RSS 1.0Bioengineering Program
For more information visit: https://bese.kaust.edu.sa/study/bioengineering
Recent Submissions
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3D Printed Triaxial Nozzles Fabricated by Stereolithography to Prevent Backflow in Soft Matter Biofabrication(Accepted by Materials Science in Additive Manufacturing, 2023-09-24) [Article]Tissue engineering has been substantially impacted by 3D bioprinting due to its capacity to produce complicated structures with complex geometries that were challenging to recreate using conventional manufacturing methods. However, the nozzle design and fabrication remain a limitation within extrusion-based 3D bioprinting, restricting and compromising such technology's overall potential. The proposed nozzle design combines three Luer-Lok compatible inlets and an outlet within the printed body, eliminating manual assembly and enhancing fabrication consistency and quality. Furthermore, a finite element analysis of the fluid flow in the nozzle demonstrated the effectiveness of the nozzle to minimize backflow, compared to a traditional nozzle design. The tetrameric IIZK (Ac-Ile-IIe-Cha-Lys-NH2) and IIFK (Ac-Ile-IIe-Phe-Lys-NH2) peptide bioinks were used to 3D print a variety of 3D scaffolds of varying complexity, with good resolution and gel continuity. Hence, our work successfully demonstrates a novel design and fabrication and its potential, demonstrated ultimately via 3D bioprinting of cell-laden constructs and proving biocompatibility and cell viability post-assessed period. This study highlights the capability of the novel design, which aids the field of tissue engineering, allowing 3D extrusion-based bioprinting to be utilized to produce cell-incorporated constructions or scaffolds.
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The Emergence of Highly Resistant and Hypervirulent Klebsiella Pneumoniae CC14 Clone in a Tertiary Hospital Over Eight Years(Elsevier BV, 2023-09-20) [Preprint]Background: Klebsiella pneumoniae is a major bacterial and opportunistic human pathogen, increasingly recognized as a healthcare burden globally. The convergence of resistance and virulence in K. pneumoniae strains has led to the formation of hypervirulent and multidrug-resistant strains with dual risk, limiting treatment options. K. pneumoniae clones are known to emerge locally and spread globally. Therefore, an understanding of the dynamics and evolution of the emerging strains in hospitals is warranted to prevent future outbreaks. Methods: In this study, we conducted an in-depth genomic analysis on a large-scale collection of 332 multidrug-resistant K. pneumoniae strains recovered from 243 patients from a single major hospital in the west of Saudi Arabia from 2014 through 2022. We employed a broad range of phylogenetic and phylodynamic methods to understand the evolution of the significant clones on epidemiological time scales, virulence and resistance determinants, and their dynamics. We also integrated the genomic data with detailed electronic health record (EHR) data for the patients to understand the clinical implications of the resistance and virulence of different strains. Findings: We discovered a diverse population underlying the infections, with most strains belonging to Clonal Complex 14 (CC14) exhibiting dominance. Specifically, we observed the emergence and continuous expansion of strains belonging to the dominant ST2096 in the CC14 clade across hospital wards in recent years. These strains acquired resistance mutations against Colistin and ESBL and carbapenemase genes, namely blaOXA-48 and blaOXA-232, located on three distinct plasmids, on epidemiological time scales. Strains of ST2096 exhibited a higher virulence level with the presence of the siderophore Aerobactin (iuc) gene situated on the same mosaic plasmid as ESBL resistance gene. Integration of ST2096 with EHR data confirmed the significant link between colonization by ST2096 and the diagnosis of sepsis and elevated in-hospital mortality. Interpretation: Overall, these results demonstrate the clinical significance of ST2096 clones and illustrate the rapid evolution of an emerging hypervirulent and MDR K. pneumoniae in a clinical setting.
