RSS 1.0Doctoral Degree Granting Institutions
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Generalized target behavior reductions and maintenance of effects following an augmented competing stimulus assessment sequenceCompeting stimulus assessments are one technology that aids in the development of treatment for automatically reinforced behavior. However, competing stimulus assessments do not always yield robust results. Stereotypic behaviors of different subtypes may require procedural modifications to successfully identify competing stimuli. The current investigation included functional analyses to determine whether participant responding aligned with proposed subtypes for such behaviors. Next, we implemented augmented competing-stimulus-assessment (A-CSA) procedures across target and generalization stimuli to determine whether (a) responding across either subtype was more likely to require intensive modifications and (b) the A-CSA procedures promoted generalized target behavior reduction within stimulus classes. Lastly, a treatment evaluation was conducted to determine the durability of these findings and the generalization of the reduced target behavior to other settings. The general applicability of the subtyping model remains unclear, but two participants demonstrated maintenance of competition effects.
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SELF-ASSEMBLING MULTIDOMAIN PROTEIN MICELLES FOR MOLECULAR IMAGING AND DRUG DELIVERYProteins are versatile biomacromolecules with strong self-assembly properties that play a vital role in virtually all forms of life. By taking advantage of these properties, it is possible to design biocompatible, biologically active materials that can be used for a range of biomedical purposes, such as molecular imaging as well as targeted drug delivery. Unlike many other material systems, proteins can be recombinantly expressed and purified with multiple functional domains encoded in a single gene, often eliminating the need for additional chemical conjugation steps. Here we describe the design and engineering of multidomain proteins containing at least one coiled-coil domain and one disordered elastin-like polypeptide domain per chain. These proteins spontaneously assemble into micelles in aqueous solution. By incorporating targeting peptides into the genetic sequence, we can additionally alter the pharmacokinetics and organ tropism of the resulting micelles. Chapter 1 provides a brief overview of the field of protein biomaterials, while Chapters 2-4 delve in the design and characterization of protein micelles with multiple functional domains. First, in Chapter 2, we devise a collagen-binding molecular imaging probe for the monitoring of metabolic associated steatohepatitis (MASH) disease progression. This probe, collagen type I-binding thermoresponsive assembled protein (Col1-TRAP), was first characterized in vitro before being used to study a mouse model of MASH. It was found to preferentially accumulate in the livers of mice with MASH compared to normal mice. Next, in Chapter 3, we investigate the effect of increasing the multiplicity of the coiled-coil domain on improving hydrophobic drug loading capacity and delivery efficiency. Increasing the number of repeats of the coiled-coil domain from 1 to 2 was found to increase the drug loading capacity by 1.7-fold while reducing micelle packing by 25%. This construct, targeted multidomain protein assembly (TMPA), was found to preferentially accumulate in tumor sites in mice implanted with glioblastoma xenografts. Finally, Chapter 4 focuses on the targeting of TMPA for specific drug delivery to HER2+ breast cancer by using the peptide P51. Targeted micelles loaded with doxorubicin displayed improved uptake into and cytotoxicity against breast cancer cells overexpressing the HER2 receptor, while showing no selectivity in triple-negative breast cancer cells. All micelle-drug formulations were found to be more effective than free drug alone, showing the utility of these protein materials.
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Brain, Environmental and Psychological Trauma: TBI and PTSD Markers, Mechanisms, and InteractionsTraumatic brain injury (TBI) and Post-traumatic stress disorder (PTSD) are significant public health concerns, particularly among individuals exposed to high-stress environments such as military combat. However, they can also occur anytime due to various head injuries and stress. This review examines the interplay between TBI and PTSD, highlighting their prevalence, symptoms, potential biomarkers, pathological mechanisms, and the interactions that occur with exposure to both conditions. Worldwide, an estimated 69 million individuals per year sustain TBI, while approximately 13 million people per year exhibit PTSD. Notably, PTSD is markedly higher among individuals with TBI, particularly in veterans, where an estimated 28% of patients with mild TBI also exhibit PTSD. Although each alone results in significant symptoms and pathology, the co-occurrence of PTSD and TBI exacerbates the situation due to overlapping symptoms and bidirectionally interacting pathological changes. The occurrence of both TBI and PTSD increased cognitive impairments, emotional dysregulation, and disability with reduced function and health. Here, I provide a synthesis of current literature and assess the relationships between TBI and PTSD. We draw upon clinical and preclinical data to provide this critical overview. TBI increases the risk of developing PTSD, and PTSD increases susceptibility to the consequences of TBI. This interaction is due primarily to several overlapping mechanisms, including disrupted fronto-limbic brain circuits, neuroinflammation, and dysregulation of the HPA axis and specific neurotransmitter systems. White matter and brain area changes affect neural connectivity and functioning. Stress systems, inflammation, neurotransmitter imbalances, and structural brain changes interact closely in both TBI and PTSD. For example, chronic stress dysregulates the HPA axis, amplifying neuroinflammation and altering cortisol levels, further impacting neurotransmitter systems like serotonin and dopamine. This biochemical cascade contributes to white matter degradation and reduced brain volume, especially in regions like the hippocampus and prefrontal cortex, worsening cognitive and emotional symptoms. These interconnected changes create a feedback loop that sustains dysfunction across neural networks, complicating recovery. These changes worsen cognitive and emotional symptoms and create a feedback loop that hinders recovery. Continued research is required to understand TBI and PTSD interactions better. Additional pathological mechanisms and targets for intervention using appropriately designed studies in experimental models and in the clinic. This “translational research” approach will help us discover future risk prevention, intervention, and rehabilitation strategies that can improve the quality of life for those impacted by these comorbid and disabling disorders.
