Characterizing and revealing biomarkers on patients with Cerebral Amyloid Angiopathy using artificial intelligence

Dissertação de mestrado em BioinformáticaCerebral Amyloid Angiopathy is a cerebrovascular disorder resulting from the deposition of an amyloidogenic protein in small and medium sized cortical and leptomeningeal vessels. A primary cause of spontaneous intracerebral haemorrhages, it manifests predominantly in the elder population. Although CAA is a common neuropathological finding on itself, it is also known to frequently occur in conjunction with Alzheimer’s disease, being sometimes misdiagnosed. Currently, CAA diagnosis is generally conducted by post-mortem examination or, in live patients by the examination of an evacuated hematoma or brain biopsy samples, which are typically unavailable. Therefore, a reliable and non-invasive method for diagnosing CAA would facilitate the clinical decision making and accelerate the clinical intervention. The main goal of this dissertation is to study the application of Machine Learning (ML) to reveal possible biomarkers to aid the diagnosis and early medical intervention, and better understand the disease. Therefore, three scenarios were tested: Classification of four neurodegenerative diseases with annotation data obtained from visual rating scores, age and gender; Classification of the diseases with radiomic data derived from the patient’s MRI; and a combination of the previous experiments. The results show that the application of Artificial intelligence in the medical field brings advantages to support the physicians in the decision making process and, at some point, make a correct prediction of the disease label. Although the results are satisfactory, there are still improvements to be done. For instance, image segmentation of cerebral lesions or brain regions and additional clinical information of the patients would be of value.Angiopatia Amiloide Cerebral (AAC) é uma doença vascular cerebral resultante da deposição de matéria amiloide. Principal causa de hemorragias cerebral espontâneas, a AAC manifesta se predominantemente na população idosa. Embora a AAC seja uma doença que por si só tem um grande impacto no grupo etário referido, ocorre em simultâneo com inúmeras outras doenças neurodegenerativas, como a doença de Alzheimer. Atualmente, o diagnóstico de AAC realiza-se quer em post-mortem, quer em pacientes vivos. No entanto, o diagnóstico em vida é conseguido por meio de biópsias de tecidos cerebrais, sendo um método invasivo, o que dificulta a intervenção clínica. Deste modo, torna-se imperativa a procura de alternativas fiáveis e não invasivas em vida para auxiliar o diagnóstico da doença e permitir a melhoria da qualidade de vida do paciente. Perante os progressos na área da tecnologia e medicina, esta dissertação propõe o estudo da aplicação de algoritmos de Machine Learning (ML) para revelar possíveis biomarcadores para auxiliar o diagnóstico e permitir uma intervenção precoce. Deste modo, foram testados três cenários distintos: a classificação de quatro doenças neurodegenerativas com dados anotados obtidos a partir de métricas visuais de avaliação da atrofia, idade e sexo; a classificação das doenças com dados gerados a partir de métodos radiómicos; e uma combinação das duas abordagens anteriores. Neste documento apresenta-se e discute-se os resultados obtidos com a aplicação de quatro diferentes algoritmos de ML que visam a deteção automática da doença associada à imagem testada. Adicionalmente, é feita uma análise crítica de quais as características mais relevantes que levaram à tomada de decisão por parte do algoritmo. Os resultados demonstram que através de aplicação de metodologias automáticas é possível o auxílio ao diagnostico médico por especialistas e, no limite, a realização de diagnostico automático com elevada precisão. Finalmente, são apresentadas possíveis alternativas de trabalho futuro para que os resultados possam ser aperfeiçoados, como por exemplo, a segmentação das regiões de interesse, i.e., identificação das lesões, aquando da anotação por especialistas. Mediante a inclusão dessa segmentação, uma vez que será mais especifica, os resultados serão, por sua vez, aprimorados

Генетичний алгоритм з жадібним стохастичним оператором схрещування для передбачення третинної структури білка