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The Genomic Landscape of Colorectal Cancer in the Saudi Arabian Population Using a Comprehensive Genomic Panel(Diagnostics, MDPI AG, 2023-09-19) [Article]Purpose: Next-generation sequencing (NGS) technology detects specific mutations that can provide treatment opportunities for colorectal cancer (CRC) patients. Patients and Methods: We analyzed the mutation frequencies of common actionable genes and their association with clinicopathological characteristics and oncologic outcomes using targeted NGS in 107 Saudi Arabian patients without a family history of CRC. Results: Approximately 98% of patients had genetic alterations. Frequent mutations were observed in BRCA2 (79%), CHEK1 (78%), ATM (76%), PMS2 (76%), ATR (74%), and MYCL (73%). The APC gene was not included in the panel. Statistical analysis using the Cox proportional hazards model revealed an unusual positive association between poorly differentiated tumors and survival rates (p = 0.025). Although no significant univariate associations between specific mutations or overall mutation rate and overall survival were found, our preliminary analysis of the molecular markers for CRC in a predominantly Arab population can provide insights into the molecular pathways that play a significant role in the underlying disease progression. Conclusions: These results may help optimize personalized therapy when drugs specific to a patient’s mutation profile have already been developed.
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Enhanced linearity through high-order antisymmetric vibration for MEMS DC power sensor(Applied Physics Letters, AIP Publishing, 2023-09-13) [Article]We present an electric power meter that capitalizes on the interaction of electrothermal strain and mechanical vibration in a micro-electro-mechanical systems (MEMS) beam undergoing the antisymmetric mode of vibration. This is achieved by using a resonant bridge driven with an electrothermal modulation technique. The change in electrical power is monitored through the alteration in the mechanical stiffness of the structure, which is tracked electrostatically. The observed deflection profile of the beam under the influence of electrothermal effects shows that the deflection geometry due to buckling exhibits similar trends as the first symmetric vibrational mode, in contrast to the antisymmetric mode. Therefore, we compare two distinct vibrational modes, converting the compressive thermal stress generated by the input electrical power via Joule heating into a shift in the resonance frequency. By employing antisymmetric vibrational mode, the output of our device is consistently monotonic to the input electrical power, even when the microbeam is experiencing buckling deflections. In addition, the sensing operation based on antisymmetric modes yields only a 1.5% nonlinear error in the response curve, which is ten times lower than that of symmetric modes. The observed deformation shape of the resonator agrees with the results obtained from multi-physics finite simulations. Finally, this approach has the potential to be extended to other frequency-shift-based sensors, allowing for higher linearity.
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Dipeptide-Based Photoreactive Instant Glue for Environmental and Biomedical Applications(Accepted by ACS Applied Materials and Interfaces, 2023-09-13) [Article]Nature-inspired smart materials offer numerous advantages over environment-friendliness and efficiency. Emulating the excellent adhesive properties of mussels foot proteins, where the Lysine is in close proximity with the 3,4-dihydroxy-L-phenylalanine (DOPA), we report the synthesis of a novel photo-curable peptide-based adhesive consisting exclusively of these two amino acids. Our adhesive is a highly concentrated aqueous solution of a monomer, a crosslinker and a photoinitiator. Lap-shear adhesion measurements on plastic and glass surfaces and comparison with different types of commercial adhesives showed that the adhesive strength of our glue is comparable when applied in the air and superior when used underwater. No toxicity of our adhesive was observed when the cytocompatibility on human dermal fibroblast cells was assessed. Preliminary experiments with various tissues and coral fragments showed that our adhesive could be applied to wound healing and coral reef restoration. Given the convenience of the facile synthesis, biocompatibility, ease of application underwater and high adhesive strength, we expect that our adhesive may find application, but not limited, to the biomedical and environmental field.