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Impact of Health Home and transition of care programs on diabetic patients' care and health outcomesA small proportion of patients accounts for a disproportionately large share of healthcare spending, often due to multiple chronic conditions and frequent hospital use. In response, New York State implemented the Health Home (HH) program to improve care coordination and reduce unnecessary hospital utilization among high-need Medicaid enrollees. This study evaluated whether early and consistent access to Primary Care Providers (PCPs) and care coordinators through the HH program improves outcomes for patients with diabetes mellitus and high acute care use, specifically by reducing hospital admissions and shortening the length of stay for readmissions. A retrospective cohort study was conducted using electronic medical record (EMR) data from a major New York healthcare system, including 16,229 diabetic patients eligible for Health Home (HH) services. The data were limited to patients over the age of 19 who were eligible for Health Home services during hospital visits between June 1, 2018, and December 31, 2019. The objective was to evaluate whether the HH program, developed by New York State to improve outcomes for high-need Medicaid patients, is achieving its intended goals. The following outcome measures were explored: hospital readmissions within 60 days post-discharge, the number of days from discharge to readmission, and the length of stay for readmitted visits. Covariates included age group, gender, race/ethnicity, primary language, marital status, LACE index (Length of stay, Acuity of admission, Comorbidities, and recent Emergency department use), and comorbidities indicated by the Charlson Comorbidity Index (CCI). All analyses were conducted using SAS software. The study found that enrollment in Health Home (HH) was significantly associated with an increase in the likelihood of readmission within 60 days in the unadjusted model (estimate = 1.0720, p <0.0001). After adjusting for race/ethnicity, age range, LACE, and CCI as confounders, the association remained significant, though attenuated (estimate =0.923; p<0.0001). Regarding the number of days between index admission and readmission, the unadjusted model indicated that HH enrollment significantly decreased the days between index discharge and readmission within 60 days, with an estimated -1.22 days (p = 0.0234). However, after accounting for LACE and CCI as confounders, the association between HH enrollment and days to readmission was no longer statistically significant (estimate = - 0.86, p = 0.1122). Similarly, the association between HH enrollment and length of stay (LOS) for readmitted visits was positive (estimate 0. 234, p= 0. 044); however, after controlling for age group, LACE, and CCI as confounders, it was no longer statistically significant (p= 0.493) and the relationship was reversed (estimate = -0.077). The findings suggest that demographic factors (specifically race/ethnicity and patient age), prior high utilization of hospital services (indicated by LACE score), and clinical burden (as indicated by CCI) significantly influence readmission outcomesindependent of HH program enrollment. While the unadjusted associations appeared statistically significant, the adjusted models underscore the role of these confounders. The results highlight the need for more tailored interventions that account for patients' demographic and clinical risk profiles to improve outcomes among diabetic patients enrolled in the HH program.
