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Dalhousie University
1.
Gaston, Daniel.
PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2012, Dalhousie University
URL: http://hdl.handle.net/10222/14439 
► With rapid advances in sequencing technologies and precipitous decreases in cost, public sequence databases have increased in size apace. However, experimental characterization of novel genes…
(more)
▼ With rapid advances in sequencing technologies and
precipitous decreases in cost, public sequence databases have
increased in size apace. However, experimental characterization of
novel genes and their products remains prohibitively expensive and
time consuming. For these reasons, bioinformatics approaches have
become increasingly necessary to generate hypotheses of biological
function. Phylogenomic approaches use phylogenetic methods to place
genes, chromosomes, or whole genomes within the context of their
evolutionary history and can be used to predict the function of
encoded proteins. In this thesis, two new phylogenomic methods and
software implementations are presented that address the problems of
subcellular localization prediction and functional divergence
prediction within protein families respectively. Most of the widely
used programs for subcellular localization prediction have been
trained on model organisms and ignore phylogenetic information. As
a result, their predictions are not always reliable when applied to
phylogenetically divergent eukaryotes, such as unicellular
protists. To address this problem, PhyloPred-HMM, a novel
phylogenomic method was developed to predict sequences that are
targeted to mitochondria or mitochondrion-related organelles
(hydrogenosomes and mitosomes). This method was compared to
existing prediction methods using an existing test dataset of
mitochondrion-targeted sequences from well-studied groups,
sequences from a variety of protists, and the whole proteomes of
two protists: Tetrahymena thermophila and Trichomonas vaginalis.
PhyloPred-HMM performed comparably to existing classifiers on
mitochondrial sequences from well-studied groups such as animals,
plants, and Fungi and better than existing classifiers on diverse
protistan lineages. FunDi, a novel approach to the prediction of
functional divergence was developed and tested on 11 biological
datasets and two large simulated datasets. On the 11 biological
datasets, FunDi appeared to perform comparably to existing
programs, although performance measures were compromised by a lack
of experimental information. On the simulated datasets, FunDi was
clearly superior to existing methods. FunDi, and two other
prediction programs, was then used to characterize the functional
divergence in two groups of plastid-targeted
glyceraldehyde-3-phosphate dehydrogenases (GAPDH) adapted to roles
in the Calvin cycle. FunDi successfully identified functionally
divergent residues supported by experimental data, and identified
cases of potential convergent evolution between the two groups of
GAPDH sequences.
Advisors/Committee Members: Dr. Marc Robinson-Rechavi (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Christian Blouin (thesis-reader), Dr. Robert Beiko (thesis-reader), Dr. Edward Susko (thesis-reader), Dr. John Archibald (thesis-reader), Dr. Andrew J. Roger (thesis-supervisor), Not Applicable (ethics-approval), Yes (manuscripts), Yes (copyright-release).
Subjects/Keywords: phylogenomics; molecular evolution; functional divergence; subcellular localization prediction; phylogenetics
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APA (6th Edition):
Gaston, D. (2012). PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/14439
Chicago Manual of Style (16th Edition):
Gaston, Daniel. “PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION.” 2012. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/14439.
MLA Handbook (7th Edition):
Gaston, Daniel. “PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION.” 2012. Web. 07 Mar 2021.
Vancouver:
Gaston D. PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION. [Internet] [Doctoral dissertation]. Dalhousie University; 2012. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/14439.
Council of Science Editors:
Gaston D. PHYLOGENOMIC APPROACHES TO THE ANALYSIS OF FUNCTIONAL
DIVERGENCE AND SUBCELLULAR LOCALIZATION. [Doctoral Dissertation]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/14439
Dalhousie University
2.
Liu, Xinwei.
The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate.
