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.
    • Outer surface protein polymorphisms linked to host‐spirochete association in Lyme borreliae

      Tufts, Danielle M.; Hart, Thomas M.; Chen, Grace F.; Kolokotronis, Sergios‐Orestis; Diuk‐Wasser, Maria A.; Lin, Yi‐Pin (Wiley, 2019-02-27)
      Lyme borreliosis is caused by multiple species of the spirochete bacteria Borrelia burgdorferi sensu lato. The spirochetes are transmitted by ticks to vertebrate hosts, including small- and medium-sized mammals, birds, reptiles, and humans. Strain-to-strain variation in host-specific infectivity has been documented, but the molecular basis that drives this differentiation is still unclear. Spirochetes possess the ability to evade host immune responses and colonize host tissues to establish infection in vertebrate hosts. In turn, hosts have developed distinct levels of immune responses when invaded by different species/strains of Lyme borreliae. Similarly, the ability of Lyme borreliae to colonize host tissues varies among different spirochete species/strains. One potential mechanism that drives this strain-to-strain variation of immune evasion and colonization is the polymorphic outer surface proteins produced by Lyme borreliae. In this review, we summarize research on strain-to-strain variation in host competence and discuss the evidence that supports the role of spirochete-produced protein polymorphisms in driving this variation in host specialization. Such information will provide greater insights into the adaptive mechanisms driving host and Lyme borreliae association, which will lead to the development of interventions to block pathogen spread and eventually reduce Lyme borreliosis health burden.
    • 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.
    • Parallel Epidemics of Community-Associated Methicillin-Resistant<i>Staphylococcus aureus</i>USA300 Infection in North and South America

      Planet, Paul J.; Diaz, Lorena; Kolokotronis, Sergios-Orestis; Narechania, Apurva; Reyes, Jinnethe; Xing, Galen; Rincon, Sandra; Smith, Hannah; Panesso, Diana; Ryan, Chanelle; et al. (Oxford University Press (OUP), 2015-06-05)
      Background: The community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) epidemic in the United States is attributed to the spread of the USA300 clone. An epidemic of CA-MRSA closely related to USA300 has occurred in northern South America (USA300 Latin-American variant, USA300-LV). Using phylogenomic analysis, we aimed to understand the relationships between these 2 epidemics. Methods: We sequenced the genomes of 51 MRSA clinical isolates collected between 1999 and 2012 from the United States, Colombia, Venezuela, and Ecuador. Phylogenetic analysis was used to infer the relationships and times since the divergence of the major clades. Results: Phylogenetic analyses revealed 2 dominant clades that segregated by geographical region, had a putative common ancestor in 1975, and originated in 1989, in North America, and in 1985, in South America. Emergence of these parallel epidemics coincides with the independent acquisition of the arginine catabolic mobile element (ACME) in North American isolates and a novel copper and mercury resistance (COMER) mobile element in South American isolates. Conclusions: Our results reveal the existence of 2 parallel USA300 epidemics that shared a recent common ancestor. The simultaneous rapid dissemination of these 2 epidemic clades suggests the presence of shared, potentially convergent adaptations that enhance fitness and ability to spread.
    • 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”.
    • Participant Interaction and Social Exchange-Centered Design in Massively Multiplayer Online Role-Playing Games: A Qualitative Study of Furcadia

      Scialdone, Michael J (2007-08-01)
      The purpose of this ethnography is to understand participant interaction in a Massively Multiplayer Online Role-Playing Game (MMORPGs). As participation and action of users are the glue of any community, it is imperative to examine how and why people congregate in graphical virtual environments. This relatively new phenomenon is studied within both existing and emerging schools of social thought. In this paper, the question is asked: how do participants interact within the context of an MMORPG, and are they encouraged to do so? This question is answered through an ethnographic study of one such MMORPG entitled Furcadia. This study applies both Human-Centered Design (to answer the how), and Social Exchange Theory (to answer the why). It is asserted that MMORPGs can be explained through a marrying of theories into a new one entitled Social Exchange-Centered Design.
    • Password Habits of Security Literate Individuals

      Mahesh, Namrata; Hash, Larry; Advisor; Marsh, John; Reviewer; White, Joshua; Reviewer (2018-05)
      In the age of the Internet, the common user has accounts on multiple websites. Basic account authentication has a username and a password. While username may be common knowledge, passwords are secret, and it is important to use good password habits. Security literate internet users, i.e, students, faculty, professionals in the IT industry are expected to know better than to use bad password habits. But that may not always be the case. This thesis aims to test the hypothesis that security literate internet users use bad password habits despite knowing better, and then proceeds to understand the underlying factors behind these habits through a survey. The survey consisted of questions about basic password habits. The responses were analyzed for better insights
    • Patients' Use and Perception of Internet-Based Orthopaedic Sports Medicine Resources.