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Sex differences in memory modulation by mTORC1 activationThe mechanistic target of rapamycin (mTOR) is a central regulator of several cellular processes that are required for learning and memory, through the mTOR complex 1 (mTORC1) signaling pathway. However, little is known about how mTORC1 signaling in the brain is affected by sex or disease. We previously reported that activation of mTORC1 by 3-benzyl-5- ((2-nitrophenoxy) methyl)–dihydrofuran-2(3H)-one (3BDO) upregulated hippocampal rRNA expression and enhanced memory on the hippocampal-dependent active place avoidance task in young wild-type (WT) male mice. Here, we set out to determine if mTORC1 activation by 3BDO could enhance or rescue learning and memory on the active place avoidance task in both male and female mice from two strains, WT and APP/PS1, a model of Alzheimer’s Disease (AD). We selected two age groups to analyze: 8–9-months-old, when plaques are established and deficits in spatial memory begin to appear in APP/PS1 mice, and 12–13-months-old, when plaques are extensive and memory is severally impaired in APP/PS1 mice. Our data showed that a single dose of 3BDO delivered systemically rescued memory in 8–9-months-old male APP/PS1 mice but did not significantly affect male WT mice at this age. Further, 3BDO improved latency during learning for 12–13-months-old male mice overall but did not impact memory at this age. Surprisingly, in female mice, we found that 3BDO impaired both learning and memory at 8–9-months-old in WT mice, while having no significant effect on 8–9-month-old APP/PS1 mice or 12–13-months-old mice of either genotype. After behavioral testing, we further analyzed the effects of 3BDO administration on mTOR expression by Western blot. In the dorsal hippocampus, we saw overall less mTOR and phosphorylated mTOR in females compared to males at 8–9-months-old, but overall more mTOR and phosphorylated mTOR in females compared to males at 12–13-months-old. These results challenge the current understanding of how mTORC1 functions in AD and provide a new avenue of research into potential therapeutics. At the same time, the opposing effects of 3BDO on males and females trained on the same learning and memory task highlight the importance of studying potential sex differences of emerging therapeutics.
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Minocycline plus N-acetylcysteine improve chronic and progressive structural and functional deficits following a single TBI in male miceTraumatic brain injury (TBI) is the leading cause of death and disability above any other trauma. The high prevalence of later life degenerative outcomes strongly suggests a single TBI can develop into a progressive neurodegenerative disorder. Clinical TBI may produce chronic deficits in limb coordination, and gait that is associated with corpus callosum damage. Detection of chronic motor deficits after TBI may be obscured by effects of aging or the development of compensatory motor strategies. Chronic motor deficits are poorly studied in rodent TBI models. The murine closed head injury (CHI) model produces diffuse, chronic white matter injury that may underlie chronic white matter dysfunction and motor deficits. DeepLabCutTM markerless limb tracking provided the data for novel assessments of limb function on beam walk and simple-complex wheel. Injured mice on beam walk do not differ from sham mice on time to traverse or foot fault number. Novel assay beam walk absition integrates time and extent of all foot faults during a beam walk trial. Injured mice have chronic absition deficits that are blocked by dosing of minocycline and N-acetylcysteine beginning 12 hours post injury (MN12). Absition deficits do not appear until 90 DPI and worsen at 180 DPI suggesting chronic and progressive motor decline. Speed is a standard method to assess performance on simple-complex wheel. Novel assays show that at 14 DPI, MN12 improves limb coordination to prevent an injury dependent decline in running speed. Ex-vivo T2 and diffusion-tensor MRI studies show that MN12 prevents most progressive gray and white matter atrophy in motor structures and improves bilateral white matter integrity. MN12 increases inflammatory cell density in corpus callosum after CHI. This increased inflammatory response is likely beneficial since MN12 improves callosal structure and function. Evoked compound action potentials (CAP) assess corpus callosum function from 3 to 180-days post injury (DPI). CHI acutely decreases CAP amplitudes that recover by 90 DPI and further increase at 180 DPI. Changes in CAP amplitude are blocked by MN12. CHI mice have chronic corpus callosum dysfunction that coincide with motor deficits. Analysis using DeepLabCutTM limb tracking reveals chronic deficits and compensatory motor strategies not seen with standard outcomes. These observations support the central hypothesis of this thesis: MINO plus NAC improves injury-dependent deficits in white matter histology, structure, and function with a favorable therapeutic time window in male mice, as well as the aim to test if MINO plus NAC reduce structural and functional deficits in white matter after a single CHI in male mice. The results of these experiments provide important information about the chronic phase of TBI in addition to developing novel methods to assay the onset, persistence, and progression of injury-dependent changes in the CHI mouse model of TBI.
