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Genome-Wide Association Study of Estimated Fat Mass in Samoan Adults
No full textObesity lowers quality of life and is associated with multiple cardiometabolic diseases, including type 2 diabetes (T2D). Excess adiposity affects normal functioning of the pancreas, cardiovascular system, immune system, and alters the balance of certain metabolites. We do not have a complete understanding of all the genetic markers that affect fat mass and how measures of adiposity can be used to predict T2D risk, especially in populations underrepresented in research, such as the Samoan adults in this study. I estimated fat mass and percent body fat in 3,094 participants based on a previously validated equation using age, sex, height, and weight. Next, I performed a genome-wide association study (GWAS) of estimated fat mass of 3,075 participants with complete genetic and phenotypic data across 9,072,005 genetic variants. Finally, since it is challenging to quantify adiposity as a single number, anthropometric measures of adiposity (weight, body mass index, abdominal circumference, hip circumference, abdominal–hip ratio, estimated fat mass, and estimated percent body fat) were examined for their ability to predict T2D risk in 2,885 participants with known T2D status in models that included sex, age, and age² as covariates. The most significant finding of the GWAS were variants in and around CREBRF, consistent with previous studies that this locus is associated with adiposity. The seven adiposity measures performed equivalently as predictors, with abdominal–hip ratio a slightly better predictor in terms of adjusted McFadden pseudo-R², area under the curve, Matthews correlation coefficient, and Akaike information criterion. Information on these genetic markers can play a crucial role in the development of prevention and treatment strategies for the many diseases attributed to obesity. Further studies are still needed to figure out how these variants affect the balance of fat and lean mass and the mechanism of how they change glucose metabolism and T2D risk. If abdominal–hip ratio or estimated fat mass can be used to improve prediction of T2D risk, underresourced communities without specialized equipment could start interventions earlier. Such precision public health approach can potentially reduce the severity of these diseases and improve quality of life for the many people affected
Patterns, Predictors, and Outcomes of Paternal Activation Parenting
No full textExtant research on paternal caregiving in early childhood has typically relied on traditional caregiving dimensions derived from research and theory on mothers. However, some have argued that fathers play a unique role in promoting children’s experiences and relationships with individuals outside of the security provided by attachment relationships through activation parenting (AP). AP includes behaviors that challenge children to approach novel situations, explore their environments, and take physical and socioemotional risks, through a balance of encouragement and limit-setting. Whereas components of AP have been linked to children’s self-regulation (SR) skills, comprehensive measures of AP and, importantly, longitudinal research on Black and Latinx families from low socioeconomic backgrounds are lacking. These limitations greatly constrain our understanding of the potential benefits of paternal AP for children’s emerging SR. Thus, the overall goal of the present study was to test associations between paternal AP (age 3), paternal characteristics (age 2), and children’s SR skills (ages 4 and 5) in a sample of low-income, ethnically diverse fathers. Participating fathers (N = 171; 9% Black, 47% white, 11% other/unknown racial group, 32% missing; 8% Latinx, 61% not Latinx, 30% missing; mean household income = $25,145) and their children (51% female and 49% male) were drawn from the Early Steps Multisite Study. Dyads participated in clean-up and teaching tasks at age 3, which were coded using a novel AP coding system. Hypothesized predictors of AP were collected at age 2 and included father-reported depressive symptoms and sociodemographic characteristics collected via interviews with the primary caregiver (mostly biological mothers): income-to-needs ratio, paternal education, and paternal race/ethnicity. Child SR was assessed via maternal and paternal reports at ages 2, 4, and 5, as well as via behavioral tasks at age 5. Although a multilevel latent factor for AP in the clean-up and teaching tasks demonstrated excellent fit, AP was not found to be associated with child SR (either directly or moderated by child characteristics) and was not significantly associated with paternal characteristics. Despite the null findings, the present study has important implications for conceptualizing and measuring AP in diverse samples of caregivers, including fathers
Functional Effects of Schizophrenia-Associated MAP2 Phosphorylation Events
