Jacob S. Deyell

Microglia have been implicated in neurodegeneration, though their role remains unclear, as microglia can perform protective functions or promote neuroinflammation. Numerous studies have found that the transcriptome state of microglia can indicate where they lie along this continuum. To understand regulation of microglia transcriptome state, we considered the transcription factor PPARδ, because it is highly expressed in microglia and is a therapeutic target for Alzheimer's disease, (AD) a neurodegenerative disorder characterized by progressive memory loss where microglia dysfunction is involved. When we delineated the microglia transcriptome in mice treated with PPARδ agonist, we noted that PPARδ activation blunted expression of inflammatory mediators and migration-enhancing genes, while boosting phagocytic genes. We then examined PPARδ function in induced transcription factor (iTF) microglia-like cells, and confirmed PPARδ agonism increases phagocyte function while reducing pro-inflammatory cytokines and migration. To understand PPARδ regulation upon CNS insult, we exposed iTF-microglia to apoptotic neuron debris and defined six microglia transcriptome states as a function of PPARδ activation, and observed PPARδ agonism can shift microglia out of a homeostatic state to a primed, disease-associated microglia-like state. As PPARδ agonism opposed gene expression favored by PU.1, a critical transcription factor in microglial inflammation and AD pathogenesis, we examined their relationship, documented a physical interaction, and found evidence for transrepression. Finally, we tested PPARδ agonism in Huntington's disease and tauopathy mice, and demonstrated PPARδ could decrease neuroinflammation in vivo. These findings suggest that PPARδ agonist therapy may mitigate microglial dysfunction by restoring beneficial functions, while suppressing detrimental inflammation.

Diffuse gliomas are brain tumors that include oligodendroglioma, astrocytoma, and glioblastoma (GBM), the most common and deadly primary brain tumor. A major challenge in glioma treatment is resistance to the first‐line chemotherapeutic, temozolomide (TMZ). Plasma membrane properties of cells with increased chemotherapeutic resistance are not well understood, despite the fact that the membrane is the first point of contact with the environment and greatly shapes cell behavior. Plasma membrane glycosylation impacts cell function, and we found significant differences in glycosylation of TMZ‐resistant cells. We further identified plasma membrane electrophysiological properties predicting glioma cell TMZ resistance. We enriched cells with higher TMZ resistance by sorting glioma cells based on electrophysiological properties, indicating the relevance of membrane properties to chemotherapeutic resistance. These findings could lead to rapid separation methods for patient tumor cells, a better understanding of the molecular profiles of resistant cells, and novel treatment options for gliomas.

Synucleinopathies are a set of devastating neurodegenerative diseases that share a pathologic accumulation of the protein α-synuclein (α-syn). This accumulation causes neuronal death resulting in irreversible dementia, deteriorating motor symptoms, and devastating cognitive decline. While the etiology of these conditions remains largely unknown, microglia, the resident immune cells of the central nervous system (CNS), have been consistently implicated in the pathogenesis of synucleinopathies. Microglia are generally believed to be neuroprotective in the early stages of α-syn accumulation and contribute to further neurodegeneration in chronic disease states. While the molecular mechanisms by which microglia achieve this role are still being investigated, here we highlight the major findings to date. In this review, we describe how structural varieties of inherently disordered α-syn result in varied microglial receptor-mediated interactions. We also summarize which microglial receptors enable cellular recognition and uptake of α-syn. Lastly, we review the downstream effects of α-syn processing within microglia, including spread to other brain regions resulting in neuroinflammation and neurodegeneration in chronic disease states. Understanding the mechanism of microglial interactions with α-syn is vital to conceptualizing molecular targets for novel therapeutic interventions. In addition, given the significant diversity in the pathophysiology of synucleinopathies, such molecular interactions are vital in gauging all potential pathways of neurodegeneration in the disease state.

Background: External urinary collection devices (EUCDs) may serve as an alternative to indwelling urinary catheters (IUCs) and decrease the rate of catheter associated urinary tract infections (CAUTIs). PureWick® is a novel female EUCD; however, no study has definitively proven benefit regarding reduction of CAUTIs. Aim: We sought to compare the CAUTI rate and IUC days before and after availability of the PureWick® EUCD at a single institution. We provide a descriptive analysis of female medical patients receiving an EUCD. Methods: A retrospective review of adult female patients admitted to a single institution on a medical service who received an IUC and/or an EUCD was performed. Patients who received an IUC in the 3 months before EUCD availability (PRE) were compared to patients who received an IUC and/or EUCD in the 12 months after (POST). Results: Out of 848 female patients, 292 received an EUCD in the POST cohort and overall, 656 received an IUC (259 (100%) PRE vs. 397 (67.4%) POST). Compared to the PRE cohort, the POST cohort had a higher number of IUC days (median, 3 vs 2 days, p = 0.001) and a higher rate of CAUTI (infections per 1000 catheter days, 9.3 vs 2.3, p = 0.001). The rate of UTI associated with EUCD use was 9.8 infections per 1000 device days. Discussion: While EUCDs might appear to be a promising alternative to IUCs for female patients, this single center pre-/post-analysis found that both the number of IUC days and the CAUTI rate increased after introduction of a female EUCD.

When treating patients with diabetes mellitus (DM), the benefits of antiplatelet therapy in preventing cardiovascular disease must be weighed against an increased risk of bleeding. Recent trials have sought to determine both the optimal anti-platelet regimen for patients with DM, and who specifically requires medication among the DM population. This paper will review recent trials and evidence recommending the use of antiplatelet therapy in the prevention of cardiovascular disease in patients with diabetes.