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Thermoregulatory Stress and the Ageing Mind: Investigating Environmental High Heat Exposure as a Risk Factor for DementiaBackground As populations age globally, the health effects of extreme heat exposure are an increasing public health concern. This study examines the association between cumulative high heat exposure and the prevalence of Alzheimer’s Disease and Related Dementias (ADRD) and Mild Cognitive Impairment (MCI) among U.S. adults. Methods Data were obtained from the All of Us Research Program (n = 286,767). Heat exposure was assessed using data from the CDC’s National Environmental Public Health Tracking Network and mapped to 3-digit ZIP codes. Two exposure metrics were examined: (1) maximum temperature and (2) maximum heat index. High heat exposure was defined as the total number of extreme heat days (≥2 consecutive days with a maximum heat index above the 90th percentile for May–September) occurring within multi-day heat events from 2019 to 2023. ADRD/MCI diagnoses and medical comorbidities (cardiovascular disease, cerebrovascular disease, type 2 diabetes, chronic obstructive pulmonary disease, hearing impairment, and depression) were identified from electronic health records. Demographics, smoking, alcohol use, and social isolation were measured via survey. Socioeconomic status (SES) was assessed at both the individual level, using educational attainment, and at the community level, using the Area Deprivation Index (ADI). Logistic regression models estimated associations between high heat exposure and ADRD/MCI risk, adjusting for demographic, medical, and socioeconomic factors. Mediation analysis examined the role of SES and social isolation. Results Each additional extreme heat day was associated with a 0.39% increase in ADRD/MCI odds (95% CI: 1.0026–1.0051) when measured by maximum temperature, and a 0.58% increase (95% CI: 1.0044–1.0071) when measured by maximum heat index. Exposure to 10 extreme heat days within multi-day heat events was associated with approximately a 4% increase in the odds of ADRD/MCI when measured by maximum temperature, and approximately a 6% increase when measured by maximum heat index. These findings indicate that sustained heat exposure has a cumulative impact on cognitive risk. The association was stronger when exposure was assessed using heat index rather than temperature alone, suggesting that humidity exacerbates heat-related cognitive risks. Mediation analysis found that ADI accounted for 8.6%–9.6% of the total effect; however, high heat exposure remained a significant independent risk factor for ADRD/MCI. Neither educational attainment (as a proxy for individual-level SES) nor social isolation significantly mediated or moderated the observed associations. Discussion These findings highlight an association between sustained extreme heat exposure and ADRD/MCI, with stronger effects observed when using heat index, suggesting humidity may exacerbate heat-related cognitive vulnerability. Area deprivation partially mediated this association, reinforcing how environmental and social inequities jointly shape cognitive health. Older adults are particularly vulnerable, and disparities in access to cooling resources may compound these risks. The urban heat island effect may further amplify exposure, underscoring the need for targeted public health interventions, such as early warning systems, urban planning strategies, and equitable access to cooling. Increasing heat exposure calls for public health approaches that recognize its potential impact on cognitive decline, especially among structurally disadvantaged populations. Given the absence of disease-modifying treatments for ADRD/MCI, addressing modifiable environmental risks remains essential to protect cognitive health in an ageing population
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Association between traumatic brain injury and depression stratified by veteran status: Findings from the National Health Interview SurveyGlobally, traumatic brain injury (TBI) is one of the major causes of morbidity and mortality, with increased incidence reported among veterans. In this study, we explored the relationship between TBI and subsequent screening of depressive symptoms, with further analysis stratified by veteran status. For this study, the National Health Interview Survey data for 2023 was used, which was conducted among 29,522 non-institutionalized U.S. adults aged 18 and older. The patient health questionnaire-2 was used to screen for depression. Self-reported incidence of lifetime TBI was documented. From a Chi-square test, a significant association was observed between TBI and depression (p<0.05), with TBI more commonly being reported among veterans compared to non-veterans. Our regression model indicated that, when adjusted for sociodemographic and health variables, TBI was associated with 1.80 times higher odds of depression among the whole sample population (adjusted odds ratio [aOR] = 1.80; 95% confidence interval [CI] 1.61 - 2.02, p<0.05). When stratified by veteran status, veterans with TBI had 2.92 times higher odds of depression (aOR = 2.92; 95% CI 2.05 - 4.14, p<0.05). Compared to the whole general population, veterans with a brain injury history have higher odds of depression, identifying them as a key group in prioritizing depression management in the United States population.
