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Seeking the Brain’s Compensatory Healing Mechanisms: A Clinical Application of Neuroplasticity-based Tools to Advance Neurorehabilitation
No full textPaper 1: Clinical Characteristics Associated with the PLP-PLS Index, a New Potential Metric to Phenotype Phantom Limb Pain
Abstract
Background: Phantom limb pain (PLP) is highly prevalent after amputation. However, the influence of non-painful sensations (PLS) remains unclear. This study examines the PLP-PLS index as a novel tool to differentiate PLP from PLS and explores the association of clinical factors with the index.
Methods: We conducted a cross-sectional analysis of baseline data from 112 participants in a previous factorial trial in patients with unilateral traumatic lower limb amputation. Linear regression models were used to examine the associations between the index and various demographic, psychological and clinical factors. Logistic and Poisson regression, and e-value calculation were utilized for sensitivity analyses.
Results: Adjusted multivariable linear regression models demonstrated significant associations of phantom movement sensation (β: -1.532; 95% CI: -2.615 to -0.449; p = 0.006) and time since amputation (β: 0.005; 95% CI: 0.0006 to 0.0101; p = 0.026) with the PLP-PLS index. These findings were confirmed by multivariable logistic regression (phantom movement sensation OR: 0.469; 95% CI: 0.200 to 1.099, p = 0.082; time since amputation OR: 1.003; 95% CI: 1.00003 to 1.007; p = 0.048) and sensitivity analyses.
Conclusions: Time since amputation and phantom movement sensation likely reflect distinct phenotypes and potential mechanisms for PLP and PLS. The PLP-PLS index is a promising clinical tool for selecting therapies to prevent/treat PLP and for measuring treatment effects to modulate phantom pain. These findings emphasize the importance of understanding the mechanisms underlying PLP and PLS for improving clinical management and guiding future research.
Paper 2: A Salutogenic Signature of the Placebo Effect in Brain Oscillations: A systematic review and meta-analysis
Abstract
Background: The placebo effect is increasingly acknowledged as a component of rehabilitation interventions, however its characterization and quantification remain poorly explored. This study investigates brain oscillatory activity as a biomarker for the placebo effect's neural mechanisms.
Methodology: A systematic literature review up to January 2025 searched PubMed, Embase, and Cochrane databases for randomized controlled and cross-over trials reporting brain oscillations in resting state from placebo-controlled neurorehabilitation trials in healthy and subjects with neurological disorders. The analysis included a semi-quantitative (albatross plots), and quantitative meta-analysis (Hedge’s g), focusing on the effect sizes of power differences between placebo and active groups.
Results: We included 63 studies with 180 healthy subjects and 1,758 neurological disorder patients. In healthy subjects, placebo showed an increase in alpha power compared to no intervention (g = 0.45, 95% CI [0.09; 0.8]). In patients, sham interventions elevated alpha power in frontal (g = 0.08, 95% CI [0.07; 0.08] ), central (g = 0.55, 95% CI [0.47; 0.65]), and parietal areas (g = 0.28, 95% CI [0.18; 0.44]), as well as beta (g = 1.31, 95% CI [1.06; 1.63]) and theta central (g = 0.58, 95% CI [0.46; 0.72]). However, these effects were non-significant when compared to active interventions.