Degree: MS, Department of Biochemistry & Molecular
Biology, 2014, Dalhousie University
URL: http://hdl.handle.net/10222/54063
► The oxysterol-binding protein OSBP-gene family is composed of 12 members with a common C-terminal sterol-binding domain (SBD). OSBP and ORP9 are members of the family…
(more)
▼ The oxysterol-binding protein OSBP-gene family is
composed of 12 members with a common C-terminal sterol-binding
domain (SBD). OSBP and ORP9 are members of the family that are
localized to the endoplasmic reticulum (ER) and Golgi apparatus by
their FFAT (two phenylalanines in an acidic tract) motif and PH
(pleckstrin homology) domain, respectively. These two proteins are
implicated in sterol transfer between these organelles. Here we
utilized Frster resonance energy transfer (FRET) between
cholestatrienol (CTL), a fluorescent cholesterol analog, and
dansyl-PE (DNS-PE) to demonstrate that both full-length ORP9L and
truncated ORP9S rapidly extract sterols from liposomes. In vitro,
OSBP, ORP9L and ORP9S specifically extracted phosphatidylinositol
4-phosphate (PI(4)P) from liposomes, suggesting PI(4)P is also a
ligand for these proteins. Overexpression of ORP9L or ORP9S
attenuated PI(4)P immunofluorescence detection in CHO cells. These
results indicate that OSBP and ORP9 may transport sterol and PI(4)P
in cells, possibly in opposite directions.
Advisors/Committee Members: N/A (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Roy Duncan, Dr. Roger McLeod, Dr. Catherine Too (thesis-reader), Dr. Neale Ridgway (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: Cholesterol; cholestatrienol; phosphatidylinositol
4-phosphate; oxysterol-binding protein (OSBP); oxysterol-binding
protein-related protein 9 (ORP9); sterol transport; Frster
resonance energy transfer (FRET)
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APA (6th Edition):
Liu, X. (2014). The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate. (Masters Thesis). Dalhousie University. Retrieved from http://hdl.handle.net/10222/54063
Chicago Manual of Style (16th Edition):
Liu, Xinwei. “The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate.” 2014. Masters Thesis, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/54063.
MLA Handbook (7th Edition):
Liu, Xinwei. “The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate.” 2014. Web. 07 Mar 2021.
Vancouver:
Liu X. The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate. [Internet] [Masters thesis]. Dalhousie University; 2014. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/54063.
Council of Science Editors:
Liu X. The study on oxysterol-binding protein (OSBP) and related
protein 9 (ORP9) ligands: sterols and phosphatidylinositol
4-phosphate. [Masters Thesis]. Dalhousie University; 2014. Available from: http://hdl.handle.net/10222/54063
Dalhousie University
3.
Mitchell, Patricia.
BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2010, Dalhousie University
URL: http://hdl.handle.net/10222/13026
► Diet plays an important role in the development of chronic metabolic diseases (diabetes, obesity, cardiovascular disease) and as dietary fat consumption has increased, so has…
(more)
▼ Diet plays an important role in the development of
chronic metabolic diseases (diabetes, obesity, cardiovascular
disease) and as dietary fat consumption has increased, so has the
incidence of these disorders. Metabolic syndrome, a clustering of
risk factors that includes central obesity, increased plasma
triacylglycerol (TG), elevated fasting glucose and glucose
intolerance is perhaps the most notorious and aggressive. Animal
and human studies indicate that bioactive fatty acids can influence
cellular energy metabolism. Using susceptible rodent models
(apoE-/- and LDLr-/- mice and Syrian Golden hamsters) this project
investigated whether supplementation of a western type diet (WD)
with bioactive fatty acids could improve hepatic lipid metabolism,
plasma lipoprotein profiles or liver markers of lipogenesis. In
mice, dietary supplementation with t-10, c-12 conjugated linoleic
acid (CLA) decreased the weight gain induced by high fat diet
compared with WD (p<0.01) and was accompanied by
hyperinsulinemia (p<0.05) in the ApoE-/- and hypoadiponectinemia
(p<0.01) in both mice strains. Although t-10, c-12 CLA
supplementation increased plasma lipids and was associated with
profound liver steatosis there was a reduction in atherosclerotic
lesions in both mouse models (p<0.05). Analysis of mRNA and
protein levels in the liver suggested that the differences in liver
and plasma lipids may reflect inappropriate lipogenic response to
t-10,c-12 CLA. In the high fat and fructose-fed hamster, the
modulating role of fish fatty acids was investigated. The addition
of DHA increased weight gain and adiposity compared to EPA and c-9,
t-11 CLA supplementation. However, glucose tolerance was improved
after 6 weeks of DHA supplementation (p? 0.01). Using
[35S]methionine radiolabelling, DHA supplementation decreased
apolipoprotein B100 synthesis and secretion. Newly synthesized
cellular and secreted TG, as measured by [3H]glycerol
incorporation, were also decreased with DHA supplementation.