No full textMicrotubules (MTs) support myriad aspects of neuromorphological development, which is thought to be altered in schizophrenia (SZ). Microtubule-associated protein 2 (MAP2) is a prominent regulator of neuronal MT assembly and organization. Diminished immunoreactivity (IR) of this protein has been repeatedly described in post-mortem brain tissue from individuals with SZ, and recent evidence has further established that its phosphorylation state is altered in disorder, with consequence for protein function. This dissertation describes a collection of studies intended to further illuminate the scope of SZ-associated MAP2 pathology and its potential downstream consequences. Chapter 2 details an immunohistochemical experiment using postmortem brain tissue from a matched cohort of SZ and non-psychiatric comparison subjects (N = 20 pairs), examining MAP2-IR in multiple cortical regions distributed across the rostral-caudal axis. This experiment reveals that MAP2-IR deficits are conserved across cortex within-subject, bearing implications for future study and treatment of MAP2 pathology. Chapter 3, using phosphomimetic MAP2C constructs, demonstrates that a subset of SZ-associated MAP2 phosphorylation events can influence MT- and actin-binding affinity as well as MT assembly kinetics in a domain-specific manner; mutants of the proline-rich domain show suppressed MT assembly and actin-binding while maintaining MT-binding, while C-terminal domain mutants additionally have reduced MT-binding capacity. Further, the C-terminal domain mutant S426E- but not the proline-rich domain mutant T293E- has a reduced capacity for process formation upon overexpression in heterologous cells relative to wild-type protein. Finally, Chapter 4 examines the effects of phosphomimetic MAP2B mutations on MT organization/stability in heterologous HEK293T cells as well as dendritic morphology of cultured cortical neurons. I find that C-terminal domain mutants S1782E and S1799D surprisingly confer increased resistance to katanin-mediated MT severing, while the proline-rich domain mutant T1649E augments basilar dendritic arborization in mature neurons. Together, these findings indicate that SZ-associated MAP2 dysregulation is a global phenomenon within-subject, and that phosphorylation of SZ-associated sites in the proline-rich or C-terminal domains of MAP2 differentially regulate its function, with distinct consequences for cellular morphogenesis
The miR-17~92 cluster regulates aldosterone signaling: Contributions to sex differences in sodium transport in the distal nephron
No full textHypertension affects over a billion individuals globally, with aldosterone playing a crucial role in blood pressure regulation through the renin-angiotensin-aldosterone-signaling (RAAS) system. Premenopausal women exhibit a lower risk of hypertension than age-matched men, attributed to both reduced aldosterone levels and estrogen signaling. While our previous work highlighted aldosterone's influence on microRNA (miR) expression in collecting duct epithelial cells, the sex-specific regulation of miRs and their impact on sex differences in blood pressure homeostasis remain unexplored. This study investigates the hypothesis that the miR-17~92 cluster contributes to sex differences in aldosterone signaling within the nephron's collecting duct epithelia. Using in vitro and in vivo models, we examined the response of miR-17~92 to aldosterone and estrogen stimulation. MiR-19, a component of miR-17~92, showed upregulation in response to both aldosterone and estrogen in cultured cells. In vivo, a sex-specific upregulation of the miR-17~92 cluster was evident in female mice on a low-Na+ diet, stimulating aldosterone release. In mCCD cells, estrogen pretreatment attenuated aldosterone stimulation by targeting the serum and glucocorticoid-induced kinase (Sgk1) mRNA. However, neither estrogen receptors (ERs) nor xenobiotic receptors (XRs) were responsible for this effect. Luciferase assays confirmed the binding of miR-19 to the 3’-UTR of Sgk1. Overexpression of miR-19 in cells inhibited aldosterone-induced Na+ transport, while inhibition of miR-19 had the opposite effect. In vivo studies on mice corroborated the sex-specific regulation of Sgk1 by miR-17~92. Female mice exhibited an elevation in relative Sgk1 expression compared to males when placed on low Na+ diets. By examining evolution of the miR-17~92 cluster, phylogenetic sequence analysis indicated that this cluster arose at the same time that other Na+-sparing and salt regulatory proteins, specifically SGK1 first emerged, indicating a conserved role for these miRs in kidney function of salt and water homeostasis. In conclusion, our findings suggest that the miR-17~92 cluster may contribute to sex-specific differences in aldosterone signaling, providing insights into the molecular mechanisms underlying sex disparities in blood pressure regulation
Permeability Via Falling Head Test in Binder Jet 3D Printed Gas Atomized and Water Atomized Inconel 625