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PNA-Pdx: Versatile Peptide Nucleic Acid-Based Detection of Nucleic Acids and SNPs(Analytical Chemistry, American Chemical Society (ACS), 2023-09-11) [Article]Monitoring diseases caused by pathogens or by mutations in DNA sequences requires accurate, rapid, and sensitive tools to detect specific nucleic acid sequences. Here, we describe a new peptide nucleic acid (PNA)-based nucleic acid detection toolkit, termed PNA-powered diagnostics (PNA-Pdx). PNA-Pdx employs PNA probes that bind specifically to a target and are then detected in lateral flow assays. This can precisely detect a specific pathogen or genotype genomic sequence. PNA probes can also be designed to invade double-stranded DNAs (dsDNAs) to produce single-stranded DNAs for precise CRISPR-Cas12b-based detection of genomic SNPs without requiring the protospacer-adjacent motif (PAM), as Cas12b requires PAM sequences only for dsDNA targets. PNA-Pdx identified target nucleic acid sequences at concentrations as low as 2 copies/μL and precisely detected the SARS-CoV-2 genome in clinical samples in 40 min. Furthermore, the specific dsDNA invasion by the PNA coupled with CRISPR-Cas12b precisely detected genomic SNPs without PAM restriction. Overall, PNA-Pdx provides a novel toolkit for nucleic acid and SNP detection as well as highlights the benefits of engineering PNA probes for detecting nucleic acids.
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Evaluation of Potential Peptide-Based Inhibitors Against SARS-CoV-2 and Variants of Concern(Accepted by BioMed Research International, 2023-09-11) [Article]The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has greatly affected all aspect of life. Although several vaccines and pharmaceuticals have been developed against SARS-CoV-2, the emergence of mutated variants has raised several concerns. The angiotensin-converting enzyme (ACE2) receptor cell entry mechanism of this virus has not changed despite the vast mutation in emerging variants. Inhibiting the spike protein by which the virus identifies the host ACE2 receptor is a promising therapeutic countermeasure to keep pace with rapidly emerging variants. Here, we synthesized two ACE2-derived peptides, P1 and P25, to target and potentially inhibit SARS-CoV-2 cell entry. These peptides were evaluated in vitro using pseudoviruses that contained the SARS-CoV-2 original spike protein, the Delta mutated spike protein, or the Omicron spike protein. An in silico investigation was also done for these peptides to evaluate the interaction of the synthesized peptides and the SARS-CoV-2 variants. The P25 peptide showed a promising inhibition potency against the tested pseudoviruses and an even higher inhibition against the Omicron variant. The IC50 of the Omicron variant was 60.8 µM, while the IC50s of the SARS-CoV-2 original strain and the Delta variant were 455.2 µM and 546.4 µM, respectively. The in silico experiments also showed that the amino acid composition design and structure of P25 boosted the interaction with the spike protein. These findings suggest that ACE2- derived peptides, such as P25, have the potential to inhibit SARS-CoV-2 cell entry in vitro. However, further in vivo studies are needed to confirm their therapeutic efficacy against emerging variants.
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A single n-type semiconducting polymer-based photo-electrochemical transistor(Nature communications, Springer Science and Business Media LLC, 2023-09-07) [Article]Conjugated polymer films, which can conduct both ionic and electronic charges, are central to building soft electronic sensors and actuators. Despite the possible interplay between light absorption and the mixed conductivity of these materials in aqueous biological media, no single polymer film has been utilized to create a solar-switchable organic bioelectronic circuit that relies on a fully reversible and redox reaction-free potentiometric photodetection and current modulation. Here we demonstrate that the absorption of light by an electron and cation-transporting polymer film reversibly modulates its electrochemical potential and conductivity in an aqueous electrolyte, which is harnessed to design an n-type photo-electrochemical transistor (n-OPECT). By controlling the intensity of light incident on the n-type polymeric gate electrode, we generate transistor output characteristics that mimic the modulation of the polymeric channel current achieved through gate voltage control. The micron-scale n-OPECT exhibits a high signal-to-noise ratio and an excellent sensitivity to low light intensities. We demonstrate three direct applications of the n-OPECT, i.e., a photoplethysmogram recorder, a light-controlled inverter circuit, and a light-gated artificial synapse, underscoring the suitability of this platform for a myriad of biomedical applications that involve light intensity changes.
