their exposed hydrophobic residues [1]. However, the conditions for the successful folding in vivo are not always favorable. The cellular environment is crowded and thus protein denaturation and aggregation will be major problems. Thus, there is the need for chaperones that also protect cells from elevated temperature or other cellular stress situations, to achieve successful folding of proteins in vivo. There are several families of Heat Shock Proteins (HSPs), each family acts to assist protein folding in a different way.An important chaperone family is the 40-kDa Heat shock protein (Hsp40). Chaperones from the Hsp40/DnaJ family play important roles in cells by working t
The Type II Hsp40 Sis1 Cooperates with Hsp70 and the E3 Ligase Ubr1 to Promote Degradation of Terminally Misfolded Cytosolic Protein
Daniel W. Summers, Katie J. Wolfe, Hong Yu Ren, Douglas M. Cyr
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0052099
Abstract: Mechanisms for cooperation between the cytosolic Hsp70 system and the ubiquitin proteasome system during protein triage are not clear. Herein, we identify new mechanisms for selection of misfolded cytosolic proteins for degradation via defining functional interactions between specific cytosolic Hsp70/Hsp40 pairs and quality control ubiquitin ligases. These studies revolved around the use of S. cerevisiae to elucidate the degradation pathway of a terminally misfolded reporter protein, short-lived GFP (slGFP). The Type I Hsp40 Ydj1 acts with Hsp70 to suppress slGFP aggregation. In contrast, the Type II Hsp40 Sis1 is required for proteasomal degradation of slGFP. Sis1 and Hsp70 operate sequentially with the quality control E3 ubiquitin ligase Ubr1 to target slGFP for degradation. Compromise of Sis1 or Ubr1 function leads slGFP to accumulate in a Triton X-100-soluble state with slGFP degradation intermediates being concentrated into perinuclear and peripheral puncta. Interestingly, when Sis1 activity is low the slGFP that is concentrated into puncta can be liberated from puncta and subsequently degraded. Conversely, in the absence of Ubr1, slGFP and the puncta that contain slGFP are relatively stable. Ubr1 mediates proteasomal degradation of slGFP that is released from cytosolic protein handling centers. Pathways for proteasomal degradation of misfolded cytosolic proteins involve functional interplay between Type II Hsp40/Hsp70 chaperone pairs, PQC E3 ligases, and storage depots for misfolded proteins.
Polyglutamine-Rich Suppressors of Huntingtin Toxicity Act Upstream of Hsp70 and Sti1 in Spatial Quality Control of Amyloid-Like Proteins
Katie J. Wolfe, Hong Yu Ren, Philipp Trepte, Douglas M. Cyr
PLOS ONE , 2014, DOI: 10.1371/journal.pone.0095914
Abstract: Protein conformational maladies such as Huntington Disease are characterized by accumulation of intracellular and extracellular protein inclusions containing amyloid-like proteins. There is an inverse correlation between proteotoxicity and aggregation, so facilitated protein aggregation appears cytoprotective. To define mechanisms for protective protein aggregation, a screen for suppressors of nuclear huntingtin (Htt103Q) toxicity was conducted. Nuclear Htt103Q is highly toxic and less aggregation prone than its cytosolic form, so we identified suppressors of cytotoxicity caused by Htt103Q tagged with a nuclear localization signal (NLS). High copy suppressors of Htt103Q-NLS toxicity include the polyQ-domain containing proteins Nab3, Pop2, and Cbk1, and each suppresses Htt toxicity via a different mechanism. Htt103Q-NLS appears to inactivate the essential functions of Nab3 in RNA processing in the nucleus. Function of Pop2 and Cbk1 is not impaired by nuclear Htt103Q, as their respective polyQ-rich domains are sufficient to suppress Htt103Q toxicity. Pop2 is a subunit of an RNA processing complex and is localized throughout the cytoplasm. Expression of just the Pop2 polyQ domain and an adjacent proline-rich stretch is sufficient to suppress Htt103Q toxicity. The proline-rich domain in Pop2 resembles an aggresome targeting signal, so Pop2 may act in trans to positively impact spatial quality control of Htt103Q. Cbk1 accumulates in discrete perinuclear foci and overexpression of the Cbk1 polyQ domain concentrates diffuse Htt103Q into these foci, which correlates with suppression of Htt toxicity. Protective action of Pop2 and Cbk1 in spatial quality control is dependent upon the Hsp70 co-chaperone Sti1, which packages amyloid-like proteins into benign foci. Protein:protein interactions between Htt103Q and its intracellular neighbors lead to toxic and protective outcomes. A subset of polyQ-rich proteins buffer amyloid toxicity by funneling toxic aggregation intermediates to the Hsp70/Sti1 system for spatial organization into benign species.
