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Rational design of peptide affinity agents: applications in elucidating biomolecular interactions, drug delivery, and bioprocessing
No full textMay 2015School of ScienceOver the next half-century advances within the fields of biotechnology and medicine must be made to address the critical issues facing society. As biopharmaceuticals continue to gain dominance in the pharmaceutical field with the growth of both the biosimilars market and increase in the number of novel biopharmaceutical therapies in development, disruptive technologies will need to be developed. The delivery of biopharmaceutical molecules within the body and their bioprocessing will take center stage with this anticipated growth of the biopharmaceuticals industry. From the drug delivery perspective, poor tissue penetration and low bioavailability of biopharmaceuticals motivate the need to better understand protein-protein interactions, while the complex product microheterogeneity of biopharmaceuticals places significant purification burden on the bioprocessing industry. Peptide affinity agents offer potential solutions to these issues across a variety of fields, with applications in elucidating biomolecular interactions, drug delivery, and bioprocessing. Utilization of rational design principles allows large libraries of peptide candidates to be generated and screened via high-throughput microarray technologies. An initial analysis of the protein-protein interactions found within the central nerv-ous system, specifically focused on the interactions of the tight-junction protein claudin-5. These studies revealed dominant trans-interactions between the two extracellular loops of claudin-5. This elucidated interaction was utilized in the subsequent design of Permeability Enhancing Peptides for the Disruption, Attenuation, & Recovery of Tight-junctions (PEPDARTs). PEPDARTs aim to alter the permeability profile of the blood-brain barrier to afford increased bioavailability of small-molecule drugs and biopharmaceuticals. Further extension of the rational design of peptide affinity agents into the field of bioprocessing permitted the design of peptide affinity ligands for the purification of a clinically utilized therapeutic enzyme. The methodologies developed in this study have since been extended to a multi-university and organization collaboration aimed at providing life-saving biopharmaceuticals on-demand in remote corners of the world. Finally, the developed peptide affinity ligand methodologies have been explored for extension into the fields of regenerative and personalized medicine for the bioprocessing of whole cells, such as induced pluripotent stem cells or stem cell derived cell types.Ph
Engineering the electronic structure of inse and inse/tmd devices
No full textAugust 2023School of EngineeringEngineering the band structure is a technique that is used to modify semiconductors in modern electronic devices. There are two problems that advancement in modern electronics currently faces: miniaturization and specialized processing. A potential solution to these problems is the use of two-dimensional (2D) semiconductors. 2D semiconductors have abundant band structure engineering capabilities that can be exploited in creating more efficient and specific applications. This can be done can be intercalating, straining, defect engineering, substrate engineering, alloying, and heterostructuring. In this thesis, heterostructuring and alloying are used to alter the band structure of InSe and InSe/TMD devices. In project one, InSe alloyed with Sulfur and Tellurium shows a change in bandgap depending on the concentration of the alloy components. In project two, multilayered InSe stacked with bilayer WS2 shows the formation of interlayer excitons that can be further tuned with electronic gating.M
Experimental investigations of the dynamics of centimeter-scale drops
No full textAugust 2022School of EngineeringHistorically the study of drop dynamics has been limited in length-scale due to the effects of bodyforces from gravity, as there is simply a limit to the size that an unsupported drop can be stably
grown on Earth. These surface tension-contained systems, being uniquely free surface-dominated,
can be utilized to pursue scientific investigations with applications to both the fields of fluid dynamics and biology. By introducing a technology capable of analyzing drop dynamics in a microgravity environment, novel scientific studies can be pursed which were not previously possible. This thesis follows, from an experimental standpoint, the development and initial works of one such technology: the Ring-Sheared Drop (RSD). The RSD is an inch diameter drop apparatus used for scientific investigations aboard the International Space Station (ISS). Pinned between two thin contact rings,
the drop can be differentially rotated, allowing for the effect of shear to be isolated and studied in
an interfacially dominated system.