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Photo-Chemical Stimulation of Neurons with Organic Semiconductors(Advanced Science, Wiley, 2023-09-03) [Article]Recent advances in light-responsive materials enabled the development of devices that can wirelessly activate tissue with light. Here it is shown that solution-processed organic heterojunctions can stimulate the activity of primary neurons at low intensities of light via photochemical reactions. The p-type semiconducting polymer PDCBT and the n-type semiconducting small molecule ITIC (a non-fullerene acceptor) are coated on glass supports, forming a p–n junction with high photosensitivity. Patch clamp measurements show that low-intensity white light is converted into a cue that triggers action potentials in primary cortical neurons. The study shows that neat organic semiconducting p–n bilayers can exchange photogenerated charges with oxygen and other chemical compounds in cell culture conditions. Through several controlled experimental conditions, photo-capacitive, photo-thermal, and direct hydrogen peroxide effects on neural function are excluded, with photochemical delivery being the possible mechanism. The profound advantages of low-intensity photo-chemical intervention with neuron electrophysiology pave the way for developing wireless light-based therapy based on emerging organic semiconductors.
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Deep-Learning–Based Screening and Ancillary Testing for Thyroid Cytopathology(The American Journal of Pathology, Elsevier BV, 2023-08-21) [Article]Thyroid cancer is the most common malignant endocrine tumor. The key test to assess preoperative risk of malignancy is cytologic evaluation of fine-needle aspiration biopsies (FNABs). The evaluation findings can often be indeterminate, leading to unnecessary surgery for benign post-surgical diagnoses. We have developed a deep-learning algorithm to analyze thyroid FNAB whole-slide images (WSIs). We show, on the largest reported data set of thyroid FNAB WSIs, clinical-grade performance in the screening of determinate cases and indications for its use as an ancillary test to disambiguate indeterminate cases. The algorithm screened and definitively classified 45.1% (130/288) of the WSIs as either benign or malignant with risk of malignancy rates of 2.7% and 94.7%, respectively. It reduced the number of indeterminate cases (N = 108) by reclassifying 21.3% (N = 23) as benign with a resultant risk of malignancy rate of 1.8%. Similar results were reproduced using a data set of consecutive FNABs collected during an entire calendar year, achieving clinically acceptable margins of error for thyroid FNAB classification.
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Metal–organic frameworks modified electrode for H2S detections in biological and pharmaceutical agents(MedComm – Biomaterials and Applications, Wiley, 2023-08-20) [Article]The development of hydrogen sulfide (H2S) sensors is essential to address H2S-related pharmacology since slow-releasing H2S medications have been identified to be prospective options for cancer treatments. Here, we described an electrochemical sensor for highly selective and sensitive detection of aqueous H2S, using a thin film of fumarate-based face-centered cubic (fcu)-based metal–organic frameworks (fum-fcu-MOF) modified on laser-scribed graphene (LSGE). The fum-fcu-MOF has shown a strong affinity and chemical stability to H2S analysis. The electrochemical and H2S catalytic properties were studied for fum-fcu-MOF/LSGE. An amperometry and differential pulse voltammetry techniques were demonstrated to validate the sensor. The resulting sensor delivered acceptable analytical parameters in terms of; detection limit (3.0 µM), dynamic range (10–500 µM), reproducibility, and stability (94.7%). The sensor's practical validity was demonstrated in bacterial cells and H2S-releasing drug, where the sensor was able to monitor the continuous release of in-situ H2S. The pharmacokinetics of a slow releasing H2S donor is accessed at different time intervals and different concentration levels. Our research indicate that this fum-fcu-MOF based H2S sensor holds potential in understanding pharmacokinetics of H2S releasing drugs.
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Wiskott-Aldrich Syndrome Protein Regulates Nucleolar Organization and Function in Innate Immune Response(Cold Spring Harbor Laboratory, 2023-08-16) [Preprint]Wiskott-Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by the dysfunction of the WAS protein (WASP). Using an isogenic macrophage model derived from genome edited induced pluripotent stem cells we demonstrated that WASP functions in the nucleolus, which plays important roles in immune regulation. The absence of WASP resulted in smaller and misshapen nucleoli, decreased fibrillar center territory, and impaired ribosomal RNA (rRNA) transcription. The nucleolar and rRNA phenotypes were confirmed in WAS patient samples. Furthermore, WASP interacts with nucleolar proteins, including nucleophosmin 1 (NPM1) and fibrillarin (FBL). NPM1 deficiency is known to cause elevated cytokine expression following lipopolysaccharide (LPS) stimulation. Consistently, WASP deficient cells displayed lower levels of NPM1 and a heightened inflammatory cytokine response to LPS, which was rescued by overexpressing NPM1. Together, our research provides novel insights into the critical role of WASP in nucleolar function and the modulation of inflammatory cytokine production.
