• JUNCTIONAL ARMADILLO (β-CATENIN) MAINTAINS PROPER TISSUE ARCHITECTURE DURINGDROSOPHILAEYE DEVELOPMENT

      Pignoni, Francesca; DeSantis, Dana F (2020)
      Formation of thecompoundeye of Drosophilarequires carefully orchestrated developmental events that occur in its progenitor epithelium, the eye imaginal disc.This tissue is composed of two continuous, apposed epithelia: the disc proper epithelium (DpE), which forms the retina, and the peripodial epithelium (PE), which ultimately forms head cuticle. In this work, I describe an armadillo (b-catenin)loss-of-function condition in which the developing DpEis disrupted and displays a phenotype that I call“retinalshift”. This developmental phenotype ultimately results in abnormal fly eye morphology that is incompatible with compound eye vision.I uncover a role for the PE in maintaining proper retinal epithelium morphology during eye formation and trace the molecular mechanism to the regulation of Hippo-Yki pathway in PE cells by the function of Armadillo at the adherens junctions.
    • Knowledge Documentation - From Text to Graphics: Can this improve help desk knowledge transfer?

      Gage, Teresa J. (2007-08-01)
      This thesis was designed to find out if graphics could improve help desk knowledge transfer. Four Web prototype presentation styles were analyzed via the Delphi Method (Michalski 2003) utilizing a panel of experts. The elements tested included the use of text and increasing amounts of graphics presented with different navigation systems. The results proved that graphics could improve knowledge transfer but that a combination of text and graphic may be more effective in a team-centric solution to help desk knowledge transfer.
    • Laboratory-Observed Behavioral Disinhibition in the Young Offspring of Parents With Bipolar Disorder: A High-Risk Pilot Study

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Henin, Aude; Faraone, Stephen V.; Cayton, Gabrielle A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2006-02)
      Objective: This study tested whether behavioral disinhibition is more prevalent among offspring of parents with bipolar disorder than among offspring of parents without bipolar disorder. Method: The authors conducted a secondary analysis of data from a preexisting high-risk study of offspring at risk for panic disorder and depression (N=278) that had included some children with parents who had bipolar disorder (N=34). Children (ages 2–6) had been classified as behaviorally inhibited, disinhibited, or neither in laboratory assessments. Results: Offspring of bipolar parents had significantly higher rates of behavioral disinhibition than offspring of parents without bipolar disorder. Behavioral inhibition did not differ between groups. Differences were not accounted for by parental panic disorder or major depression or by parental history of attention deficit hyperactivity disorder, conduct disorder, antisocial personality, or substance use disorders. Conclusions: Results suggest a familial link between bipolar disorder in parents and behavioral disinhibition in their offspring. Behavioral disinhibition may be a familially transmitted predisposing factor for dysregulatory distress later in life.
    • Lack of Association Between Behavioral Inhibition and Psychosocial Adversity Factors in Children at Risk for Anxiety Disorders

      Hirshfeld-Becker, Dina R.; Biederman, Joseph; Faraone, Stephen V.; Segool, Natasha; Buchwald, Jennifer; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2004-03)
      Objective: In a previous controlled study of offspring at risk for anxiety disorders, the authors found that parental panic disorder with comorbid major depression was associated with child behavioral inhibition, the temperamental tendency to be quiet and restrained in unfamiliar situations. To explore whether this association was mediated by environmental factors, the authors examined associations between psychosocial adversity variables and behavioral inhibition in this group of children. Method: Subjects included 200 offspring of parents with panic disorder and/or major depression and 84 comparison children of parents without mood or anxiety disorders. Behavioral inhibition was assessed through laboratory observations. The associations between behavioral inhibition and the following psychosocial factors were examined: socioeconomic status; an index of adversity factors found in previous studies to be additively associated with child psychopathology; family intactness, conflict, expressiveness, and cohesiveness; exposure to parental psychopathology; sibship size; birth order; and gender. Results: The results showed no associations between behavioral inhibition and any of the psychosocial factors in the study group as a whole, despite adequate power to detect medium effect sizes. Among low-risk comparison children only, some definitions of behavioral inhibition were associated with low socioeconomic status, low family cohesion, and female gender. Conclusions: The results suggest that the psychosocial adversity factors examined in this study do not explain the previous finding that offspring of parents with panic disorder are at high risk for behavioral inhibition.
    • Lack of Association Between Parental Alcohol or Drug Addiction and Behavioral Inhibition in Children

