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Scholarly Works (9 results)

  • Thesis
  • Peer Reviewed
UC Irvine Electronic Theses and Dissertations (2022)

This dissertation explores the effects of ancillary ligands on reductive lanthanide (Ln) chemistry and describes the isolation of Ln(II)-containing complexes with novel structural or magnetic properties. Chapter 1 demonstrates a molecular approach to developing qubits through the synthesis and reduction of the tris(aryloxide) Lu(III) complex, Lu(OAr*)3 (OAr* = 2,6-Ad2-4-tBu-C6H2O−, where Ad is 1-adamantyl). Potassium reduction of Lu(OAr*)3 in the presence of 2.2.2-cryptand (crypt) generated the formally 4f 145d1 Lu(II) complex, [K(crypt)][Lu(OAr*)3]. The OAr* ligand greatly shielded the [Xe]4f 145d1 Lu2+ ion, which increased its thermal stability and enhanced the amount of s mixing into the 5dz² SOMO. The increase in s character led to a large hyperfine clock transition in its EPR spectrum and one of the largest hyperfine interactions ever observed for a molecular system.In contrast to Chapter 1, which described the synthesis of the sterically saturated Lu(II) complex, Chapter 2 explores the limits of steric unsaturation of isolable Ln(II) ions by employing one of the smaller cyclopentadienyl ligands, (C5H4Me)1−. The reduction of CpMe3Ln(THF) (CpMe = C5H4Me; Ln = Nd, Gd) with KC8 in the presence of 18-crown-6 generated the [(18-crown-6)K(μ-(CpMe))K(18-crown-6)][(CpMe)3Ln] complexes, which were isolated and characterized by X-ray crystallography and EPR spectroscopy. The degree of steric saturation was quantified and comparative analysis found that these complexes were the least sterically saturated Ln(II) complexes reported to date. These results corroborated the hypothesis that degree of shielding of the Ln(II) ion by its ancillary ligands has an influence on the thermal stability of the complex. Chapter 3 describes the synthesis of unusual reduced arene complexes of the Ln(II) ions. These bimetallic lanthanide complexes containing reduced bridging ligands may be of value to the field of single-molecule magnet research because these compounds have shown remarkably enhanced magnetic exchange interactions. Previously, the only four crystallographically characterized examples of bimetallic lanthanide (II) complexes containing reduced arene bridging ligands contain cyclopentadienyl ancillary ligands. Reduction of the tris(amide) complexes, Ln(NR2)3 (Ln = La, Ce; R=SiMe3), with potassium in the presence of toluene and crypt allows the isolation of the reduced arene bridged complexes, [K(crypt)]2[{(R2N)2LnII}2(μ-η6:η6-C6H5Me)], with amide ancillary ligands. The crystallographic and spectroscopic data, as well as computational analysis are consistent with the presence of two Ln(II) ions bridged by a toluene diradical dianion. Reduction of [(THF)(R2N)2Tb]2(μ-Cl)2 with KC8 in the presence of toluene and crypt allows the isolation of the first terbium reduced arene bridged complex, [K(crypt)]3[{(R2N)2TbII}2(μ-η6:η6-C6H5Me)][K(NR2)2(THF)2].

    Cover page: Exploring the Intricacies of Ancillary Ligand Effects on 4fn5d1 Ln(II) IonsCreative Commons 'BY' version 4.0 license
    • Article
    • Peer Reviewed
    UC Davis Previously Published Works (2023)

    Introduction

    Rhesus macaques are natural hosts to multiple viruses including rhesus cytomegalovirus (RhCMV), rhesus rhadinovirus (RRV), and Simian Foamy Virus (SFV). While viral infections are ubiquitous, viral transmissions to uninfected animals are incompletely defined. Management procedures of macaque colonies include cohorts that are Specific Pathogen Free (SPF). Greater understanding of viral transmission would augment SPF protocols. Moreover, vaccine/challenge studies of human viruses would be enhanced by leveraging transmission of macaque viruses to recapitulate expected challenges of human vaccine trials.