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Molecularly Imprinted Polymers: A Closer Look at the Removal and Rebinding of Templates(Elsevier BV, 2023-08-15) [Preprint]Molecularly imprinted polymers (MIPs), which first appeared three decades ago, are now attracting considerable attention as artificial receptors, particularly for sensing. MIPs, especially applied to biomedical analysis in biofluids, contribute significantly to patient diagnosis at the point of care, thereby allowing health monitoring. Despite the importance given to MIPs, removal and rebinding of templates have received little attention and are currently the least focused steps in MIP development. The primary focus of this review is to analyze and discuss the advanced ideas on this topic. The review aims to provide an overview of the removal and rebinding of different templates including ions, molecules, proteins, viruses, and bacteria. Furthermore, the current challenges and perspectives in removal and rebinding processes are highlighted. Our review, at the interface of chemistry and sensors, will offer a wide range of opportunities for researchers whose interests include MIPs, (bio)sensors, analytical chemistry, and diagnostics.
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Early-stage organoid formation in biofunctionalized self-assembling peptide matrices combinations(2023-08-14) [Thesis]
Advisor: Hauser, Charlotte
Committee members: Schmidt, Fabian; Al-Sulaiman, DanaAs the third most commonly diagnosed cancer in the world, colorectal cancer (CRC) has become a pressing and urgent problem, requiring the disease mechanism research and therapeutic development. The field of tissue engineering has considerably progressed since the advent of synthetic matrices for 3D cell culture, providing in vitro models for CRC disease research. Compared to animal-derived matrices such as matrigel, synthetic matrices have several advantages including controllable properties, avoiding ethical problems and batch-to-batch variation. Ultrashort self-assembly peptides of amphiphilic nature have recently proven to be excellent matrices for 3D cell culture of many types of cells. In this thesis, we aimed to use biofunctional peptides to promote the growth of colorectal cancer organoids in the early stage of development. A peptide-based biofunctional hydrogel for organoid culture has been developed for the purpose of establishing a reproducible colorectal cancer model. The hydrogel is composed of self-assembly peptides designed to induce cell-matrix interactions. The hydrogel is mechanically tunable with customizable cell-adhesive ligands and has the ability to promote the formation and growth of colorectal cancer organoids in vitro. One of these biofunctionalized peptide matrices was particularly suitable for CRC lumen development, apical protein expression, and cell differentiation level compared to the gold-standard ECM Matrigel. -
Programmable site-specific DNA double-strand breaks via PNA-assisted prokaryotic Argonautes(Nucleic Acids Research, Oxford University Press (OUP), 2023-08-10) [Article]Programmable site-specific nucleases promise to unlock myriad applications in basic biology research, biotechnology and gene therapy. Gene-editing systems have revolutionized our ability to engineer genomes across diverse eukaryotic species. However, key challenges, including delivery, specificity and targeting organellar genomes, pose barriers to translational applications. Here, we use peptide nucleic acids (PNAs) to facilitate precise DNA strand invasion and unwinding, enabling prokaryotic Argonaute (pAgo) proteins to specifically bind displaced single-stranded DNA and introduce site-specific double-strand breaks (DSBs) independent of the target sequence. We named this technology PNA-assisted pAgo editing (PNP editing) and determined key parameters for designing PNP editors to efficiently generate programable site-specific DSBs. Our design allows the simultaneous use of multiple PNP editors to generate multiple site-specific DSBs, thereby informing design considerations for potential in vitro and in vivo applications, including genome editing.