Although the effects of EPA were similar to those with DHA, the
magnitude was generally lower. These results suggest that
supplementation with fish fatty acids can improve several of the
risk factors of the metabolic syndrome. Taken together, these
observations indicate that some, but not all, bioactive fatty acids
may be useful supplements for mediating cardiovascular risk
factors.
Advisors/Committee Members: Dr. Andrew Salter (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Barbara Karten (thesis-reader), Dr. Chris Sinal (thesis-reader), Dr. Hyo-Sung Ro (thesis-reader), Dr. Roger McLeod (thesis-supervisor), Received (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: Fatty acids; metabolic syndrome; lipid and lipoprotein
metabolism
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APA (6th Edition):
Mitchell, P. (2010). BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/13026
Chicago Manual of Style (16th Edition):
Mitchell, Patricia. “BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME.” 2010. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/13026.
MLA Handbook (7th Edition):
Mitchell, Patricia. “BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME.” 2010. Web. 07 Mar 2021.
Vancouver:
Mitchell P. BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME. [Internet] [Doctoral dissertation]. Dalhousie University; 2010. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/13026.
Council of Science Editors:
Mitchell P. BIOACTIVE FATTY ACID SUPPLEMENTATION AND RISK FACTORS FOR
THE METABOLIC SYNDROME. [Doctoral Dissertation]. Dalhousie University; 2010. Available from: http://hdl.handle.net/10222/13026
Dalhousie University
4.
McDonald, William.
Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein.
Degree: MS, Department of Biochemistry & Molecular
Biology, 2011, Dalhousie University
URL: http://hdl.handle.net/10222/13336
► ?4 phosphoprotein (also known as IGBP1) is a component of the mammalian target-of-rapamycin (mTOR) pathway that controls the initiation of translation and cell-cycle progression in…
(more)
▼ ?4 phosphoprotein (also known as IGBP1) is a component
of the mammalian target-of-rapamycin (mTOR) pathway that controls
the initiation of translation and cell-cycle progression in
response to nutrients and growth factors. Aberrant signaling of the
mTOR pathway has been reported in many cancers. ?4 interacts with
the catalytic subunit of protein phosphtase 2A (PP2Ac) to mediate
the dephosphorylation of eukaryotic initiation factor 4E-binding
protein1 (4E-BP1) and p70S6 kinase (p70S6K). Our laboratory has
reported that EDD E3 ubiquitin ligase (EDD/UBR5) and
poly(A)-binding protein (PABP) are novel binding partners of ?4
phosphoprotein. In the present study, the interaction of EDD and
PABP with ?4 was confirmed in human MCF-7 breast cancer and African
green monkey COS-1 kidney cell lines, using immunoprecipitation and
immunoblotting (IP/IB) analysis. However, co-IP of total MCF-7 cell
lysates with anti-EDD antibodies revealed that EDD does not
physically interact with PP2Ac. Several ?4 deletion constructs,
that contained either the N-terminal or C-terminal regions of ?4,
were transfected into MCF-7 and COS-1 cells. Co-IP studies with
anti-EDD and PABP antibodies revealed that EDD interacts with the
C-terminal region of ?4 whereas PABP, like PP2Ac, binds to the
N-terminal region. EDD and PABP were found to interact with ?4 in
both quiescent and actively growing cells. EDD is known to
ubiquitinate poly(A)-binding protein-interacting protein 2 (Paip2),
targeting it for proteosomal degradation. Paip2 is an antagonist of
PABP activity. When ?4 levels in MCF-7 cells were knocked down
using small interfering RNA (siRNA), there was no effect on EDD
protein levels. There was also no effect on Paip2 levels,
indicating that ?4 is not involved in the EDD- mediated
ubiquitination of Paip2. Knockdown of EDD gene expression by siRNA
did not alter mono-ubiquitination of ?4, indicating that ?4 is not
a substrate of EDD. However, knockdown of EDD gene expression
decreased poly-ubiquitination of PP2Ac and increased the overall
cellular levels of PP2Ac, suggesting PP2Ac as a novel substrate of
EDD. The present study suggests a potential role for ?4 in
PABP-mediated initiation of mRNA translation. Furthermore, this
study suggests a role for EDD in regulating PP2Ac levels through
its interaction with ?4. In summary, the ?4 partners EDD, PABP and
PP2Ac interact at specific regions of ?4. PP2Ac, but not ?4, is a
substrate of EDD. The interaction of PABP with ?4 suggests a
potential role for ?4 in PABP-mediated initiation of mRNA
translation.
