• 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.
    • Measuring the incessant need of Social Media as a marketing and communication tool in a small camp business.

      Brown, Darilyn (2014-12-01)
      This project was created to examine Facebook, Twitter, and Constant Contact as a communication and marketing tool in a small camp business. Upon revealing how the three tools contribute to the businesses marketing and communication efforts, a social media strategy plan will be created based on the results. As social media and email marketing are said to have many effects on a company, primarily positive and beneficial, this research takes an unbiased approach to how it contributes to the business’ marketing and communication efforts. The Human Centered Design and Social Presence Theory will be used to help illustrate how my proposed social media strategy can be implemented to create an optimal user experience. Qualitative methods will also be utilized in the research and review of the business’ online marketing and communication activity. The overall goal of the project is to review how Facebook, Twitter, and Constant Contact on tribute to a business, how the business utilizes the platforms it is provided, and finally how these platforms can/should be used by creating a proposed social media strategy.
    • MECHANISM OF ANT1-INDUCED HUMAN DISEASES AND STRESS SIGNALING

      Liu, Yaxin (2016)
      Adenine nucleotidetranslocase(Ant) is a mitochondrial inner membraneprotein, the primaryfunction of which is to mediate the ADP/ATP exchange acrossthe inner membrane. Missense mutations in Ant1, the skeletal muscle-and heart-specificisoform, induce human disordersincluding autosomal dominant ProgressiveExternalOpthalmoplegia(adPEO), cardiomyopathyand myopathy. Several models were proposed to interpret the pathogenesis of mutant Ant1-induced diseases, but no consensus has been reached.Our lab has previouslyfound that mutant Aac2, the homologof Ant1 in yeast, causes cell death due to the mitochondrialbiogenesis defect. In the present study, we provided biochemical evidencesupporting the idea that themutant Aac2 proteins are misfolded, which derailsthe proteostasis on the inner membrane.We found that the assemblyand stability of multipleprotein complexeson the inner membrane are affected, including those involved in mitochondrialrespirationand protein transport. In human cells, the mutant Ant1 proteinshave reduced steady-state levels and increased degradation, consistent with misfolding and increased susceptibility to protein quality control machineries. In the second part of thework, we sought to identify the cellularsignalingpathways that respond to Ant1-induced proteostatic stress on the mitochondrialinner membrane. We generatedANT1alleles that have enhanced toxicity and are able to induce proteostatic stress on the inner membrane in human. Although these mutant Ant1 proteins only mildly affectmitochondrialrespiration, they trigger robust transcriptional responses in the nucleus to remodel cellular signaling. The upregulationof the cytosolic chaperone/ubiquitin-proteasome systems, and the downregulation of mTOR signaling may serveas adaptiveresponses to mitigate mitochondrial PrecursorOver-AccumulationStress (mPOS), a novel pathway of cell death recently discovered in yeast. We also found that humancells respond to mitochondrialinner membrane stress by increasingEgr1 signaling and the alternative splicing of many genes important for cell survival/deathcontrol. Insummary, the data suggested that protein misfoldingcauses Ant1-induced pathogenesisin human diseases. Our study provided support for mitochondria-induced proteostatic stress in the cytosol (or mPOS) in human cells. We also identified several novel mitochondria-to-nucleus signaling pathways, which may help in developingtherapeutic interventionsfor the treatmentof mitochondria-induced pathologies.
    • Mechanism of gene regulation of HNF4α

