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School of Biological Sciences

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https://hdl.handle.net/1853/70750

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College of Sciences

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Center for the Study of Systems Biology

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https://finding-aids.library.gatech.edu/agents/corporate_entities/1131

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Publication Search Results

Now showing 1 - 10 of 94

Spatiotemporal patterns of parietofrontal activity and eye movements underlying the visual perception of complex human tool use

(Georgia Institute of Technology, 2015-11-16) Natraj, Nikhilesh

When watching a child learning to use a spoon, a mother is immediately able to recognize the error when the child grabs the bowl rather than the stem, or when the child uses the spoon to try and scoop paper. Recognizing proper tool grasp-postures and use-contexts is an ability vital for daily life and can be lost due to brain injury. A better understanding of how the brain encodes contextual and grasp-specific tool-use not only furthers basic neuroscience, but also has strong relevance to deficits arising from neural pathologies. However, the majority of research till date has studied the neural response to viewing tools in isolation or viewing simple tool-grasps. These studies have shown that the recognition of tools to be a complex visuomotor process, as not only was the visual cortex engaged but also parietal and frontal regions that underlie actual tool-use. The recognition of tools therefore involves automatically recalling their motor information (graspability and manipulability) via activation of parietofrontal motor regions, a property called action affordances. Yet, it is still unclear how parietofrontal regions encode the combination of contextual and grasp-specific tool-use scenes. In addition, parietofrontal regions are multifaceted and also underlie visuospatial attention and eye movements. It is possible a relationship might exist between eye movements, attention and tool-use understanding over parietofrontal regions. Therefore the overall goal of this thesis was to understand the spatiotemporal patterns of parietofrontal activity and eye movements underlying the perceptual of contextual and grasp-specific static tool use images. Electroencephalography (EEG) was used to measure neural activity, combined with eye tracking to measure fixation and saccades. Overall, results from this thesis present evidence that the affordances of non-functional grasp-postures perturbed an observer from understanding the contextual uses of tools, with corresponding unique patterns of parietofrontal activity and eye movements. This effect was most robust when the tool was placed in contexts that afforded a certain degree of tool-use. Results also revealed a relationship between attention, eye movements and action perception over parietofrontal regions. Specifically, saccades perturbed activity over frontal regions during the perception of non-functional grasp postures and in addition, there was greater engagement of the left precuneus in the superior parietal lobe if the observer had to quickly parse the scene information using peripheral vision and rely on short term memory. In contrast, there was greater engagement of the left middle temporal gyrus if the observer had the ability to parse scene information continuously using foveal attention. Results in this thesis shed light on the neural and visual mechanisms in understanding the affordances of non-functional grasp postures, and the relation between the two mechanisms. The automatic sensitivity in understanding the intent of non-functional grasp-postures may correspond to a lifetime of learning the affordances of grasp-specific action outcomes with tools. Such cognitive motor knowledge may be vital in navigating a human environment almost entirely constructed on advanced tool-use knowledge and findings from this thesis have many potential applications in the field of neuro-rehabilitation.
Neuromechanics of locomotion: Insights from the walk-to-run transition in amputees and pedaling in able-bodied individuals

(Georgia Institute of Technology, 2015-10-16) Norman, Tracy L.

Afferent feedback is important for modulating locomotion and maintaining stability. Studying locomotor extremes and applying perturbations to normal locomotion allows us to probe the effects of afferent feedback on the control of normal gait. Investigating the walk-to-run gait transition specifically provides a unique locomotor event to investigate the fundamental determinants of legged locomotion (walking or running) and identify the sensory inputs important to the ongoing neuromuscular control of walking and running. The first goal of this dissertation was to investigate the contributions of plantarflexor muscles during stance (Aim 1) and flexor muscles during swing (Aim 2) to the walk-to-run transition. To accomplish this I used unilateral, transtibial amputee subjects as a means to assess the affects of unilaterally eliminating plantarflexor propulsive force production and below-knee flexor activation on the walk-to-run transition speed. The main objective of Aim 1 was to determine the preferred gait transition speeds of unilateral, transtibial amputee subjects, and the influence of kinetics on the walk-to-run gait transition speed. Unilateral, transtibial amputee subjects transition between gaits at a lower speed than able-bodied controls and are still able to generate higher propulsive forces walking at speeds above their preferred gait transition speed. This finding indicates that their walk-to-run transition is not likely dictated by the force-length-velocity characteristics of the intact plantarflexor muscles. Thus, as an experimental model, unilateral, transtibial amputee subjects can provide unique insights for decoupling the previously identified performance limit of plantarflexor muscles from the preferred gait transition speed in order to probe other potential determinants. The main objective of Aim 2 was to quantify the muscle activation during walking and running gaits relative to the walk-to-run gait transition speed for unilateral, transtibial amputee subjects. The swing phase tibialis anterior muscle activation is a major determinant of the walk-to-run transitions in unilateral, transtibial amputee subjects. Swing phase dorsiflexion moments alone do not explain these results and additional work is necessary to probe potential mechanical and neural explanations. Furthermore, in unilateral, transtibial amputee subjects, swing-phase rectus femoris and biceps femoris long head activations and their respective joint moments are a function of changes in absolute speed and thus not indicative of their significantly lower gait transition speed. The second goal of this dissertation was to probe the potential contributions of afferent feedback to the underlying neuromuscular mechanism ultimately responsible for the transition (Aim 3). The main objective of Aim 3 was to evaluate the effects of contralateral sensory loss on the motor output of the ipsilateral leg. Unilateral below-knee, ischemic deafferentation has significant effects on both inter- and intra- limb motor output. The net effect of contralateral sensory loss below the knee is a significant decrease in ipsilateral flexor muscle activations during the transition from flexion to extension in pedaling (Q1). Due to the rapid time course of these responses, I speculate either i) contralateral below-knee afferents (most likely Ia and/or cutaneous) have a net excitatory effect on the ipsilateral flexor muscles or ii) contralateral above knee afferents (most likely Ib) have an inhibitory effect on the ipsilateral flexor muscles.
Translational bioinformatics for personalized medicine and integrative biology: Data integration, extraction, knowledge discovery, and visualization