This doctoral work accomplishes this goal through a series of published (or soon to be)
academic investigations. These studies serve to (I) develop a density-matched liquid analogue
system to characterize the deformation of a differentially sheared drop, (II) quantify the influence
of the outer bath in such density matched analogue systems and validate an asymptotic theory
predicting drop shape, (III) quantify any influence of microorganisms on the stability of a growing
liquid-gas drop in a microgravity environment, (IV) apply knowledge gained from the subsequent
studies to begin the RSD’s mission aboard the ISS of studying the causes of neurodegenerative
diseases by analyzing the kinetics of amyloid fibrils in shearing flow, and (V) develop a particletracking technique to enhance the scientific capabilities of the RSD beyond its original design.Ph
Novel imaging strategies illuminate selective trafficking pathways in neurons
No full textDecember 2022School of ScienceThe fundamental unit of the nervous system is the neuron. Neurons develop many anatomically and functionally distinct domains to fulfill their role in electrochemical signaling. These domains require different complements of membrane proteins. To accurately localize to their respective domains, membrane proteins undergo three trafficking steps: selective sorting, selective transport, and selective fusion. Little is known about the mechanisms that dictate neuronal protein trafficking, and many contradictory models have been proposed. This dissertation engages with two fundamental questions: what is the predominant trafficking pathway of axonal membrane proteins, and what are the mechanisms that explain kinesin-based selective transport. Chapter 2 develops a novel strategy to selectively label vesicles in different axonal trafficking pathways. It reveals that multiple pathways contribute simultaneously, although most axonal membrane proteins are directly delivered to the axon. It also identifies a novel degradative pathway by which wayward axonal proteins are targeted to lysosomes. Chapter 3 reviews the explanatory power of different kinesin transport models by comparing findings produced from two kinesin-based labeling strategies: truncated motor accumulation, and kinesin tail vesicle labeling. This allows a systematic comparison of the transport preferences of kinesin motor domains to the transport behavior of the vesicles each kinesin binds. For axon-selective transport it concludes that all available data are consistent with the smart motor model. Dendrite-selective transport cannot be explained by the smart motor model alone and may instead involve a variation of cargo steering via on-vesicle regulation.
These findings underscore the importance of new technologies in driving our understanding of selective protein trafficking in neurons. They attempt to reconcile longstanding discrepancies within the field by evaluating multiple contradictory models simultaneously, and in doing so provide new insights into the complexities of neuronal trafficking machinery.Ph
Essays on cognition, digitization, and competitive behavior of firms
No full textAugust 2021School of ManagementABSTRACTThis dissertation proposal consists of three distinct but related essays about the effect of managerial cognition and digitization on the competitive behavior of firms. Managerial cognition reflects the decision-maker’s (as well as the organization’s) knowledge of external and internal environment, and it is critical for guiding the strategic decision-making and the firm’s competitive behavior. Firms act variously depending not only on the objective factors such as external environmental change, but more importantly, depending on how the organization and key managers sense and understand these objective changes. In this dissertation, we ask how managerial cognition could affect a firm’s competitive behavior. Moreover, as digitization is playing an increasingly important role in business models, we also examine how digitization shapes a firm’s competitive behavior. In the first essay, focusing on the action-response dyad, we study how managerial cognition and digitized capability affect the way focal firms respond to their rivals. In particular, we examine whether managerial cognition and digitized capability differential could result in a higher likelihood of response and how this relationship could be moderated by alliance with rivals and common shareholders with rivals. We find that a focal firm is more likely to respond to a rival’s action under two conditions: (1) the rival’s action is salient; and (2) the rival’s action is aligned with the focal firm’s attention focus. Moreover, our results show that digitized capability differential between a firm and its rival has a curvilinear relationship with response likelihood. In addition, we find that alliance with rivals and common shareholders with rivals could negatively moderate the relationship between digitized capability and response likelihood, indicating that the decision-making process could be influenced by external stakeholders.
In the second essay, we focus on the action-repertoire of firms and examine how cognitive complexity, digitization, and managerial incentives shape a firm’s competitive aggressiveness. Cognitive complexity reflects the breadth and comprehensiveness of a firm’s knowledge. We focus on two dimensions of cognitive complexity: (1) differentiation and (2) connectedness. Differentiation refers to the breadth of environmental, strategic, and organizational concepts embedded in the cognitive framework, and connectedness refers to the development of connections and sophistication among the various concepts. We find that cognitive complexity, has a mixed effect on a firm's competitive behavior. Differentiation has a positive effect on competitive aggressiveness, while connectedness has a negative effect. Further, we also find that firms with higher digitized analytics capability and higher cognitive complexity would compete more aggressively. Finally, our results suggest that providing risk incentives to executives could reduce the motivational bias of shirking and thereby influence the competitive aggressiveness of firms. However, this effect is contingent on the awareness in that only when the organization has a clear strategic plan does risk incentives motivate the CEO to take actions aggressively.