      Biederman, Joseph; Hirshfeld-Becker, Dina R.; Rosenbaum, Jerrold F.; Perenick, Sarah G.; Wood, Julia; Faraone, Stephen V. (American Psychiatric Association Publishing, 2001-10)
      Objective: “Behavioral inhibition to the unfamiliar” has been proposed as a precursor to anxiety. A recent study proposed that it may also be a precursor to alcoholism. The authors sought to replicate the latter finding through a secondary analysis of data from a large study of young children (age 2–6 years)—offspring of parents with panic and depressive disorders—who had been assessed for behavioral inhibition through laboratory-based observations. Method: The offspring were stratified on the basis of presence or absence of parental lifetime history of DSM-III-R alcohol dependence (N=115 versus N=166, respectively) or drug dependence (N=78 versus N=203). The rates of behavioral inhibition were then compared between groups. Results: Despite adequate power to detect associations, neither parental alcohol dependence nor drug dependence was associated with a higher risk for behavioral inhibition in the offspring. Conclusions: These results are not consistent with the hypothesis linking behavioral inhibition to addictions
    • Laminins regulate retinal angiogenesis

      Brunken, William J.; Biswas,Saptarshi (2017)
      Vascular pathologies are the leading causes of acquired blindness in the developed world. While many studies sought to unravel cell-intrinsic and growth factor-mediated regulations of angiogenesis, it is only recently that the role of the basement membrane (BM) components in angiogenesis began to be explored. Several diseases with ocular manifestations are known to alter vascular BM compositions. Therefore, a detailed knowledge of the BM-mediated signals that regulate angiogenesis is of great importance. Laminins, a critical component of the BM, have been shown to regulate several aspects of angiogenesis in the retina. Our laboratory previously demonstrated that the laminin composition of the inner limiting membrane (ILM) regulates astrocyte migration, and consequently vascular expansion along the retinal surface. Here, I examined the role of γ3- and β2-containing laminins in two specific aspects of angiogenesis: 1) vascular branching and endothelial cell proliferation in the nascent vascular plexus, and 2) arterial morphogenesis in the remodeling zone. Results presented in Chapter 2 and Appendix 1 demonstrate that laminin composition of the BM is a critical regulator of microglial recruitment to the growing nascent plexus, where microglia facilitate vascular branching. Furthermore, microglia interact with the astrocyte-derived layer of the vascular BM, and that this interaction regulates iii microglial activation. The activation state of microglia, in turn, regulates endothelial cell proliferation. Results presented in Chapter 3 and Appendix 2 demonstrate that vascular BM laminins are critical regulators of arterial morphogenesis. Specifically, my results reveal a novel mechanism where γ3- containing laminins signal through dystroglycan to induce Dll4/Notch signaling in arterial endothelial cells, regulating proper arterial morphogenesis. Finally, in Appendix 3, I examined the coordinated expression of different laminin chains in the vascular BM. My preliminary results suggest that expressions of laminin α2-, α5- and γ3-chains in the retinal vascular BM are coordinately regulated with the expression of laminin β2-chain. In conclusion, this study sheds light on hitherto unexplored mechanisms by which BM laminins regulate retinal vascular development.
    • Laptop’s In Education – Hype or Help?

      Cronn, Patrick (2006-12-01)
      This study examines the impact of introducing a laptop program for educational teaching in the classroom. By interviewing experts in the field, teachers, administrators, and students at a college level, a phenomenology was completed on the impact of laptops in pedagogy. These ideals were then applied to the Human-Centered Design Theory. “It was not until twenty years ago that serious progress was achieved in applying the available computer and internet technology to support teaching and learning in schools and institutions of higher education. The technology that was previously only available to large corporations and organizations began to be available in homes, schools and universities. This new shift in technology application has provided both students and educators many new advantages and learning possibilities (Altalib, 4).” The numerous ways in which professors and their students interact has always been a critical issue in higher educational institutes. With the increase in technological enhancements over the past several years, study is needed on how collaboration between faculty and students advance.
    • Linkage of chromosome 13q32 to schizophrenia in a large veterans affairs cooperative study sample