    Materials and methods

    This study characterizes viral transmissions to uninfected animals following inadvertent introduction of RhCMV/RRV/SFV-infected adults to a cohort of uninfected juveniles. Following co-housing with virus-positive adults, juveniles were serially evaluated for viral infection.

    Results

    Horizontal viral transmission was rapid and absolute, reaching 100% penetrance between 19 and 78 weeks.

    Conclusions

    This study provides insights into viral natural histories with implications for colony management and modeling vaccine-mediated immune protection studies.
      Cover page: Horizontal transmission of endemic viruses among rhesus macaques (Macaca mulatta): Implications for human cytomegalovirus vaccine/challenge design
      • Article
      • Peer Reviewed
      UC Irvine Previously Published Works (2021)
      The investigation of the coordination chemistry of rare-earth metal complexes with cyanide ligands led to the isolation and crystallographic characterization of the Ln III cyano-tri-phenyl-borate complexes di-chlorido-(cyano-tri-phenyl-borato-κN)tetra-kis-(tetra-hydro-furan-κO)lanthanide(III), [LnCl2(C19H15BN)(C4H8O)4] [lanthanide (Ln) = dysprosium (Dy) and yttrium Y)] from reactions of LnCl3, KCN, and NaBPh4. Attempts to independently synthesize the tetra-ethyl-ammonium salt of (NCBPh3)- from BPh3 and [NEt4][CN] in THF yielded crystals of the phenyl-substituted cyclic borate, tetra-ethyl-aza-nium 2,2,4,6-tetra-phenyl-1,3,5,2λ4,4,6-trioxatriborinan-2-ide, C8H20N+·C24H20B3O3 - or [NEt4][B3(μ-O)3(C6H5)4]. The mechanochemical reaction of BPh3 and [NEt4][CN] without solvent produced crystals of tetra-ethyl-aza-nium cyano-diphenyl-λ4-boranyl di-phenyl-borinate, C8H20N+·C25H20B2NO- or [NEt4][NCBPh2(μ-O)BPh2]. Reaction of BPh3 and KCN in THF in the presence of 2.2.2-cryptand (crypt) led to a crystal of bis-[(2.2.2-cryptand)potassium] 2,2,4,6-tetra-phenyl-1,3,5,2λ4,4,6-trioxatriborinan-2-ide cyano-methyl-diphenyl-borate tetra-hydro-furan disolvate, 2C18H36KN2O6 +·C24H20B3O3 -·C14H13BN-·2C4H8O or [K(crypt)]2[B3(μ-O)3(C6H5)4][NCBPh2Me]·2THF. The [NCBPh2(μ-O)BPh2]1- and (NCBPh2Me)1- anions have not been structurally characterized previously. The structure of 1-Y was refined as a two-component twin with occupancy factors 0.513 (1) and 0.487 (1). In 4, one solvent mol-ecule was disordered and included using multiple components with partial site-occupancy factors.
        Cover page: Crystallographic characterization of rare-earth cyano­tri­phenyl­borate complexes and the cyano­borates [NCBPh3]1−, [NCBPh2Me]1−, and [NCBPh2(μ-O)BPh2]1−
        • Article
        • Peer Reviewed
        UC Davis Previously Published Works (2016)

        Background

        Hematologic variables are often analyzed in animal analogs during the investigation of complex disease etiologies such as necrotizing enterocolitis. However, reference intervals (RI) can vary depending on animal strain, age, and sampling site. Reference intervals have been published for adult C57BL/6J mice, but not newborn C57BL/6J mice.

        Objectives

        The purpose of the present study was to determine hematologic RI in newborn C57BL/6J mice up to day 35.

        Methods

        C57BL/6J mice founders from The Jackson Laboratory were bred at the University of Iowa. Blood samples were obtained via facial vein sampling at postnatal days 0 (p0), p7, p14, p21, p28, or young adulthood (p35). CBCs were determined with the Sysmex XT-2000iV analyzer within 30 minutes of blood collection at a 1:10 dilution. Statistics were determined using nonparametric methods following ASVCP guidelines.