      Lu, Hong; Guo, Shangdong (2018)
      Hepatocyte Nuclear Factor 4 alpha(HNF4α)is a masterregulatorthat modulatesthe liver development andfunction. The dysfunction of HNF4αcauses multiplehumandiseases, such as hepatocellular carcinoma(HCC) and maturity onset diabetes of the young1 (MODY1). Incontrast,the restoration of HNF4α can inhibit the development of liver cancer and improve the liver function simultaneously.However, HNF4αis anorphan nuclear receptor whose activating ligand remains elusive. Therefore, an alternative approach to enhance the HNF4αactivity is to up-regulate the proteinexpression.While a great progress has been made on the functional study of HNF4α,the mechanistic details regarding the gene regulationofHNF4αare still a vast knowledge gap. The present study was aimed to investigatethe mechanism of gene regulation ofHNF4αsystematically. In chapter 2 and chapter 3, we reported the strong translational inhibition of both humanand mouse HNF4αinduced by the nucleicacid secondary structuretermed “G-quadruplex”(G4)within the 5` untranslated region(UTR).By performing the deletion/mutation studies, we determined the compositionof the G4in HNF4A 5`UTR. We further speculated thatthis G4 required the adjacent cis-elements, such as the RNA-binding proteins and other secondary structures, to form a conjunction for the strong translational inhibition. We for the first time reported the RNA-G4 induced translational repression within the 5`UTR of a tumor suppressor and highlighted the significanceof the “biostability”of G4s in exerting their biological functions. In chapter 4, we conductedacomprehensivestudy that coveredthe auto-regulation, transcriptionalregulation and transactivation activity of HNF4α. By creatingvariousreporter constructs, we were able to validate the self-stimulation of HNF4αand discovered the strong correlation between HNF4αand its corresponding anti-sense RNA, HNF4A-AS1. Additionally, we identified novel HNF4αmutations such as Q277X that may affect the crosstalk of HNF4αwith other transcriptionfactors.Overall, the novel findings from our study shedlight on the gene regulation of HNF4αand providefurther insights into ourultimate goal that is to up-regulate HNF4αprotein expression/activity to treat human diseases.
    • Mechanisms of aseptic loosening in total knee arthroplasty

      Cyndari, Karen (2017)
      Introduction: Cemented Total Knee Arthroplasty (TKA) is the gold standard of care for end-stage, multi-etiologic arthritis. While the longevity of these devices may now reach or even surpass 15 years in service, a minority (~10%) will fail prematurely due to a process called aseptic loosening. Historically, this process has been attributed to an inflammatory reaction against wear debris from the TKA polyethylene (PE) insert. However, we have previously estimated supraphysiologic fluid shear stress (FSS) (exceeding 900 Pa) at the cement-bone interface of cemented joint replacements, and examined this as a possible alternative cause of increased osteoclast activity. Methods: We analyzed the cement-bone interlock of tibial and femoral components from en-bloc, postmortem-retrieved, non-revised TKAs to explore the process of loss of fixation, prior to any clinical loosening. For the tibial components, we used a novel protocol wherein whole undecalcified bone+PMMA cement segments from the proximal tibia were embedded in Spurr’s resin and thinly sectioned. Polarized light microscopy was used to identify and quantify co-located PE debris. Using a novel bioreactor developed by our lab called the Multi-Well Fluid Loading (MFL) System, we examined static, subphysiologic, physiologic, and supraphysiologic FSS on RAW 264.7 osteoclast activity and morphology, with and without PE particle treatment. Results: We found no association been the amount or presence of PE debris and the amount or location of loss of interlock in retrieved TKAs. FSS up to 17 Pa increased the ability of osteoclasts to resorb mineral, and FSS up to 4.4 Pa induced the formation of larger osteoclasts. FSS and fluid shear rate interacted together to increase the area of actin rings, while PE treatment increased the number of actin rings and TRAP production. FSS up to 4.4 Pa decreased expression of Ctsk and Il1a, but PE co-treatment abolished this effect. Conclusions: These results indicate there may be alternative factors leading to aseptic loosening apart from PE debris. We demonstrated that osteoclasts are mechanosensitive and able to adjust activity, morphology, and gene expression based on FSS. Further, PE interferes with osteoclast gene downregulation in response to FSS, indicating PE could be a potentiator of osteoclast activity or differentiation.
    • MECHANISMS OF WISKOTT ALDRICH SYNDROME PROTEIN WSP1 POSITIONING AND REGULATION AT SITES OF ENDOCYTOSIS IN S. POMBE