      Faraone, Stephen V.; Skol, Andrew D.; Tsuang, Debby W.; Bingham, Stephen; Young, Keith A.; Prabhudesai, Sarita; Haverstock, Susan L.; Mena, Felicitas; Menon, Aerath Sri Kumar; Bisset, Darren; et al. (Wiley, 2002-07-29)
      Several prior reports have suggested that chromosomal region 13q32 may harbor a schizophrenia susceptibility gene. In an attempt to replicate this finding, we assessed linkage between chromosome 13 markers and schizophrenia in 166 families, each with two or more affected members. The families, assembled from multiple centers by the Department of Veterans Affairs Cooperative Studies Program, included 392 sampled affected subjects and 216 affected sib pairs. By DSM-III-R criteria, 360 subjects (91.8%) had a diagnosis of schizophrenia and 32 (8.2%) were classified as schizoaffective disorder, depressed. The families had mixed ethnic backgrounds. The majority were northern European-American families (n = 62, 37%), but a substantial proportion were African-American kindreds (n = 60, 36%). Chromosome 13 markers, spaced at intervals of approximately 10 cM over the entire chromosome and 2-5 cM for the 13q32 region were genotyped and the data analyzed using semi-parametric affected only linkage analysis. For the combined sample (with race broadly defined and schizophrenia narrowly defined) the maximum LOD score was 1.43 (Z-score of 2.57; P = 0.01) at 79.0 cM between markers D13S1241 (76.3 cM) and D13S159 (79.5 cM). Both ethnic groups showed a peak in this region. The peak is within 3 cM of the peak reported by Brzustowicz et al.
    • Live Tweet Map with Sentimental Analysis

      Kotrika, Rohila; Chen-Fu Chiang; Reviewer; Saumendra, Sengupta; Advisor; Andriamanalimanana, Bruno; Reviewer (2016-05-01)
      This project basically aims to build a system for the real-time analysis of the trends and public views around the whole world by storing and analyzing the stream of tweets from the Twitter live API which produces a huge amount of data . The tweets, tweet ID, time and other relevant elements are stored into a database and are represented in a map that is being updated in near real time with the help of Google map API. This project also aims to achieve the sentimental analysis of the tweets by sending the tweets to the natural language processing API which in turn processes the tweets using the natural language processing and gives a result If those tweets are positive, negative or neutral in nature. The map clusters tweet as to show where people are tweeting most from according to the sample tweets we get from the streaming API. These clusters will be shown in different colors according to the sentimental evaluation we receive from the sentiment API by Vivek Narayanan which works by examining individual words and short sequences of words (n-grams) and comparing them with a probability model. The probability model is built on a pre labeled test set of IMDb movie reviews. It can also detect negations in phrases, i.e., the phrase "not bad" will be classified as positive despite having two individual words with a negative sentiment. The web service uses a co routine server based on event, so that the trained database can be loaded into shared memory for all requests, which makes it quite scalable and fast. The API is specified here, it supports batch calls so that network latency isn't the main bottleneck. For Instance, if a tweet is negative in evaluation then it is shown in a red color marker on the map, green for positive and grey for the neutral. This analytic will also demonstrate the heat map for all the tweets that are stored in the database which gives a satisfying answer demonstrating from which part of the world are most of the tweets from. In this project we create a dynamic web application with the target runtime environment as Apache Tomcat Server. The server will also be initialized with the context listener which starts running the code to get the tweets into the database till the server is stopped. The most popular trends among worldwide and citywide would be provided in a drop down to be selected from which gives a clear perspective on how each trend behaves. It also offers the public, the media, politicians and scholars a new and timely perspective on the dynamics of the world wide trends and public opinion.
    • Liver-specific glucocorticoid action in alcoholic liver disease