(Georgia Institute of Technology, 2015-10-13) Uppal, Karan

This thesis focuses on developing a computational framework to support the Precision Medicine Initiative. The newly developed tools and algorithms use machine learning, text mining and visualization techniques for extracting salient information from heterogeneous sources such as scientific literature, clinical text, and –omics technologies to enhance clinical decision making and improve the quality of healthcare. Various advances in biomedical technologies have enhanced our ability to study disease processes at different molecular levels (genes, metabolites, histones, etc.). Similarly, technological advances in healthcare domain such as adoption of Electronic Health Record systems (EHRs) provide us a unique opportunity to develop a learning healthcare system where intelligent tools and algorithms can be utilized to extract information from clinical notes, patient medication records, laboratory results, etc. for early detection of medical risks and prevention of adverse drug events. The key novel contributions of this thesis are: a) development of novel full-text summarization algorithms that have been incorporated into a web application (CoReViz) for visualizing clinically relevant information and extracting relevant sentences from clinical text and scientific articles; b) development of novel association mining algorithms and graph summarization techniques incorporated into a web application (SEACOIN2.0) for interactive drill-down summarization and hypothesis generation to extend the functionality of PubMed; c) introduction of the concept of literature based Phenotype-wide Association Studies (Lit-PheWAS); d) development of an ensemble feature selection framework for biomarker discovery using agent-based modeling and stochastic optimization techniques.
RNA ligation by hammerhead ribozymes and DNAzyme in plausible prebiotic conditions

(Georgia Institute of Technology, 2015-08-21) Lie, Lively

This work is focused on the ligation activity of the hammerhead ribozyme and DNAzymes in plausible prebiotic conditions. Before the Great Oxidation Event, RNA may have interacted with soluble Fe2+, as a replacement or in combination with Mg2+. Divalent metal cations are sometimes necessary in ribozyme activity by interacting with mostly phosphates to influence the tertiary structure of an RNA. In some cases, these metal cations help in the acid/base chemistry in catalytic cores. Chapter 2 reveals the benefits and drawbacks of hammerhead ribozyme ligation with Fe2+. Both ligation and cleavage of the hammerhead is enhanced, but an unexpected problem arose, RNA aggregation that is difficult to denature. Chapter 3 and 4 focuses on the hammerhead ligation in ice. Freeze-induced ligation frees the hammerhead from divalent metal requirements and when combined with heat-freeze cycles to mimic day and night, yield reaches 60%. Freezing the reaction mixture also reduces sequence specificity between enzyme and substrates. Chapter 5 reveals a RNA-cleaving DNAzyme that can ligate cleaved RNA substrates when the reaction mixture is frozen. The significance behind this chapter is that previous ligating DNAzymes require high-energy triphosphates and instead uses a 2’3’-cyclic phosphate. This 2’3’-cyclic phosphate is already a product of the cleavage reaction of the DNAzyme and the cleavage/ligation reaction is in effect recycling the same materials.
Computational tools for the analysis of biological networks in plants