      Koenig, Scott; Nadarajah, Vidushan; Smuda, Michael P; Meredith, Sean; Packer, Jonathan D; Henn, R Frank (2018-09-20)
      Background: Current research is sparse regarding how patients with orthopaedic injuries perceive and use internet-based information resources. Hypothesis: The majority of patients use the internet to research their orthopaedic condition and are receptive to guidance from their provider. Study design: Cross-sectional study. Methods: A total of 213 patients attending a sports medicine clinic on the East Coast of the United States were asked to complete a questionnaire regarding their use of internet-based information. Data from 185 patients were available for analysis. Bivariate and multivariate statistical analyses were used to determine the significance of identified associations. Results: Overall, 54% of patients used the internet to find information about their orthopaedic condition prior to their consultation. A higher percentage of internet users were women (P = .01), were white (P = .03), and had internet access at home (P = .02). Multivariable analysis found home internet access to be the only significant independent factor predictive of patients using internet-based information sources (P < .01). The majority of patients (61%) were neutral toward orthopaedic information found online, and only 32% of patients trusted the orthopaedic information they found online. The majority of patients (83%) reported they would be receptive to providers' guidance on which internet resources to use. Conclusion: Only half of patients use the internet to research their orthopaedic condition. Most patients were either neutral toward or did not trust the internet-based information that they found and may forgo internet sources altogether. To help patients avoid misleading information, sports medicine providers should understand how patients are using the internet and guide patients in selecting high-quality, peer-reviewed sources of information. Doing so allows physicians to proactively educate their patients even after the clinic visit.
    • Patterns of Psychopathology and Dysfunction in High-Risk Children of Parents With Panic Disorder and Major Depression

      Biederman, Joseph; Faraone, Stephen V.; Hirshfeld-Becker, Dina R.; Friedman, Deborah; Robin, Joanna A.; Rosenbaum, Jerrold F. (American Psychiatric Association Publishing, 2001-01)
      Objective: The purpose of the study was to evaluate 1) whether an underlying familial predisposition is shared by all anxiety disorders or whether specific risks are associated with specific disorders, and 2) whether panic disorder and major depression have a familial link. Method: The study compared four groups of children: 1) offspring of parents with panic disorder and comorbid major depression (N=179), 2) offspring of parents with panic disorder without comorbid major depression (N=29), 3) offspring of parents with major depression without comorbid panic disorder (N=59), and 4) offspring of parents with neither panic disorder nor major depression (N=113). Results: Parental panic disorder, regardless of comorbidity with major depression, was associated with an increased risk for panic disorder and agoraphobia in offspring. Parental major depression, regardless of comorbidity with panic disorder, was associated with increased risks for social phobia, major depression, disruptive behavior disorders, and poorer social functioning in offspring. Both parental panic disorder and parental major depression, individually or comorbidly, were associated with increased risk for separation anxiety disorder and multiple (two or more) anxiety disorders in offspring. Conclusions: These findings confirm and extend previous results documenting significant associations between the presence of panic disorder and major depression in parents and patterns of psychopathology and dysfunction in their offspring.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
      Despite ongoing controversy, the view that pediatric mania is rare or nonexistent has been increasingly challenged not only by case reports, but also by systematic research. This research strongly suggests that pediatric mania may not be rare but that it may be difficult to diagnose. Since children with mania are likely to become adults with bipolar disorder, the recognition and characterization of childhood-onset mania may help identify a meaningful developmental subtype of bipolar disorder worthy of further investigation. The major difficulties that complicate the diagnosis of pediatric mania include: 1) its pattern of comorbidity may be unique by adult standards, especially its overlap with attention-deficit/hyperactivity disorder, aggression, and conduct disorder; 2) its overlap with substance use disorders; 3) its association with trauma and adversity; and 4) its response to treatment is atypical by adult standards. Biol Psychiatry 2000;48: 458–466 © 2000 Society of Biological Psychiatry.
    • Pediatric mania: a developmental subtype of bipolar disorder?

      Biederman, Joseph; Mick, Eric; Faraone, Stephen V.; Spencer, Thomas; Wilens, Timothy E; Wozniak, Janet (Elsevier BV, 2000-09)
    • Penetrance and Pleiotropy of Polygenic Risk Scores for Schizophrenia, Bipolar Disorder, and Depression Among Adults in the US Veterans Affairs Health Care System.

