• Nanoscale Schottky Barrier Visualization Utilizing Computational Modeling and Ballistic Electron Emission Microscopy

      Nolting, Westly; LaBella, Vincent; Advisor (2018-05)
      Understanding the properties and performance of semiconductor interfaces on the nanoscale advances semiconductor device technology which has had tremendous impact on nearly all aspects of our daily lives. Investigating the nanoscale fluctuations in the electrostatics of metal-semiconductor, or Schottky, interfaces is crucial. However, techniques for directly measuring the electrostatics at an interface are limited. Current state-of-the-art finFETs use metal-semiconductor silicides, such as Ti-Si/Si, for Schottky source-drain contacts. Studying the underlying physics of the Schottky barrier interface of silicides and other metal-semiconductor systems is critical for measuring the Schottky barrier accurately, which can be accomplished with ballistic electron emission microscopy (BEEM), a scanning tunneling microscopy (STM) based technique. In this work, the visualization of the interface to nanoscale dimensions is enhanced by computational modelling of threshold histograms acquired by the BEEM measurement technique. Modelling using a kinetic Monte-Carlo approach is utilized to simulate the distributions of barrier heights that includes effects from the interface and transport of the hot electrons as well as indication of a multi-barrier heights present at the interface. The aid of this modelling enables the discovery of several underlying properties of the interface. Analyzing the parameters of the modelling and comparing to measured data provides detailed insight into the effects that both electron scattering and incomplete silicide formation in W/Si(001) and WSi2/Si(001) have upon the transport of electrons through these structures, which is difficult to detect with conventional current-voltage measurements. The modelling also includes simulation of multiple barriers present at the interface due to the intermixing of similar metals such as Au and Ag at the interface of Si(001) In this regard, Schottky barrier visualization as the combination of histograms, mapping, and modelling provides a new insight into the local nanoscale phenomenon of the Schottky barrier. This thesis investigates the modelling of these metal-semiconductor systems and uses modelling to look at metal thickness dependent effects on the Schottky barrier from Fermi-level pinning in Au/Cr-Si/Si(001) and Au/Cr-Si/Si(111) silicide.
    • NautiCode: Coding for Kids

      Zeo, Brittany; Mullick, Rosemary; Adviser; Sarner, Ronald; Reviewer; Urban, Christopher; Reviewer (2016-05-08)
      Throughout my college career, I have asked students what made them decide to major in Computer Science. The answers I received very seldom revealed previous coding experience. Unfortunately, this is the system: you don’t know what you want to major in and so you choose something that looks interesting. You just hope it works out for the best. Fortunately for me, I had four years of programming experience in classes before reaching college as well as being a programmer on my high school’s FIRST Robotics team. This previous exposure to coding allowed me to make an educated decision about what I wanted to major in. It is not always the case that an individual gets this experience, and I want to change that. For my Masters Project, I have decided to come up with a website to get kids to learn and practice some basic concepts of coding: NautiCode. My target audience is mid to upper elementary school children. And best of all, there is no previous coding experience needed when using NautiCode. Even if Computer Science is not their career choice, they can have the exposure at an early age. Coding does not only benefit computer scientists; just having the background knowledge of concepts such as: logic, data storage, and how things relate, can be beneficial to an individual for any major. These ideas can help individuals think about problems differently and come up with solutions that would not have been possible had they not been exposed to computer science concepts. What better time in an individual’s life to introduce these concepts than childhood. Children’s brains are magnificent. They can absorb so much information and they think differently about the world. This leads to creative solutions and a new perspective. What I aim to do with NautiCode is to get children thinking in new ways and exploit their creativity and spark new ideas. I aim to give an explanation of the simple concepts in an introduction and gradually work up towards more difficult problems. Children are more capable than they know and with a little guidance, they can start creating their own technologies in no time. NautiCode is a fully functional website that I created on my own. The front end is using Scss, and HTML5 while the backend is using PHP, SQL, JS, and AJAX. My databases are being hosted locally through phpMyAdmin and MAMP.
    • NEAR-ATOMIC RESOLUTION STRUCTURE OF THE YEAST VACUOLAR (V-) ATPASE MEMBRANE SECTOR Vo IN LIPID NANODISC