Advisors/Committee Members: N/A (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Barbara Karten (thesis-reader), Dr. Roger McLeod (thesis-reader), Dr. Graham Dellaire (thesis-reader), Dr. Catherine Too (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Yes (copyright-release).
Subjects/Keywords: Alpha 4 phosphoprotein; EDD E3 ubiquitin ligase; PABP
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APA (6th Edition):
McDonald, W. (2011). Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein. (Masters Thesis). Dalhousie University. Retrieved from http://hdl.handle.net/10222/13336
Chicago Manual of Style (16th Edition):
McDonald, William. “Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein.” 2011. Masters Thesis, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/13336.
MLA Handbook (7th Edition):
McDonald, William. “Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein.” 2011. Web. 07 Mar 2021.
Vancouver:
McDonald W. Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein. [Internet] [Masters thesis]. Dalhousie University; 2011. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/13336.
Council of Science Editors:
McDonald W. Characterization of the Interaction of Alpha4 Phosphoprotein
with Novel Binding Partners: EDD E3 Ubiquitin Ligase and
Poly(A)-Binding Protein. [Masters Thesis]. Dalhousie University; 2011. Available from: http://hdl.handle.net/10222/13336
Dalhousie University
5.
Arsenault, Daniel.
The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells.
Degree: MS, Department of Biochemistry & Molecular
Biology, 2012, Dalhousie University
URL: http://hdl.handle.net/10222/15710
► Phosphatidylcholine (PC) is an essential component of biological membranes and is synthesized by the CDP-choline pathway under the control of the rate-limiting enzyme CTP:phosphocholine cytidylyltransferase-alpha…
(more)
▼ Phosphatidylcholine (PC) is an essential component of
biological membranes and is synthesized by the CDP-choline pathway
under the control of the rate-limiting enzyme CTP:phosphocholine
cytidylyltransferase-alpha (CCT?). Ras transformed cells have
increased lipid synthesis; the aim of this study was to determine
if upregulation of CCT? was part of this transformed phenotype. Rat
intestinal epithelial cell lines (IEC) and three oncogenic H-ras
expressing IEC (IEC-Ras) were used to investigate the role of CCT?
and phosphatidylcholine (PC) synthesis in resistance to detachment
dependant apoptosis, termed anoikis. IEC-Ras have increased CCT?
expression within the nucleus. Reduction of CCT? expression with
lentiviral short hairpin RNA sensitized IEC-Ras to anoikis and
decreased PC degradation, but did not change PC synthesis. Thus, in
addition to CCT? being involved in anoikis-resistance in IEC-Ras
these data indicate the possibility that it may also have
nuclear-specific functions.
Advisors/Committee Members: N/A (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Graham Dellaire (thesis-reader), Dr. Paul Liu (thesis-reader), Dr. Catherine Too (thesis-reader), Dr. Neale Ridgway (thesis-supervisor), Received (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: H-ras; Anoikis; Phosphatidylcholine; Cancer
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APA (6th Edition):
Arsenault, D. (2012). The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells. (Masters Thesis). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15710
Chicago Manual of Style (16th Edition):
Arsenault, Daniel. “The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells.” 2012. Masters Thesis, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/15710.
MLA Handbook (7th Edition):
Arsenault, Daniel. “The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells.” 2012. Web. 07 Mar 2021.
Vancouver:
Arsenault D. The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells. [Internet] [Masters thesis]. Dalhousie University; 2012. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/15710.
Council of Science Editors:
Arsenault D. The role of the CDP-choline pathway in the anoikis resitance
of Ras transformed intestinal epithelial cells. [Masters Thesis]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/15710
Dalhousie University
6.
Langelaan, David.
Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2013, Dalhousie University
URL: http://hdl.handle.net/10222/22285
► Apelin, the endogenous ligand to the apelin receptor, is a small peptide involved with cardiovascular regulation. Using nuclear magnetic resonance (NMR) spectroscopy, I demonstrate that…
(more)
▼ Apelin, the endogenous ligand to the apelin receptor,
is a small peptide involved with cardiovascular regulation. Using
nuclear magnetic resonance (NMR) spectroscopy, I demonstrate that
at low temperature, residues R6-L9 and G13-F17 of apelin are more
structured than the rest of the peptide. I also study the
interactions of apelin with sodium dodecylsulphate (SDS),
dodecylphosphocholine (DPC) and 1-palmitoyl-2-hydroxy-sn-
glycero-3-[phospho-RAC-(1-glycerol)] (LPPG) micelles. Apelin binds
to SDS micelles through residues R6-L9, with structure being
induced in this region as well as the C- terminus of the peptide.
The binding to micelles along with the corresponding change in
structure make it likely that apelin binds to the apelin receptor
following the membrane catalysis hypothesis. NMR spectroscopy was
used to determine the structure of the N- terminal tail and first
transmembrane segment of the apelin receptor (AR55) in DPC
micelles. AR55 has two disrupted helices from D14-K25 and from
A29-K57. The second helix is the membrane spanning region of AR55
and has a significant kink located at N46. Mutagenesis of the
apelin receptor and functional assays indicate that G42, G45 and
N46 are essential for the proper trafficking and function of AR. In
the N-terminal tail, the functionally critical residues E20 and D23
form an anionic face that could take part in initial binding of
apelin to AR. The structure of AR55 was also determined in SDS
micelles, LPPG micelles and a 1:1 water:
1,1,1,3,3,3-hexafluoroisopropanol (HFIP) solution. Overall, the
micelle spanning region of AR55 has a consistent structure with a
kink near N46. The N-terminal tail of AR55 is more variable, having
similar structures in the micelle conditions but being largely
helical in 50% HFIP. NMR relaxation experiments indicate that the
N-terminal tail of AR55 undergoes much more motion in LPPG micelles
compared to SDS and DPC micelles. Finally, I created a program
named MC-HELAN that characterizes the kinks that occur in protein
helices. I used MC- HELAN to analyze all non-redundant membrane
protein structures as of March 2010. Membrane protein helix kinks
are remarkably common and diverse. Initial attempts to predict
membrane protein kinks using only the protein sequence were
unsuccessful.
Advisors/Committee Members: Dr. Pierre Lavigne (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Roy Duncan (thesis-reader), Dr. Roger McLeod (thesis-reader), Dr. Stephen Bearne (thesis-reader), Dr. Jan Rainey (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: G-protein coupled receptor; Nuclear magnetic resonance spectroscopy; Apelin
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APA ·
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APA (6th Edition):
Langelaan, D. (2013). Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/22285
Chicago Manual of Style (16th Edition):
Langelaan, David. “Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks.” 2013. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/22285.
MLA Handbook (7th Edition):
Langelaan, David. “Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks.” 2013. Web. 07 Mar 2021.
Vancouver:
Langelaan D. Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks. [Internet] [Doctoral dissertation]. Dalhousie University; 2013. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/22285.
Council of Science Editors:
Langelaan D. Structural Studies Of Apelin And Its Receptor As Well As The
Characteristics And Causes Of Membrane Protein Helix Kinks. [Doctoral Dissertation]. Dalhousie University; 2013. Available from: http://hdl.handle.net/10222/22285
7.
Surette, Alexi P.
REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2013, Dalhousie University
URL: http://hdl.handle.net/10222/15959
► Endothelial cells form the inner lining of vascular networks and maintain blood fluidity by inhibiting blood coagulation and promoting blood clot dissolution (fibrinolysis). Plasmin, the…
(more)
▼ Endothelial cells form the inner lining of vascular
networks and maintain blood fluidity by inhibiting blood
coagulation and promoting blood clot dissolution (fibrinolysis).
Plasmin, the primary fibrinolytic enzyme, is generated by the
cleavage of the plasma protein, plasminogen, by its activator,
tissue plasminogen activator (tPA). This reaction is regulated by
plasminogen receptors at the surface of the vascular endothelial
cells. Previous studies have identified the plasminogen receptor
protein, S100A10 as a key regulator of plasmin generation by cancer
cells and macrophages. Here we examine the role of S100A10 and its
annexin A2 binding partner in endothelial cell function using a
homozygous S100A10-null mouse. Compared to wild-type mice,
S100A10-null mice displayed increased deposition of fibrin in the
vasculature and reduced clearance of batroxobin-induced vascular
thrombi, suggesting a role for S100A10 in fibrinolysis in vivo.
