The loss of a spouse is often cited as the most traumatic event in a person's life. However, for most people, the severity of grief and its maladaptive effects subside over time via an understudied adaptive process. Like humans, socially monogamous prairie voles (Microtus ochrogaster) form opposite-sex pair bonds, and upon partner separation, show stress phenotypes that diminish over time. We test the hypothesis that extended partner separation diminishes pair bond-associated behaviors and causes pair bond transcriptional signatures to erode. Pairs were cohoused for 2 weeks and then either remained paired or were separated for 48hrs or 4wks before collecting fresh nucleus accumbens tissue for RNAseq. In a separate cohort, we assessed partner-directed affiliation at these time points. We found that these behaviors persist despite prolonged separation in both same-sex and opposite-sex paired voles. Opposite-sex pair bonding led to changes in accumbal transcription that were stably maintained while animals remained paired but eroded following prolonged partner separation. Eroded genes are associated with gliogenesis and myelination, suggesting a previously undescribed role for glia in pair bonding and loss. Further, we pioneered neuron-specific translating ribosomal affinity purification in voles. Neuronally-enriched transcriptional changes revealed dopaminergic-, mitochondrial-, and steroid hormone signaling-associated gene clusters sensitive to acute pair bond disruption and loss adaptation. Our results suggest that partner separation erodes transcriptomic signatures of pair bonding despite core behavioral features of the bond remaining intact, revealing potential molecular processes priming a vole to be able to form a new bond.

T Cell Lymphomas are a rare subtype of Lymphoma, occurring in ~1% of all cancers and response rates to current therapies reach only ~23%. The lack of unique targetable T cell antigens as well as their tendency to overcome chemotherapies results in a high incidence of relapse in most patients leading to remission rates of approximately two years. Immunotherapies, especially immune-checkpoint blockade, have slightly improved outcomes in refractory disease, but there remains a need for stronger and more durable responses. The chemotherapeutic potential of epigenetic modifiers is just beginning to be explored. HDAC inhibitors, DNA demethylating agents, and histone methyltransferase inhibitors reshape the transcriptome, potentially altering the expression of immune modulatory pathways. We hypothesized that pretreating T cell malignancies with epigenetic modifiers will alter key genetic signatures that sensitize them to CD8+ T cell-mediated cytotoxicity. We pretreated five T cell lymphoma cell lines, representative of different T cell malignant diseases with compounds from an FDA-approved 700+ epigenetic modifying drug library at four different concentrations and then co-cultured them with a tumor-reactive HLA-A2-matched primary (derived from PBMCs) cytotoxic CD8+ T cell line. Changes in T cell mediated cytotoxicity and alterations in immune modulating surface markers and potential CAR-T cell targets (CD30, CCR4, and CD47) were assessed by flow cytometry. Several promising compounds were identified by their ability to improve T cell mediated cytotoxicity, increase expression of immune stimulatory markers, decrease expression of immune inhibitory markers, and augment expression of existing CAR-T target antigens. Supported by NIH and the Colorado Clinical and Translational Sciences Institute (CCTSI)

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