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Leveraging AI Advances and Online Tools for Structure-Based Variant Analysis.(Current protocols, Wiley, 2023-08-04) [Article]Understanding how a gene variant affects protein function is important in life science, as it helps explain traits or dysfunctions in organisms. In a clinical setting, this understanding makes it possible to improve and personalize patient care. Bioinformatic tools often only assign a pathogenicity score, rather than providing information about the molecular basis for phenotypes. Experimental testing can furnish this information, but this is slow and costly and requires expertise and equipment not available in a clinical setting. Conversely, mapping a gene variant onto the three-dimensional (3D) protein structure provides a fast molecular assessment free of charge. Before 2021, this type of analysis was severely limited by the availability of experimentally determined 3D protein structures. Advances in artificial intelligence algorithms now allow confident prediction of protein structural features from sequence alone. The aim of the protocols presented here is to enable non-experts to use databases and online tools to investigate the molecular effect of a genetic variant. The Basic Protocol relies only on the online resources AlphaFold, Protein Structure Database, and UniProt. Alternate Protocols document the usage of the Protein Data Bank, SWISS-MODEL, ColabFold, and PyMOL for structure-based variant analysis.
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Crystallization and time-dependent changes in betaine-urea-water natural deep eutectic solvents(Journal of Molecular Liquids, Elsevier BV, 2023-08-02) [Article]The ability to predict eutectic compositions resulting in a liquid (natural) deep eutectic solvent [(NA)DES] at room temperature or below widens their applicability range. This study examines the effect of the components’ molar ratio and water content on the stability and supramolecular network of betaine-urea-water (BUW) NADES. It also explores time-dependent changes in the solvents and possible methods to determine the stability. After being prepared at elevated temperatures (≥70 °C), some BUW crystallized upon cooling or seeding with pre-existing crystals, creating orthorhombic betaine hydrate crystals. BUW ratios yielding liquid NADES were determined by proton nuclear magnetic resonance (1H NMR), identifying a solid–liquid boundary. Moreover, BUW conductivity decreased continually over time, suggesting a dynamic state of the solvents. Our results indicate that betaine crystallization depends on water and urea concentrations, supporting the reported synergistic effect. Additionally, this work demonstrates 1H NMR as a method to predict BUW ratios forming liquid NADES.
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Fusing Peptide Epitopes for Advanced Multiplex Serological Testing for SARS-CoV-2 Antibody Detection(Accepted by ACS Bio & Med Chem Au, 2023-08-01) [Article]The tragic COVID-19 pandemic, which has seen a total of 655 million cases worldwide and a death toll of over 6.6 million seems finally tailing off. Even so, new variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) continue to arise, the severity of which cannot be predicted in advance. This is concerning for the maintenance and stability public health, since immune evasion and increased transmissibility may arise. Therefore, it is crucial to continue monitoring antibody responses to SARS-CoV-2 in the general population. As a complement to polymerase chain reaction (PCR) tests, multiplex immunoassays are elegant tools that useindividual protein or peptide antigens simultaneously to provide a high level of sensitivity and specificity. To further improve these aspects of SARS-CoV-2 antibody detection, as well as accuracy, we have developed an advanced serological peptide-based multiplex assay using antigen-fused peptide epitopes derived from both, the spike and the nucleocapsid proteins. The significance of the epitopes selected for antibody detection has been verified by in silico molecular docking simulations between the peptide epitopes and reported SARS-CoV-2 antibodies. Peptides can be more easily and quickly modified and synthesized than full length proteins and can therefore be used in a more cost-effective manner. Three different fusion-epitope peptides (FEPs) were synthesized and tested by enzyme-linked immunosorbent assay (ELISA). A total of 145 blood serum samples were used, compromising 110 COVID-19 serum samples from COVID-19 patients and 35 negative control serum samples taken from COVID-19 free individuals before the outbreak. Interestingly, our data demonstrates that the sensitivity, specificity, and accuracy of the results for the FEP antigens are higher than for single peptide epitopes or mixtures of single peptide epitopes. Our FEP concept can be applied to different multiplex immunoassays testing not only for SARS CoV-2 but also for various other pathogens. A significantly improved peptide-based serological assay may support the development of commercial point-of-care tests, such as lateral-flow-assays (LFAs).