No full textAdditive manufacturing (AM) is increasingly utilized to create parts with complex external and internal geometries. Binder jet 3D printing, a sinter-based AM method, can produce parts with controlled connected porosity that could be used for industrial applications such as filtration. In order to better understand the relationship between porosity and inherent permeability of binder jet printed material, the permeability of binder jet 3D printed Inconel 625 samples was examined using the falling head test. The samples were printed from both gas atomized and water atomized powder feedstock of comparable particle size. Green parts were sintered at different temperatures and for different durations to generate a range of final densities between 60% and 90% for each powder type. A custom falling head test apparatus was designed to test the permeability of the sintered samples. The permeability of both gas atomized and water atomized Inconel 625 was found to decrease as density increased. Neither powder type was found to generate an overall higher permeability than the other across comparable densities. A baseline for permeability of additively manufactured Inconel 625 was established for future work examining specific questions of permeability in binder jet printed materials. Avenues to calibrate the falling head test to suit sample properties for increased precision and extended applications are identified
Exploring Network Heterogeneity Effects on Butyl Acrylate Elastomers through a Double Network Approach
No full textIn the last decade, the double network approach has emerged as a novel way to overcome the challenge of engineering soft, but still tough, crosslinked polymer networks. However, much remains unknown about the structure-property relationships bridging first network molecular features and the bulk double network response. Recently, synthetic rules have been identified that allow for the synthesis of networks with precisely controlled topological features. Here, we utilize these design rules and synthesize multiple series of butyl acrylate networks with systematically varied topological features including crosslink heterogeneity, dangling ends, loops, and strand dispersity. The networks are then swollen into double net- works. Because all the first network samples are prepared in duplicate, we can characterize the uniaxial stress-strain response of the first networks and analyze their resulting effect on the prepared double networks. Our results show that changing features in the first network topology, for example crosslink distribution, can alter the modulus of the first network independent of the observed strain stiffening response in the double network. We also show that other network defects, such as loops and dangling ends, can also independently tune the modulus and onset of strain stiffening by changing the density of elastically effective strands, but not necessarily the lengths of the global percolated paths in the network. Finally, we present our attempts to synthesize mechanochemically active randomly and regularly crosslinked single and double networks. While we unfortunately ran into chemical incompatibilities with our mechanophore and network syntheses, we identify suspected degradation pathways, which can help to inform future mechanophore choices for these experiments. In summary, this thesis provides important fundamental insights about the relationship between first network molecular structure and the bulk double network stress-strain response. We expect that the findings presented herein will be helpful for informing future design of soft, tough, crosslinked polymer materials with precisely tuned stress-strain behavior
MALT1 protease as a mediator of chemotherapy resistance in triple-negative breast cancer
No full textBackground: Breast cancer is the most commonly diagnosed malignancy in American women. The triple-negative breast cancer (TNBC) subtype has among the worst prognosis due to high rates of recurrence and metastasis. Since TNBC lacks targetable receptor proteins, treatment relies upon non-specific chemotherapy, which can become ineffective upon onset of resistance. One potential driver of TNBC treatment resistance is MALT1 protease, the effector component of the CARMA-BCL10-MALT1 signaling complex, which induces pro-survival NF-ΚB transcriptional activity in multiple cancer cell types. Notably, it has been suggested that breast cancer cells demonstrate increased sensitivity to chemotherapies, doxorubicin and cisplatin, when MALT1 is depleted. Hence, we hypothesize that MALT1 protease is a pharmaceutically targetable driver of TNBC treatment resistance.
Results/Conclusions: We found that MALT1 is highly expressed in basal breast cancer (a subtype largely composed of TNBC) and its expression in this context is associated with decreased response to anthracycline chemotherapies and reduced survival. MALT1 blockade, via siRNA knockdown or MALT1 protease inhibition increases doxorubicin sensitivity. Alternatively, overexpressing MALT1 leads to increased viability for doxorubicin-treated TNBC cells as compared to TNBC cells overexpressing empty vector or protease-deficient MALT1. These findings were confirmed in vivo by demonstrating that combination treatment of MALT1 protease inhibitor (JNJ-67856633) and doxorubicin resulted in significantly reduced tumor growth as compared to doxorubicin treatment alone.