      Bigdeli, Tim B; Voloudakis, Georgios; Barr, Peter B; Gorman, Bryan R; Genovese, Giulio; Peterson, Roseann E; Burstein, David E; Velicu, Vlad I; Li, Yuli; Gupta, Rishab; et al. (2022-09-14)
      Importance: Serious mental illnesses, including schizophrenia, bipolar disorder, and depression, are heritable, highly multifactorial disorders and major causes of disability worldwide. Objective: To benchmark the penetrance of current neuropsychiatric polygenic risk scores (PRSs) in the Veterans Health Administration health care system and to explore associations between PRS and broad categories of human disease via phenome-wide association studies. Design, setting, and participants: Extensive Veterans Health Administration's electronic health records were assessed from October 1999 to January 2021, and an embedded cohort of 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder were found. The performance of schizophrenia, bipolar disorder, and major depression PRSs were compared in participants of African or European ancestry in the Million Veteran Program (approximately 400 000 individuals), and associations between PRSs and 1650 disease categories based on ICD-9/10 billing codes were explored. Last, genomic structural equation modeling was applied to derive novel PRSs indexing common and disorder-specific genetic factors. Analysis took place from January 2021 to January 2022. Main outcomes and measures: Diagnoses based on in-person structured clinical interviews were compared with ICD-9/10 billing codes. PRSs were constructed using summary statistics from genome-wide association studies of schizophrenia, bipolar disorder, and major depression. Results: Of 707 299 enrolled study participants, 459 667 were genotyped at the time of writing; 84 806 were of broadly African ancestry (mean [SD] age, 58 [12.1] years) and 314 909 were of broadly European ancestry (mean [SD] age, 66.4 [13.5] years). Among 9378 individuals with confirmed diagnoses of schizophrenia or bipolar 1 disorder, 8962 (95.6%) were correctly identified using ICD-9/10 codes (2 or more). Among those of European ancestry, PRSs were robustly associated with having received a diagnosis of schizophrenia (odds ratio [OR], 1.81 [95% CI, 1.76-1.87]; P < 10-257) or bipolar disorder (OR, 1.42 [95% CI, 1.39-1.44]; P < 10-295). Corresponding effect sizes in participants of African ancestry were considerably smaller for schizophrenia (OR, 1.35 [95% CI, 1.29-1.42]; P < 10-38) and bipolar disorder (OR, 1.16 [95% CI, 1.11-1.12]; P < 10-10). Neuropsychiatric PRSs were associated with increased risk for a range of psychiatric and physical health problems. Conclusions and relevance: Using diagnoses confirmed by in-person structured clinical interviews and current neuropsychiatric PRSs, the validity of an electronic health records-based phenotyping approach in US veterans was demonstrated, highlighting the potential of PRSs for disentangling biological and mediated pleiotropy.
    • People’s Perception of Smart Home Devices in their Homes & the Factors which Influence this Perception

      Thakur, Versha; Hash, Larry; Adviser; Marsh, John; Reviewer; Tekeoglu, Ali; Reviewer (2016-12-01)
      This thesis is to determine people’s perception of Smart home devices and the factors which influence this perception. Smart Home devices are becoming more common as many companies are launching various such devices. Although many companies are pushing these devices with extensive marketing, do people feel a need for these devices in their home? This thesis tries to find the answer to this question and what factors are affecting these opinions. Focus group methodology is used for this thesis. It is commonly used to perform qualitative researches. Based on the analysis of the Focus Group discussions, it is found that most people (from the targeted population) will be interested in adopting these smart home devices. There are some concerns which will still need to be addressed by the company such as security, Privacy and some health concerns to make the consumers more comfortable in adopting these devices.
    • PEP Tutorials: Using Cognitive Learning Theory in Creating Online Library Instruction

      Covino, Laura (2013-05-01)
      This paper describes the creation of online tutorials that teach about the PEP (Psychoanalytic Electronic Publishing) Archive, a full-text bibliographic database, for two small, graduate-level psychoanalytic institutes. ,QFUHDWLQJWKHWXWRULDOV WKHLQVWLWXWHV¶OLEUDULDQ used Camtasia Studio software and incorporated principles of cognitive learning theory. Research questions are, first, the practicality of creating and maintaining such online tutorials, and second, their effectiveness in providing PEP training. Methodology includes a literature review, pre-project survey, software choice and training, and preparation of recording scripts. The resulting tutorials do display features of cognitive learning theory, including learner control, encoding and individual differences, perception and attention, memory, and active learning. Conclusions are that for future projects, it would be best to create shorter tutorials along with additional, text-based training materials. The second research question is yet to be answered, and finding effective means of evaluation and assessment remains a challenge.
    • A Personal Web Portfolio: Creating an Online Presence from Conception to Implementation