      Lu, Hong; Wang, Yazheng (2021)
      The number of deaths due to alcoholic liver disease is increasing every year. Glucocorticoids (GCs) are the only first-line drugs for alcoholic hepatitis (AH) treatment but have limited efficacy. Long-term high-dose GC use can cause various side effects on extrahepatic tissues, such as immunosuppression and neuromuscular side effects, which may be a limiting factor for GC treatment of AH. Therefore, liver-specific GC-targeted therapy may have multiple advantages compared with systemic GC for AH. This research explored the role of liver-specific deficiency of glucocorticoid receptor (GR) in AH induced by a high-fat diet (HFD) plus ethanol binge. Females are less prone to AH induced by HFD plus acute binge drinking, likely due to sex differences in estrogen (E2) signaling. We found that hepatic GR deficiency worsened steatosis in both genders of AH mice but only aggravated the liver injury in male AH mice. Multiple signaling pathways were dysregulated in GR knockout AH mice. Interestingly, hepatic expression of estrogen receptor (ERα) was induced, and the E2-inactivating enzyme was markedly down-regulated in GR knockout AH mice, suggesting enhanced E2 signaling in these mice. Our data mining found marked dysregulation of many GR-target genes important for lipid catabolism, cytoprotection, and inflammation in patients with severe AH. These key GR-target genes were similarly induced or down-regulated by our liver-targeting GC prodrugs and the parent drug at 1μM in primary human hepatocytes. In contrast, GC prodrugs had much weaker inhibitory effects than the parent drug on LPS-induction of IL-1B in mouse macrophages, suggesting a good liver selectivity of our liver-targeting GC prodrugs. The ultimate goal of this study is to determine the mechanistic role of GR in alcoholic fatty liver disease and develop targeted drug therapies to treat alcoholic hepatitis.
    • Localization of sarcomeric proteins during muscle assembly in mouse cardiomyocytes and skeletal myotubes

      Sanger, Jean; Sanger, Joseph; Welchons, Matthew J (2017)
      This study seeks to investigate the role of contractions in myofibrillogenesis, and structure of nascent myofibrils. The model system employed in these experiments was cultured quail myotubes. In order to determine the role of contractions in myofibrillogensis, contractions were indirectly inhibited with elevated KCl, and directly inhibited with 2,3 butanedione monoxime (BDM), a small cell-permeable inhibitor of actin & muscle myosin interactions. Myotubes were treated with contraction inhibitors at 2½days –soon after the main fusion event. On the 6thculture day, there was significant delay in myofibrillogensis in myotubes exposed to elevated KCl. This delay was characterized by the expansion of nascent myofibrils at the spreading edges of myotubes. This delay in myofibrillogenesis was not accompanied by diminished accumulations of muscle myosin. On the 4thculture day, there was complete arrest of myofibrillogenesis at the nascent step with the treatment of BDM. As a result, it is concluded that contractions are necessary for the progression of nascent myofibrils to mature myofibrils. The structure of nascent myofibrils was further investigated with super resolution microscopy. Structured illumination microscopy (SIM) and stimulated emission depletion (STED) microscopy revealed mini-A-bands –shorter than 1.5 μmin length –associated with nascent myofibrils. These structures were spaced at varying intervals, and oriented at angles deviating the from the actin superstructure of the nascent myofibril. Mini-A-bands were also observed to progressively in expand in length distal to the spreading edges of myotubes. STED imaging indicates that some mini-A-band are adjacent to, and not integrated within, the actin superstructure of nascent myofibrils.
    • Long-term outcome of pediatric obsessive-compulsive disorder: a meta-analysis and qualitative review of the literature

      Stewart, S. E.; Geller, D. A.; Jenike, M.; Pauls, D.; Shaw, D.; Mullin, B.; Faraone, Stephen V. (Wiley, 2004-07)
      Objective: To review the extant literature on the long-term outcome of child/adolescent-onset obsessive–compulsive disorder (OCD). Method: Medline and Psychlit databases were systematically searched for articles regarding long-term outcomes of child/adolescent-onset OCD. Meta-analysis regression was applied to evaluate predictors and persistence of OCD. Results: Sixteen study samples (n ¼ 6–132; total ¼ 521 participants) in 22 studies had follow-up periods ranging between 1 and 15.6 years. Pooled mean persistence rates were 41% for full OCD and 60% for full or subthreshold OCD. Earlier age of OCD onset (z ¼ )3.26, P ¼ 0.001), increased OCD duration (z ¼ 2.22, P ¼ 0.027) and inpatient vs. out-patient status (z ¼ 2.94, P ¼ 0.003) predicted greater persistence. Comorbid psychiatric illness and poor initial treatment response were poor prognostic factors. Although psychosocial function was frequently compromised, most studies lacked comprehensive outcome measures. Conclusion: Long-term persistence of pediatric OCD may be lower than believed. Future studies should include broader measures of outcome including symptomatic persistence and functional impairment in multiple domains.
    • Lost Memories: Exploring Childhood Amnesia and Nostalgia Through Autoethnographic Research

