Publications by authors named "Nicole M Marlatt"

8 Publications

  • Page 1 of 1

Bilateral sequential theta burst stimulation for multiple-therapy-resistant depression: A naturalistic observation study.

J Psychiatr Res 2020 11 22;130:342-346. Epub 2020 Aug 22.

Department of Psychiatry, Schulich School of Medicine and Dentistry, Western University, London, Ontario, Canada; Lawson Health Research Institute & Robarts Research Institute, London, Ontario, Canada.

Depression is a significant health issue with treatment resistance reported in about one third of patients. Treatment resistance results in significant disability, impaired quality of life, and increased healthcare costs. Repetitive transcranial magnetic stimulation (rTMS) is a treatment option for treatment resistant depression (TRD) with response and remission rates in open-label studies being as high as 58% and 37% respectively. Theta-burst is a faster and novel rTMS paradigm that has shown promise as a treatment for TRD in some preliminary studies. In a naturalistic design, we evaluated the response, remission and tolerability of bilateral sequential (right then left) prefrontal theta-burst rTMS (bsTBS) in 50 patients with TRD (600 pulses/session, 20 sessions, 100% of resting motor threshold (80% if intolerant to 100%, n = 2), F4/F3 of 10-20-20 EEG localization). Data was collected over 36 months from a specialized academic TMS clinic. Patients had multiple-treatment resistance with at least two failed trials of different antidepressants with 20% also having failed electroconvulsive therapy and 66% having received professional therapy. We found a 28% remission rate (HAMD-17 score of ≤7) and a 52% response rate (≥50% reduction in HAMD-17) with a 42% reduction in average HAMD-17 score. The treatment was well tolerated, with muscle contractions, mild pain or discomfort, headache, scalp irritation, and changes to vitals being captured as occasional adverse events with two instances of syncope (0.22% of treatments). This naturalistic study shows that bsTBS is a promising paradigm for a multiple-TRD patient population with approximately one-third of treatments achieving remission and over half achieving significant response.
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http://dx.doi.org/10.1016/j.jpsychires.2020.08.009DOI Listing
November 2020

A subset of calcium-binding S100 proteins show preferential heterodimerization.

FEBS J 2019 05 21;286(10):1859-1876. Epub 2019 Feb 21.

Department of Biochemistry, The University of Western Ontario, London, Canada.

The assembly of proteins into dimers and oligomers is a necessary step for the proper function of transcription factors, muscle proteins, and proteases. In uncontrolled states, oligomerization can also contribute to illnesses such as Alzheimer's disease. The S100 protein family is a group of dimeric proteins that have important roles in enzyme regulation, cell membrane repair, and cell growth. Most S100 proteins have been examined in their homodimeric state, yet some of these important proteins are found in similar tissues implying that heterodimeric molecules can also be formed from the combination of two different S100 members. In this work, we have established co-expression methods in order to identify and quantify the distribution of homo- and heterodimers for four specific pairs of S100 proteins in their calcium-free states. The split GFP trap methodology was used in combination with other GFP variants to simultaneously quantify homo- and heterodimeric S100 proteins in vitro and in living cells. For the specific S100 proteins examined, NMR, mass spectrometry, and GFP trap experiments consistently show that S100A1:S100B, S100A1:S100P, and S100A11:S100B heterodimers are the predominant species formed compared to their corresponding homodimers. We expect the tools developed here will help establish the roles of S100 heterodimeric proteins and identify how heterodimerization might alter the specificity for S100 protein action in cells.
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http://dx.doi.org/10.1111/febs.14775DOI Listing
May 2019

Role of Hybrid Brain Imaging in Neuropsychiatric Disorders.

Diagnostics (Basel) 2015 Dec 4;5(4):577-614. Epub 2015 Dec 4.

Lawson Health Research Institute, London, ON N6C 2R5, Canada.