      Sirotkin, Vladimir; Macquarrie, Cameron Dale (2020-12-30)
      Branched actin networks nucleated by the Arp2/3 complex provide force needed to carry out endocytosis. The Arp2/3 complex is activated by Nucleation Promoting Factors (NPFs) including Wiskott-Aldrich Syndrome protein WASp. The WASp Interacting Protein WIP binds WASp, protecting it from degradation. Humans with mutations disrupting this interaction develop a serious immune disorder, Wiskott-Aldrich Syndrome. However, in the fission yeast S. pombe WASp homolog Wsp1 remains stable in the absence of WIP homolog Vrp1, providing an ideal environment to study additional WASp and WIP functions. In fission yeast, Wsp1, Vrp1, and the class-1 myosin Myo1 localize to sites of endocytosis, known as actin patches. Wsp1 and Myo1 play an important role in activating the Arp2/3 complex and initiating the actin network needed to internalize endocytic vesicles. S. pombe endocytosis is a rapid, reproducible event involving over 40 proteins. While several of these proteins are throught to regulate branched actin assembly, many still have poorly defined functions. Importantly, how WASp proteins are regulated at sites of endocytosis remains unclear. The following studies explore mechanisms of Wsp1 regulation using quantitative live cell imaging. In Chapter 2, we observed Wsp1, Vrp1, and Myo1 forming a transient complex near the membrane, positioning branched filaments in a way that optimizes force generation. In Chapter 3, we explored the role of WIP homolog Vrp1 in actin assembly and discovered the Vrp1-Wsp1 interaction is essential for Wsp1-mediated branched actin assembly. In Chapter 4, we examined how a separate module of endocytic coat proteins contributes to actin patch assembly and discovered the coat protein Sla1 inhibits Wsp1 NPF activity, after the endocytic vesicle begins to internalize. In Chapter 5, we examined how Wsp1 and Myo1 impact additional endocytic modules and discovered Wsp1 plays an important role in expediating endocytosis and Myo1 contributes to the localization of several proteins. Lastly, in Chapter 6, we observed that blocking the fastgrowing end of actin filaments does not impact actin assembly in patches. These studies provide key insight into how WASp family proteins are regulated in vivo.
    • Memory and Effector B cell Responses to Viral and Intracellular Bacterial Infection

      Gary M. Winslow; Newell, Krista (2021)
      Infection with an intracellular pathogen presents the host with the immunological challenge of intracellular access and of clearing infection without excessive damage to host tissues. This challenge was long thought to be addressed primarily by cell-mediated immunity, but is now known to include a significant humoral component. To better understand the B cell-mediated contribution to intracellular pathogen control, we investigated memory and effector B cell responses to the intracellular bacterial pathogen Ehrlichia muris, and SARS-CoV-2 infection. B cells expressing the transcription factor T-bet were identified in both mice and humans, and T-bet played an important role in directing antibody class switch recombination, but not in the generation of memory B cells during E. muris infection. T-bet expression was identified in cells resembling murine B-1 B cells, an innate-like subset of B cells important for early T cell-independent B cell responses. These results suggest that T-bet expression in B-1 B cells may contribute to their participation in the early B cell response to murine intracellular bacterial infection. Following human SARS-CoV-2 infection, we revealed that in addition to the canonical class-switched B cell memory response, the presence of a substantial pool of peripheral blood unswitched IgM+ memory B cells was correlated with reduced symptom duration and enhanced generation of antigen-specific antibody. These IgM+ memory B cells were stable, unlike the contracting plasmablast response. These studies underscore the importance of innate and unswitched B cell subsets to the functional plasticity of the humoral response and contribute to our understanding of correlates of innate protection and adaptive immunity.
    • Meta-Analysis of Alzheimer's Disease Risk with Obesity, Diabetes, and Related Disorders

      Profenno, Louis A.; Porsteinsson, Anton P.; Faraone, Stephen V. (Elsevier BV, 2010-03)
      Background: Late-onset Alzheimer’s disease (AD) is a multifactorial and heterogeneous disorder with major risk factors including advanced age, presence of an apolipoprotein E 4 (APOE4) allele, and family history of AD. Other risk factors may be obesity and diabetes and related disorders, which are highly prevalent. Methods: We reviewed longitudinal epidemiological studies of body mass, diabetes, metabolic syndrome, and glucose and insulin levels on risk for AD. We conducted meta-analyses of the results from these studies. Results: For obesity assessed by body mass index, the pooled effect size for AD was 1.59 (95% confidence interval [CI] 1.02–2.5; z 2.0; p .042), and for diabetes, the pooled effect size for AD was 1.54 (95% CI 1.33–1.79; z 5.7; p .001). Egger’s test did not find significant evidence for publication bias in the meta-analysis for obesity (t 1.4, p .21) or for diabetes (t .86, p .42). Since these disorders are highly comorbid, we conducted a meta-analysis combining all studies of obesity, diabetes, and abnormal glucose or insulin levels, which yielded a highly significant pooled effect size for AD of 1.63 (95% CI 1.39 –1.92; z 5.9; p .001). Conclusions: Obesity and diabetes significantly and independently increase risk for AD. Though the level of risk is less than that with the APOE4 allele, the high prevalence of these disorders may result in substantial increases in future incidence of AD. Physiological changes common to obesity and diabetes plausibly promote AD.
    • Meta-Analysis of the Association Between the 7-Repeat Allele of the Dopamine D4Receptor Gene and Attention Deficit Hyperactivity Disorder