Compared to WT cells, endothelial cells from S100A10-null mice
demonstrated a 40% reduction in plasminogen binding and plasmin
generation in vitro. Furthermore, S100A10-deficient endothelial
cells demonstrated impaired neovascularization of Matrigel plugs in
vivo suggesting a role for S100A10 in angiogenesis. These results
establish an important role for S100A10 in the regulation of
fibrinolysis and angiogenesis in vivo, suggesting S100A10 plays a
critical role in endothelial cell function.
Advisors/Committee Members: Dr Lindsey Miles (external-examiner), Dr John Archibald (graduate-coordinator), Dr Paola Marignani (thesis-reader), Dr Brent Johnston (thesis-reader), Dr Andrew Issekutz (thesis-reader), Dr David Waisman (thesis-supervisor), Received (ethics-approval), Yes (manuscripts), Yes (copyright-release).
Subjects/Keywords: fibrinolysis
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APA (6th Edition):
Surette, A. P. (2013). REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15959
Chicago Manual of Style (16th Edition):
Surette, Alexi P. “REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO.” 2013. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/15959.
MLA Handbook (7th Edition):
Surette, Alexi P. “REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO.” 2013. Web. 07 Mar 2021.
Vancouver:
Surette AP. REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO. [Internet] [Doctoral dissertation]. Dalhousie University; 2013. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/15959.
Council of Science Editors:
Surette AP. REGULATION OF FIBRINOLYSIS BY S100A10 IN VIVO. [Doctoral Dissertation]. Dalhousie University; 2013. Available from: http://hdl.handle.net/10222/15959
8.
Reddy, Tyler.
Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2012, Dalhousie University
URL: http://hdl.handle.net/10222/15719
► Nuclear magnetic resonance (NMR) spectroscopy was used to determine the structure of transmembrane (TM) segment IX of the Na+/H+ exchanger isoform 1 (NHE1) in dodecylphosphocholine…
(more)
▼ Nuclear magnetic resonance (NMR) spectroscopy was used
to determine the structure of transmembrane (TM) segment IX of the
Na+/H+ exchanger isoform 1 (NHE1) in dodecylphosphocholine
micelles. Studying isolated TM segments in this fashion constitutes
a well-established "divide and conquer" approach to the study of
membrane proteins, which are often extremely difficult to produce,
purify, and reconstitute in full-length polytopic form. A similar
approach was combined with NMR spin relaxation experiments to
determine the peptide backbone flexibility of NHE1 TM VII. The
combined NMR structural and dynamics studies are consistent with an
important role for TM segment flexibility in the function of NHE1,
a protein involved in apoptosis and myocardial disease. The study
of the rhomboid protease system is also described from two
perspectives: 1) I attempted to produce several TM constructs of
the substrate spitz or a related construct and the production and
purification are described in detail; and 2) I present
coarse-grained molecular dynamics simulation results for the E.
coli rhomboid ecGlpG and a spitz TM construct. Spitz appears to
preferentially associate with rhomboid near TMs 1 and 3 rather than
the proposed substrate gate at TM 5. The two proteins primarily
interact at the termini of helices rather than within the
hydrocarbon core of the bilayer. Finally, I present a detailed
analysis of coarse-grained molecular dynamics simulations of the
fibroblast growth factor receptor 3 TM domain dimerization.
Specifically, algorithms are described for analyzing critical
features of wild-type and G380R mutant constructs. The G380R
mutation is the cause of achondroplasia, the most common form of
human dwarfism. The results suggest that the proximity of a residue
to the dimer interface may impact the severity of the mutant
phenotype. Strikingly, heterodimer and mutant homodimer constructs
exhibit a secondary dimer interface which may explain the increased
signaling activity previously reported for the G380R mutation – the
helices may rotate with the introduction of G380R. The unifying
theme of this work is the 'study of membrane proteins' using
complementary techniques from structural biology and computational
biochemistry.
Advisors/Committee Members: Dr. Ayyalusamy Ramamoorthy (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Neale Ridgway (thesis-reader), Dr. Christian Blouin (thesis-reader), Dr. Raymond Syvitski (thesis-reader), Dr. Jan K. Rainey (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: Nuclear Magnetic Resonance Spectroscopy (NMR); Membrane Proteins; Coarse-grained molecular dynamics simulations; NMR spin relaxation experiments; Structural Biology
…Dalhousie University provided assistance for parts of my project: Bruce Stewart, Caitlin
Reid… …Neurobiology Department at Dalhousie University.