      Wilkens, Stephan; Stam, Nicholas J (2020-04-10)
      Vacuolar ATPase (V-ATPase) is a large multisubunit enzyme that acidifies subcellular organelles and the extracellular space. Its activity is regulated by reversible disassembly, causing V-ATPase dissociation into soluble V1-ATPase and membrane-integral Voproton channel sectors.The goal of this thesis project was to observethe yeast Voin a physiologically relevant, auto-inhibited state, i.e. in its form dissociated from the ATPase sector, V1, in order to better visualizethe closed pore and to identify testable hypotheses on why the pore remains closed following dissociation from V1. Towards this aim we present two chapters:In Chapter 1, we detail a single-particle negative stain EM study of lipid nanodisc reconstituted Vo,which suggesteddissociated Vois halted in theso-called rotational state 3 of the holo-enzyme.We performed site directed mutagenesis and binding studies of subunits aand dto test and validate this hypothesis.In Chapter 2,we further detaillipid nanodisc reconstitutedVoin a high-resolutioncryoEM structure,confirmingour earlier identification of Voresting in rotational state 3, andproviding structural information of the sectorat the amino acid level. Through this work we proposed apossible mechanism for transmembrane proton transport in the V-ATPaseandidentifieda new subunit member of Vo, assembly factor Voa1.The studies shown here highlight the potential of lipid nanodisc reconstitution of membrane protein complexes, give insight into a conformational mismatch between autoinhibited V1and halted Vowith the implication that the mismatch may serve to prevent unintended reassembly of V-ATPase upon activity silencing, and propose a chemical basis for transmembrane proton transport in the Voproton pore.
    • Nearwork-Induced Transient Myopia (NITM) Following Marked and Sustained, but Interrupted, Accommodation at Near

      Arunthavaraja, Mathangi (2010-07-16)
      Purpose: It has been speculated that non-decayed NITM (accommodatively-based nearwork-induced transient myopia) may be myopigenic in nature. Thus, the purpose of the present investigation was to determine objectively the initial magnitude and decay of NITM, and its potential additivity, following successive but interrupted periods of marked, sustained accommodation at near in asymptomatic young-adult myopic subjects. Methods: Fifteen visually-normal, asymptomatic young adults (ages 18 – 28 years) were tested with full distance refractive correction. They included 9 early-onset (EOM) and 6 late-onset (LOM) myopic subjects. Accommodation was assessed objectively with a Canon R-1, open-field, infrared auto-refractor under monocular viewing conditions (RE). The distance refractive state was measured immediately before and after a ten minute period of focusing upon a moderate contrast (50%), very near target (12 cm; 8D) subtending a visual angle of 1 degree. The task was repeated twice with a 5-minute inter-task rest period of imposed far viewing. NITM was defined as the post-task minus pre-task change in distance refractive state immediately following each task. Results: Significant amounts of NITM were generated following nearly each trial in each subject. These ranged from 0.11 to 0.71D, with a mean of 0.31D. The group mean NITM was 0.32, 0.29, and 0.31D for trials 1, 2, and 3, respectively. For the EOMs subgroup, NITM was 0.28, 0.30, and 0.34D, while for the LOMs subgroup, it was 0.38, 0.29, and 0.26D, for for trials 1, 2, and 3, respectively. Decay of NITM was prolonged in many of the subjects (67%). However, additivity of NITM was not found following the sequences of interrupted near tasks. Conclusions: There was no evidence of NITM additivity following a marked and sustained, but interrupted, near task. Although NITM has been reported to be additive following long periods of uninterrupted and sustained reading at lower dioptric levels, providing rest periods between each near task trial appears to prevent a cumulative effect (i.e., additivity effect). These findings support the idea of far viewing being protective in nature from myopia development.
    • Neuropsychological intra-individual variability explains unique genetic variance of ADHD and shows suggestive linkage to chromosomes 12, 13, and 17