This is a focused review of imaging literature to scope the utility of hybrid brain imaging in neuropsychiatric disorders. The review focuses on brain imaging modalities that utilize hybrid (fusion) techniques to characterize abnormal brain molecular signals in combination with structural and functional changes that have been observed in neuropsychiatric disorders. An overview of clinical hybrid brain imaging technologies for human use is followed by a selective review of the literature that conceptualizes the use of these technologies in understanding basic mechanisms of major neuropsychiatric disorders and their therapeutics. Neuronal network abnormalities are highlighted throughout this review to scope the utility of hybrid imaging as a potential biomarker for each disorder.
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http://dx.doi.org/10.3390/diagnostics5040577DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4728476PMC
December 2015

Creating an Ethnodrama to Catalyze Dialogue in Home-Based Dementia Care.

Qual Health Res 2015 Nov;25(11):1551-9

Western University, London, Ontario, Canada St. Joseph's Health Care London, London, Ontario, Canada.

This article describes the development of a theater script derived from a critical ethnographic study that followed people living with dementia--and their family and professional caregivers--over an 18-month period. Analysis of the ethnographic data yielded four themes that characterized home-based dementia care relationships: managing care resources, making care decisions, evaluating care practices, and reifying care norms. The research team expanded to include a colleague with playwright experience, who used these themes to write a script. A theater director was included to cast and direct the play, and finally, a videography company filmed the actors on a realistic set. To contribute to the qualitative health research and the research-based theater knowledge translation literatures, this article describes and explains the creative decisions taken as part of our effort to disseminate research focused on home-based dementia care in a way that catalyzes and fosters critical (actionable) dialogue.
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http://dx.doi.org/10.1177/1049732315609572DOI Listing
November 2015

Codon optimization for enhanced Escherichia coli expression of human S100A11 and S100A1 proteins.

Protein Expr Purif 2010 Sep 27;73(1):58-64. Epub 2010 Mar 27.

Department of Biochemistry, University of Western Ontario, London, Ontario, Canada N6A 5C1.

The cloning, expression and purification for the recombinant full-length human proteins S100A11 and human S100A1 is described. The genes were synthesized by overlapping complementary single-stranded oligonucleotides of various lengths. The coding sequence for both genes were codon optimized by selecting only the most preferential codons according to the Escherichia coli bias. In order to assemble the various oligonucleotides into the correct full-length genes, a unique one-step PCR procedure was implemented. The expression and purification procedures were also optimized for each protein. A single phenyl-Sepharose column was sufficient for the purification of human S100A11 whereas HiTrap Q anion exchange followed by phenyl-Sepharose columns were required for the purification of S100A1. By optimizing the S100A1 and S100A11 gene, expression and purification protocols, more than 45 and 150mg, respectively of the purified human proteins were obtained per litre of media. Protein identity was verified by both SDS-PAGE and mass spectrometry (MS) and further characterized by NMR spectroscopy. These results have established an efficient method for the expression and purification of large quantities of human S100A1 and S100A11 proteins for biophysical characterization.
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http://dx.doi.org/10.1016/j.pep.2010.03.015DOI Listing
September 2010

Formation of monomeric S100B and S100A11 proteins at low ionic strength.

Biochemistry 2009 Mar;48(9):1954-63

Department of Biochemistry, University of Western Ontario, London, Ontario N6A 5C1, Canada.

The S100 proteins comprise a group of EF-hand proteins that undergo a calcium-induced conformational change allowing them to interact with other proteins and produce a biological response. A unique feature of these proteins is the fact that they can form both homo- and heterodimers independent of calcium binding. The reported dissociation constants for several S100 proteins span a very large range, from 1-4 microM to <1 nM, suggesting that differing interface surface areas could govern the strength of the binding affinity. In this work, we examine the dimerization mechanism of S100B and S100A11 in the absence of calcium. Using electrospray mass spectrometry, we demonstrate that the monomer-dimer equilibrium in these S100 proteins is strongly dependent on the ionic strength of the solution. At higher ionic strengths (>or=22 mM), both S100A11 and S100B exist predominantly as homodimers. For apo-S100A11, a K(dimer) near 0.01 microM is estimated, while concentration-dependent experiments under these conditions show the K(dimer) for apo-S100B must be even lower. In contrast, lowering the ionic strength results in the formation of monomeric proteins with poorer dimer propensity. For example, the estimated K(dimer) for apo-S100A11 is more than 400 microM at 0.1 mM NH(4)Ac. (1)H-(15)N HSQC NMR experiments in combination with circular dichroism studies show that monomeric S100B and S100A11 proteins are alpha-helical and retain a significant amount of tertiary structure. Our results indicate that apo-S100B has at least a 10-fold stronger propensity to form dimers than does apo-S100A11 in line with a 400 A(2) greater buried surface area for apo-S100B at its dimer interface. These experiments are the first to show that folded monomeric S100 proteins can be isolated, thus paving the way for future experiments aimed at examining the possible role of these monomers in folding and calcium signaling.
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http://dx.doi.org/10.1021/bi802086aDOI Listing
March 2009