Identification of Regions Involved in Substrate Binding and Dimer Stabilization within the Central Domains of Yeast Hsp40 Sis1
Júlio C. Borges, Thiago V. Seraphim, David Z. Mokry, Fabio C. L. Almeida, Douglas M. Cyr, Carlos H. I. Ramos
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0050927
Abstract: Protein folding, refolding and degradation are essential for cellular life and are regulated by protein homeostatic processes such those that involve the molecular chaperone DnaK/Hsp70 and its co-chaperone DnaJ. Hsp70 action is initiated when proteins from the DnaJ family bind an unfolded protein for delivery purposes. In eukaryotes, the DnaJ family can be divided into two main groups, Type I and Type II, represented by yeast cytosolic Ydj1 and Sis1, respectively. Although sharing some unique features both members of the DnaJ family, Ydj1 and Sis1 are structurally and functionally distinct as deemed by previous studies, including the observation that their central domains carry the structural and functional information even in switched chimeras. In this study, we combined several biophysical tools for evaluating the stability of Sis1 and mutants that had the central domains (named Gly/Met rich domain and C-terminal Domain I) deleted or switched to those of Ydj1 to gain insight into the role of these regions in the structure and function of Sis1. The mutants retained some functions similar to full length wild-type Sis1, however they were defective in others. We found that: 1) Sis1 unfolds in at least two steps as follows: folded dimer to partially folded monomer and then to an unfolded monomer. 2) The Gly/Met rich domain had intrinsically disordered characteristics and its deletion had no effect on the conformational stability of the protein. 3) The deletion of the C-terminal Domain I perturbed the stability of the dimer. 4) Exchanging the central domains perturbed the conformational stability of the protein. Altogether, our results suggest the existence of two similar subdomains in the C-terminal domain of DnaJ that could be important for stabilizing each other in order to maintain a folded substrate-binding site as well as the dimeric state of the protein.
Dermal benefits of topical D-ribose
Linda M Shecterle, John A St. Cyr
Clinical, Cosmetic and Investigational Dermatology , 2009, DOI: http://dx.doi.org/10.2147/CCID.S7487
Abstract: mal benefits of topical D-ribose Commentary (6786) Total Article Views Authors: Linda M Shecterle, John A St. Cyr Published Date September 2009 Volume 2009:2 Pages 151 - 152 DOI: http://dx.doi.org/10.2147/CCID.S7487 Linda M Shecterle, John A St. Cyr Jacqmar, Inc., Minneapolis, MN, USA Abstract: Our aging skin undergoes changes with reductions in collagenous and elastic fibers, fibroblasts, mast cells, and macrophages with free radical production, which can result in reduced skin tone and wrinkle formation. Fibroblasts are important for dermal integrity and function with a decrease in function producing less skin tone, thinning, and wrinkle formation. Dermal levels of adenosine triphosphate (ATP) decline with aging, potentially altering dermal function. Supplemental D-ribose, a natural occurring carbohydrate, enhances ATP regeneration. D-ribosebased studies demonstrated benefits in both cell culture fibroblastic activities and a subsequent clinical study in women with decreased skin tone with wrinkles. Supplemental D-ribose may offer this needed cellular benefit.
Dermal benefits of topical D-ribose
Linda M Shecterle,John A St. Cyr
Clinical, Cosmetic and Investigational Dermatology , 2009,
Abstract: Linda M Shecterle, John A St. CyrJacqmar, Inc., Minneapolis, MN, USAAbstract: Our aging skin undergoes changes with reductions in collagenous and elastic fibers, fibroblasts, mast cells, and macrophages with free radical production, which can result in reduced skin tone and wrinkle formation. Fibroblasts are important for dermal integrity and function with a decrease in function producing less skin tone, thinning, and wrinkle formation. Dermal levels of adenosine triphosphate (ATP) decline with aging, potentially altering dermal function. Supplemental D-ribose, a natural occurring carbohydrate, enhances ATP regeneration. D-ribosebased studies demonstrated benefits in both cell culture fibroblastic activities and a subsequent clinical study in women with decreased skin tone with wrinkles. Supplemental D-ribose may offer this needed cellular benefit.Keywords: dermal, fibroblast, ATP, aging, wrinkles
Use of metakaolin in grouts intended for soil nailing
Trinh M.,Cyr M.,Husson B.,Casaux-Ginestet G.