      Frazier-Wood, Alexis C.; Bralten, Janita; Arias-Vasquez, Alejandro; Luman, Marjolein; Ooterlaan, Jaap; Sergeant, Joseph; Faraone, Stephen V.; Buitelaar, Jan; Franke, Barbara; Kuntsi, Jonna; et al. (Wiley, 2012-01-05)
      Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neuropsychiatric disorder that is usually accompanied by neuropsychological impairments. The use of heritable, psychometrically robust traits that show association with the disorder of interest can increase the power of gene-finding studies. Due to the robust association of intra-individual variability with ADHD on a phenotypic and genetic level, intra-individual variability is a prime candidate for such an attempt. We aimed to combine intra-individual variability measures across tasks into one more heritable measure, to examine the relatedness to other cognitive factors, and to explore the genetic underpinnings through quantitative trait linkage analysis. Intra-individual variability measures from seven tasks were available for 238 ADHD families (350 ADHD-affected and 195 non-affected children) and 147 control families (271 children). Intra-individual variability measures from seven different tasks shared common variance and could be used to construct an aggregated measure. This aggregated measure was largely independent from other cognitive factors related to ADHD and showed suggestive linkage to chromosomes 12q24.3 (LOD ¼ 2.93), 13q22.2 (LOD ¼ 2.36), and 17p13.3 (LOD ¼ 2.00). A common intra-individual variability construct can be extracted from very diverse neuropsychological tasks; this construct taps into unique genetic aspects of ADHD and may relate to loci conferring risk for ADHD (12q24.3 and 17p13.3) and possibly autism (12q24.3). Given that joining of data across sites boosts the power for genetic analyses, our findings are promising in showing that intra-individual variability measures are viable candidates for across site analyses where different tasks have been used.
    • The new neuropsychiatric genetics

      Faraone, Stephen V.; Smoller, J.W.; Pato, C.N.; Sullivan, P.; Tsuang, M.T. (Wiley, 2008-01-05)
    • New Techniques for Public Key Encryption with Sender Recovery

      Godi, Murali; Viswanathan, Roopa; Adviser; Novillo, Jorge; Reviewer; Chiang, Chen-Fu; Reviewer (2016-12-15)
      In this paper, we consider a situation where a sender transmits a ciphertext to a receiver using a public-key encryption scheme, and at a later point of time, wants to retrieve the plaintext, without having to request the receiver’s help in decrypting the ciphertext, and without having to store a set of plaintext/ciphertext pairs for every receiver the sender interacts with. This problem, known as public key encryption with sender recovery has intuitive solutions based on KEM/DEM schemes. We propose a KEM/DEM-based solution that is CCA-secure, and only requires the receiver to be equipped with a public/secret key pair (the sender needs only a symmetric recovery key), and has much simplified proofs compared to prior work in this area. We prove our protocols secure in the single receiver and multi-receiver setting. To achieve our goals, we use an analysis technique called plaintext randomization that results in greatly simplified and intuitive proofs for protocols that use a PKE internally as a component and compose the PKE with other primitives. We instantiate our protocol for public key encryption with sender recovery with the well-known KEM/DEM scheme due to Cramer and Shoup.
    • NIMH genetics initiative millennium schizophrenia consortium: Linkage analysis of African-American pedigrees

      Kaufmann, Charles A.; Suarez, Brian; Malaspina, Dolores; Pepple, John; Svrakic, Dragan; Markel, Paul D.; Meyer, Joanne; Zambuto, Christopher T.; Schmitt, Karin; Matise, Tara Cox; et al. (Wiley, 1998-07-10)
      The NIMH Genetics Initiative is a multi-site collaborative study designed to create a national resource for genetic studies of complex neuropsychiatric disorders. Schizophrenia pedigrees have been collected at three sites: Washington University, Columbia University, and Harvard University. This article—one in a series that describes the results of a genome-wide scan with 459 short-tandem repeat (STR) markers for susceptibility loci in the NIMH Genetics Initiative schizophrenia sample—presents results for African-American pedigrees. The African-American sample comprises 30 nuclear families and 98 subjects. Seventy-nine of the family members were considered affected by virtue of having received a DSMIII-R diagnosis of schizophrenia (n = 71) or schizoaffective disorder, depressed (n = 8). The families contained a total of 42 independent sib pairs. While no region demonstrated evidence of significant linkage using the criteria suggested by Lander and Kruglyak, several regions, including chromosomes 6q16-6q24, 8pter-8q12, 9q32-9q34, and 15p13-15q12, showed evidence consistent with linkage (P = 0.01–0.05), providing independent support of findings reported in other studies. Moreover, the fact that different genetic loci were identified in this and in the European-American samples, lends credence to the notion that these genetic differences together with differences in environmental exposures may contribute to the reported differences in disease prevalence, severity, comorbidity, and course that has been observed in different racial groups in the United States and elsewhere. Am. J. Med. Genet. (Neuropsychiatr. Genet.) 81:282–289, 1998. © 1998 Wiley-Liss, Inc.
    • Non-Convex Optimization: RMSProp Based Optimization for Long Short-Term Memory Network