Розроблено новий генетичний алгоритм, особливістю якого є запропонований жадібний стохастичний оператор схрещування. Застосування пропонованого алгоритму досліджується на задачі передбачення третинної структури білка. Наведено результати обчислювального експерименту.Цель работы. Описание генетического алгоритма с новым жадным стохастическим оператором скрещивания. В сравнении предлагаемого алгоритма с лучшими известными имплементациями генетических и миметических алгоритмов, используемых для определения пространственной структуры белка. Результат. Работа предлагаемого алгоритма сравнивается с другими на базе 10 известных цепей длиной 48, для которых найден глобальный минимум свободной энергии, впервые предложенных в [13]. Алгоритм нашел 9 из 10 пространственных структур, на которых достигается глобальный минимум свободной энергии, а также продемонстрировал лучшее среднее значение решений, чем алгоритмы, с которыми он сравнивался.The purpose of the article is to describe a genetic algorithm with a new greedy stochastic crossover operator, reveal its advantages and disadvantages, compare the proposed algorithm with the best-known implementations of genetic and memetic algorithms for the spatial protein structure prediction, and make conclusions with future steps suggestion afterward. Result. The work of the proposed algorithm is compared with others on the basis of 10 known chains with a length of 48 first proposed in [13]. For each of the chain, a global minimum of free energy was already pre-calculated. The algorithm found 9 out of 10 spatial structures on which a global minimum of free energy is achieved and also demonstrated a better average value of solutions than the comparing algorithms

Machine Learning based Protein Sequence to (un)Structure Mapping and Interaction Prediction

Proteins are the fundamental macromolecules within a cell that carry out most of the biological functions. The computational study of protein structure and its functions, using machine learning and data analytics, is elemental in advancing the life-science research due to the fast-growing biological data and the extensive complexities involved in their analyses towards discovering meaningful insights. Mapping of protein’s primary sequence is not only limited to its structure, we extend that to its disordered component known as Intrinsically Disordered Proteins or Regions in proteins (IDPs/IDRs), and hence the involved dynamics, which help us explain complex interaction within a cell that is otherwise obscured. The objective of this dissertation is to develop machine learning based effective tools to predict disordered protein, its properties and dynamics, and interaction paradigm by systematically mining and analyzing large-scale biological data. In this dissertation, we propose a robust framework to predict disordered proteins given only sequence information, using an optimized SVM with RBF kernel. Through appropriate reasoning, we highlight the structure-like behavior of IDPs in disease-associated complexes. Further, we develop a fast and effective predictor of Accessible Surface Area (ASA) of protein residues, a useful structural property that defines protein’s exposure to partners, using regularized regression with 3rd-degree polynomial kernel function and genetic algorithm. As a key outcome of this research, we then introduce a novel method to extract position specific energy (PSEE) of protein residues by modeling the pairwise thermodynamic interactions and hydrophobic effect. PSEE is found to be an effective feature in identifying the enthalpy-gain of the folded state of a protein and otherwise the neutral state of the unstructured proteins. Moreover, we study the peptide-protein transient interactions that involve the induced folding of short peptides through disorder-to-order conformational changes to bind to an appropriate partner. A suite of predictors is developed to identify the residue-patterns of Peptide-Recognition Domains from protein sequence that can recognize and bind to the peptide-motifs and phospho-peptides with post-translational-modifications (PTMs) of amino acid, responsible for critical human diseases, using the stacked generalization ensemble technique. The involved biologically relevant case-studies demonstrate possibilities of discovering new knowledge using the developed tools

Exploiting Toxoplasma gondii MAF1 locus diversity to identify essential host proteins required for mitochondrial sequestration and manipulation

Recent genomic comparisons identified multiple expanded loci in Toxoplasma gondii that are unique compared to close Apicomplexan relatives. One of these loci, mitochondrial association factor 1 (MAF1), encodes distinct paralogs of secreted dense granule effector proteins, some of which mediate the host mitochondrial association (HMA) phenotype. MAF1b drives HMA, MAF1a does not. Through sequence and functional analysis of multiple MAF1 paralogs, we have identified regions of the protein that have undergone paralog-specific selection-driven diversification. Using structure and alignment-guided site-directed mutagenesis of MAF1b and MAF1a, we identified three critical residues in the C-terminal helix that are required for HMA. Using this MAF1b mutant as a new tool to probe the function of MAF1b and HMA in T. gondii interactions, we performed an unbiased quantitative mass spectrometry screen comparing co-IP samples of MAF1b, MAF1a, and MAF1b mutant parasite infections. Of the 1,360 proteins identified in all samples, 13 candidate proteins were uniquely enriched in the MAF1b samples compared to both MAF1a and MAF1b mutant samples. Of these 13 candidate host binding proteins, nine play roles in mitochondrial biology. RNAi knockdown of each of the nine candidates followed by either Type II:MAF1b infection or GFP-MAF1b expression identified TOM70 and its mitochondrial chaperone, HSPA9, as partners required for MAF1b-mediated HMA. TOM70 enrichment at the T. gondii vacuolar membrane and parasite exclusion of the ER at this interface illustrate an intricate manipulative strategy on the part of parasite. Both TOM70 and HSPA9 are implicated in specific ER-mitochondrial contact site functions like immune modulation, mitochondrial dynamics, autophagy, and calcium homeostasis. The requirement of both TOM70 and HSPA9 could explain key phenotypes previously described in an HMA+ T. gondii infection such as an in vivo growth advantage, modulated immune response, and mitochondrial fusion around the vacuole. Taken together, the neofunctionalization of the MAF1 locus drove the evolution of an intermolecular network capable of mediating intimate interactions between host mitochondria and the T. gondii-containing vacuole

