Now showing items 21-40 of 203

    • Distinct Interaction Modes for the Eukaryotic RNA Polymerase Alpha-like Subunits and Implications for Disease Modeling

      Knutson, Bruce; Belkevich, Alana (2023-08)
      Eukaryotic DNA-dependent RNA Polymerases (Pols I-III) encode two distinct ⍺- like heterodimers where one is shared between Pols I and III, and the other is unique to Pol II. Human alpha-like subunit mutations are associated with several diseases including Treacher Collins Syndrome (TCS), 4H Leukodystrophy, and Primary Ovarian Sufficiency. Yeast is commonly used to model human disease mutations, yet it remains unclear whether the alpha-like subunit interactions are functionally similar between yeast and human homologs. To examine this, we mutated several regions of the yeast and human small alpha-like subunits and used biochemical and genetic assays to establish the regions and residues required for heterodimerization with their corresponding large alpha-like subunits. Here we show that different regions of the small alpha-like subunits serve differential roles in heterodimerization, in a polymerase- and species-specific manner. We found that the small human alpha-like subunits are more sensitive to mutations, including a "humanized" yeast that we used to characterize the molecular consequence of the TCS-causing POLR1D G52E mutation. These findings help explain why some alpha subunit associated disease mutations have little to no effect when made in their yeast orthologs and offer a better yeast model to assess the molecular basis of POLR1D associated disease mutations.
    • Disorder in the Loop: Identification of a Role for Intrinsic Disorder and Liquid-Liquid Phase Separation in R-Loop Biology

      Bah, Alaji; Garcia Dettori, Leonardo (2023-08)
      R-loops are non-canonical nucleic acid structures composed of a DNA:RNA hybrid, a displaced single-stranded (ss)DNA, and a trailing ssRNA overhang. R-loops perform critical biological functions under normal and disease conditions. To elucidate their cellular functions, we need to understand the mechanisms underlying R-loop formation, recognition, signaling, and resolution. Previous high-throughput screens identified multiple proteins that bind R-loops, including Enzymes and non-enzymatic Readers. However, the precise mechanisms by which these proteins modulate R-loop functions are not fully known. The Fragile X Protein (FMRP) has been recently shown to prevent R-loop-mediated DNA double strand breaks (DSBs), but the mechanism was unknown. FMRP has been previously shown to undergo Liquid-Liquid Phase Separation (LLPS) by itself and with another non-canonical nucleic acid structure, RNA G-quadruplexes, via its C-terminal intrinsically disordered region (C-IDR). Here, we identified the same C-IDR as the predominant R-loop binding site. This unexpected discovery prompted us to explore the hypothesis that disordered regions of other R-loop binding proteins are also utilized to recognize R-loops. Our analysis of the R-loop interactome revealed that low-complexity IDRs are prevalent in this interactome, and that Readers and Enzyme IDRs are distinct (Gly, Ser, Arg, and Pro-rich vs. Glu, Lys, Arg, and Ser-rich, respectively). Furthermore, like FMRP, both R-loop Readers and Enzymes are not only modular, (i.e., contain folded domain(s) interspersed with IDRs), but are also predicted to undergo LLPS. Next, we demonstrated that the IDRs from the R-loop binding protein RBM3 and the R-loop helicase DDX21 also bind to R-loops, providing additional examples of IDR-mediated R-loop binding from an R-loop Reader and Enzyme, respectively. Finally, we demonstrated that FMRP C-IDR and DDX21 N-IDR can undergo co-LLPS with R-loops suggesting that IDR-based R-loop binding and co-LLPS is a universal mechanism shared by all members of the interactome. Therefore, we propose that IDRs can provide a functional link between R-loop recognition and downstream signaling through the assembly of LLPS-mediated membrane-less R-loop foci, where the activities of the folded domains are coordinated to regulate the biological functions of R-loops. Mutations or dysregulation of the function of IDR-enriched R-loop interactors can potentially lead to severe genomic defects, such as the R-loop-mediated DSBs observed in Fragile X patient-derived cells.
    • Effects of the hepatic glucocorticoid receptor in the setting of sepsis, infection, and inflammation