      Andriamanalimanana, Bruno; Committee Chair; Chiang, Chen-Fu; Thesis Committee; Novillo, Jorge; Thesis Committee; Yan, Jianzhi (2020-05)
      This project would give a comprehensive picture of non-convex optimization for deep learning, explain in details about Long Short-Term Memory (LSTM) and RMSProp. We start by illustrating the internal mechanisms of LSTM, like the network structure and backpropagation through time (BPTT). Then introducing RMSProp optimization, some relevant mathematical theorems and proofs in those sections, which give a clear picture of how RMSProp algorithm is helpful to escape the saddle point. After all the above, we apply it with LSTM with RMSProp for the experiment; the result would present the efficiency and accuracy, especially how our method beat traditional strategy in non-convex optimization.
    • Non-Convex Optimization: RMSProp Based Optimization for Long Short-Term Memory Network

      Andriamanalimanana, Bruno; Yan, Jianzhi; Andriamanalimanana, Bruno; First Reader; Chiang, Chen-Fu; Second Reader; Novillo, Jorge; Third Reader (SUNY Polytechnic Institute, 2020-05-09)
      This project would give a comprehensive picture of non-convex optimization for deep learning, explain in details about Long Short-Term Memory (LSTM) and RMSProp. We start by illustrating the internal mechanisms of LSTM, like the network structure and backpropagation through time (BPTT). Then introducing RMSProp optimization, some relevant mathematical theorems and proofs in those sections, which give a clear picture of how RMSProp algorithm is helpful to escape the saddle point. After all the above, we apply it with LSTM with RMSProp for the experiment; the result would present the efficiency and accuracy, especially how our method beat traditional strategy in non-convex optimization.
    • A Normative Architecture for an Online Agent-Based Healthcare System

      Bhaiya, Neha; Novillo, Jorge; Advisor; Rezk, Mohamed; Reviewer (2017-05)
      In this thesis, we envisage an opportunistic Multi-Agent System (MAS) system in Health Care Domain by using wearable and ingestible body sensors. This thesis develops an integrated and an emergent normative logical collection, computation and communication architecture providing a foundation plane for a total healthcare system based on Body Area Network sensors under the supervision of a physician or a team of physicians. Such an online healthcare system as yet does not exist; this thesis anticipates the necessary framework an online healthcare system need to proceed in the near future. The thesis is centered upon the notion of an anomalous system state that may arise owing to temporal anomalous behavior of one or more locally monitored state variables. The system that is envisaged in this thesis is an anomaly-driven event-oriented system triggering doctor’s office for further action if and when such a system enters into a state of anomaly. The data is constantly monitored for anomalous pattern by an ‘Intelligent Server’ which intimates the user’s physician upon receiving an anomalous data like sudden drop in blood pressure, pulse and other vital statistics. The physician then alerts the patient of a declining reading, or calls for emergency services and decides if the patient needs to be admitted in the hospital. We discuss our proposed system architecture for the same.
    • Nursing Home Website Review: Are they accessible, usable, and do they meet consumer needs?