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Endosome Traffic, Metabolism, and Proinflammatory Signaling in Lupus T CellsSystemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by immune dysregulation and metabolic disturbance, where T cells play a critical role in disease pathogenesis. This dissertation investigates the molecular mechanisms underlying T cell dysfunction in SLE, focusing on the interplay between endosomal trafficking, NAD+ metabolism, and pro-inflammatory signaling. A central focus of this work is the role of the small GTPase Rab4A, which is overexpressed in SLE T cells and drives the endosomal recycling and surface expression of key immune receptors, like CD38, an NAD+-hydrolyzing ectoenzyme. CD38 activity depletes intracellular NAD+, reducing Sirtuin-1 function, and increases acetylation and activation of STAT3. In turn, STAT3 promotes expression of the transcription factor FOXO1, which represses IL-2, a cytokine essential for regulatory T cell function and immune tolerance. Concurrently, Rab4A-CD38 signaling amplifies mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 activation, further promoting differentiation of pro-inflammatory T cell subsets. Furthermore, we show preliminary results from the open-label phase of an ongoing clinical trial assessing the impact of antioxidant N-acetylcysteine (NAC) treatment in SLE patients. NAC treatment has previously been shown to restore redox balance and improve disease severity. NAC treatment normalized mTOR activation in CD4+ and CD8+ memory T cells, reversed the expansion of TH1 and TFH subsets, and was associated with reduced disease activity and improved patient-reported outcomes. Together, these studies identify Rab4A as a key upstream driver of T cell dysregulation in SLE and reveal a novel signaling axis linking receptor trafficking, NAD+ metabolism, and mTOR activation. The results highlight therapeutic opportunities for targeting redox-sensitive pathways to restore immune balance and suppress autoimmunity in lupus. Future research and directions are proposed to expand upon these discoveries and further refine targeting of these interconnected pathways for improved disease management and clinical outcomes in SLE.
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Out-of-Context Activation of Memory: Limits of Stress-Induced Memory EnhancementPosttraumatic stress disorder (PTSD) can be a sequela of a traumatic event that elicits an extremely fearful reaction, and is accompanied by re-experiencing of the trauma, numbing or avoidance behavior, and persistent hyperarousal. A signature feature of PTSD is the recurrent, involuntary, and intrusive recollection of a traumatic memory, colloquially referred to as flashbacks, which occur outside of the original experience. Whether an aberrant stress response is a contributing factor to eliciting these intrusive memories, our rodent studies suggest that the response to a stressful experience can activate previously acquired memories in a context that is unrelated to the original learning situation. This observation, which we call 'out-of-context activation of memory' (OCAM), may be a useful model with which to study how an extreme stress response can influence unrelated memories, and that the subsequent modification of these unrelated memories may interfere with normal functioning and contribute to the behavioral alterations and disturbances that characterize disorders such as PTSD. Our previous work reported that after a swim-stress experience, the expression of an unrelated memory was enhanced. The learning environment and the swim environment had no physically identifiable common feature, and yet swim-stress, conducted one day after learning a left/right (L/R) discrimination task, enhanced the subsequent recall of the L/R discrimination task. In addition, swim-stress induced a stable memory to become susceptible to amnestic treatments such as propranolol and electro-convulsive shock. Taken together, this evidence suggests that the stress response to an adverse situation can modify stable, unrelated memories. The goal of my work was to evaluate and characterize the limitations of a stress-induced modification of stable, unrelated memories. There four main findings: (1) the level of physiological stress was not a common feature between the learning and swim-stress experience, (2) corticosteroids play a necessary but not sufficient role in enhancing the expression of a stable, unrelated memory, (3) swim-stress can enhance the expression of a stable, unrelated memory within a time-limited window of up to at least one week after learning, and (4) swim-stress does not enhance memories that are dependent on the hippocampus for its expression.