(Georgia Institute of Technology, 2015-08-20) Das, Abhiram

This thesis presents research associated to phenotyping of plants by applying informatics techniques which includes databases, web technologies, image processing and feature measurements of 2D and 3D images. The thesis presents two enabling bioinformatics tools related by a shared set of research objectives and distinct by the nature of their applications. The first project called ClearedLeavesDB, is a common platform for plant biologists to share data and metadata about cleared leaf images. This project resulted in an online interactive database of cleared leaf images. The second project called Digital Imaging of Root Traits (DIRT), is an application to store, manage, share and process root images as well as analyze root image traits with respect to different experiments. This application is deployed on iPlant's cyber-infrastructure and currently supports management of 2D root images and high-throughput processing and structural descriptor/trait estimation from root images. The application enables storage, management and sharing heterogeneous image data and metadata including dynamic environmental and descriptor data. In the final part of the thesis, I describe ongoing challenges in developing new methods to measure global and local descriptors from reconstructed 3D root images.
Role of histone H1 in neural differentiation of embryonic stem cells

(Georgia Institute of Technology, 2015-07-27) Pan, Chenyi

Linker histone H1 is a key structural protein facilitating the formation of higher order chromatin structures and regulates specific gene expression. In mammals, there exist 11 closely related H1 variants. Previous studies show that H1 depletion by 50% impairs specific gene regulation and differentiation of embryonic stem cells (ESCs). However, the mechanisms by which H1 and its variants regulate ESC differentiation remain elusive. Here, we demonstrate a dosage effect of H1 variants in mouse ESCs through severe H1 depletion and mutation analysis. We establish ultra-low H1 ESCs by sequential depletion of six somatic H1 variants. These cells exhibit normal ESC morphology and self-renewal. During neural differentiation, the total H1 level gradually increases, and H1 depletion reveals a dosage effect in neurite formation, induction of neural lineage-specific genes, and silencing of pluripotency-associated genes such as Oct4 and Nanog. In addition, severe H1 depletion causes reduced cell proliferation and cellular senescence in neural lineages. Significantly, Oct4 knockdown effectively restores neural differentiation and partially rescues the reduction in cell proliferation and cellular senescence. These results suggest that H1 is crucial for neural differentiation of ESCs and its regulation in the process acts in a dosage dependent, rather than a variant specific, manner. Another part of this thesis centers on analysis of H1 mutations frequently occurred in follicular lymphoma or transformed follicular lymphoma. These mutations in H1 are clustered in the globular and C-terminal domains directly involved in chromatin binding. By comparing the properties of wild-type human H1c (hH1c) and mutant hHcS102F expressed in H1c/H1d/H1e triple knockout mouse ESCs, we find that S102F mutation dramatically impairs the association of hH1c with chromatin. These results suggest that the identified H1 mutations in follicular lymphoma most likely result in a loss-of-function phenotype by reducing the binding affinity of H1 for chromatin, thus compromising chromatin compaction and the regulation of specific genes.
Altered intermuscular force feedback after spinal cord injury in cat

(Georgia Institute of Technology, 2015-07-24) Niazi, Irrum Fawad

Bipeds and quadrupeds are inherently unstable and their bodies sway during quiet stance and require complex patterns of muscle activation to produce direction-specific forces to control the body’s center of mass. The relative strength of length and force feedback within and across muscles collectively regulates the mechanical properties of the limb as a whole during standing and locomotion (Bonasera and Nichols 1994; Ross and Nichols 2009). Loss of posture control following spinal cord injury (SCI) is a major clinical challenge. While much is known about intermuscular force feedback during crossed extension reflex (XER) and locomotion in decerebrate cats, these have not been well characterized in animals with spinal cord injury. In this study, we mapped the distribution of heterogenic force feedback in hindlimb ankle extensor muscles using muscle stretch (natural stimulation) in intercollicular, non-locomoting, decerebrate cats with chronic lateral spinal hemisection (LSH). We also, determined the time of onset of redistribution of heterogenic force feedback following LSH by collecting force feedback data from cats with acute sci. In addition we revisited heterogenic force feedback between ankle extensors in decerebrate non-locomoting cats during mid-stance to ascertain whether these cats with intact spinal cord depict a certain pattern of force feedback. The goal was to ascertain whether the patterns and strength of feedback was different between the two states (cats with intact spinal cord and cats with SCI). We found that heterogenic feedback pathways remained inhibitory in non-locomoting decerebrate cats in two states. The latencies of inhibition also corresponded to those observed for force feedback from Golgi tendon organs. We observed variable patterns of force feedback between ankle extensors in decerebrate/control cats. On the other hand we observed consistent results in cats with chronic LSH exhibiting very strong distal to proximal pattern of inhibition from 2 weeks to 20 weeks following chronic LSH. The same results were obtained in acute LSH cats suggest that the change in neuromuscular system appears immediately after SCI and persists even after the animal start walking following SCI. The observed altered pattern of force feedback after spinal cord injury suggests either presence of a pattern intrinsic to the spinal cord or a unique pattern exhibited by the damaged spinal cord. The results are important clinically because even with vigorous rehabilitation attempts patients do not regain posture control after SCI even though they regain ability to walk. Therefore, to effectively administer treatment and therapy for patients with compromised posture control, a complete understanding of the circuitry is required.
Microbes in the atmosphere: prevalence, species composition, and relevance to cloud formatio