      Lu, Hong; Winkler, Rebecca (2023-08)
      Each year hundreds of thousands of people develop life-threatening sepsis, defined by a combination of infection and organ dysfunction. Although many affected biological pathways are typically regulated by the glucocorticoid receptor (GR), during sepsis this is deficient and supplementation with exogenous glucocorticoids is often ineffective in reducing mortality. The GR has different effects in different organs. In liver many effects are beneficial, whereas in immune or muscular systems many effects are deleterious. A sampling of this literature is reviewed in chapter 1. With the hypothesis that liver-specific glucocorticoid therapy will be more clinically beneficial than systemic therapy, we studied liver-specific GR effects in infection, inflammation, or sepsis. Chapter 2 describes in-vitro chemokine alterations from GR activation in primary human hepatocytes, with inflammation or infection modeled by TNFα and/or lipopolysaccharide. Comparisons were made in primary human hepatocytes, the human hepatoma cell line HEPG2, and the non-liver cell line HEK293t. Chapter 3 outlines outcomes of liver-specific GR deficiency using mice with inducible liver-specific GR knockout, modeling sepsis with cecal ligation and puncture. Results of these two models show mRNA and/or protein changes induced by GR in chemokines; transcription factors; genes related to protein degradation, metabolism, metal management, inflammation, liver regeneration, and hemodynamic stability. Results of these 2 models demonstrate a significant role of the hepatic GR in many pathways dysregulated during sepsis. Therefore, targeting GR therapy to the liver instead of systemic treatment may prove more clinically beneficial to reducing the morbidity and mortality of sepsis.
    • Defining the mechanism of STAT3 regulation by ABI1 in prostate cancer

      Kotula, Leszek; Li, Xiang (2023-07)
      Prostate cancer, driven by hormones and the androgen receptor (AR), initially responds to AR pathway-targeted treatments. However, tumor relapse arises from a process called the prostate cancer cell lineage switch. This switch involves transcriptional and epigenetic reprogramming, allowing cancer cells to acquire a new identity and bypass the stress caused by anti-AR treatments, resulting in increased proliferation and metastasis. Our study delves into the regulatory mechanism of STAT3, a key modulator, by the tumor suppressor ABI1 during the process of lineage switch. We observed an inverse correlation between ABI1 expression and the progression of the lineage switch. Using tumor models, we demonstrated that ABI1 modulates the phosphorylation of STAT3 by regulating kinase activities. Additionally, we discovered that ABI1 interacts with DNA through unique intrinsic disordered DNA binding regions. Notably, during prostate cancer lineage switch, a specific ABI1 EXON4 undergoes abnormal splicing, enhancing the ABI1-DNA interaction and influencing epigenetic remodeling by modulating chromatin accessibility. Our findings highlight the role of ABI1 in regulating STAT3 activities through its DNA interaction and reveal a reciprocal regulation between ABI1 and STAT3 in terms of nuclear localization, thereby influencing the lineage switch driven by STAT3. Overall, we propose that ABI1 acts as a master regulator of the lineage switch by maintaining the homeostasis of epigenetic and transcriptional processes.
    • Pharmacological inhibition of protein phosphatase-5 and induction of the extrinsic apoptotic pathway in kidney cancer

      Mollapour, Mehdi; Ahanin, Elham (2023-05)
      Serine/threonine protein phosphatase-5 (PP5) is involved in tumor progression and survival, making it an attractive therapeutic target. Specific inhibition of protein phosphatases has remained challenging because of their conserved catalytic sites. PP5 contains its regulatory domains within a single polypeptide chain, making it a more desirable target. Here we used an in silico approach to screen and develop a selective inhibitor of PP5. Compound P053 is a competitive inhibitor of PP5 that binds to its catalytic-domain and causes apoptosis in renal cancer. We further demonstrated that PP5 interacts with FADD, RIPK1 and caspase 8, components of the extrinsic apoptotic pathway complex II. Specifically, PP5 dephosphorylates and inactivates the death effector protein FADD, preserving complex II integrity and regulating extrinsic apoptosis. Our data suggests that PP5 promotes renal cancer survival by suppressing the extrinsic apoptotic pathway. Pharmacological inhibition of PP5 activates this pathway, presenting a viable therapeutic strategy for renal cancer.
    • Specific Structural Features of the RNA Polymerase I Core Promoter Element Targeted by Core Factor