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Endolysosomal phosphoinositides PI3P and PI(3,5)P2 regulate mammalian lysosomal V-ATPases containing the V0 a1-isoformLysosomal acidification is critical for maintaining luminal acidic pH─ requirement for lysosome function in macromolecule processing, metabolite transport, and trafficking. Conversely, impaired acidification of lysosomes is associated with a wide array of diseases, including lysosomal storage disorders (LSDs) and multiple neurological disorders. The multi-subunit vacuolar-ATPase (V-ATPase) enzyme is the key player in acidifying lysosomes. V-ATPase, an ATP-dependent proton translocating pump, causes the lumenal acidification of lysosomes by proton translocation across the lysosomal membrane, emphasizing the importance of regulating V-ATPase function in lysosomes. The regulation of V-ATPase proton pump is multifaceted. The multi-subunit V-ATPase has a membrane-embedded V0 sub-complex, where the V0 a-subunit dictates organelle-specific distribution and assembly of V-ATPases. The V0 a-subunit has four isoforms (a1-a4) in mammals, whereas the a1 and a3 isoforms both localize to endolysosomal compartments and are involved in lysosomal acidification in many cells. However, the a-isoform-specific regulation of lysosomal V-ATPase function is not completely understood. Here, we used 4T1 mouse breast cancer cell line and it's a1-isoform knockout and partial a3-knockdown counterparts to unveil a-isoform-specific regulation and function of V-ATPases in lysosomes. Pulse-chase endocytosis of FITC-Dextran revealed that V-ATPase-mediated lysosomal acidification still occurs both in a1KO and a3KO cell lines as well as wild-type (WT) 4T1 cells. Regardless of the complete loss of a1 or partial expression of a3; the lysosomal pH, luminal proteolytic activity remain unperturbed in a1KO and a3KD cells. Partial overlapping of V0a1 and V0a3 antigen under immunofluorescence microscopy corroborates the redundant functions of both isoforms and suggests the rescue of lysosomal pH and function by the alternative a-isoform in case any one a-isoform is lost or partially expressed. Interestingly, lysosome-containing cell lysates from 4T1-a1KO and 4T1-a3KD cell lines fail to re-establish the pH gradient in vitro, indicating a possibility of different regulatory mechanisms for a1- and a3-containing lysosomes. Removal of PI3P and PI(3,5)P2 from WT and mutant cells unveiled that endolysosomal PIP removal reduces only the a1-containing V-ATPase proton pumping activity. We previously reported that the N-terminal cytosolic domain (NT) of endolysosomal V0 a1 binds specifically to endolysosomal phosphoinositides (PIPs) ─ PI3P and PI(3,5)P2. A potential PIP binding site was identified in a1 isoform. Mutation in this site abolishes the interaction with these PIPs in vitro. Given this finding, we exploited a CRISPR-Cas9-based homology-directed repair approach (HDR) to introduce this specific mutation into genomic V0 a1 of 4T1 cells. We noticed no notable changes in lysosomal acidification, pH and cathepsin B protease activity in the a1-PIP binding mutant. However, due to the Y214VH>AVA mutation in a1NT, the resulting a1-PIP mutant displayed significantly reduced proton pumping activity, a similar pattern noted in the untreated a1KO cell lysate. Endolysosomal PIPs removal and generation of a1-PIP binding mutant cells confirmed the endolysosomal PIP-dependent regulation of a1- containing V-ATPase activity in lysosomes, where PI3P and PI(3,5)P2 interacts with the 'Y214VH' residue of a1NT. Altogether, the findings of our study elucidates an unresolved mechanisms of V-ATPase regulation and provide new insight for target-based development of therapeutics to treat lysosomal disorders caused by V-ATPase dysregulation and dysfunction.
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Cholesterol Regulation in the Brain: a Clinical and Genetic Link to Neuropsychiatric DisordersEpidemiological studies have reported associations between blood cholesterol levels and the risk of psychiatric and neurodegenerative disorders, with suggestions that pharmacological modulation of cholesterol may benefit brain health. This study aimed to investigate the biological basis of these associations by applying an integrative analytical framework that combined clinical and genetic data with methodological approaches of Mendelian randomization (MR) and genetic colocalization. Specifically, we investigated statistically supported causal and pleiotropic relationships between blood cholesterol levels and neuropsychiatric disorders, while also examining associations with grey and white matter phenotypes derived from MRI data. Our findings indicate that genetic alterations in cholesterol metabolism may influence the risk of both psychiatric and neurodegenerative conditions. We also found evidence for a causal relationship between blood levels of high-density cholesterol (HDL) and region-specific structural brain phenotypes, including grey matter volume and white matter microstructure. Notably, a proatherogenic lipid profile may increase the risk of attention-deficit disorders by modulating grey matter volume in the right caudate nucleus. Additionally, we observed that structural brain changes and disease status may, in turn, influence peripheral lipid levels. Specifically, increased grey matter volume in the putamen has demonstrated causal association with elevated HDL levels, while Alzheimer's disease showed a direct reverse causal relationship with both high- and low-density cholesterol (LDL) levels. In addition, our analyses reveal a genetic basis for the association between peripheral cholesterol levels and susceptibility to neuropsychiatric disorders, identifying multiple pleiotropic loci that influence both traits. Genetic variants associated with blood cholesterol levels may impact brain function through brain cell type-specific regulatory effects on gene expression, implicating molecular pathways involved in lipid metabolism, neural signaling, and neuroinflammation in the etiology of psychiatric and neurodegenerative disorders.