I have been supported by an NSERC Canada Graduate… …Dalhousie
University. I also acknowledge support from the Department of Biochemistry &
Molecular… …Biology at Dalhousie University, and the SBCB and Department of Biochemistry at the University…
Record Details
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Reddy, T. (2012). Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15719
Chicago Manual of Style (16th Edition):
Reddy, Tyler. “Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations.” 2012. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/15719.
MLA Handbook (7th Edition):
Reddy, Tyler. “Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations.” 2012. Web. 07 Mar 2021.
Vancouver:
Reddy T. Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations. [Internet] [Doctoral dissertation]. Dalhousie University; 2012. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/15719.
Council of Science Editors:
Reddy T. Structure, Flexibility, And Overall Motion Of Transmembrane
Peptides Studied By NMR Spectroscopy And Molecular Dynamics
Simulations. [Doctoral Dissertation]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/15719
9.
Phipps, Kyle.
S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS.
Degree: PhD, Department of Biochemistry & Molecular
Biology, 2012, Dalhousie University
URL: http://hdl.handle.net/10222/15718
► Hematopoietic cells are recruited to and co-opted by the growing tumor making expansive tumor growth possible. Although several cell types become associated with the growing…
(more)
▼ Hematopoietic cells are recruited to and co-opted by
the growing tumor making expansive tumor growth possible. Although
several cell types become associated with the growing tumor,
macrophages play a fundamental role. The movement of macrophages
across the basement membrane and through the extracellular matrix
to the tumor site requires the activation of proteases, such as
plasmin, at their cell surface. The proteolytic aspect of
macrophage recruitment may represent an exploitable aspect of tumor
growth in terms of therapeutic strategies. Here I show that the
S100A10 protein facilitates the infiltration of macrophages into
the site of tumor growth by stimulating the generation of the
protease plasmin at their surface. Using a mouse model in which
wild-type (WT) and S100A10-null mice are inoculated with tumor
cells, a decrease in tumor-associated macrophages (TAMs) and
greatly diminished tumor growth in tumors grown in S100A10-null
mice was observed. Although tumor growth in S100A10-null mice could
be restored by intraperitoneal injection of WT macrophages,
S100A10-null macrophages only restored tumor growth when directly
injected into the tumor. Lastly, selective depletion of macrophages
from a WT mouse by liposome encapsulated clodronate treatment
resulted in similar tumor growth deficits as in the S100A10-null
mouse. These results highlight a new role for the S100A10 protein
in the recruitment of TAMs to the tumor site and demonstrate a
potential therapeutic strategy in which the tumor associated cells
may be targeted.
Advisors/Committee Members: Dr. Harvey Pollard (external-examiner), Dr. John Archibald (graduate-coordinator), Dr. Graham Dellaire (thesis-reader), Dr. Catherine Too (thesis-reader), Dr. Hyo-Sung Ro (thesis-reader), Dr. David Waisman (thesis-supervisor), Not Applicable (ethics-approval), Not Applicable (manuscripts), Not Applicable (copyright-release).
Subjects/Keywords: Tumor; cancer; s100a10; plasminogen; plasmin; macrophage;
tam; protease
Record Details
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❌
APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Phipps, K. (2012). S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS. (Doctoral Dissertation). Dalhousie University. Retrieved from http://hdl.handle.net/10222/15718
Chicago Manual of Style (16th Edition):
Phipps, Kyle. “S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS.” 2012. Doctoral Dissertation, Dalhousie University. Accessed March 07, 2021.
http://hdl.handle.net/10222/15718.
MLA Handbook (7th Edition):
Phipps, Kyle. “S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS.” 2012. Web. 07 Mar 2021.
Vancouver:
Phipps K. S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS. [Internet] [Doctoral dissertation]. Dalhousie University; 2012. [cited 2021 Mar 07].
Available from: http://hdl.handle.net/10222/15718.
Council of Science Editors:
Phipps K. S100A10 FACILITATES THE TUMOR PROMOTING ASSOCIATION OF
MACROPHAGES WITH TUMOR CELLS. [Doctoral Dissertation]. Dalhousie University; 2012. Available from: http://hdl.handle.net/10222/15718
. 
Open Access Theses and Dissertations