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An Experimental Setup based on 3D Printing to test Viscoelastic Arterial Models(2023-08) [Thesis]
Advisor: Laleg-Kirati, Taous-Meriem
Committee members: Hauser, Charlotte; Elatab, NazekCardiovascular diseases (CVDs) are a leading cause of death worldwide, emphasizing the need for advanced and effective intervention and treatment measures. Hypertension, a significant risk factor for CVDs, is characterized by reduced vascular compliance in arterial vessels. There is a significant rise in interest in exploring the viscoelastic properties of arteries in the last few years, for the treatment of these diseases. This study aims to develop an experimental setup using 3D Printing Technology to test viscoelastic arterial models for the validation of a diagnostic device for cardiovascular diseases. The research investigates the selection of polymer-based materials that closely mimic the viscoelastic properties of arterial vessels. An experimental setup is designed and fabricated to perform mechanical tests on 3D-printed specimens. The study utilizes a mathematical model to describe the viscoelastic behavior of the materials. The model's predictions are validated using experimental data obtained from the mechanical tests. This study demonstrates the potential of 3D printing technology in fabricating specimens using elastic and flexible resin materials. These specimens closely replicate the mechanical properties of native arteries, offering a tangible platform for controlled mechanical testing. Stress relaxation tests on the3D printed specimens highlight the viscoelastic properties of fabricated materials, shedding light on their behavior under strain. The study goes further to model the mechanics of these materials, utilizing the Fractional Voigt model to capture the intricate balance between elastic and resistive behaviors under varying deformation levels. The results highlight the successful fitting of the Fractional Voigt model to the experimental data, confirming the viscoelastic behavior of the specimens. The obtained values of α and RMSE indicate a good representation of arterial mechanical properties within the viscoelastic arterial model, under different loading conditions. This research contributes to improving cardiovascular device validation and offers a practical and reliable alternative to invasive experiments. Future works include exploring different materials and conditions for arterial modeling and enhancing the precision and scope of the viscoelastic model. Overall, this study advances the understanding of cardiovascular biomechanics, contributing to the development of more effective diagnostic devices for cardiovascular diseases. -
Mining Structural and Functional Patterns in Pathogenic and Benign Genetic Variants through Non-negative Matrix Factorization(2023-08) [Thesis]
Advisor: Arold, Stefan T.
Committee members: Henao, Ricardo; Reversade, BrunoThe main challenge in studying genetics has evolved from identifying variations and their impact on traits to comprehending the molecular mechanisms through which genetic variations affect human biology, including disease susceptibility. Despite having identified a vast number of variants associated with human traits through large scale genome wide association studies (GWAS) a significant portion of them still lack detailed insights into their underlying mechanisms [1]. Addressing this uncertainty requires the development of precise and scalable approaches to discover how genetic variation precisely influences phenotypes at a molecular level. In this study, we developed a pipeline to automate the annotation of structural variant feature effects. We applied this pipeline to a dataset of 33,942 variants from the ClinVar and GnomAD databases, which included both pathogenic and benign associations. To bridge the gap between genetic variation data and molecular phenotypes, I implemented Non-negative Matrix Factorization (NMF) on this large-scale dataset. This algorithm revealed 6 distinct clusters of variants with similar feature profiles. Among these groups, two exhibited a predominant presence of benign variants (accounting for 70% and 85% of the clusters), while one showed an almost equal distribution of pathogenic and benign variants. The remaining three groups were predominantly composed of pathogenic variants, comprising 68%, 83%, and 77% of the respective clusters. These findings revealed valuable insights into the underlying mechanisms contributing to pathogenicity. Further analysis of this dataset and the exploration of disease-related genes can enhance the accuracy of genetic diagnosis and therapeutic development through the direct inference of variants that are likely to affect the functioning of essential genes.