      Faraone, Stephen V.; Doyle, Alysa E.; Mick, Eric; Biederman, Joseph (American Psychiatric Association Publishing, 2001-07)
      Objective: Family, twin, and adoption studies show attention deficit hyperactivity disorder (ADHD) to have a substantial genetic component. Although several studies have shown an association between ADHD and the 7-repeat allele of the dopamine D4 receptor gene (DRD4), several studies have not. Thus, the status of the ADHD-DRD4 association is uncertain. Method: Meta-analysis was applied to case-control and family-based studies of the association between ADHD and DRD4 to assess the joint evidence for the association, the influence of individual studies, and evidence for publication bias. Results: For both the case-control and family-based studies, the authors found 1) support for the association between ADHD and DRD4, 2) no evidence that this association was accounted for by any one study, and 3) no evidence for publication bias. Conclusions: Although the association between ADHD and DRD4 is small, these results suggest that it is real. Further studies are needed to clarify what variant of DRD4 (or some nearby gene) accounts for this association.
    • Metabolic Control of Autoimmunity in the Liver

      Perl, Andras; Oaks, Zachary (2016)
      Autophagy,literally meaning “self-eating,” is an integral part of cellularturnover of damaged organelles and proteins.This process is inextricably linked to mitochondrial function and turnover. Mitochondria can be degraded viaautophagy, known as mitophagy, as well as donate lipid membraneto generate autophagosomes fordigestingother organelles and proteins. On a larger scale, autophagy is essential for organ homeostasis. In the liver, autophagy ensures the turnover of damaged mitochondria that may otherwise increase oxidative stress which modifies DNA, proteins, and lipids resulting in the production of autoantigens or neoplasia. We investigated the role of autophagy and mitochondrial dysfunction prior to disease onset in mouse models of systemic lupus erythematosus (SLE). Patients and mice with SLE exhibit overexpression of transaldolase (TAL) and show predisposition to anti-phospholipid antibody production and associated liver diseases, including hepatocellular carcinoma. Wediscovered deficient mitophagy in the liver of lupus-prone mice prior to disease onset. Furthermore, these mice had increased mitochondrial respirationwith concomitant inner membrane hyperpolarization. These changes were coupled to overexpression of Rab4A, which depletes Drp1and thus inhibitsmitophagy.In addition,activation of complex I of the mechanistic target of rapamycin (mTORC1)was noted along with enhanced production of autoantibodies against mitochondrial phospholipids in lupus-prone mice. These changes were reversed by blockade of mTORC1 by rapamycin treatment in vivo. We then examined the role of TAL, a key enzyme of the pentose phosphate pathway (PPP) in mitochondrial dysfunction and oxidative stress. TAL-deficientmice showedincreased mitochondrial electron transport chain (ETC) activity and mTORC1 activation andreduced autophagy.Since inactivation of TAL caused oxidative stress via depletion of NADPH, we tested the hypothesis that aldose reductase(AR), a NADPH dependent enzymecan correct this metabolic defect without reversing the accumulation of TAL-specific substrates, sedoheptulose 7-phosphate and erythrose 4-phosphate. Moreover, deletion of AR reversed mTORC1 activation without affecting enhanced mitochondrial ETC activity or diminished autophagy. On a more global scale, predisposition to neoplasia and acetaminophen-induced liver failurewere reversed, while anti-phospholipid autoantibody production and liver fibrosis persisted in TAL/AR double-knockout mice indicatingthat the PPPmay act as a metabolic rheostat of organ-specific disease pathogenesis.
    • Metabolic Control of Autoimmunity Through Autophagy