Identification of a dimeric intermediate in the unfolding pathway for the calcium-binding protein S100B.

J Mol Biol 2008 Oct 6;382(4):1075-88. Epub 2008 Aug 6.

Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.

The S100 proteins comprise 25 calcium-signalling members of the EF-hand protein family. Unlike typical EF-hand signalling proteins such as calmodulin and troponin-C, the S100 proteins are dimeric, forming both homo- and heterodimers in vivo. One member of this family, S100B, is a homodimeric protein shown to control the assembly of several cytoskeletal proteins and regulate phosphorylation events in a calcium-sensitive manner. Calcium binding to S100B causes a conformational change involving movement of helix III in the second calcium-binding site (EF2) that exposes a hydrophobic surface enabling interactions with other proteins such as tubulin and Ndr kinase. In several S100 proteins, calcium binding also stabilizes dimerization compared to the calcium-free states. In this work, we have examined the guanidine hydrochloride (GuHCl)-induced unfolding of dimeric calcium-free S100B. A series of tryptophan substitutions near the dimer interface and the EF2 calcium-binding site were studied by fluorescence spectroscopy and showed biphasic unfolding curves. The presence of a plateau near 1.5 M GuHCl showed the presence of an intermediate that had a greater exposed hydrophobic surface area compared to the native dimer based on increased 4,4-dianilino-1,1'-binaphthyl-5,5'-disulfonic acid fluorescence. Furthermore, (1)H-(15)N heteronuclear single quantum coherence analyses as a function of GuHCl showed significant chemical shift changes in regions near the EF1 calcium-binding loop and between the linker and C-terminus of helix IV. Together these observations show that calcium-free S100B unfolds via a dimeric intermediate.
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http://dx.doi.org/10.1016/j.jmb.2008.07.083DOI Listing
October 2008

Amide exchange shows calcium-induced conformational changes are transmitted to the dimer interface of S100B.

Biochemistry 2007 Jun 31;46(25):7478-87. Epub 2007 May 31.

Department of Biochemistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1.

S100B is a 21 kDa member of the S100 calcium-binding protein family. This protein comprises a symmetric homodimer with each subunit having two EF-hands arranged from four alpha-helices (I-IV). S100B binds calcium and undergoes a conformation change leading to the exposure of hydrophobic surface residues that enable the protein to interact with biological target molecules. The most significant structural change that occurs during calcium binding results in a change in the orientation of helix III with respect to helices II and IV. In this work, the calcium-sensitive conformational change has been studied by utilizing fast 1H-15N HSQC experiments and water-transfer methods to follow the amide exchange in apo-S100B and Ca-S100B at 35 degrees C. In apo-S100B, the protection factors are 2-3 orders of magnitude lower for helix III than for helix I, II, or IV. In addition, the exchange stability measured here for the dimer interface helices (I, I', IV, and IV'), in the absence of calcium, is similar to the stability obtained from chemical denaturation experiments. When calcium binds, significant decreases in the protection factors for helices I and IV indicate a modification in the stability of the dimer interface has occurred. In contrast, helix II protection factors increase slightly, which is consistent with a decreased level of surface exposure of this helix. These data have been compared with those of the monomeric S100 protein, calbindin D9k, to illustrate that upon calcium binding there is a balance maintained between the amide exchange rates in helices II and III, although largely the rates are dissimilar for each of these proteins. This distinguishing feature may be important for the calcium-induced conformational change in S100B, where calcium binding is transmitted to the dimer-forming helices.
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http://dx.doi.org/10.1021/bi6026242DOI Listing
June 2007