      Warchol, Gail (2005-05-01)
      This study addresses a two-part research question: Are nursing home websites easily accessible and used and do they offer enough information for consumers to make informed choices? Research indicated that generally, hospital discharge planners are the ones who initially explain nursing homes to their patients with brochures and other hard copy information. Some consumers, (generally family members of the patients) have visited nursing home websites. A review of nursing home websites found that nursing home guide sites are often used for giving an array of information, including state survey results, quality assurance, staff ratio, and occupancy rates. The internet users who were interviewed stated that nursing home websites are often difficult to locate. Once having found the sites, interviewees ranked resident rights information as being most interesting, especially information on choice-making and how they are treated once in the nursing home.
    • NYS Fair Events Mobile Application With Client-Side Caching

      Kanala, Sumant; Cheng, Chen-Fu; Advisor; Gherasoiu, Iulian; Reviewer; Tekeoglu, Ali; Reviewer (2017-12)
      NYS Fair Events collects data about fair events which happen in New York state throughout the year, bundles them, displays the upcoming events and useful information about the event itself, the weather and forecast prediction, and a Google Maps to show the route to the event from the user’s location. The motivation for creating this project arose with understanding the growing market for mobile applications and by working for a startup for several months now in the field of web development. A trend has been established in which more users are switching towards mobile apps as their preferred information exchange tool than their traditional PCs and hence the development of better apps should be geared towards mobile phones and tablet PCs. The development of the app is mainly divided into two steps, the client and server side. For the client side I developed a Cordova-based mobile app which is cross-platform and can be compiled to work on Android and IOS based mobile devices. For the server side, I used Node.js runtime environment and deployed it onto Heroku’s free dyno tier which is a cloudbased Platform as a service (paaS). Based on user’s actions, data is requested from the server’s endpoints and appropriate information is served and shown to the user in an intuitive manner.
    • OBJECT ORIENTED ARTIFICIAL NEURAL NETWORK SIMULATOR IN TEXT AND SYMBOL RECOGNITION

      Piszcz, Alan; Ishaq, Naseem; Advisor; Novillo, Jorge E; Reviewer; Sengupta, Saumendra; Reviewer (1993)
      Objected oriented languages and artificial neural networks are new areas of research and development. This thesis investigates the application of artificial neural networks using an object oriented C++ backpropagation simulator. The application domain investigated is hand printed text and engineering symbol recognition. An object oriented approach to the simulator allows other simulator paradigms to reuse a large body of the object classes developed for this particular application. The review and implementation of image feature extraction methodologies is another area researched in this paper. Four feature techniques are researched, developed, applied and tested, using digits, upper case alphabet characters and engineering symbol images. Final implementation and testing of the feature extraction methods with a baseline technique is analyzed for applicability in the domain of hand printed text and engineering symbols
    • Objective Assessment of Retinal Ganglion Cell Function in Glaucoma

      Joshi, Nabin (2017-09-25)
      Glaucoma refers to a group of diseases causing progressive degeneration of the retinal ganglion cells. It is a clinical diagnosis based on the evidence of structural damage of the optic nerve head with corresponding visual field loss. Structural damage is assessed by visualization of the optic nerve head (ONH) through various imaging and observational techniques, while the behavioral loss of sensitivity is assessed with an automated perimeter. However, given the subjective nature of visual field assessment in patients, visual function examination suffers from high variability as well as patient and operator- related biases. To overcome these drawbacks, past research has focused on the use of objective methods of quantifying retinal function in patients with glaucoma such as electroretinograms, visually evoked potentials, pupillometry etc. Electroretinograms are objective, non-invasive method of assessing retinal function, and careful manipulation of the visual input or stimulus can result in extraction of signals particular to select classes of the retinal cells, and photopic negative response (PhNR) is a component of ERG that reflects primarily the retinal ganglion cell function. On the other hand, pupillary response to light, measured objectively with a pupillometer, also indicates the functional state of the retina and the pupillary pathway. Hence, the study of both ERGs and pupillary response to light provide an objective avenue of research towards understanding the mechanisms of neurodegeneration in glaucoma, possibly affecting the clinical care of the patients in the long run.
    • Objective assessment of visual dysfunction in the acquired brain injury (ABI) population using the visual-evoked potential (VEP)