      Choudhary, Gourav (2019)
      Metabolism plays a key role in immune cell activation and differentiation. Immune cell activation depending on their biosynthetic and bioenergetic needs leads to profound metabolic reprograming. Proinflammatory subsets of immune system cells such as effector T cells show dependency on glycolysis, whereas, regulatory T cells rely on oxidative phosphorylation. Under metabolic stress, immune cells utilize autophagy to overcome nutrient scarcity, an alternate method of recycling amino acids and other metabolic precursors. Limitation of nutrients such as amino acids activates mechanistic target of rapamycin (mTOR) in the immune cells. mTOR acts as a metabolic mediator, associated with mitochondria and metabolic needs of the immune cells. Homeostasis between mTOR activation and autophagy decides the fate and functionality of specific immune cells. The activation of mTOR is widely acknowledged in the pathogenesis of SLE, whereas, autophagy has been linked with antigen processing, presentation, and immunoregulation. In this study, we focused on Rab4A, an endosomal GTPase and Transaldolase, a rate limiting enzyme of the pentose phosphate pathway (PPP). Rab4A is over expressed in SLE T cells and facilitates lysosomal degradation of CD4 and CD3. Transaldolase is also overexpressed in T cells from SLE patients and SLE prone mice. First, we examined the role of Rab4A in a pristane-induced mouse model of SLE. Since Rab4A protects from pristane-induced alveolar lung hemorrhage, we tested the hypothesis that Rab4A will also protect from pristane-induced lupus nephritis. We found that overexpression of a constitutively active form of Rab4A limits antinuclear antibody production. Further, we found that Rab4A protects from pristane-induced renal injury by restricting immune complex depositions in the kidney. In additions, we found that Rab4A abrogates kidney-infiltration by lymphocytes and protects from podocyte injury. Furthermore, Rab4A facilitates the lysosomal mediated activation of mTOR. Possibly, the Rab4A mediated activation of mTOR in regulatory T cells leads to suppression of pristane-induced pro-inflammation signaling. In the second part, we investigated if aldose reductase (AR) deficiency can protect from Transaldolase mediated pathogenesis of liver disease. We found a coordinated regulation between AR and TAL, leading to the disease progression.
    • Microsoft Office 365 and SharePoint as an Educational Platform

      Crosby, Kenneth M.; Kahn, Russell; Thesis Adviser; Schneider, Steven; Second Thesis Adviser (2018-05)
      This study looks at social constructivist learning theory and andragogy as a means of evaluating Microsoft Office 365® and SharePoint® as a platform for delivering online classes in the basic use of SharePoint to an audience of adult learners (New York State employees). The already wide access within New York State agencies to Office 365 and SharePoint makes it a good candidate for examination. If successful, online learning utilizing Office 365 would help to eliminate the geographical and existing software barriers to delivering occupational training to the more than 130,000 employees. Social constructivist and andragogical learning theories were examined, and key elements identified to establish criteria to aid in evaluating Office 365, and potentially other platforms not specifically geared toward online education. Means of facilitating reflection, metacognition, sociocultural learning, prior and authentic experiences, and generative learning strategies were looked for in addition to support of Malcolm Knowles’ andragogical assumptions. Through prototyping and pilot testing of Office 365’s functionality and features, several affordances were able to be made in support of criteria gathered from the literature review. Areas of strength and weakness as a platform for the delivery of online learning were identified in this process. Its success would vary based on the type of learning. Technical courses and corporate training would be more successful than a soft-skill or creative subject. Out of the box SharePoint provides most of the needed functionality to deliver content but, lacks elements such as a grading system.
    • Mild Traumatic Brain Injury (mTBI) and Photosensitivity: Objective Pupillometric Findings