MATEC Web of Conferences , 2012, DOI: 10.1051/matecconf/20120202002
Abstract: The aim of this work was to carry out a feasibility study to evaluate the pertinence of using metakaolin in grout intended for soil nailing. After a first step of grout optimisation based on technical and environmental constraints, an in-situ study was performed to evaluate the compatibility of metakaolin with this kind of application. This part highlights the minimum performance levels necessary if grout is to fulfil its role of transferring stresses between soil and nail.
Etude de l’activité pouzzolanique d’une roche andésitique en Algérie Study of the pozzolanic activity of an andesitic rock in Algeria
Hamidi M.,Kacimi L.,Cyr M.,Clastres P.
MATEC Web of Conferences , 2012, DOI: 10.1051/matecconf/20120201007
Abstract: Ce travail s’inscrit dans le cadre de l’accord programme Tassili N° 09 MDU 773 entre le Laboratoire de Physicochimie des Matériaux, USTO-Oran et le Laboratoire des Matériaux et Durabilité des Constructions (LMDC), INSA-UPS-Toulouse, France. La présente étude est une contribution aux travaux de la recherche de nouvelles sources d’approvisionnement en ajouts et en matières premières et la valorisation des matériaux naturels locaux utilisés dans la fabrication du ciment. Cette étude porte sur l’activité pouzzolanique des roches volcaniques, elle a pour but de comparer les caractéristiques physiques et mécaniques d’un mortier témoin à ciment de type CEMI 52,5R fourni par la firme Lafarge et d’un mortier à ciment du même type avec ajout dont les taux de substitution de la roche Andésitique est de 0- 40%. Dans notre travail, nous avons utilisé des roches volcaniques appartenant à la famille des Andésites, provenant de la région de Tipaza, Nord Ouest Algérois. L’étude des caractéristiques mécaniques et de l’indice de pouzzolanicité ont montré que les ciments fabriqués sont capables de remplacer certains ciments Portland pour une éventuelle utilisation dans le domaine de construction. This work is a part of the agreement programs Tassili N° 09 MDU 773 between Laboratory of Physic-chemistry Materials, USTO-Oran and Laboratory of Materials and Durability of Constructions (LMDC), INSA-UPS-Toulouse, France. The present study is an attempt to the research of new supply sources in admixtures and raw materials and the evaluation of local natural materials used in the manufacture of cement. It deals with the pozzolanic activity of the volcanic rocks and aims to compare the physical and mechanical characteristics of a mortar control made with cement CEMI 52,5R provided by Lafarge firm and of a mortar made with the same cement incorporated by different replacement rate of andesitic rock in a range of 0 – 40%. Volcanic rocks belonging to andesitic family and provided from Tipaza region (Western North of Algiers) were used in this study. The results found have shown that the cement made with andesitic rock may replace some Portland cements for a possible use in the field of construction.
Heroism and Risk of Harm  [PDF]
Douglas M. Stenstrom, Mathew Curtis
Psychology (PSYCH) , 2012, DOI: 10.4236/psych.2012.312A160
Abstract:

Although the positive traits and qualities that compose heroism such as courage, bravery and empathy have received research support, little experimental research has directly investigated the perception of heroic acts. The primary purpose of the current research was to address this gap in the literature by investigating a basic question about a central defining feature of heroism, namely the risk of potential harm. A related objective was investigating how implicit theories of personality and moral character influence perceptions of heroism, particularly as it relates to risk of harm. Results revealed how incrementally escalating the level of risk to the actor can transform an otherwise prosocial behavior into heroism through separating altruism from heroism. Implicit theories impacted perceptions of heroism consistent with the theorizing behind entity/incremental orientations, and produced an interactive effect with the situational manipulation through information about the particular level of risk differentially affecting entity and incremental belief systems.

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