Conclusion: Alpha oscillations in fronto-central regions are the primary biomarkers of the placebo effect, with beta and theta oscillations also indicative, especially in patients with neurological disorders. These effects were reversed when compared to active interventions, suggesting that active rehabilitation also encompass the placebo effect. Intriguingly, these placebo effects vary based on baseline brain activity, highlighting a tendency towards more stable, salutogenic rhythms in different populations.Medical Scienc
Do All Roads Lead to Rome? Exploring Representational Similarities Between Latent Spaces of Generative Image Models
No full textGenerative image models learn to produce images by transforming vectors drawn from a marginally simple latent space. Extensive research has shown that latent spaces develop meaningful structure; images with different values of an attribute (e.g. bright versus dark lighting) correspond to vectors from different parts of the latent space. Less work has gone into comparing the latent spaces of different models. In this thesis, we investigate this question, building on a preliminary work that showed that it is possible to take a vector in the latent space of one model corresponding to some image and lin- early map it to a vector in the latent space of another model corresponding to a very similar image. Using this methodology in tandem with other metrics, we compare 4 model architectures trained on 2 datasets and find that much of the semantic structure between their latent spaces is the same up to a linear transformation. The level of similarity is highest between models with similar architectures as well as between expressive models. The set of similarly represented features is not always intuitive; while gender is represented similarly in all face-generating models, class (e.g. airplane, horse, etc...) is represented differently among multi-class image generating models. We also use linear maps as tools to investigate how the structure of a face-generating model’s latent space changes during training, concluding that the representation of gender-related concepts becomes more disjoint while that of orthogonal concepts like skin tone remain stable. We also find that intermediate latent spaces in models with hierarchical latent space structures are similar.Computer Scienc
Self-assembly of chiroptical ionic co-crystals from silver nanoclusters and organic macrocycles
No full textAtomically precise nanoclusters can be assembled into ordered superlattices with unique electronic, magnetic, optical, and catalytic properties. The co-crystallization of nanoclusters with functional organic molecules provides opportunities to access an even wider range of structures and properties but can be challenging to control synthetically. Here, we introduce a supramolecular approach to direct the assembly of atomically precise Ag nanoclusters into a series of nanocluster‒organic ionic cocrystals (NOICs) with tunable structures and properties. By leveraging non-covalent interactions between anionic Ag nanoclusters and cationic organic macrocycles with tunable sizes, the orientation of nanocluster surface ligands can be manipulated to achieve in-situ resolution of enantiopure NOICs that feature large chiroptical effects. Beyond chirality, this cocrystal assembly approach provides a promising platform for designing functional solid-state nanomaterials through a combination of supramolecular chemistry and atomically precise nanochemistry.Proo
Strategies for Catalyzing Sterically Hindered Stereoselective Matteson Homologations
No full textIn Chapter 1, we describe the development of an iterative Matteson homologation reaction with catalyst-controlled diastereoselectivity. This work relies on the development of a catalyst capable of efficiently catalyzing the homologation of secondary boronic esters. This reaction was applied to the selective synthesis of each stereoisomer of benzestrol, a bioactive compound with estrogenic activity featuring three contiguous stereocenters. The eight different stereoisomers were assayed to determine their binding affinities for the estrogen receptor α (ERα), and the absolute configuration of the compound that exhibited uniquely high activity was determined.
In Chapter 2, we provide further biological characterization of all eight benzestrol stereoisomers and propose a structural rationale for the uniquely high binding activity of the most potent isomer. Two cellular activity assays, proliferation of ER-positive breast cancer cells and stimulation of estrogenic gene activity, demonstrate that the potencies of the eight isomers parallel their binding affinities as described in Chapter 1. In all cases, only one isomer exhibited high activity. A small-molecule crystal structure of the highly active isomer was examined, revealing conformational flexibility within the solid-state crystal lattice. Computational modeling of each isomer bound to ERα established that calculated binding energies and internal torsional energies correlate with experimentally measured binding affinities and potencies. The modeled binding conformation of the most active isomer was shown to overlay well with that of the well-studied, potent, non-steroidal estrogen, trans-diethylstilbestrol, making similar key interactions in the ERα ligand-binding pocket.
In Chapter 3, we describe our ongoing efforts to develop an enantioselective, catalytic Matteson homologation to access tertiary α-chloro pinacol boronic esters from commercially available boronic esters and 1,1-dichloroethane. Relative to previous work on secondary boronic esters and the iterative homologations presented in Chapter 1, this system initially exhibited significantly lower reactivity. We present efforts to enhance the yield and enantioselectivity of this reaction, achieving up to 55% yield with 83% ee. Enantioselectivities as high as 89% were observed in reactions with lower yields. Additionally, we describe an observed negative correlation between yield and selectivity and propose a kinetic hypothesis to account for this trend. Finally, we explore the reaction scope and the potential to transform tertiary α-chloro pinacol boronic esters into other tetrasubstituted stereocenters via enantiospecific chloride and boron elaboration.Chemistry and Chemical Biolog
Study of Genetic Determinants of Antibiotic Resistance in Endodontic Pathogen; Enterococcus faecalis
No full textEnterococcus faecalis is a resilient Gram-positive bacterium commonly associated with persistent infections in endodontics, including root canal treatment failures. This dissertation explores the genetic determinants of antibiotic resistance and persister formation in E. faecalis, as well as its survival strategies under antibiotic stress. Understanding these mechanisms is essential for developing more effective therapeutic approaches in endodontic and clinical settings.
Chapter 1 provides an overview of E. faecalis as a significant pathogen in endodontics, detailing its ability to survive harsh environments and form biofilms, which contribute to its persistence in root canals. The chapter further discusses the bacterium’s intrinsic resistance to common antibiotics and its ability to acquire resistance genes through horizontal gene transfer, with a focus on vancomycin-resistant strains. Additionally, the phenomenon of persister cell formation, which allows E. faecalis to survive in a dormant state under antibiotic pressure, is introduced as a key factor in treatment failure.