      Knutson, Bruce; Munoff, Nathan (2023-07)
      In yeast, Core Factor (CF) is a critical and essential RNA Polymerase I (Pol I) transcription factor that plays fundamental roles in the transcription process by recruiting Pol I and opening Pol I promoter DNA before initiation. CF binds to a ~24 bp region in the rDNA promoter called the Core Element (CE) prior to Pol I recruitment. Pol I transcribes the rDNA gene into the 35S precursor rRNA (pre-rRNA) which serves both catalytic and structural roles in the ribosome. Up-regulation of Pol I transcription has been linked to a variety of human cancers, as increased protein production can facilitate the rapid growth of cancer cells. Thus, Pol I transcription is a promising target for therapeutic development. Previous studies from our lab suggest that CF and its human orthologue, Selectivity Factor 1 (SL1), use an evolutionarily conserved mechanism to target DNA, governed by the structural features of their respective promoters. Eukaryotic rDNA promoters also exhibit conserved structural features, such as intrinsic curvature and kinks but show a distinct lack of sequence conservation. These sequence independent structurally conserved features of rDNA promoters might explain how they are being recognized by CF and its orthologues. Our findings here revealed that CF is capable of tolerating mutations at some positions of the CE while mutation in the rigid “A” patch being particularly sensitive to mutations changing structural properties. Along with conditional tolerance for sequence mutations, our results show that CF prefers a variety of structural features such as overall increased bendability and decreased curvature as well as specific profiles of bendability. Furthermore, we describe the preferences of CF for the parameters of helix twist, propeller twist, roll, and minor groove width.
    • Uncovering a new phase: the interactions that mediate MBD2 and MBD3 LLPS

      Bah, Alaji; Maurici, Nicole (2023-06-27)
      Chromatin structure and organization controls DNA's accessibility to regulatory factors and influences gene regulation. Heterochromatin, or condensed chromatin containing mostly silenced genes, self-assembles through weak, multivalent interactions with its associated proteins that contain intrinsically disordered regions (IDRs) and undergoes liquid-liquid phase separation (LLPS). However, the details of the intricate molecular interactions that drive heterochromatin LLPS are not fully understood. It is crucial that we uncover the molecular mechanisms involved as it regulates vital nuclear functions, and dysregulation is implicated in neurological disorders and cancer. Here, we focus on two members of the methyl-CpG-binding domain (MBD) family of proteins, MBD2 and MBD3, that recognize and interpret methylated residues on heterochromatin's underlying DNA. We use an integrated approach to explore the driving forces that allow them to undergo LLPS and how known interactors influence this process. Using computational approaches that assess amino acid sequence features, we found that MBD2 and MBD3 are highly disordered proteins predicted to undergo LLPS. Although they are highly similar in sequence, they have distinct clustering patterns of certain residue types that suggest the molecular basis of how they phase separate differs between them. We have tested these predictions in vitro and in cellulo and have demonstrated their ability to phase separate individually, together and with methylated DNA using UV-Vis spectroscopy and microscopy. Through truncations of MBD2 and MBD3, we have found that their ability to undergo LLPS is dictated by a balance between hydrophobic interactions, likely arising from their associative domains, and electrostatic interactions, arising from their highly charged termini, occurring within or between the proteins and DNA. Finally, using scattering techniques such as small-angle X-ray scattering (SAXS) and dynamic light scattering (DLS), we have demonstrated that MBD2 and MBD3 are self-interacting proteins that form large assemblies. We propose that MBD2 and MBD3, through their ability to self-interact via hydrophobic and electrostatic forces, undergo LLPS and foster a biochemically unique environment to sequester binding partners and perform their functions as transcriptional repressors and heterochromatin organizers. Uncovering the driving forces that assemble MBD protein-based droplets will give us insight into the higher-order, LLPS-mediated organization of heterochromatin and how it functions within this structure. Additionally, understanding how disease-related aberrations influence biomolecular condensate dynamics will provide novel therapeutic targets.
    • Enhancing response of a protein conformational switch by using two disordered ligand binding domains.