In the third essay, we are trying to understand how Red Queen competition aligning with CEO temporal focus influences a firm’s digital strategic posture. The Red Queen competition can be explained as a race where each firm needs to match or exceed the actions from rivals to improve its competitive positions in the market (Derfus et al. 2008). Furthermore, as CEOs’ temporal focus (i.e., the degree of CEOs attending to the past, present, and future) is important for decision making, we examine the implications of CEOs’ present and future focus for digital strategic posture. We find that rivals’ innovation-oriented actions will positively impact the digital strategic posture while rivals’ resource-oriented actions will negatively influence the digital strategic posture. Furthermore, we also find that the present focus of CEO will strengthen the above relationships.Ph
Using nano-engineered surfaces to control optical properties for solarthermal management
No full textDecember 2022School of EngineeringThis doctoral thesis has investigated the nanostructure geometry effect on the material’soptical properties for solar-thermal management. This study includes two aspects: solar-thermal
desalination and radiative heating and cooling. Both parts include investigating the identification
of materials, fabrication of nano/microstructures, and a proof-of-concept demonstration.
For solar-thermal desalination, prior experimental studies have focused mainly on the
broadband solar absorber. In this thesis, the spectral selective absorber is investigated in detail by
combining experimental and computational techniques to achieve high efficiency of solar-thermal
desalination. A computational model is developed and validated to understand the nanostructure
geometry effects of nickel-infused alumina on solar-thermal energy conversion. Then, a
manageable fabrication technique using electrochemical deposition is studied to control the
nanostructure geometry achieving spectral-selective optical behavior. Finally, a scalable approach
involving the use of wicking materials interfaced with the spectral selective absorber is
demonstrated for desalination. This achieves enhanced efficiency compared with the broadband
absorber.
For radiative heating and cooling, previous studies on daytime radiative cooling typically
focused on materials with fixed and cooling-optimized optical properties. In this thesis, the porous
polymeric structures with dynamically switchable optical properties have been studied in detail.
First, a computational model is developed and validated to investigate the geometry effects of
porous polymeric fibers on high-performance solar reflection. Secondly, a fabrication technique
using the electrospinning process is studied to control fiber geometry achieving high solar
reflection. Lastly, a switchable method for solar-thermal regulation is proposed using porousxiv
polymeric layers integrated with a spectral selective absorber. A significant energy reduction is
predicted when applied to buildings as roofing materials.Ph
Characterizing noncanonical cellular pathways underlying alzheimer's disease
No full textMay 2023School of EngineeringLate-onset Alzheimer’s Disease (LOAD) is a devastating neurodegenerative disorder that causes significant cognitive debilitation in tens of millions of patients worldwide. Throughout disease progression in a significant subset of LOAD patients, abnormal secretase activity results in the aberrant cleavage and subsequent aggregation of neurotoxic amyloid-beta (Αβ) plaques in the cerebral extracellular space and hyperphosphorylation and destabilization of structural tau proteins surrounding neuronal microtubules. Both pathologies are correlated with the propagation of a disease-associated subset of microglia – the principal immune cells of the brain – characterized by distinctively pro-inflammatory cytokine secretion and inhibited AD substrate uptake capacity, which together further contribute to neuronal degeneration. For decades, chronic neuroinflammation has been purported as one of the cardinal pathophysiological driving features of AD; however, despite several works postulating the underlying mechanisms of inflammation-mediated neurodegeneration, its pathogenesis, and its relation to the inception of cognitive impairment, remain elusive. Moreover, the limited clinical success of treatments targeting these specific pathological features in the central nervous system (CNS) illustrates the need to investigate alternative approaches for ameliorating AD outcomes. Accumulating preclinical and clinical evidence suggests that dysregulation in the following categories of intrinsic cellular stress resistance mechanisms is involved in the pathogenesis and progression of Alzheimer’s disease: neuronal autophagic homeostasis, epigenetic regulation, and redox balance. Furthermore, while AD was previously apprehended as a condition relegated to the CNS, multiple retrospective analyses report that peripheral chronic inflammatory conditions, including