        Results

        Hematologic RI were determined for each of the 6 groups (n = 247, n ≥ 39 per group). Significantly higher values for HGB, RBC, and PLT counts were observed with advancing developmental age. Total WBC counts remained relatively stable during the first 35 days of life. However, WBC differential counts were dominated by neutrophils and lymphocytes in the younger mice, with a trend toward a lymphocytic leukogram on day 35.

        Conclusions

        These results illustrate the dynamic changes in hematologic variables during murine development after birth. Utilization of age-specific RI is advised when evaluating data derived from experimental perinatal mouse models.
          Cover page: Evaluation of hematologic variables in newborn C57/BL6 mice up to day 35
          • Article
          • Peer Reviewed
          UC Davis Previously Published Works (2016)
          Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation.
            Cover page: Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development
            • Article
            • Peer Reviewed
            UC San Diego Previously Published Works (2021)
            The mechanisms by which macrophages regulate energy storage remain poorly understood. We identify in a genetic screen a platelet-derived growth factor (PDGF)/vascular endothelial growth factor (VEGF)-family ortholog, Pvf3, that is produced by macrophages and is required for lipid storage in fat-body cells of Drosophila larvae. Genetic and pharmacological experiments indicate that the mouse Pvf3 ortholog PDGFcc, produced by adipose tissue-resident macrophages, controls lipid storage in adipocytes in a leptin receptor- and C-C chemokine receptor type 2-independent manner. PDGFcc production is regulated by diet and acts in a paracrine manner to control lipid storage in adipose tissues of newborn and adult mice. At the organismal level upon PDGFcc blockade, excess lipids are redirected toward thermogenesis in brown fat. These data identify a macrophage-dependent mechanism, conducive to the design of pharmacological interventions, that controls energy storage in metazoans.
              Cover page: Diet-regulated production of PDGFcc by macrophages controls energy storage
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2015)

              Background

              Both HIV and depression are associated with increased heart failure (HF) risk. Depression, a common comorbidity, may further increase the risk of HF among adults with HIV infection (HIV+). We assessed the association between HIV, depression, and incident HF.

              Methods and results

              Veterans Aging Cohort Study (VACS) participants free from cardiovascular disease at baseline (n=81 427: 26 908 HIV+, 54 519 without HIV [HIV-]) were categorized into 4 groups: HIV- without major depressive disorder (MDD) [reference], HIV- with MDD, HIV+ without MDD, and HIV+ with MDD. International Classification of Diseases, Ninth Revision codes from medical records were used to determine MDD and the primary outcome, HF. After 5.8 years of follow-up, HF rates per 1000 person-years were highest among HIV+ participants with MDD (9.32; 95% confidence interval [CI], 8.20-10.6). In Cox proportional hazards models, HIV+ participants with MDD had a significantly higher risk of HF (adjusted hazard ratio, 1.68; 95% CI, 1.45-1.95) compared with HIV- participants without MDD. MDD was associated with HF in separate fully adjusted models for HIV- and HIV+ participants (adjusted hazard ratio, 1.21; 95% CI, 1.06-1.37; and adjusted hazard ratio, 1.29; 95% CI, 1.11-1.51, respectively). Among those with MDD, baseline antidepressant use was associated with lower risk of incident HF events (adjusted hazard ratio, 0.76; 95% CI, 0.58-0.99).