      Sekhon, Harsimranjit; Ha, Jeung-Hoi; Loh, Stewart N (Frontiers in Molecular Biosciences, 2023-03-02)
      Protein conformational switches are often constructed by fusing an input domain, which recognizes a target ligand, to an output domain that establishes a biological response. Prior designs have employed binding-induced folding of the input domain to drive a conformational change in the output domain. Adding a second input domain can in principle harvest additional binding energy for performing useful work. It is not obvious, however, how to fuse two binding domains to a single output domain such that folding of both binding domains combine to effect conformational change in the output domain. Here, we converted the ribonuclease barnase (Bn) to a switchable enzyme by duplicating a C-terminal portion of its sequence and appending it to its N-terminus, thereby establishing a native fold (OFF state) and a circularly permuted fold (ON state) that competed for the shared core in a mutually exclusive fashion. Two copies of FK506 binding protein (FKBP), both made unstable by the V24A mutation and one that had been circularly permuted, were inserted into the engineered barnase at the junctions between the shared and duplicated sequences. Rapamycin-induced folding of FK506 binding protein stretched and unfolded the native fold of barnase the mutually exclusive folding effect, and rapamycin-induced folding of permuted FK506 binding protein stabilized the permuted fold of barnase by the loop-closure entropy principle. These folding events complemented each other to turn on RNase function. The cytotoxic switching mechanism was validated in yeast and human cells, and with purified protein. Thermodynamic modeling and experimental results revealed that the dual action of loop-closure entropy and mutually exclusive folding is analogous to an engine transmission in which loop-closure entropy acts as the low gear, providing efficient switching at low ligand concentrations, and mutually exclusive folding acts as the high gear to allow the switch to reach its maximum response at high ligand concentrations.
    • Characterization of the Role of Myosin 1e in the Progression of Breast Cancer and Focal Segmental Glomerulosclerosis

      Krendel, Mira; Garone, Michael (2023-06-22)
      Myosin 1e (myo1e) is a long-tailed class I myosin implicated in breast cancer progression and the development of focal segmental glomerulosclerosis (FSGS). This dissertation characterizes how myosin functions in these distinct pathologies. In chapter 2, I dissect the role that myo1e plays in the metastasis of breast cancer cells. Using the highly invasive 4T1 cell line, I demonstrate that cells deficient in myo1e exhibit altered morphologies and slower migration rates. Dissection of the migration defects in myo1e KO cells led us to investigate the role of myo1e in organelle trafficking, integrin endocytosis and the assembly and disassembly of focal adhesions. Our preliminary results suggest that cells deficient in myo1e exhibit reduced rate of focal adhesion disassembly. In chapter 3, I characterize three novel mutations in myosin 1e that were isolated from patients with FSGS: A92E, H506D, and G562R. Using in silico and comparative sequence analyses, I demonstrate that these mutations are likely pathogenic and highly evolutionarily conserved. Expressing these mutants in Madin-Darby Canine Kidney (MDCK) cells, I demonstrate that mutants myo1eH506D and myo1eG562R exhibit proper membrane enrichment, while the myo1eA92E mutant mislocalizes to the cytoplasm. Additional characterization of the properly localizing myo1eG562R mutant demonstrated that its junctional dynamics were not different from the junctional dynamics of myo1eWT. Taken together, our findings in chapter 3 demonstrate functional differences among myo1eA92E and myo1eH506D and myo1eG562R mutants and how these differences may contribute to their pathogenicity.
    • Investigating how FHOD-family formin promotes Z-line organization and striation formation in C. elegans striated muscles

      Pruyne, David; Sundaramurthy, Sumana (2022-01-31)
      Striated muscles are composed of basic structural and functional units called sarcomeres. The assembly of these sarcomeres is a well-studied process among vertebrates and multiple lines of evidence suggest formins as regulators of sarcomere assembly. Formins are regulators of unbranched actin networks and thus were ideal candidates to test for the initiators of thin filament assembly. We examined how Caenorhabditis elegans formins, FHOD-1 and CYK-1 regulate striated body wall muscle (BWM) growth. We found that FHOD family-related, FHOD-1 was the only formin that promoted BWM growth in a cell autonomous manner. However, the DIAPH-family related CYK-1 effect on BWMs was rather indirect. Interestingly, both these formins did not function as thin filament initiators. Our focus was to investigate the mechanisms of how FHOD-1 regulates striated muscle development. Loss of FHOD-1 however caused disorganized Z-lines in BWMs. Dense bodies (DBs) are analogous to Z-lines and are also similar to integrin-based focal adhesions. They are often arranged in rows that appear parallel in wild-type animals. We investigated how the loss of FHOD-1 affects the distribution, arrangement and morphology of the DBs. We found that loss of FHOD-1 led to the accumulation of non-parallel striations and FHOD-1 was enriched at the sites of new DB assembly as well as at sites where non-parallel striations would intersect. FHOD-1 supports the orientation of new striations. We also found that DBs from worms that lack FHOD-1 were fragile and were not able to withstand prolonged contractions. We interpret that FHOD-1 could regulate the actin dynamics or act as a linker to bundle actin filaments that are a part of this unique DB-associated cytoskeletal system, which provides structural integrity to the DBs.
    • Do the Rules Always Apply? An Analysis of Exceptions to a COVID-19-Era Pediatric Visitation Policy