MECHANICAL ENERGY HARVESTER FOR POWERING RFID SYSTEMS COMPONENTS: MODELING, ANALYSIS, OPTIMIZATION AND DESIGN

Finding alternative power sources has been an important topic of study worldwide. It is vital to find substitutes for finite fossil fuels. Such substitutes may be termed renewable energy sources and infinite supplies. Such limitless sources are derived from ambient energy like wind energy, solar energy, sea waves energy; on the other hand, smart cities megaprojects have been receiving enormous amounts of funding to transition our lives into smart lives. Smart cities heavily rely on smart devices and electronics, which utilize small amounts of energy to run. Using batteries as the power source for such smart devices imposes environmental and labor cost issues. Moreover, in many cases, smart devices are in hard-to-access places, making accessibility for disposal and replacement difficult. Finally, battery waste harms the environment. To overcome these issues, vibration-based energy harvesters have been proposed and implemented. Vibration-based energy harvesters convert the dynamic or kinetic energy which is generated due to the motion of an object into electric energy. Energy transduction mechanisms can be delivered based on piezoelectric, electromagnetic, or electrostatic methods; the piezoelectric method is generally preferred to the other methods, particularly if the frequency fluctuations are considerable. In response, piezoelectric vibration-based energy harvesters (PVEHs), have been modeled and analyzed widely. However, there are two challenges with PVEH: the maximum amount of extractable voltage and the effective (operational) frequency bandwidth are often insufficient. In this dissertation, a new type of integrated multiple system comprised of a cantilever and spring-oscillator is proposed to improve and develop the performance of the energy harvester in terms of extractable voltage and effective frequency bandwidth. The new energy harvester model is proposed to supply sufficient energy to power low-power electronic devices like RFID components. Due to the temperature fluctuations, the thermal effect over the performance of the harvester is initially studied. To alter the resonance frequency of the harvester structure, a rotating element system is considered and analyzed. In the analytical-numerical analysis, Hamilton’s principle along with Galerkin’s decomposition approach are adopted to derive the governing equations of the harvester motion and corresponding electric circuit. It is observed that integration of the spring-oscillator subsystem alters the boundary condition of the cantilever and subsequently reforms the resulting characteristic equation into a more complicated nonlinear transcendental equation. To find the resonance frequencies, this equation is solved numerically in MATLAB. It is observed that the inertial effects of the oscillator rendered to the cantilever via the restoring force effects of the spring significantly alter vibrational features of the harvester. Finally, the voltage frequency response function is analytically and numerically derived in a closed-from expression. Variations in parameter values enable the designer to mutate resonance frequencies and mode shape functions as desired. This is particularly important, since the generated energy from a PVEH is significant only if the excitation frequency coming from an external source matches the resonance (natural) frequency of the harvester structure. In subsequent sections of this work, the oscillator mass and spring stiffness are considered as the design parameters to maximize the harvestable voltage and effective frequency bandwidth, respectively. For the optimization, a genetic algorithm is adopted to find the optimal values. Since the voltage frequency response function cannot be implemented in a computer algorithm script, a suitable function approximator (regressor) is designed using fuzzy logic and neural networks. The voltage function requires manual assistance to find the resonance frequency and cannot be done automatically using computer algorithms. Specifically, to apply the numerical root-solver, one needs to manually provide the solver with an initial guess. Such an estimation is accomplished using a plot of the characteristic equation along with human visual inference. Thus, the entire process cannot be automated. Moreover, the voltage function encompasses several coefficients making the process computationally expensive. Thus, training a supervised machine learning regressor is essential. The trained regressor using adaptive-neuro-fuzzy-inference-system (ANFIS) is utilized in the genetic optimization procedure. The optimization problem is implemented, first to find the maximum voltage and second to find the maximum widened effective frequency bandwidth, which yields the optimal oscillator mass value along with the optimal spring stiffness value. As there is often no control over the external excitation frequency, it is helpful to design an adaptive energy harvester. This means that, considering a specific given value of the excitation frequency, energy harvester system parameters (oscillator mass and spring stiffness) need to be adjusted so that the resulting natural (resonance) frequency of the system aligns with the given excitation frequency. To do so, the given excitation frequency value is considered as the input and the system parameters are assumed as outputs which are estimated via the neural network fuzzy logic regressor. Finally, an experimental setup is implemented for a simple pure cantilever energy harvester triggered by impact excitations. Unlike the theoretical section, the experimental excitation is considered to be an impact excitation, which is a random process. The rationale for this is that, in the real world, the external source is a random trigger. Harmonic base excitations used in the theoretical chapters are to assess the performance of the energy harvester per standard criteria. To evaluate the performance of a proposed energy harvester model, the input excitation type consists of harmonic base triggers. In summary, this dissertation discusses several case studies and addresses key issues in the design of optimized piezoelectric vibration-based energy harvesters (PVEHs). First, an advanced model of the integrated systems is presented with equation derivations. Second, the proposed model is decomposed and analyzed in terms of mechanical and electrical frequency response functions. To do so, analytic-numeric methods are adopted. Later, influential parameters of the integrated system are detected. Then the proposed model is optimized with respect to the two vital criteria of maximum amount of extractable voltage and widened effective (operational) frequency bandwidth. Corresponding design (influential) parameters are found using neural network fuzzy logic along with genetic optimization algorithms, i.e., a soft computing method. The accuracy of the trained integrated algorithms is verified using the analytical-numerical closed-form expression of the voltage function. Then, an adaptive piezoelectric vibration-based energy harvester (PVEH) is designed. This final design pertains to the cases where the excitation (driving) frequency is given and constant, so the desired goal is to match the natural frequency of the system with the given driving frequency. In this response, a regressor using neural network fuzzy logic is designed to find the proper design parameters. Finally, the experimental setup is implemented and tested to report the maximum voltage harvested in each test execution