              Conclusions

              Our study is the first to suggest that MDD is an independent risk factor for HF in HIV+ adults. These results reinforce the importance of identifying and managing MDD among HIV+ patients. Future studies must clarify mechanisms linking HIV, MDD, antidepressants, and HF and identify interventions to reduce HF morbidity and mortality in those with both HIV and MDD.
                Cover page: Depression and Human Immunodeficiency Virus Infection Are Risk Factors for Incident Heart Failure Among Veterans
                • Article
                • Peer Reviewed
                UC San Francisco Previously Published Works (2023)
                Mechanisms of resilience against tau pathology in individuals across the Alzheimer's disease spectrum are insufficiently understood. Longitudinal data are necessary to reveal which factors relate to preserved cognition (i.e. cognitive resilience) and brain structure (i.e. brain resilience) despite abundant tau pathology, and to clarify whether these associations are cross-sectional or longitudinal. We used a longitudinal study design to investigate the role of several demographic, biological and brain structural factors in yielding cognitive and brain resilience to tau pathology as measured with PET. In this multicentre study, we included 366 amyloid-β-positive individuals with mild cognitive impairment or Alzheimer's disease dementia with baseline 18F-flortaucipir-PET and longitudinal cognitive assessments. A subset (n = 200) additionally underwent longitudinal structural MRI. We used linear mixed-effects models with global cognition and cortical thickness as dependent variables to investigate determinants of cognitive resilience and brain resilience, respectively. Models assessed whether age, sex, years of education, APOE-ε4 status, intracranial volume (and cortical thickness for cognitive resilience models) modified the association of tau pathology with cognitive decline or cortical thinning. We found that the association between higher baseline tau-PET levels (quantified in a temporal meta-region of interest) and rate of cognitive decline (measured with repeated Mini-Mental State Examination) was adversely modified by older age (Stβinteraction = -0.062, P = 0.032), higher education level (Stβinteraction = -0.072, P = 0.011) and higher intracranial volume (Stβinteraction = -0.07, P = 0.016). Younger age, higher education and greater cortical thickness were associated with better cognitive performance at baseline. Greater cortical thickness was furthermore associated with slower cognitive decline independent of tau burden. Higher education also modified the negative impact of tau-PET on cortical thinning, while older age was associated with higher baseline cortical thickness and slower rate of cortical thinning independent of tau. Our analyses revealed no (cross-sectional or longitudinal) associations for sex and APOE-ε4 status on cognition and cortical thickness. In this longitudinal study of clinically impaired individuals with underlying Alzheimer's disease neuropathological changes, we identified education as the most robust determinant of both cognitive and brain resilience against tau pathology. The observed interaction with tau burden on cognitive decline suggests that education may be protective against cognitive decline and brain atrophy at lower levels of tau pathology, with a potential depletion of resilience resources with advancing pathology. Finally, we did not find major contributions of sex to brain nor cognitive resilience, suggesting that previous links between sex and resilience might be mainly driven by cross-sectional differences.
                  Cover page: Determinants of cognitive and brain resilience to tau pathology: a longitudinal analysis
                  • Article
                  • Peer Reviewed
                  UCLA Previously Published Works (2023)

                  Background

                  Deep learning has shown potential in various scientific domains but faces challenges when applied to complex, high-dimensional multi-omics data. Alzheimer's Disease (AD) is a neurodegenerative disorder that lacks targeted therapeutic options. This study introduces the Circular-Sliding Window Association Test (c-SWAT) to improve the classification accuracy in predicting AD using serum-based metabolomics data, specifically lipidomics.

                  Methods

                  The c-SWAT methodology builds upon the existing Sliding Window Association Test (SWAT) and utilizes a three-step approach: feature correlation analysis, feature selection, and classification. Data from 997 participants from the Alzheimer's Disease Neuroimaging Initiative (ADNI) served as the basis for model training and validation. Feature correlations were analyzed using Weighted Gene Co-expression Network Analysis (WGCNA), and Convolutional Neural Networks (CNN) were employed for feature selection. Random Forest was used for the final classification.

                  Findings

                  The application of c-SWAT resulted in a classification accuracy of up to 80.8% and an AUC of 0.808 for distinguishing AD from cognitively normal older adults. This marks a 9.4% improvement in accuracy and a 0.169 increase in AUC compared to methods without c-SWAT. These results were statistically significant, with a p-value of 1.04 × 10ˆ-4. The approach also identified key lipids associated with AD, such as Cer(d16:1/22:0) and PI(37:6).

                  Interpretation

                  Our results indicate that c-SWAT is effective in improving classification accuracy and in identifying potential lipid biomarkers for AD. These identified lipids offer new avenues for understanding AD and warrant further investigation.

                  Funding

                  The specific funding of this article is provided in the acknowledgements section.
                    Cover page: Circular-SWAT for deep learning based diagnostic classification of Alzheimer's disease: application to metabolome data
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