Chapter 2 investigates the genetic basis of persister formation in E. faecalis using the Dunny transposon mutant library. The library, containing mutants covering approximately 70% of the E. faecalis genome, was screened for genes associated with persister formation under antibiotic stress. Genes such as PhoU, uvrD/REP, and Fis were identified as potential candidates for regulating persister formation. However, experimental results showed no significant difference in persister formation between knockout mutants and the wild-type strain, suggesting that other genetic factors may play a critical role in this process.
Chapter 3 focuses on the identification of antibiotic resistance genes in E. faecalis using the same transposon mutant library. A screening for resistance to ampicillin led to the identification of several mutants with resistance-associated genes, including sensor histidine kinases and phosphate-binding proteins. These findings highlight the complexity of resistance mechanisms in E. faecalis, with metabolic regulation, stress responses, and biofilm formation playing integral roles in survival under antibiotic pressure.
Chapter 4 presents experiments assessing the microbial contamination and disinfection efficacy of gutta-percha (GP) cones in endodontics. While GP cones are generally clean, they can harbor bacteria, which may lead to infections if not properly disinfected. The effectiveness of sodium hypochlorite (NaOCl) as a disinfecting agent was evaluated in clinical settings. 16S rRNA sequencing revealed that NaOCl treatment significantly reduced bacterial contamination on GP cones, underscoring the importance of disinfection protocols in preventing infection during root canal therapy.
This dissertation provides insights into the genetic determinants of antibiotic resistance and persister formation in E. faecalis, contributing to the understanding of its role in endodontic infections. It also emphasizes the need for improved disinfection strategies to ensure the safety and success of root canal treatments. Further exploration of the genetic factors involved in E. faecalis persistence and resistance is necessary to develop novel therapeutic strategies to combat this challenging pathogen.Endodontic
Building Stronger Nanofiber Scaffolds for Regenerative Aortic Valves
No full textFor the many patients in need of heart valve replacements, a lifetime of medical difficulties accompanies the available mechanical and bioprosthetic implant options. Scientists are working to address these comorbidities by developing regenerative heart valves made of biodegradable fibrous scaffolds that are immediately capable of controlling one-way blood flow while guiding the patient’s own cells to reconstruct the valve with native tissue. Our group’s state-of-the-art regenerative valve scaffolds are manufactured quickly and consistently with focused rotary jet spinning of a PLA/PCL copolymer (PLCL). However, this valve design has thus far only proven to be functional in the pulmonary position, and a more robust design is needed for a valve scaffold to operate in the higher-pressure aortic position. This project presents an upgraded regenerative valve design for functionality in the aortic position by engineering a new PLCL scaffold material suitable for more extreme pressure and flow conditions by altering the copolymer composition to improve mechanical strength without sacrificing regenerative capability. The experiments conducted to analyze the potential of this novel material demonstrate initial success in biocompatibility with 2D scaffold cell culture and valve functionality with in vitro flow testing in a simulated aortic environment.Engineering Sciences S
Mediterraneanizing Turkey: Gateways to Regional Agrarian Transformation
No full textGreenhouse tomato farming has arrived in Antalya at the same time as its ancient Roman sites are revived in what has become cast as the quintessential Mediterranean city of Turkey. Becoming a major off season vegetable production center with a new wholesale market (hal), regulating the regional, national and global circulation of tomatoes, Antalya region has become globally indexed by tomatoes as the tomato itself has become naturalized as a Mediterranean fruit. Juxtaposing the archival findings on the regional development project, which paved the way for global investments in tourism, mining, real estate and agriculture, with the ethnography of region-formation on the ground, this dissertation focuses on the transformation of social relations since the inception of greenhouse tomato farming in the region. The contract farming arrangements became formative of new class relations, and in contrast to predominant representations of this form of farming in the town, the tomato has meant new dependencies and loyalties. Diverging from the prevailing metaphors of verticality, this ethnography offers the locally embedded concept, or role, of kâhya to understand the formation of new class relations.Middle Eastern Studies Committe
Pathways to Progress: The Role of Academic and Technical High Schools in Black Economic Advancement, 1900-1940