      Yadav, Naveen K. (2014-07-09)
      Purpose: To assess quantitatively and objectively selected visual dysfunctions in patients with mild traumatic brain injury (mTBI) (i.e., increased abnormal visual motion sensitivity (VMS), attentional deficits) and stroke (i.e., hemianopic visual field defects) by using empirically-derived, optimized pattern visual evoked potential (VEP) parameters derived from our laboratory. Furthermore, the goal was to develop simple and reliable clinical VEP protocols to assess the aforementioned visual dysfunctions in acquired brain injury. Methods: Four experiments were performed binocularly with full refractive correction using an objective, pattern VEP technique. Experiments #1-3 included both visually-normal (VN) adults and adults with mTBI, all ages 18-70 years. Experiment #4 included adult patients with stroke and hemianopic visual field defects, all ages 18-70 years. The following tests and stimulus conditions were used in Experiments #1-4: Experiment #1 – central field VEP with 10, 20, and 40 min arc check sizes at low (20%) and high (85%) contrast levels; Experiment #2 – central field VEP (baseline), binasal occlusion only (BNO), base-in prism (BI) only (4 pd total), and BNO with 4 pd BI; Experiment #3 – central field VEP (eyes open (EO), baseline), eyes-closed (EC, “relaxed”), and eyes-closed number counting (ECNC, “increased attentional state”); Experiment #4 – central field VEP, intact hemi-field only, and hemianopic field only. Results: The followings results were found: Experiment #1 – The 20 min arc check size provided the largest VEP amplitude and normative latency values at both contrast levels in both the VN and mTBI groups. These optimal parameters were then used to measure VEP responses in Experiments #2-4. Experiment #2 – With BNO alone, the VEP amplitude was larger in individuals with mTBI (90%) and smaller in the VN (100%) groups, as compared to other two test conditions and baseline. In addition, with BNO only, those with mTBI demonstrated improvement in their visual impressions and in performing specific sensorimotor tasks. Experiment #3 – Objectively-based alpha attenuation ratio (AR = EC ÷ EO, ECNC ÷ EC) was able to detect, assess, and differentiate between mTBI with versus without an attentional deficits, as well as between VNs. These objective AR findings were correlated with the subjective Adult ADHD Self-Report Scale (ASRS) questionnaire scores. Experiment #4 – The group and individual VEP findings showed that the central field and the intact hemi-field VEP amplitudes were larger than found in the hemianopic field. Moreover, these objective findings were correlated with the subjective clinical perimetric results. Conclusions: The optimized VEP parameters provided quantitative, rapid, reliable, and repeatable responsivity in all experiments. These findings demonstrated that the conventional pattern VEP could be beneficial for researchers in general, as well as clinicians to differentiate between mTBI versus the VN group with a high probability, and also between mTBI with versus without an attentional deficit. In addition, the VEP could be used clinically to detect and assess hemianopic visual field defects in patients with stroke. Based on these findings, the VEP has the potential to be used as an objective visual system biomarker for the diagnosis of mTBI/concussion, and also as an objective adjunct clinical tool to detect visual field defects in patients with stroke.
    • Oculomotor rehabilitation for reading dysfunction in mild traumatic brain injury