      Wong, Roger; Shim, Ashley; Searles, Madison; Caruso, Amy (Children's Minnesota, 2022)
      Background The COVID-19 pandemic abruptly reversed the long-standing practice of open visitation in children’s hospitals, due to the concern that hospital visitors might contribute to the spread of disease. However, little is known about the unintended consequences of such policies, including the potential that they may disproportionately impact children and families of color and those from low-income communities. Methods We reviewed requests for an exception to a pediatric visitation policy made between August and November 2020 at a midsize American children’s hospital and collected data regarding details of the requests, demographics, family characteristics, and the patients’ medical histories. We compared the sample to the general patient population using bivariate tests and developed a logistic regression model to explore factors associated with the receipt of requests for an exception to a visitation policy. Results Regression models indicated that Black families were less likely to have their request for an exception to the visitation policy granted, compared to White families (odds ratio, OR = 0.06; 95 percent confidence interval, CI 0.01-0.84; p < .05). The families of children who were admitted to critical care were more likely to have their request for an exception granted (OR = 28.35; 95 percent CI 1.43-562.37, p < .05). Two of the three reviewers of requests for exceptions were found to be less likely to grant a request for an exception (OR = 0.05; 95 percent CI 0.00-0.84; p < .05; OR = 0.03; 95 percent CI 0.00-0.67; p < .05). Conclusions Our findings highlight the need to reconsider the risks and benefits of highly restrictive visitation policies that disproportionately impact vulnerable and marginalized children and their families. This study also provides a model for the broader, prospective analysis of the potential for disparities in the impact of any institutional policy.
    • Unraveling differential origin firing and replication stress mediated genome instability using S. cerevisiae as a model organism

      Feng, Wenyi; Joshi, Ishita (2023-06)
      Yeasts have been used as model organisms because of their compact genome size, simple growth requirements, and homology to higher eukaryotes. The sites for origin initiation are well defined in the S. cerevisiae genome, and several metabolism and resistance genes are well conserved to higher eukaryotes, making it an ideal model system to study origin dynamics and replication inhibitor mediated genome instability. In this thesis, using S. cerevisiae as a model we answered two big questions. First, we studied factors regulating differential origin firing between two commonly used laboratory strains. Second, we identified the general mechanism used by replication inhibitors to induce genome-wide DSBs. To identify the factors regulating differential origin firing we compared, 1) S-phase progression, 2) the relative level of checkpoint protein, and 3) the binding of Rad53 and Cdc45 at a select few origins. Amongst the three, we found that difference in binding of Rad53 at the origins was responsible for differential firing between the two strains. In a new origin class, "Rad53 dependent" we looked the role of active transcription in regulating origin firing. Our results show that active transcription during S-phase does not wipe out the origin firing activity. To study replication inhibitor-induced genome instability, we used a broad range of inhibitors that induce replication stress differently. Our results suggested that replication-transcription collision is a common mechanism used by these inhibitors to induce DSBs. Associating each DSB with an upregulated gene, we found an enrichment in the head-on orientations. As these inhibitors are regularly used in the clinic as anticancer therapeutics, studying the gene expression helped us identify their mechanism of action to specifically target cancer cells. We found that all of these individually upregulate the oxidation-reduction pathway, and downregulate glycolysis. Finally, at one locus on chromosome II which induces DSB specifically in CPT, we were able to demonstrate replication fork pause and correlation of the DSB with active transcription-deposited histone marks.
    • Local Health Departments Tweeting About Ebola: Characteristics and Messaging