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Engineering Molecular Probes for Diagnostic ApplicationsAbstract In the wake of the SARS-CoV-2 pandemic, the need for rapid and highly sensitive pathogen testing became apparent. The use of lateral flow and PCR-based assays were limited by sensitivity and time, respectively. Biosensors with an electronic transduction element provide a way to address the needs of rapid detection arising from the pandemic and can be applied to various industries and fields of biomedical sciences. In this thesis, I address some of the key limitations in detecting SARS-CoV-2 using field effect transistor technology, while exploring key conditions to enhance biomolecular detection and build a platform for multiplexed detection of target analytes in a highly sensitive fashion. Through collaboration with investigators at the NYU Tandon School of Engineering, we designed and fabricated a graphene field effect transistor (GFET) platform for broad pathogen detection and demonstrate its ability to detect live SARS-CoV-2 viral particles, as well as spike protein. By implementing thermochemical scanning probe lithography, we conjugated multiple probe types and tested their performance, including antibodies, aptamers and peptides. Through systematic testing, we evaluated the probe length and ionic strength of the testing matrix as key determinants of the theoretical sensitivity, as they affect a critical factor: the Debye length (detection distance from the surface of the FET). In addition to viral detection, we engineered a novel probe for bacterial detection, which exploits the ability of bacteria to cleave specific DNA sequences using highly conserved enzymes (restriction endonucleases). For proof of concept, we tested our probe using a commonly exploited restriction enzyme, EcoRI, and demonstrate viability with a clinically relevant, pathogenic strain of Neisseria gonorrhea. These DNA-based probes exhibit regenerative capabilities and are highly customizable to different pathogens and detection modalities. Together, this work highlights progress in the effort for increased efficiency in pathogen detection using biosensors; both structurally and through designing a new class of molecular probes.
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Challenges to the translation of genomic information into clinical practice and health policy: Utilization, preferences and economic value.It is important to understand how knowledge of genomics can be translated from research into clinical practice and health policies. This review examines existing evidence on three key factors in the adoption of personalized medicine: utilization, preferences, and economic value, using two cancer examples: HER2/neu antigen testing and trastuzumab (Herceptin) treatment and genetic testing for Lynch syndrome. Our findings highlight areas in which additional research is required to build an evidence base addressing utilization of, preferences for, and the potential costs and benefits of personalized medicine. Major challenges include a lack of linked data, the need for relevant research frameworks and methodologies, and the clinical complexities of genomic-based diagnostics and treatment.
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Acculturation and Colorectal Cancer Screening Among Older Latino Adults: Differential Associations by National OriginBackground: Although modest improvements in colorectal cancer (CRC) screening utilization have occurred, rates remain low among Latinos. It is unclear whether acculturation plays a role in the utilization of CRC screening. Objective: This study aimed to examine the relationships between acculturation and CRC screening among older Mexican, Puerto-Rican and Cuban adults. Design: Cross-sectional observational study. Subjects: Latinos 50 years and older, never diagnosed with CRC, and who were surveyed in the 2000, 2003 and 2005 National Health Interview Survey (NHIS). Measures: We measured acculturation with US nativity and language of interview, and examined three different CRC screening outcomes: fecal occult blood test (FOBT) in the past year, up-to-date endoscopy and any up-to-date CRC screening. Logistic regression models were adjusted for predisposing, enabling and health-care need factors consistent with the behavioral model of health-care utilization. Main results: In adjusted analyses, US nativity was positively associated with up-to-date endoscopy among Mexicans (OR: 1.5; 95% CI: 1.1, 2.2), but negatively associated with FOBT in the past year among Puerto Ricans (OR: 0.3; 95% CI: 0.2, 0.7). In contrast to this latter finding among Puerto Ricans, English language interview was positively associated with FOBT in the past year (OR: 2.5; 95% CI: 1.1, 5.4). Conclusion: Results underscore the importance of stratification by national origin in studies of acculturation and cancer screening and of targeting less acculturated adults to promote CRC screening. Clinicians, however, should consider the complexity of acculturation and treat US nativity and language preference as independent dimensions among their Latino patients.