(Georgia Institute of Technology, 2015-07-14) De Leon, Natasha Isabel

The composition and prevalence of microorganisms in the upper troposphere and their role in aerosol-cloud-precipitation interactions represent important, unresolved questions for biological and atmospheric sciences. Most studies to date were restricted to samples taken near the Earth’s surface and/or to laboratory incubations that do not simulate well in-situ conditions. Further, the ability of most microbial taxa to serve (or not) as cloud condensation nuclei (CCN) remains uncharacterized. Therefore, the major objectives of this research effort were to characterize the composition and relative abundance of airborne bacteria in the troposphere, and measure their CCN activity under different growth conditions. To this end, low- and high-altitude air masses were sampled before, during, and after two tropical storms, and the microorganisms present in the samples were assessed based on quantitative PCR and microscopy. Viable bacterial cells represented on average around 20% of the total particles in the 0.25- to 1-μm diameter range, revealing that bacteria represent an important and underestimated fraction of coarse mode aerosols. Twenty bacterial isolates were recovered from these and additional rain samples, and the degree of their cell hygroscopicity was measured based on the contact angle of the bacterial cells with water. A wide range of contact angles was observed, with isolates ranging from very hydrophilic to very hydrophobic. The CCN activity of each isolate was studied by introducing aerosolized bacteria into a continuous flow stream-wise thermal gradient CCN counter. Hydrophilic bacteria were found to have a critical supersaturation of 0.1% compared to hydrophobic bacteria, which showed a critical supersaturation of 0.2% or higher. These supersaturation conditions are relevant for cloud formation in continental areas. Collectively, these findings suggested that airborne bacterial cells represent an underappreciated aspect of the troposphere, with potentially significant impacts on the hydrological cycle, clouds, and climate.
Functional significance of sequence variation among miR-200/205 families of miRNAs in ovarian cancer

(Georgia Institute of Technology, 2015-07-10) Jabbari, Neda

MicroRNAs are short non-coding RNAs that regulate large suites of target genes. A family of miRNAs known as the miR-200 is implicated in the epithelial-mesenchymal/ mesenchymal-epithelial transition (EMT/MET), a process associated with cancer metastasis. Overexpression of miR-200 family miRNAs results in the induction of MET and increased sensitivity to chemotherapeutic drugs. We demonstrated here that the molecular changes and drug sensitivities induced by overexpression of miR-200 family members in mesenchymal-like ovarian cancer cells are highly variable and correlated with sequence variation within the seed and non-seed regions of individual family members. Analysis of the functional and evolutionary significance of sequence variation within the human miRNA seed regions indicates that as little as a single nucleotide change within miRNA seed regions dramatically changes the spectrum of mRNAs regulated by the overexpressed miRNA and that additional seed nucleotide changes have no significant added effect. These findings help explain the highly conserved nature of miRNA seed regions within and across species and develop a better understanding of the evolution of miRNA mediated regulation of target mRNAs. Finally, we provide evidence for seed region/non-seed interactions in the regulation of miRNA induced changes in response to cisplatin in ovarian cancer cells. Our results provide a better understanding of miRNA mediated regulation and their potential as new therapeutic agents.
Rare and common genetic variant associations with quantitative human phenotypes

(Georgia Institute of Technology, 2015-07-01) Zhao, Jing

This dissertation aims at investigating the association between genotypes and phenotypes in human. Both common and rare regulatory variants have been studied. The phenotypes include disease risk, clinical traits and gene expression levels. This dissertation describes three different types of association study. The first study investigated the relationship between common variants and three sub-clinical traits as well as three complex diseases in the Center for Health Discovery and Well Being study (CHDWB). The second study is GWAS analysis of TNF-α and BMI/CRP conducted as a contribution to meta-GWAS analyses of these traits with investigators at the University of Groningen in the Netherlands, and the 1000 Genomes Consortium. The third study was the most original contribution of my thesis as it assessed the association between rare regulatory variants in promoter regions and gene expression levels. The results clearly show an enrichment of rare variants at both extremes of gene expression. This dissertation provides insight into how common and rare variants associate with broadly-defined quantitative phenotypes. The demonstration that rare regulatory variants make a substantial contribution to gene expression variation has important implications for personalized medicine as it implies that de novo and other rare alleles need to be considered as candidate effectors of rare disease risk.