      Wong, Roger; Harris, Jenine K.; Staub, Mackenzie; Bernhardt, Jay M. (Ovid Technologies (Wolters Kluwer Health), 2017-03)
      Context: The first imported U.S. Ebola Hemorrhagic Fever case during the 2014 West Africa Ebola outbreak triggered an increase in online activity through various social media platforms, including Twitter. Objectives: The purpose of our study was to examine characteristics of local health departments (LHDs) tweeting about Ebola, in addition to how and when LHDs were communicating Ebola-related messages. Design: All tweets sent by 287 LHDs known to be using Twitter were collected from September 3 to November 2, 2014. Twitter data were merged with the 2013 National Association of County and City Health Officials (NACCHO) Profile study to assess LHD characteristics associated with sending Ebola-related tweets. To examine the content of Ebola tweets, we reviewed all such tweets and developed a codebook including four major message categories: information-giving, news update, event promotion, and preparedness. A timeline tracking the trends in Ebola tweets was created by aligning daily tweets with major Ebola news events posted on the Centers for Disease Control and Prevention (CDC) Ebola website. Results: Approximately 60% (n=174) of all LHDs using Twitter sent a total of 1 648 Ebola-related tweets during the study period. Sending more tweets in general (OR: 2.42; 95% CI: 1.00-5.84) and employing at least one Public Information Specialist (OR: 2.61; 95% CI: 1.14-5.95) significantly increased the odds that an LHD tweeted about Ebola. Of all the Ebola tweets collected, 78.6% were information-giving, 22.5% were on preparedness, 20.8% were news updates, and 10.3% were event promotion tweets. A temporal analysis of Ebola tweets indicated five distinct waves, each corresponding with major Ebola news events. Conclusions: Twitter has become a communication tool frequently used by many LHDs to respond to novel outbreaks, but messaging strategies vary widely across LHDs. We present several recommendations for LHDs using this novel communication channel during outbreaks and other emergent events.
    • Role of Neighborhood Physical Disorder and Social Cohesion on Racial and Ethnic Disparities in Dementia Risk

      Wong, Roger; Wang, Yi (SAGE Publications, 2022-05-17)
      Objectives: To analyze how neighborhood physical disorder and social cohesion are associated with racial and ethnic disparities in dementia risk. Methods: Nine years of data (2011-2019) were retrieved from the National Health and Aging Trends Study, a nationally-representative U.S. older adult (age 65+) sample. Cox regression analyzed time to dementia diagnosis using composite scores for neighborhood physical disorder and social cohesion. Results: Higher baseline neighborhood physical disorder (Adjusted Hazard Ratio [aHR]=1.11, 95% Confidence Interval [CI]=1.01-1.23) and increased disorder at follow-up (aHR=1.10, 95% CI=1.01-1.19) significantly increased dementia risk. Hispanic older adults with higher physical disorder at baseline (aHR=0.62, 95% CI=0.49-0.79) and follow-up (aHR=0.81, 95% CI=0.67-0.98) had a significantly decreased dementia risk. There were no significant associations for social cohesion. Discussion: Physical but not social neighborhood characteristics are associated with dementia risk. Future research is needed to understand protective mechanisms for dementia among Hispanic older adults in neighborhoods with high physical disorder.
    • Relationship between dementia, COVID‐19 risk, and adherence to COVID‐19 mitigation behaviors among older adults in the United States

      Wong, Roger; Lovier, Margaret Anne (Wiley, 2022-05-17)
      Objectives: To examine how dementia is associated with COVID-19 risk and adherence to COVID-19 mitigation behaviors, and whether mitigation behaviors mediate the relationship between dementia and COVID-19 risk. Methods/Design: We analyzed 2019 and 2020 data from the National Health and Aging Trends Study, a national prospective cohort study of United States older adults age 65+. Outcomes were COVID-19 diagnosis and adherence to COVID-19 mitigation behaviors (handwashing, mask-wearing, and social distancing). Results: Among the 3257 older adults in this study, 485 (14.9%) had dementia in 2019 and 98 (3.1%) were COVID-19 positive in 2020. Dementia significantly increased the odds of COVID-19 by 129% (odds ratio [OR] = 2.29, 95% confidence interval [CI] 1.32 to 3.97), and remained elevated after adjusting for sociodemographics and health (OR = 1.67, 95% CI 0.90 to 3.11). Dementia significantly decreased the odds of handwashing by 72% (OR = 0.28, 95% CI 0.17 to 0.44), which remained lower after adjusting for sociodemographics and health (OR = 0.53, 95% CI 0.23 to 1.21). Dementia was not significantly associated with mask-wearing and social distancing. The relationship between dementia and COVID-19 was primarily mediated by functional impairment, income, and residential setting. Conclusions: Dementia was associated with an increased COVID-19 risk and lower adherence to handwashing among U.S. older adults. Adherence to COVID-19 mitigation behaviors did not mediate COVID-19 risk by dementia status. For older adults with dementia, COVID-19 risk could be decreased by prioritizing health interventions.
    • COVID-19 risk factors and predictors for handwashing, masking, and social distancing among a national prospective cohort of US older adults