Bioinformatics and Machine Learning for Cancer Biology

Cancer is a leading cause of death worldwide, claiming millions of lives each year. Cancer biology is an essential research field to understand how cancer develops, evolves, and responds to therapy. By taking advantage of a series of “omics” technologies (e.g., genomics, transcriptomics, and epigenomics), computational methods in bioinformatics and machine learning can help scientists and researchers to decipher the complexity of cancer heterogeneity, tumorigenesis, and anticancer drug discovery. Particularly, bioinformatics enables the systematic interrogation and analysis of cancer from various perspectives, including genetics, epigenetics, signaling networks, cellular behavior, clinical manifestation, and epidemiology. Moreover, thanks to the influx of next-generation sequencing (NGS) data in the postgenomic era and multiple landmark cancer-focused projects, such as The Cancer Genome Atlas (TCGA) and Clinical Proteomic Tumor Analysis Consortium (CPTAC), machine learning has a uniquely advantageous role in boosting data-driven cancer research and unraveling novel methods for the prognosis, prediction, and treatment of cancer

Using MapReduce Streaming for Distributed Life Simulation on the Cloud

Distributed software simulations are indispensable in the study of large-scale life models but often require the use of technically complex lower-level distributed computing frameworks, such as MPI. We propose to overcome the complexity challenge by applying the emerging MapReduce (MR) model to distributed life simulations and by running such simulations on the cloud. Technically, we design optimized MR streaming algorithms for discrete and continuous versions of Conway’s life according to a general MR streaming pattern. We chose life because it is simple enough as a testbed for MR’s applicability to a-life simulations and general enough to make our results applicable to various lattice-based a-life models. We implement and empirically evaluate our algorithms’ performance on Amazon’s Elastic MR cloud. Our experiments demonstrate that a single MR optimization technique called strip partitioning can reduce the execution time of continuous life simulations by 64%. To the best of our knowledge, we are the first to propose and evaluate MR streaming algorithms for lattice-based simulations. Our algorithms can serve as prototypes in the development of novel MR simulation algorithms for large-scale lattice-based a-life models.https://digitalcommons.chapman.edu/scs_books/1014/thumbnail.jp