      Lizardi, Ryan; Thesis Advisor; Stam, Kathryn; Second Reader; Danielle, Pastore (2021-04)
      Memory, especially at a young age, is unstable. Memories can easily be remapped and misremembered. Generally, memory retention follows a predictable pattern, known as the reminiscence bump, and memory retention reaches its peak around twenty years old. While memory retention does increase exponentially as a child ages, there is a tendency for early childhood memories to vanish - a phenomenon known formally as childhood amnesia. Photographs and videos can act as memory aids to assist recall, but can lead to misremembering. People also view photographs and videos (especially physical versions such as photo albums) as memory storage devices, and often experience a great deal of nostalgia when flipping through and reminiscing. However, just as society experienced a shift from analogue to digital film and video, users shifted their intentions of photography from memory to communication. To further explore these topics I performed extensive autoethnographic research. In the hopes of shedding light on lost or forgotten memories and to better understand personal nostalgia, I had twenty-eight rolls of undeveloped childhood film developed, which I then personally scanned. Additionally, I digitally transferred and watched eighty-six never-before-seen childhood home video cassettes. Using both written, photo, and video footage-based context clues, I assembled a video timeline to represent my lost memories. Video Link: https://youtu.be/7OCfjgm1YkU
    • Machine Learning And MRI-Based Diagnostic Models For ADHD: Are We There Yet?

      Zhang-James, Yanli; Hoogman, Martine; Franke, Barbara; Faraone, Stephen V. (Cold Spring Harbor Laboratory, 2020-10-23)
      Machine learning (ML) has been applied to develop magnetic resonance imaging (MRI)-based diagnostic classifiers for attention-deficit/hyperactivity disorder (ADHD). This systematic review examines this literature to clarify its clinical significance and to assess the implications of the various analytic methods applied. We found that, although most of studies reported the classification accuracies, they varied in choice of MRI modalities, ML models, cross-validation and testing methods, and sample sizes. We found that the accuracies of cross-validation methods inflated the performance estimation compared with those of a held-out test, compromising the model generalizability. Test accuracies have increased with publication year but were not associated with training sample sizes. Improved test accuracy over time was likely due to the use of better ML methods along with strategies to deal with data imbalances. Ultimately, large multi-modal imaging datasets, and potentially the combination with other types of data, like cognitive data and/or genetics, will be essential to achieve the goal of developing clinically useful imaging classification tools for ADHD in the future.
    • Machine-Learning Prediction of Comorbid Substance Use Disorders in ADHD Youth Using Swedish Registry Data

      Zhang-James, Yanli; Chen, Qi; Kuja-Halkola, Ralf; Lichtenstein, Paul; Larsson, Henrik; Faraone, Stephen V. (Cold Spring Harbor Laboratory, 2019-06-06)
      Background: Children with attention-deficit/hyperactivity disorder (ADHD) have a high risk for substance use disorders (SUDs). Early identification of at-risk youth would help allocate scarce resources for prevention programs. Methods: Psychiatric and somatic diagnoses, family history of these disorders, measures of socioeconomic distress, and information about birth complications were obtained from the national registers in Sweden for 19,787 children with ADHD born between 1989 and 1993. We trained (a) a cross-sectional random forest (RF) model using data available by age 17 to predict SUD diagnosis between ages 18 and 19; and (b) a longitudinal recurrent neural network (RNN) model with the Long Short-Term Memory (LSTM) architecture to predict new diagnoses at each age. Results: The area under the receiver operating characteristic curve (AUC) was 0.73(95%CI 0.70–0.76) for the random forest model (RF). Removing prior diagnosis from the predictors, the RF model was still able to achieve significant AUCs when predicting all SUD diagnoses (0.69, 95%CI 0.66–0.72) or new diagnoses (0.67, 95%CI: 0.64, 0.71) during age 18–19. For the model predicting new diagnoses, model calibration was good with a low Brier score of 0.086. Longitudinal LSTM model was able to predict later SUD risks at as early as 2 years age, 10 years before the earliest diagnosis. The average AUC from longitudinal models predicting new diagnoses 1, 2, 5 and 10 years in the future was 0.63. Conclusions: Population registry data can be used to predict at-risk comorbid SUDs in individuals with ADHD. Such predictions can be made many years prior to age of the onset, and their SUD risks can be monitored using longitudinal models over years during child development. Nevertheless, more work is needed to create prediction models based on electronic health records or linked population registers that are sufficiently accurate for use in the clinic.
    • Magnesium Oxide Tunneling Current and Ferromagnetic Film Characterization