      Wong, Roger; Grullon, J.R.; Lovier, M.A. (Elsevier BV, 2022-10)
      Objectives: Older adults have a disproportionately higher COVID-19 risk, however, there is limited research investigating adherence to the major COVID-19 mitigation behaviors (handwashing, masking, social distancing) for older populations. We examined COVID-19 risk factors and predictors for adherence to COVID-19 mitigation behaviors among a national sample of U.S. older adults. Study Design: Data were retrieved for 3,257 respondents from the National Health and Aging Trends Study, a nationally representative prospective sample of U.S. Medicare beneficiaries age 65 or older. COVID-19 variables were collected in 2020, while all other data were collected in 2019. Methods: We utilized multiple logistic regression to analyze COVID-19 risk factors and predictors for handwashing, masking, and social distancing to minimize COVID-19 spread. Missing data were imputed, and all models applied survey sampling weights. Results: Factors significantly associated with increased odds of COVID-19 diagnosis among U.S. older adults were Hispanic ethnicity, low-income household, residential care or nursing home, and generalized anxiety disorder. We identified multiple factors significantly associated with adherence to handwashing, masking, and social distancing. Most notably, older males had a significantly lower odds of practicing all three COVID-19 mitigation behaviors, and Black older adults had a significantly higher odds of masking and handwashing. Conclusions: When prioritizing COVID-19 prevention efforts for older adults, risk factors that should be considered are race and ethnicity, income, residential setting, and anxiety. To effectively mitigate COVID-19 disease spread, public health professionals must also recognize sociodemographic and health factors may influence whether older adults adhere to handwashing, masking, and social distancing.
    • Geospatial Distribution of Local Health Department Tweets and Online Searches About Ebola During the 2014 Ebola Outbreak

      Wong, Roger; Harris, Jenine K. (Cambridge University Press (CUP), 2017-08-24)
      Objective This study compared the geospatial distribution of Ebola tweets from local health departments (LHDs) to online searches about Ebola across the United States during the 2014 Ebola outbreak. Methods Between September and November 2014, we collected all tweets sent by 287 LHDs known to be using Twitter. Coordinates for each Ebola tweet were imported into ArcGIS 10.2.2 to display the distribution of tweets. Online searches with the search term “Ebola” were obtained from Google Trends. A Pearson correlation was conducted to access the relationship between online search activity and per capita number of LHD Ebola tweets by state. Results Ebola tweets from LHDs were concentrated in cities across the northeast states, including Philadelphia and New York City. In contrast, states with the highest online search queries for Ebola were primarily in the south, particularly Oklahoma and Texas. A weak, negative, non-significant correlation (r=-.03, p=.83, 95% CI -.30-.25) was observed between online search activity and per capita number of LHD Ebola tweets by state. Conclusions We recommend LHDs consider using social media to communicate possible disease outbreaks in a timely manner, and consider using online search data to tailor their messages to align with the public health interests of their constituents.
    • Food Insecurity and COVID-19 Diagnosis: Findings from a National United States Sample