      Truong, James Q. (2016-06)
      Background Given the extensive neural network of the human, binocular, pupillary system including its sympathetic and parasympathetic innervation, it is plausible that a mild traumatic brain injury (mTBI) could compromise pupillary control, thus causing pupillary asymmetry and dysfunction. Furthermore, presence of such pupillary abnormalities could exacerbate mTBI-related visual symptomatology, such as photosensitivity. There have only been two studies in the area, and they both used monocular pupillometry with only one test condition; hence they were limited. Furthermore, their results were in part equivocal. There remain many unanswered questions (i.e., gaps) in this important field of study including: 1) does mTBI affect the pupillary light reflex (PLR)?, 2) is there an increase in inter-ocular pupillary asymmetry (IOPA) in mTBI?, and 3) are there PLR differences related to one of the most prominent and prevalent dysfunctions resulting from mTBI, namely photosensitivity? Aim The overall aim of the present dissertation was twofold. First, to evaluate comprehensively the effect of mTBI on the human pupillary system, and furthermore to determine if pupillometry could be used as an objective visual biomarker for mTBI. Second, to evaluate comprehensively the effect of photosensitivity on the human pupillary system, and furthermore to determine if pupillometry could be used as an objective biomarker for photosensitivity. Methods The binocular pupillary light reflex was evaluated in mTBI, and it was compared to normal individuals, with and without photosensitivity, under a range of test conditions. Nine pupillary parameters (maximum, minimum, and final pupillary diameter; latency; amplitude; and peak and average constriction and dilation velocities) and 6 stimulus conditions (dim pulse, dim step, bright pulse, bright step, bright red step, and bright blue step) were assessed in 32 adults with mTBI (21-60 years of age) and compared to 40 normals (22-56 years of age). The Neuroptics, infrared, DP-2000 binocular pupillometer was used (30Hz sampling rate; 0.05mm resolution) with binocular stimulation and recording. Results and Discussion 1. Inter-ocular pupillary asymmetry: There were no statistical differences in either static or dynamic inter-ocular pupillary asymmetry (IOPA) between the normal and mTBI groups. Thus, the pupillary effects of mTBI appear to be symmetrical rather than asymmetrical in nature, which suggests post-chiasmal involvement. The mean average (across groups) static IOPA was 0.26 + 0.20mm or 4.17 + 3.29%. The mean average dynamic IOPA was dependent on the light stimulus condition, with the average across all test conditions and groups being 0.11 + 0.10mm or 1.84 + 1.70%. 2. Pupillometry in mTBI: mTBI has been reported to cause the pupillary light reflex (PLR) to be globally attenuated (i.e., slower in onset and more sluggish in response dynamics). The present results showed that there were many statistically significant differences (p < 0.05) in the PLR parameters between the mTBI and normal groups. Furthermore, different test conditions allowed for discrimination of different parameters between the two groups. For any of the given six test conditions, 5 to 8 of the 9 pupillary parameters were statistically different (p < 0.05) between the two groups. The overall trends revealed that the mTBI cohort had longer constriction latency, slower constriction and dilation velocities, and smaller pupillary diameters (baseline, minimum, and 6PSPD). The most consistent and robust pupillary parameters that differentiated between the two groups were the pupillary diameters (maximum, minimum, and 6SPSD; p < 0.01 under all 6 test conditions), and peak dilation velocity (p < 0.02, under all applicable conditions). This suggests that mTBI adversely affects both the sympathetic and parasympathetic systems, however, the effect appears to be greater on the sympathetic system. 3. Pupillometry in photosensitivity: There were statistically significant differences (p < 0.05) in the PLR parameters of those with versus without photosensitivity in both groups. Interestingly, these differences depended upon whether the photosensitivity was mTBI related. Those with mTBI and photosensitivity manifested six significant differences (p < 0.05) as compared with those with mTBI cohort without photosensitivity: larger baseline diameter, larger minimum diameter, faster peak dilation velocity, faster T50 and T75 recovery times, and a larger pupil diameter at 6 seconds post-stimulus. Normal (non-mTBI) subjects with photosensitivity exhibited four significant differences (p < 0.05) as compared with their normal cohort without photosensitivity: larger constriction amplitude, faster average constriction
    • MITOCHONDRIAL ELECTRON TRANSPORT CHAIN ACTIVITY IN SYSTEMIC LUPUS ERYTHEMATOSUS

      Perl, Andras; Doherty, Edward (2014)
      Systemic lupus erythematosus (SLE) is an autoimmune disorder, characterized by T cell and B cell dysfunction. SLE mitochondria have been shown to be dysfunctional with increased mass, mitochondrial potential, decreased ATP, elevated reactive oxygen species (ROS) and reactive nitrogen species (RNS) concentrations, and altered Ca2+ stores. Drug treatments that target the mitochondria have shown efficacy in treating SLE. Here we have investigated electron transport chain (ETC) activity in SLE, to better understand the causes of mitochondrial dysfunction in SLE. We have found that mitochondrial complexes I and IV of the ETC have elevated respiration in SLE compared to healthy controls after both overnight resting and anti-CD3/CD28 stimulation. We have also shown that SLE complex I is resistant to NO inhibition of respiration. SLE peripheral blood lymphocytes (PBL) have increased S-nitrosylation (SNO) while immunoprecipitated complex I had decreased SNO of proteins compared to healthy controls. The drug Nacetylcysteine (NAC) was able to inhibit complex I activity in SLE, and was found to reduce the amount of complex I protein NDUFS3 after 15 minutes as measured by western blotting. These results have led us to the conclusion that SLE mitochondrial complex I is in an active form which is resistant to SNO and is driving the production of ROS and RNS that are associated with SLE. The drug NAC is able to inhibit complex I respiration which may have therapeutic efficacy by reducing the ROS and RNS stress in SLE.