      Thiagarajan, Preethi (2013-06-04)
      Abstract: Aim Considering the extensive neural network of the oculomotor subsystems, global damage as a result of traumatic brain injury could compromise precise oculomotor control, thus causing reading dysfunction. The aim of the present thesis was to evaluate comprehensively the effect of oculomotor-based vision rehabilitation in symptomatic individuals with respect to nearwork and reading and having a mild traumatic brain injury (mTBI). A wide range of laboratory and clinical parameters related to reading involving vergence, accommodation, and version were tested. Methods Twelve subjects with documented mTBI and nearvision-related symptoms participated in the study. A cross-over, interventional experimental design was used involving true “oculomotor” training and “SHAM” training. Each training protocol was performed for 6 weeks, 2 sessions a week, 45 minutes of actual training per session. During each training session, all three oculomotor subsystems (vergence/accommodation/version) were trained for 15 minutes each in a randomized order. All laboratory and clinical parameters were measured before (baseline) and after true oculomotor (post-OMT) and SHAM (post-SHAM) training. In addition, nearvision-related symptoms were assessed using the Convergence Insufficiency Symptom Survey (CISS) scale. Lastly, subjective attention was measured using the Visual Search and Attention Test (VSAT). iv Results Following true oculomotor training, there was a marked improvement in various laboratory and clinical parameters assessed. Over 80% of the abnormal parameters found at baseline testing were found to significantly improve with training. Dynamics of vergence and accommodation, along with clinically assessed maximum amplitudes, improved markedly. Versional saccadic eye movements demonstrated improved rhythmicity and accuracy. These results together had a significant positive impact on overall reading ability. The improved reading-related oculomotor behavior was reflected in reduction of symptoms. In addition, subjective attention was found to also improve with true oculomotor training. In contrast, none of the aforementioned parameters changed with SHAM training. Conclusions Oculomotor-based vision rehabilitation had a strong positive effect on reading-related oculomotor control. This oculomotor learning effect is suggestive of intact neuroplasticity mechanisms in a compromised brain following TBI.
    • The p53-Zn2+ Energy Landscape and Metallochaperone Hypothesis

      Loh, Stewart; Blanden, Adam (2017)
      p53 is a tumor suppressor protein found mutated in essentially half of human cancers, and dysfunctional in nearly all human cancers. Each DNA-binding domain of the protein contains a critical tetrahedrally coordinated Zn2+. In this work, we present a quantitative thermodynamic model describing the energetics of the p53-Zn2+ interaction, as well as the mechanism of action of a new class of therapeutic compounds we call synthetic zinc metallochaperones (ZMC) that restore proper structure and function to many mutant p53s by delivering Zn2+ to the protein in the cell. We combine recombinant protein expression and in vitrobiophysical characterization with cell biology, molecular biology, medicinal chemistry, and live cell imaging to address these issues. Our model for both the mechanism of action of ZMCs and the p53-Zn2+interaction are broadly based on the Metallochaperone Hypothesis originally proposed by our group in 2010. We find that the core tenants of the Metallochaperone Hypothesis are accurate, and have expanded that model to quantitatively describe the link between p53-Zn2+ binding and protein stability noted for decades in the field. We find that at physiological temperature and Zn2+ concentrations, wild-type p53 has a folding energy of ~0 kcal mol-1, and as such is exquisitely sensitive to inactivation by mutation, and rapidly changes the fraction folded in response to changes in Zn2+ concentration. We demonstrate that ZMCs are ionophores, transport Zn2+ from the extracellular space into cells, and rescue mutant p53 by increasing the intracellular free Zn2+ concentration. This increase in Zn2+ stabilizes the mutant proteins via the same mechanism previously described for substrate stabilization of enzymes, and is only seen in a "Goldilocks Zone" of Zn2+ concentrations and ZMC Kds. This presents a fundamentally new way to interact with and reactivate mutant p53s, and raises questions about the potential for biological exploitation of this interaction for signaling or other functions.
    • A Parent's Interactive guide to the Social Network

      Wasecka, Joseph James (2013-05-01)
      This project hopes to determine what characteristics of an eBook will afford learning and be an effective tool for educating parents and their children on the responsible use of social networking sites. Two separate literature reviews of related studies are conducted. The first begins by examining findings from previous research on the use of social media by young children. The purpose of this review is to determine the focus and content of the eBook. Literature was collected in an electronic database by using the following key words: Cyber bullying, Web 2.0 tools, Internet Safety. The second review looks at the characteristics of an Ebook that affords learning. Literature was collected in an electronic database by using the following key words: Multimedia, Hypertext, Online Learning, Interactivity, E-books and education. E-book prototypes of an eBook were created using Flip Book Creator Professional. The Prototypes were designed using information from previous studies, Information Interactive Design and applying some of the Universal Principles of Design that afford learning. The hope is that the eBook will bridge the gap between what schools are doing and what parents need to do. The idea is that parents are going to stay connected with their children while they are online. The E-book will help educate and prepare parents to guide their children while using the “Social Network”.