      Searles, Madison; Wong, Roger (Informa UK Limited, 2022-09-27)
      This study explores the association between experiencing food insecurity and COVID-19 diagnosis in the United States, and what sociodemographic characteristics moderate this relationship. We analyzed a national sample of adults in the United States (n=6,475). Multiple logistic regression results revealed respondents experiencing food insecurity had approximately 3.0 times significantly higher odds of a positive COVID-19 diagnosis (Odds Ratio [OR]=2.95, 95% Confidence Interval [CI]=1.38-6.32, p<.01), which remained significant after adjusting for sociodemographics and COVID-19 mitigation behaviors (OR=2.59, 95% CI=1.09-6.18, p<.05). Age group had a significant moderating effect (OR=42.55, 95% CI=3.13-579.15, p<.01). Results indicate experiencing food insecurity is associated with contracting COVID-19.
    • Sleep Disturbances and Dementia Risk in Older Adults: Findings From 10 Years of National U.S. Prospective Data

      Wong, Roger; Lovier, Margaret Anne (Elsevier BV, 2023-06)
      Introduction: Prior research has identified a link between sleep disturbances and cognitive impairment, however, no study has examined this relationship using a national U.S. sample. This study examines how multiple longitudinal measures of sleep disturbances (sleep-initiation insomnia, sleep-maintenance insomnia, sleep medication usage) are associated with dementia risk. Methods: Ten annual waves (2011–2020) of prospective cohort data from a nationally representative U.S. sample of older adults age 65 and older were analyzed from the National Health and Aging Trends Study (NHATS). Sleep disturbances were converted into a longitudinal score and measured as sleep-initiation insomnia (trouble falling asleep in 30 minutes), sleep-maintenance insomnia (trouble falling asleep after waking up early), and sleep medication usage (taking medication to help sleep). Cox regression models analyzed time to dementia diagnosis for a sample of 6,284 respondents. Results: In the unadjusted model, sleep-initiation insomnia was significantly associated with a 51% increased dementia risk (hazard ratio [HR]=1.51, 95% confidence interval [CI]=1.19–1.90). Adjusted for sociodemographics, sleep medication usage was significantly associated with a 30% increased dementia risk (aHR=1.30, 95% CI=1.08–1.56). Adjusted for sociodemographics and health, sleep-maintenance insomnia was significantly associated with a 40% decreased dementia risk (aHR=0.60, 95% CI=0.46–0.77). Conclusions: These findings suggest sleep-initiation insomnia and sleep medication usage may elevate dementia risk. Based on the current evidence, sleep disturbances should be considered when assessing the risk profile for dementia. Future research is needed to examine other sleep disturbance measures and to explore mechanisms for decreased dementia risk among older adults with sleep-maintenance insomnia.
    • Strategies for the Recruitment and Retention of Racial/Ethnic Minorities in Alzheimer Disease and Dementia Clinical Research

      Wong, Roger; Amano, Takashi; Lin, Shih-Yin; Zhou, Yuanjin; Morrow-Howell, Nancy (Bentham Science Publishers Ltd., 2019-05-21)
      Background Racial/ethnic minorities have among the highest risks for Alzheimer disease and dementia, but remain underrepresented in clinical research studies. Objective To synthesize the current evidence on strategies to recruit and retain racial/ethnic minorities in Alzheimer disease and dementia clinical research. Method We conducted a systematic review by searching CINAHL, EMBASE, MEDLINE, PsycINFO, and Scopus. We included studies that met four criteria: (1) included a racial/ethnic minority group (African American, Latino, Asian, American Indian or Alaska Native, and Native Hawaiian or Other Pacific Islander); (2) implemented a recruitment or retention strategy for Alzheimer disease or dementia clinical research; (3) conducted within the U.S.; and (4) published in a peer-reviewed journal. Results Of the 19 included studies, 14 (73.7%) implemented recruitment strategies and 5 (26.3%) implemented both recruitment and retention strategies. Fifteen studies (78.9%) focused on African Americans, two (10.6%) on both African Americans and Latinos, and two (10.5%) on Asians. All articles were rated weak in study quality. Four major themes were identified for recruitment strategies: community outreach (94.7%), advertisement (57.9%), collaboration with health care providers (42.1%), and referral (21.1%). Three major themes were identified for retention strategies: follow-up communication (15.8%), maintain community relationship (15.8%), and convenience (10.5%). Conclusion Our findings highlight several promising recruitment and retention strategies investigators should prioritize when allocating limited resources, however, additional well-designed studies are needed. By recruiting and retaining more racial/ethnic minorities in Alzheimer disease and dementia research, investigators may better understand the heterogeneity of disease progression among marginalized groups. PROSPERO registration #CRD42018081979.