      Bull, Horace (SUNY Polytechnic Institute, 2016-05-01)
      Magnetic Tunnel Junctions are a very promising technology with the potential to replace numerous forms of computer memory a well as a wide range of other applications. Three novel studies are done demonstrating various aspects of MTJ design and manufacturing showing their importance in understanding device performance. First, a Vibrating Sample Magnetometer (VSM) study comparing Co40Fe40B20 and Co20Fe60B20 films of varying thicknesses between 0.6 nm and 3.2 nm is reported. Greater iron content is shown to increase the overall magnetic moment of the samples. Second, a Current in Plane Tunneling (CIPT) study is done showing the dependence Magnetoresistance (MR) has on the thickness of the MTJ free layer and the crystallinity of the active region of devices. A full MTJ device stack is developed, with free layer thicknesses from 0.6-1.75 nm and 1.5-3.3 nm creating a wedge profile on each sample wafer. CIPT shows a significant increase to MR with anneal, verifying the presence of the [001] crystal structure in post anneal samples using TEM. Third, Ta/Co40Fe40B20/MgO/Co40Fe40B20/Ta thin film metal-insulator-metal capacitors were developed to measure the tunneling effect and how it changes as a result of MgO thickness and CoFeB crystallinity. Devices were designed with: varied MgO thickness from 0.5 nm to 2 nm thick, with pre and post anneal CoFeB. Current-Voltage data was collected and device resistance was found to have a linear dependence on MgO thickness in the post anneal CoFeB/MgO/CoFeB samples. The uniformity of the IV data indicates potential for use monitoring devices during MTJ manufacturing.
    • Managing Social Media in Half the Time: Creating an Infographic for Small Businesses

      Hazen, Kimberly; Lizardi, Ryan; First Reader; Yucel, Ibrahim; Second Reader (2017-12)
      Research suggests that social media is arguably more important for small businesses because they often lack the traditional resources to market their products or services. However, it is often difficult for small businesses managers to implement social media due to the many demands on their time and limited staff. The infographic visually displays the tools small businesses can use to save time when implementing social media, through an interactive longform infographic designed specifically for the web. This paper explores how small businesses use social media; the hurdles small businesses face when implementing social media; and how different social media platforms speak to different demographics. It also provides an overview of the design process, the project’s production, and the design rules that were used in the creation and design of the infographic. In addition, it will include a project analysis with the challenges involved in the project and the project’s limitations. It also suggests future project directions related to this topic.
    • Mapping, Implementing, and Programming Spiking Neural Networks

      Cady, Nathaniel; Chair; Cafaro, Carlo; LaBella, Vincent; Oktyabrsky, Serge; Plank, James; External Committee Member; Olin-Ammentorp, Wilkie (2019-03)
      Computer architectures inspired by biological neural networks are currently an area of growing interest, due to immense utility of these systems which is shown by their near-ubiquity within animals. An essential aspect of these systems is their ability to compute through the exchange of temporal events called ‘spikes.’ However, many aspects of biological computation remain unknown. To improve our ability to measure neural systems, we create an efficient implementation and statistical testing method to calculate an information-theory based metric, transfer entropy, on signals recorded from cultures of neurons. Taking inspiration from established knowledge regarding biological neurons, we investigate the impact which stochastic behavior has on the robustness of spiking networks when their synaptic weights are inaccurate. We find that a level of stochasticity can help improve this robustness. Lastly, we investigate methods of creating programs for spike-based computation through evolutionary optimization methods, and identify opportunities and challenges in this area.
    • A matter of life and death: human cytomegalovirus induction of monocyte survival and differentiation into macrophages through manipulation of the PI3K/Akt pathway