No full textThis thesis examines the role of high school education in stimulating Black economic progress from 1900-1940 by tracing the outcomes of Blacks who attended high school in the Jim Crow South. By utilizing linkages of people across Census years and a novel hand-classified dataset of 1,500 Black high schools built in the South between 1900 and 1940, I estimate the returns to schooling for Blacks who attended academic versus technical high schools along the lines of wages, white-collar labor force participation, and migration. I find that Blacks who attended academic high schools earned higher wages, worked white-collar jobs with higher frequency, and migrated with less frequency compared to Blacks who attended technical high schools. This thesis contributes to an important literature on the relationship between school quality and earnings and the muted progress of Blacks in the 20th Century relative to other racial groups. By allowing Black Americans to have a more general and adaptable education, I argue that academic schools helped Blacks retain their skills in the face of technological change, and greater access to academic high schools would have accelerated Black economic progress during this period.Applied Mathematic
Commemoration as Culture Dukhrana and Shahra Rituals in Assyrian Tradition
No full textVersion of Recor
Neural Stem Cell (NSC) Secretome and Wnt/β-catenin Signaling Pathway in Alzheimer’s Disease (AD): A Systematic Literature Review and Bioinformatics Analysis
No full textAlzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by neuronal loss, synaptic dysfunction, and cognitive impairment, with no current cure (DeTure & Dickson, 2019; Kumar et al., 2023). The Wnt/β-catenin signaling pathway plays a crucial role in neurogenesis and synaptic plasticity; however, its dysregulation in AD, due to pathological factors such as amyloid-β (Aβ) plaques and neurofibrillary tangles (NFTs), contributes to disease progression (Jia et al., 2019; Priya et al., 2024). Neural stem cell (NSC) secretome, a collection of bioactive molecules secreted by NSCs, has shown potential in activating the Wnt/β-catenin signaling pathway and promoting neurogenesis in AD (Bahlakeh et al., 2022; Hijroudi et al., 2022). However, the specific components within the NSC secretome that contribute to Wnt/β- catenin activation and their underlying mechanisms remain unknown. This study aimed to identify the components of the NSC secretome, specifically growth factors and neurotrophic factors, that are responsible for activating the Wnt/β-catenin signaling pathway in AD, thereby enhancing neurogenesis, and to investigate their potential mechanisms of action through a comprehensive literature review and bioinformatics analysis. A systematic literature review identified eight growth factors – epidermal growth factor (EGF), fibroblast growth factor 2 (FGF2), fibroblast growth factor 8 (FGF8), hepatocyte growth factor (HGF), insulin-like growth factor-1 (IGF-1), platelet- derived growth factor (PDGF), stem cell factor (SCF), vascular endothelial growth factor (VEGF) – and three neurotrophic factors – brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF), nerve growth factor (NGF) – within the NSC secretome that may contribute to Wnt/β-catenin activation in AD. Bioinformatics analysis categorized these proteins using UniProt database, assessed their molecular and biological functions through Gene Ontology (GO) analysis using PANTHER database, and identified their pathway involvement through KEGG database. STRING-based protein-protein analysis (PPI) network analysis provided insight into the intricate crosstalk between PI3K/Akt, MAPK/ERK, and Wnt/β-catenin signaling pathways. Then a targeted literature review was conducted to validate bioinformatics predictions, identifying two direct and one indirect crosstalk mechanism of Wnt/β-catenin signaling pathway activation. The first direct mechanism involves growth factors and neurotrophic factors activating the PI3K/Akt signaling pathway, leading to Akt-mediated phosphorylation and inhibition of glycogen synthase kinase-3β (GSK-3β), which stabilizes β-catenin and promotes its nuclear translocation to activate Wnt target genes. The second direct mechanism involves EGF binding to epidermal growth factor receptor (EGFR) triggering MAPK/ERK activation, where extracellular signal-regulated kinase (ERK) phosphorylates casein kinase 2 (CK2), which subsequently phosphorylates α- catenin. This phosphorylation event disrupts the β-catenin-E-cadherin complex, allowing β-catenin to dissociate and translocate into the nucleus to drive Wnt target gene transcription. The indirect mechanism involves MAPK/ERK signaling activation by growth factors and neurotrophic factors, where rat sarcoma (Ras) activation converts phosphatidylinositol 4,5-biphosphate (PIP2) to phosphatidylinositol (3,4,5)-trisphosphate (PIP3), reinforcing PI3K/Akt pathway activation and enhancing β-catenin stabilization. A final pathway interaction map was constructed to visualize the complex interplay between these signaling pathways and their potential therapeutic implications in AD. Collectively, these findings highlight the potential of NSC secretome components in restoring Wnt/β-catenin signaling in AD through intracellular crosstalk with PI3K/Akt and MAPK/ERK signaling pathway. This study provides a molecular framework for future exploration of NSC secretome-based therapies in AD.Extension Studie