osteoporosis, may exacerbate inflammatory neurodegeneration and accelerate AD progression. Toward achieving a more holistic understanding of AD as a systemic disorder involving mechanisms beyond those currently considered canonical, we first sought to interrogate the processes underlying sympathetic hyperactivity-mediated osteopenia by implementing the sympathetic neuron (SN)-like rat neuroendocrine pheochromocytoma-12 (PC12) cell line in 3D transwell coculture with human mesenchymal stem cells (hMSCs), in the presence of an AD-analogous inflammatory environment. We then characterized alterations in a subset of the intrinsic cellular mechanisms which significantly contribute to AD related neuronal deficits by comparing iPSC-differentiated cortical neurons derived from an AD patient to those derived from an age- and sex-matched healthy control. A subset of AD-derived neurons was treated with the P2 purinergic receptor antagonist suramin to evaluate the putative role of extracellular adenosine triphosphate (ATP) signaling in neuronal pathology. Finally, we further probed the involvement of intrinsic neuronal mechanisms found to be dysregulated in an expanded panel of AD derived, iPSC-differentiated cortical neurons in the context of two hypothesized risk factors for AD development: hyperhomocysteinemia and environmental toxin exposure.Ph
A Cognitive Immersive Room for Intelligence Analysis Scenarios (CIRIAS)
No full textIntelligence can be understood as the timely delivery of actionable information. Our Cognitive Immersive Room for Intelligence Analysis Scenarios (CIRAS) supports foraging and processing information during time-critical scenarios. Intelligence has an ambiguous meaning and could either refer to the ability to learn and reason well using a logical approach or to use a standard procedure to gather and process public and secret information about an adverse entity (e.g., a foreign country) to forecast threats and opportunities. While the latter definition of intelligence roots in military operations, similar methods have been successfully applied in the civil domain, for example, forensic sciences and corporate business decisions. In this paper, we describe the use of cognitive immersive environments for collaborative decision-making using the general procedures of intelligence analysis, especially the concept of the foraging loop by Pirolli and Card (2005). We focus on three use cases, traffic-pattern analysis, bibliographic search, and travel planning, to explain the benefit of virtual environments for the efficient and time-constrained decision-making process. Each of these examples leans heavily on information-foraging behaviors, which have been historically a bottleneck for intelligence gathering. By leveraging the cognitive immersive technology, we will transfer some of the granular search and sort activities to the system, reducing the cognitive load experienced by users during intelligence tasks. The progressive dialog system paired with our map views allows users to plan points of interest across travel itineraries and allows users to plan routes during challenging traffic. Our brainstorming tool supports text source discovery, allowing users to build a knowledge base, and supports bibliography creation.This approach aids analysis in reducing time and time and effort; timely analysis is typically critical in reconnaissance and other intelligence analyst tasks. During collection and analysis, information has to be pulled from various sources and shared among an expert team. CIRIAS possesses matured technologies to source information through personal interfaces such as computer terminals, handheld devices, and dialog systems while also allowing interfacing between groups of people.The latter is important within the shared context between analysts to allow sharing the most relevant information while deferring other information. To bridge this technology gap, we propose a Situations Room environment that enables small teams to pursue intelligence analyst tasks together. In this room, each member can gather information individually while also exchanging and displaying relevant data among each other on large immersive displays. The room provides immersive audio/visual displays to facilitate this as a shared resource while connecting participants to personal devices. The room tracks participants via gestural and acoustic sensors, displays information in spatial relationships to users and extracts speech information and gestures. An existing audio/visual tracking system provides continuous locations of team members using a 6-camera network and a 16-channel spherical microphone. The latter is also used for speech recognition, and assigns input to individual participants for context-based dialog functions utilizing beamforming and tracking. The system can be adapted to different tasks in a flexible manner, which we will explore during our use case discussion
Protease-catalyzed synthesis of oligopeptides and glycan-terminated peptides