      Stam, Kathryn; Thesis Advisor; Jofre, Ana; Second Reader; Pierre, Marvin (2020-05)
      Approaching the end of my two-year journey through SUNY Poly’s online IDT program, I felt it was necessary for me to create an artifact showcasing my growth and progression as an Information Designer. Since I completed my degree entirely online (via distance learning), I decided to create a web portfolio representing my work in the program. This paper maps, from concept to execution, my process for creating a personal portfolio website. It includes research and analysis of existing portfolios websites, and it investigates how technology and selected design principles influence a website’s creation. The research presented here culminates with the creation and launch of my own personal portfolio website.

      Mollapour, Mehdi; Dushukyan, Natela (2018)
      Protein Phosphatase 5 (PP5) is a serine/threonine phosphatase known to regulate many essential cellular functions including steroid hormone signaling, stress response, proliferation, apoptosis, and DNA repair. PP5 is a knownco-chaperone of the molecular chaperone heat shock protein 90 (Hsp90), and its regulation of Hsp90aidswiththe proper activation of Hsp90 clients and withsteroid hormone signaling.Hsp90 is also one of the strongest activators of PP5, as it releases the auto-inhibition of PP5 by interacting with the N-terminal tetratricopeptide repeat (TPR) domain of PP5. Our lab has recently shown that PP5 is phosphorylated at T362, and that this phosphorylation acts as an “on switch” resultingin the hyperactivation of PP5. Misregulation of this key phosphatase has been shown to aid in the tumor progression of ER-dependent and independent breast cancer. Elevated PP5 levels have also been linked to colorectalcancer, hepatocellular carcinoma (HCC), lymphoma, and prostate cancer. The work presented here reveals the pro-survival role that PP5 plays in kidney cancer. Clear cell renal cell carcinomas (ccRCC) are most often driven by mutations in the von Hippel-Lindau tumor suppressor (VHL). The data in this thesis shows that VHL binds and multi mono-ubiquitinates PP5 at two lysine residues K185 and K199. This post-translational modification negatively regulates PP5 likean “off switch” and ultimately leads to its degradation bythe proteasome. Mutations in the VHLgene that result in inactive mutants or a lack of VHL protein expression lead to ccRCC tumors. The data in this thesis shows that these VHL-nulltumors become dependent on elevated levels of PP5, and that both PP5 knockdown and inhibition lead to cancer cell death. The data further shows that the decrease in PP5 activity in VHL-null cells results in the induction of the extrinsic apoptotic pathway with a dramatic increase in the cleavage of PARP and caspases 3, 7, and 8.
    • Phylogenomic Diversity Elucidates Mechanistic Insights into Lyme Borreliae-Host Association

      Combs, Matthew; Marcinkiewicz, Ashley L.; Dupuis, Alan P.; Davis, April D.; Lederman, Patricia; Nowak, Tristan A.; Stout, Jessica L.; Strle, Klemen; Fingerle, Volker; Margos, Gabriele; et al. (American Society for Microbiology, 2022-08-08)
      Host association—the selective adaptation of pathogens to specific host species—evolves through constant interactions between host and pathogens, leaving a lot yet to be discovered on immunological mechanisms and genomic determinants. The causative agents of Lyme disease (LD) are spirochete bacteria composed of multiple species of the Borrelia burgdorferi sensu lato complex, including B. burgdorferi (Bb), the main LD pathogen in North America—a useful model for the study of mechanisms underlying host-pathogen association. Host adaptation requires pathogens’ ability to evade host immune responses, such as complement, the first-line innate immune defense mechanism. We tested the hypothesis that different host-adapted phenotypes among Bb strains are linked to polymorphic loci that confer complement evasion traits in a host-specific manner. We first examined the survivability of 20 Bb strains in sera in vitro and/or bloodstream and tissues in vivo from rodent and avian LD models. Three groups of complement-dependent host-association phenotypes emerged. We analyzed complement-evasion genes, identified a priori among all strains and sequenced and compared genomes for individual strains representing each phenotype. The evolutionary history of ospC loci is correlated with host-specific complement-evasion phenotypes, while comparative genomics suggests that several gene families and loci are potentially involved in host association. This multidisciplinary work provides novel insights into the functional evolution of host-adapted phenotypes, building a foundation for further investigation of the immunological and genomic determinants of host association.