      Chan, Gary; Cojohari, Olesea (2017)
      Human cytomegalovirus (HCMV) is a ubiquitous β-herpesvirus infecting up to 80% of the US population and reaching 100% seroprevalence in many parts of the world. In mostindividuals HCMV infection is usually asymptomatic. In contrast, in immunodeficient or immunonaive people, such as transplant recipients and the developing fetus, the virus is a major cause of morbidity and mortality. During a primary infection, HCMVcan spread very effectively in the body infecting many organ types and monocytes are believed to be the principal cell type responsible for HCMV dissemination throughout the body. Monocytes, however, are naturally programmed to undergo apoptosis after 48h in the circulation and are not permissive for viral replication. Our lab has shown that in order to combat these biological hurdles, HCMV promotes survival of these short-lived cells past their 48h “viability gate”. Besides inducing survival, the virus also mediates the differentiation of monocytes into macrophages skewed towards an M1 pro-inflammatory phenotype with select M2 anti-inflammatory features, which are long-lived cells, permissive for viral replication. However, the mechanisms used by HCMV to concomitantly induce survival and macrophage differentiation -two linked but separate processes, are not fully understood. The studies in this thesis reveal that upon binding and entry, HCMV initiates a survival program in monocytes by inducing a rapid and sustained activation of the PI3K/Akt pathway, which isdifferent from that induced by myeloid growth factors. Moreover, after inducing cellular survival across the 48-h viability gate, the virus also employsthe PI3K/Akt pathway to regulate caspase 3 activation which mediatesthe atypical M1/M2 polarization. Our work suggests that virus not only makes use of the PI3K/Akt pathway, but manipulates it at multiple levels toallow for viral-specific downstream functional changes.Deciphering how the virus uniquely maneuvers signaling pathways in monocytes to drive their survival and differentiation might allow us to develop new treatments targeting HCMV-infected monocytes and preventing viral spread and disease.
    • MAXIMIZING THE CHEMICAL REMOVAL OF CERIA ABRASIVES IN CMP FOR SILICON OXIDE AND METAL POLISHING

      Thiel, Brad; Defense Committee; Carpenter, Michael; Defense Committee; Borst, Christopher; Defense Committee; Hatzistergos, Michael; Defense Committee; Dunn, Kathleen; Committee Chair; Netzband, Christopher M. (2020-08)
      Cerium oxide or ceria has garnered a wide range of applications due to its redox active nature. This redox activity is due to oxygen vacancies on the surface of the ceria creating a layer of mixed oxide with the unstable oxide Ce2O3 (Ce[superscript 3+]) present at the same time as the bulk oxide CeO2 (Ce[superscript 4+]). Possible applications for ceria include water splitting, oxidation of carbon monoxide, oxidation of reactive oxygen species and polishing of glass films. In recent years, ceria nanoparticles have been used for polishing thermal silicon oxide during the early steps of semiconductor fabrication in a process referred to as chemical mechanical planarization (CMP). The advantage of these particles is their ability to abrade an oxide surface chemically using the aforementioned redox properties, as well as mechanically. To meet the needs of manufacturing, mainly removal rate and surface roughness, the particles used must have well controlled physical properties such as size and shape for mechanical removal and ratio of cerium oxidation state for chemical removal. This study encompasses three parts following the design of ceria slurries, their implementation in the existing silicon oxide polish and applying these findings to create novel slurries for polishing metals. To design ceria slurry, the ratio of Ce[superscript 3+]/Ce[superscript 4+] on the surface of abrasive was maximized by altering the slurries’ chemical environment. Maximizing this ratio increases the proportion of active Ce[superscript 3+] sites which participate in removal reactions. The effect of chemical environment on the Ce[superscript 3+]/Ce[superscript 4+] ratio was determined through XPS analysis of the Ce 3d spectrum. The knowledge gained in this first section informed the design of ceria slurries for the following two parts to maximize their effectiveness. The second part of this thesis applies this knowledge to create ceria iv slurries that polished thermal oxide with higher material removal rate (MRR) and lower postpolish roughness than slurries that are currently being used in industry. The basis of ceria polishing is known as the tooth-comb model. In this model oxygen at Ce[superscript 3+] sites will undergo a condensation reaction with oxygen on the surface to be polished. As the particle leaves this will rip material off of the wafer surface. While the tooth-comb model was proposed for polishing silica, the final part of this thesis seeks to generalize it to encompass polishing any oxide given the correct conditions. To demonstrate this, I created ceria slurries to polish metals relevant to the semiconductor industry (copper, tungsten and ruthenium) with polishing metrics that equal or exceed those of industry standard slurries.