Mechanistically, we have shown for the first time that MALT1 protease is activated in response to treatment of TNBC cells with the DNA damaging agent, doxorubicin. We have found that MALT1 is not required for doxorubicin-induced NF-ΚB activation. Instead, our studies suggest a unique link between MALT1 and the DNA repair protein, ATM in which MALT1 protease activation in doxorubicin-treated cells partially depends on ATM. This may suggest a potential role for MALT1 in repair of doxorubicin-induced DNA damage. Altogether, our studies suggest that MALT1 inhibition may be a promising approach to improving chemotherapy response in TNBC
Modeling and Optimization Frameworks for Assessing Environmental Impacts and Dependencies of Food Systems at Multiple Spatial Scales
No full textHumans have harnessed animals for thousands of years for a variety of reasons and today animals play crucial roles in food systems. Both their contributions and environmental consequences must be acknowledged for integrated management and moving towards sustainable agricultural practices. On one hand, animal-based products constitute a significant portion of diets. Cattle production has been linked to a series of environmental impacts while occupying almost 41% of land in the contiguous United States between pastureland and cropland for feed production. On the other hand, animal-mediated pollination is critical for production of many food crops. Approximately 90% of flowering plants and at least a third of total crop weight produced globally are dependent on pollinators, mostly wild and managed bees. This work focuses on cattle (animals as products) and bees (animals as resources) as critical avenues to understand interconnections between food systems and the environment. The major goal of the proposed research is two-fold, 1) develop a framework to elucidate the consumption-based environmental impacts (virtual water and nitrogen) of animal-based products via two studies with a specific focus on the US beef supply chain, 2) develop frameworks to assess how agriculture simultaneously impacts and depends on wild bees and their ecosystem services via two studies. For the first goal, modeling and optimization are used to trace and quantify impacts of the beef supply chain. An optimization framework to trace supply chain networks is combined with information on resource use to quantify embodied water and nitrogen emissions associated with beef consumption in the United States. This provides a unique opportunity to understand impacts at the county level, while highlighting clear spatial patterns and discrepancy between production- and consumption-based accounting. Subsequently for the second goal, reported data on soybean yields is coupled with a methodology based on earth observations and machine learning to estimate soybean yield at a fine scale of 250 meters. This fine scale yield data is utilized to map and quantify the interactions between productivity, insecticides, and wild bee abundance across the United States through Bayesian modeling. Finally, a spatial network model of pollination service flows is developed and coupled with an optimization approach to identify areas for bee habitat restoration ultimately pointing towards strategic placement of nesting resources to achieving higher ecosystem service levels in cropland. Overall, this body of work discusses challenges and opportunities for utilizing modeling and optimization for improving the sustainability of food systems
Understanding the Functionality of Zeolite-Stabilized Single-Atom Catalysts
No full textA swift transition from growth-oriented development to sustainable development is an inevitable necessity for the future. Without drastic measures across all the economic sections to limit the Earth’s temperature rise, present and future generations will encounter catastrophic, life-threatening climate changes. Catalysts are key materials for mitigating the carbon footprint of chemical processes. Single-atom catalysts (SACs) have emerged as a new frontier in heterogeneous catalysis due to their superior activity and metal utilization efficiency. Zeolites are promising support materials for SACs due to their shape selectivity and tunable physicochemical properties. The atomic dispersion of active metals in the micropores of zeolites can give rise to exceptionally high catalytic performances.
This dissertation focuses on advancing the understanding of zeolite-stabilized SACs with the use of first-principles calculations and multiscale modeling. Specifically, computational findings rationalize experimental observations in nucleation, phase transition, and modification of zeolites, guiding methodologies for their targeted synthesis for catalytic applications. Furthermore, the computational framework for simulating complex catalytic reactions presented herein paves the way for discovering and designing novel catalysts. The crucial role of oxidation states of the metal sites and their synergistic effects with zeolite supports are addressed in detail, suggesting key features that need to be emphasized in future research endeavors. Overall, this dissertation offers fundamental knowledge for the synthesis, manipulation, and application of zeolite-stabilized SACs, bridging the gap in our current understandings and highlighting their potential to sustainable chemical processes
An Examination of the Epistemology of Prejudiced Belief
No full textIn “Racial Prejudice and Friction,” John Dewey writes: “Too often we try to discuss race prejudice morally before we have dealt with it scientifically. That is, we justify or condemn it before we understand it.” Dewey’s remark applies well to contemporary work on the epistemology of prejudiced belief, in which there are dueling tendencies either to condemn or to justify these beliefs without sufficient care. In this dissertation, I chart a middle path between these extremes.
I first critique Amia Srinivasan’s radical epistemology, according to which judgments about the epistemic status of morally and politically problematic beliefs should be guided by considerations of moral and political utility. I argue instead that we must uphold the priority of the epistemic, keeping separate epistemic evaluations of problematic beliefs and concerns about the utility of our epistemological judgments.
I then examine the role of testimony in the formation of prejudiced belief. I defend testimonial reductionism, which holds that hearers must have sufficient positive reasons to regard speakers as trustworthy in order to be justified in believing what they say. I then argue that while prejudiced testimonial beliefs can be epistemically justified, this is true most often when these beliefs are formed in highly isolated and evidentially impoverished environments. Most prejudiced agents in societies like our own, however, are not in such dire epistemic straits. So, although perhaps not all prejudiced beliefs are epistemically unjustified, there is prima facie reason to regard such beliefs with suspicion.
Finally, I discuss prejudiced beliefs based on biased perceptual experiences, disputing Susanna Siegel’s position that biased experiences can be irrational and, when they are, this irrationality transmits to beliefs formed on their basis. Drawing on Anil Gupta’s Conscious Experience, I present a coherentist account on which the epistemic status of an agent’s perceptual beliefs depends on the epistemic status of her antecedent view that in part gives rise to her experiences. I then apply this to prejudiced beliefs based on biased experiences that result from prejudiced antecedent views, concluding that in a restricted range of cases agents can be epistemically rational in forming these beliefs