No full textAugust 2023School of SciencePeptides and peptide conjugates are used for many applications, including as therapeutics and biomedical materials. At present, established synthetic routes to peptides and their conjugates include solid-phase peptide synthesis (SPPS), liquid-phase peptide synthesis (LPPS), N-carboxyanhydride ring opening polymerization (NCA-ROP) and recombinant peptide synthesis. While each of these methodologies can provide the target structures, their use is limited due to high product cost. SPPS, LPPS and NCA-ROP require toxic reagents, multiple protection-deprotection steps, and excessive solvent utilization. Protease-catalyzed peptide synthesis (PCPS) provides a green alternative method to prepare peptides and peptide conjugates. Furthermore, PCPS is conducted in an aqueous environment, using amino acid ethyl ester starting materials, requires short reaction times (i.e. a few minutes up to a couple hours), and product isolation from reaction mixture is normally simple. This thesis reveals a strategy by which PCPS was used to prepare glycan terminated peptide conjugates. ‘Grafters’ were synthesized that consist of a glycan conjugated directly, or through a short ethylene glycol ([CH2-CH2-O-]x)spacer, to the amine group of L-Phe-ethyl ester (Phe-OEt). Phe-OEt increases the grafter’s recognition at the protease (papain) catalytic active site. While glycan-PheOEt grafters that lacked an oligo(ethylene glycol) spacer resulted in low grafter efficiency (8.3 ± 2.0%), insertion of a short oligo(ethylene glycol) spacer (glycan-[CH2-CH2-O-]x -Phe-OEt, x ≥ 3) increased the grafter efficiency by 3-fold to 24.5 ± 1.8%. Spacers with one and two ethylene glycol units were too short to relieve detrimental papain-glycan interactions that resulted in low grafter efficiencies. Computational modeling performed with Rosetta software identified specific papain-glycan interactions that appear to destabilize the complex formed when the spacer has less than three ethylene glycol units.
In addition, the polymerization of L-His-OEt by both papain and α-chymotrypsin was conducted, and the monomer conversion over time was monitored by NMR spectroscopy. The DPavg of oligo(His) was calculated by ESI-MS. Within 15 min, crude papain catalyzed the conversion of L-His-OEt to water-soluble oligo(His) with a DPavg of 9.3 ± 0.05. In addition, computational modeling performed by Rosetta Software compared the pocket energy for hydrolysis and synthesis of His oligomers catalyzed by crude papain and αchymotrypsin. Lastly, recombinant papain and its isozymes were heterologously expressed, purified, and evaluated individually for their peptide synthetic activity. The literature of papain biotransformations is dominated by the use of the natural powder isolated from papaya latex consisting of a mixture of proteases, of which papain is a minor component. Knowledge of whether papain is the only protease of the natural mixture with peptide synthesis activity, or whether peptide synthesis results from some combination of activities of its constituent proteases, is unknown. Herein, the peptide synthetic activity of recombinant papain, as well as its isozymes (chymopapain (I-IV), proteinase omega) was determined for Leu-OEt oligomerization using NMR in situ monitoring. Recombinant papain exhibited a 31% higher yield than commercial papain, using equivalent enzyme units measured by an azocasein assay. Furthermore, each isozyme was active to different extents for oligo(Leu) synthesis.Ph
An analytical and numerical study on the fracture toughness of fibrous network materials
No full textMay 2023School of EngineeringMany materials have a network of fibers as their main structural component and are referred to as network materials. Their strength and toughness are important in both engineering and biology. In this work we consider stochastic model fiber networks without pre-existing cracks and study their rupture mechanism. These materials soften as the crosslinks or fibers fail and exhibit either brittle failure immediately after the peak stress, or a more gradual, ductile rupture in the post peak regime. We observe that ductile failure takes place at constant energy release rate defined in the absence of pre-existing cracks as the strain derivative of the specific energy released. The network parameters controlling the energy release rate are identified and discussed in relation to the Lake-Thomas theory which applies to crack growth situations. We also observe a ductile to brittle failure transition as the network becomes more affine and relate the embrittlement to the reduction of mechanical heterogeneity of the network. Further, we confirm previous reports that the network strength scales linearly with the bond strength and with the crosslink density. The present results extend the Lake-Thomas theory to networks without pre-existing cracks which fail by the gradual accumulation of distributed damage and contribute to the development of a physical picture of failure in stochastic network materials.M