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This study seeks to understand how social interactions are associated with emotional well-being and how these associations differ as one ages.

This study aims to identify and explore age differences in workplace behaviors, emotions, and activities. Specifically, we are interested in examining how engagement in helping behaviors (e.g., providing informal support to a colleague) and learning at work differ with age. Drawing on theoretical accounts of changes with motivations and goals with age, we expect that engagement in prosocial and learning activities will affect older and younger workers differently.

The current study will develop and validate the Time Savoring Scale. We argue that age-related shifts in goals occur when people become aware of their lifetime limits and place increasing importance on the time remaining. Individuals begin to attend to, appreciate and enhance -- that is “savor” -- the positive experiences in their lives (Bryant & Veroff, 2007).

Convection-enhanced drug delivery (CED) enables faster convective dispersion of drug molecules through soft, porous tissues than diffusion, which is beneficial for treating aggressive tumors. Advancing the CED technology requires rigorous characterization of fluid transport through soft, porous tissues. When a fluid flows through soft, porous tissues, the deformation and/or structural rearrangement of the hosting solid alters the pattern and efficiency of fluid propagation. Such hydro-mechanical coupling can be understood by experimentally studying fluid flows through hydrogel phantoms that mimic soft, porous tissues in vitro. However, current studies using hydrogel-based models are limited because homogenous hydrogel models with uniform properties have been employed. To overcome this limitation, we aim to develop heterogeneous hydrogel models for CED studies by embedding agar beads (1 w/v%) in an agarose gel block (0.2 or 0.6 w/v%), and this paper introduces our fabrication method in detail. The fabrication process includes two steps: fabrication of the gel beads and dispensing the gel beads in the agarose gel. In the first step, agar gel beads were fabricated with the rotating-liquid-based drop generation method. Hot agar gel solution (∼95°C) was injected through a syringe needle with its tip immersed in cold mineral oil (∼4°C) that rotates in rigid body motion. As agar gel solution drops were sheared off from the needle tip by the bulk mineral oil motion, they became spherical due to surface tension. While falling through the mineral oil, the gel drops were cooled and became gel beads. These agar gel beads were harvested, washed in water, and stored at 4°C. Microscopy imaging of the created gel beads confirmed that the sizes of the beads were uniform. In the second step of fabrication, agarose solution was prepared at 95°C, and the precooled agar beads were mixed in the agarose solution. Then, the mixture was poured into a precooled mold (a petri dish at −20°C), and then the mold was moved into a refrigerator immediately for quick cooling and gelation. Microscopy imaging of the embedded gel beads showed two heterogeneous agarose gel blocks with embedded agar beads were produced with different sized agar gel beads, different concentration of agarose gel, and different distribution of agar gel beads in agarose gel. The presented method has the following advantages. First, the size of agar beads can be adjusted by changing the injection speed of the agar solution and the rotation speed of the mineral oil. Second, the level of heterogeneity can be modulated by changing the properties of the gel beads and block and by adjusting the volume fraction between the gel beads and the gel block. Also, it is expected that the degree of fusion between the gel beads and the gel block could be controlled by adjusting the temperature of the agar gel beads and the agarose solution, and the cooling process of their mixture. Therefore, the suggested heterogeneous gel model has the potential to elucidating fluid flow through deformable, heterogeneous porous media and thus to advancing convection-enhanced drug delivery.

Androgen receptor (AR), a transcription factor, is a validated therapeutic target for prostate cancer. All current AR-targeting therapies inhibit the growth of prostate cancer cells by blocking the ligand-binding domain (LBD), where androgen binds to activate the receptor. Unfortunately, these therapies fail to maintain a durable clinical effectiveness, as patients eventually succumb to castration-resistant prostate cancer (CRPC). The clinical onset and progression of most CRPC is accompanied by rising levels of serum prostate specific antigen (PSA), a gene transcriptionally regulated by AR. This indicates aberrant AR transcriptional activity is involved in driving CRPC and conferring therapy-resistance. Therefore, it is imperative to continue the research and development of novel AR inhibitors that can overcome molecular mechanisms underlying aberrant AR transcriptional activity. This dissertation presents three research projects: 1) Discovery of novel AR inhibitors; 2) Evaluation of EPI-002, an AR N-terminal domain (NTD) antagonist; and 3) Generation of a prostate cancer cell line model with resistance to EPI-002. To discover novel AR inhibitors, candidate compounds identified from high throughput screening were characterized by fluorescent ligand binding assays, AR-driven reporter assays, qPCR gene expression analyses, and proliferation assays. AR NTD inhibitor EPI-002 was evaluated against several mechanisms believed to cause aberrant AR transcriptional activity, including coactivator overexpression, AR gain-of-function mutations, and constitutively active AR splice variants with truncated LBD. To generate a prostate cancer cell line model that developed resistance to EPI-002, LNCaP human prostate cancer cells were cultured under chronic EPI-002 exposure. First, spongian diterpenoids were discovered as novel antiandrogens that bind to the AR LBD. The diterpenoids blocked androgen-dependent AR transcriptional activity with a structure-activity relationship, reduced androgen-regulated gene expression, and inhibited the proliferation of androgen-sensitive prostate cancer cells. Secondly, EPI-002 was effective against aberrant AR transcriptional activity caused by overexpressed coactivators; AR gain-of-function mutations; and constitutively active AR splice variants such as AR-V7. Importantly, EPI-002 inhibited the growth of CRPC cells driven by AR-V7, whereas antiandrogens had no effect. Finally, a human prostate cancer cell line model resistant to growth inhibition by EPI-002 was generated, allowing future studies to investigate mechanisms of resistance against AR inhibition through the NTD.

Newborns have frequent infections and manifest impaired vaccine responses, motivating a search for neonatal vaccine adjuvants. Alum is a neonatal adjuvant but might confer a T(H)2 bias. Toll-like receptor (TLR) agonists are candidate adjuvants, but human neonatal cord blood monocytes demonstrate impaired T(H)1-polarizing responses to many TLR agonists caused by plasma adenosine acting through cyclic AMP. TLR8 agonists, including imidazoquinolines (IMQs), such as the small synthetic 3M-002, induce adult-level TNF from neonatal monocytes, but the scope and mechanisms of IMQ-induced activation of neonatal monocytes and monocyte-derived dendritic cells (MoDCs) have not been reported.We sought to characterize IMQ-induced activation of neonatal monocytes and MoDCs.Neonatal cord and adult peripheral blood monocytes and MoDCs were cultured in autologous plasma; levels of alum- and TLR agonist-induced cytokines and costimulatory molecules were measured. TLR8 and inflammasome function were assayed by using small interfering RNA and Western blotting/caspase-1 inhibitory peptide, respectively. The ontogeny of TLR8 agonist-induced cytokine responses was defined in rhesus macaque whole blood ex vivo.IMQs were more potent and effective than alum at inducing TNF and IL-1β from monocytes. 3M-002 induced robust TLR pathway transcriptome activation and T(H)1-polarizing cytokine production in neonatal and adult monocytes and MoDCs, signaling through TLR8 in an adenosine/cyclic AMP-refractory manner. Newborn MoDCs displayed impaired LPS/ATP-induced caspase-1-mediated IL-1β production but robust 3M-002-induced caspase-1-mediated inflammasome activation independent of exogenous ATP. TLR8 IMQs induced robust TNF and IL-1β in whole blood of rhesus macaques at birth and infancy.IMQ TLR8 agonists engage adenosine-refractory TLR8 and inflammasome pathways to induce robust monocyte and MoDC activation and represent promising neonatal adjuvants.