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Immigrant generation and physical activity among Mexican, Chinese & Filipino adults in the U.S.Migrant studies of physical activity (PA) can provide insight into the prevention of chronic disease. It is unclear, however, whether PA increases or decreases the longer migrants live in their host country. In the US, studies on immigrants' length of residence in the US and PA are inconclusive and many studies do not adequately consider the role of socioeconomic status (SES). Using California data, we examine relationships between immigrant generation and physical activity (PA) among Mexican, Chinese and Filipino adults, who represent the three largest immigrant groups in the US, and the extent to which the relationships are confounded by SES. Data from the 2000 US Census was linked with data on adults 18 years and older from the 2005 California Health Interview Survey. PA was measured in three different domains: leisure time (LTPA), non-leisure time (NLTPA) and any PA. Logistic regression was used to examine whether a wide range of SES factors, measured at the respondent and neighborhood levels, influenced the relationship between immigrant generation and PA in all domains and in different ethnic origin groups. Generation was significantly associated with LTPA among Mexican and Chinese adults and with NLTPA among all 3 ethnic origin groups; however the nature of the relationships varied. After adjusting for individual and neighborhood SES factors, a positive association between generation and LTPA remained among Mexican adults, and negative association between generation and NLTPA remained among Chinese and Filipino adults. These results underscore the importance of comparative studies of immigrant generation and PA and consideration of SES factors to identify pathways linking generation to PA. In the context of increasing rates of chronic disease, the study of transitions in PA among immigrants will continue to be critical to promoting the public health of diverse populations in countries such as the US.
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Disparities in cancer screening in individuals with a family history of breast or colorectal cancerBackground: Understanding racial/ethnic disparities in cancer screening by family history risk could identify critical opportunities for patient and provider interventions tailored to specific racial/ethnic groups. The authors evaluated whether breast cancer (BC) and colorectal cancer (CRC) disparities varied by family history risk using a large, multiethnic population-based survey. Methods: By using the 2005 California Health Interview Survey, BC and CRC screening were evaluated separately with weighted multivariate regression analyses, and stratified by family history risk. Screening was defined for BC as mammogram within the past 2 years for women aged 40 to 64 years; for CRC, screening was defined as annual fecal occult blood test, sigmoidoscopy within the past 5 years, or colonoscopy within the past 10 years for adults aged 50 to 64 years. Results: The authors found no significant BC screening disparities by race/ethnicity or income in the family history risk groups. Racial/ethnic disparities were more evident in CRC screening, and the Latino-white gap widened among individuals with family history risk. Among adults with a family history for CRC, the magnitude of the Latino-white difference in CRC screening (odds ratio [OR], 0.28; 95% confidence interval [CI], 0.11-0.60) was more substantial than that for individuals with no family history (OR, 0.74; 95% CI, 0.59-0.92). Conclusions: Knowledge of their family history widened the Latino-white gap in CRC screening among adults. More aggressive interventions that enhance the communication between Latinos and their physicians about family history and cancer risk could reduce the substantial Latino-white screening disparity in Latinos most susceptible to CRC.
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Early Developments in Gene-Expression Profiling of Breast Tumors: Potential for Increasing Black–White Patient Disparities in Breast Cancer Outcomes?New prognostic tests, such as gene-expression profiling (GEP) of breast tumors, are expected to prolong survival and improve the quality of life for many breast cancer patients. In this article, we argue that GEP has not been adequately validated in minority populations, and that both biological and social factors might affect the broad utility of these tests in diverse populations. We suggest that the widespread use of this technology could potentially lead to suboptimal treatment for black women, resulting in a further increase in black-white patient disparities in treatment response, morbidity and mortality rates. We argue for the need to build a large and diverse evidence base for GEP and other emerging technologies in personalized medicine.
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Immigrant Generation and Diabetes Risk Among Mexican Americans: The Sacramento Area Latino Study on AgingObjectives: We examined whether acculturation and immigrant generation, a marker for assimilation, are associated with diabetes risk in an aging Mexican-origin population. Methods: We analyzed data on 1789 adults aged 60 to 101 years from the Sacramento Area Latino Study on Aging. We ascertained type 2 diabetes on the basis of diabetic medication use, self-report of physician diagnosis, or a fasting glucose of 126 milligrams/deciliter or greater. Logistic regression modeled prevalent diabetes. Results: Adjusting for age and gender, we observed significant but divergent associations between immigrant generation, acculturation, and diabetes risk. Relative to first-generation adults, second-generation adults had an odds ratio (OR) of 1.8 (95% confidence interval [CI] = 1.4, 2.4) and third-generation adults had an OR of 2.1 (95% CI = 1.4, 3.1) of having diabetes. Greater US acculturation, however, was associated with a slightly decreased diabetes rate. In the full model adjusting for socioeconomic and lifestyle factors, the association between generation (but not acculturation) and diabetes remained significant. Conclusions: Our study lends support to the previously contested notion that assimilation is associated with an increased diabetes risk in Mexican immigrants. Researchers should examine the presence of a causal link between assimilation and health more closely.
