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The proteasome degrades proteins, which is essential for cellular homeostasis. Ubiquitin independent proteolysis degrades highly disordered and misfolded proteins. A decline of proteasomal activity has been associated with multiple neurodegenerative diseases due to the accumulation of misfolded proteins. In this work, cyclic peptide proteasome stimulators (CyPPSs) that enhance the clearance of misfolded proteins were discovered. In the initial screen of predicted natural products (pNPs), several cyclic peptides were found to stimulate the 20S core particle (20S CP). Development of a robust structural activity relationship led to the identification of potent, cell permeable CyPPSs. In vitro assays revealed that CyPPSs stimulate degradation of highly disordered and misfolded proteins without affecting ordered proteins. Furthermore, using a novel flow-based assay for proteasome activity, several CyPPSs were found to stimulate the 20S CP in cellulo. Overall, this work describes the development of CyPPSs as chemical tools capable of stimulating the proteasome and provides strong support for proteasome stimulation as a therapeutic strategy for neurodegenerative diseases.

In celebration of the 30th anniversary of Cell Chemical Biology , the editors introduce the September special issue and reflect on the significant evolution and multidisciplinary nature of the chemical biology field and the journal since its inception. They provide a glimpse of the evolving scope and direction of Cell Chemical Biology. [ABSTRACT FROM AUTHOR]

Individuals with intellectual and developmental disabilities are often prescribed psychotropic medication to treat behaviors such as aggression and self-injury. Evaluation of these medications is often based on caregiver report or changes in frequency of behavior. The purpose of this research was to characterize the rate and function of problem behavior within an analogue functional analysis for three individuals diagnosed with autism as they experienced psychotropic medication changes. Results revealed that problem behavior, in terms of rate and function, were different across the various drugs prescribed. These data suggest that medication changes did not only produce changes in the rate of behavior but also in its function; that is, in behavioral parlance, medications can become motivating operations. This finding is lending support for the usefulness of conducting functional assessments throughout psychotropic medication changes. The importance of monitoring functional changes of target behavior is that concurrent behavioral interventions may have to be adjusted in accordance with those altered functional properties. Recommendations regarding future directions for research and implications of this line of research for treatment are discussed. (Contains 2 figures.)

The objective of this study was to review the diagnostic accuracy of clinicians identifying leukoplakia and the diagnostic terminology used to indicate leukoplakic lesions at the University of Nebraska Medical Center (UNMC) oral biopsy service. Biopsy archives from the years 1983,1995, 2005, and 2015 in the UNMC College of Dentistry were reviewed. Cases with a clinical diagnosis of leukoplakia (or white plaque), hyperkeratosis, dysplasia, and/or carcinoma were included in the study. Demographic and clinical information was recorded and descriptive statistics were utilized. Of 6113 cases, 517 lesions (8.46%) from 508 patients met the inclusion criteria. The mean age of the patients was 56.87 years, and the sample included 286 men and 222 women. Of these 517 lesions, 195 (37.72%) were clinically diagnosed as leukoplakia or white plaque. The records revealed that 133 (68.21%) of 195 clinical diagnoses were correct, with lesions histologically exhibiting hyperkeratosis (75 cases), dysplasia (52 cases), or carcinoma (6 cases). The remaining 62 lesions (31.79%) were found to have other histologic diagnoses. Hyperkeratosis made up the largest portion of the correct diagnoses. In general, the ability of clinicians to successfully identify leukoplakia improved over the years (46.15%, 73.68%, 64.29%, and 76.00% in 1983,1995, 2005, and 2015, respectively). However, clinicians continue to misclassify identifiable pathoses such as lichen planus, lichenoid mucositis, and fibroma as leukoplakia. Hyperkeratosis and dysplasia, both of which represent histologic diagnoses, appear to be popularly misused clinical terms. [ABSTRACT FROM AUTHOR]

Introduction: Triggering receptor expressed on myeloid cells‐2 (TREM2) is an immune receptor expressed on microglia that also can become soluble (sTREM2). How TREM2 engages different ligands remains poorly understood. Methods: We used comprehensive biolayer interferometry (BLI) analysis to investigate TREM2 and sTREM2 interactions with apolipoprotein E (apoE) and monomeric amyloid beta (Aβ) (mAβ42). Results: TREM2 engagement of apoE was protein mediated with little effect of lipidation, showing slight affinity differences between isoforms (E4 > E3 > E2). Another family member, TREML2, did not bind apoE. Disease‐linked TREM2 variants within a "basic patch" minimally impact apoE binding. Instead, TREM2 uses a unique hydrophobic surface to bind apoE, which requires the apoE hinge region. TREM2 and sTREM2 directly bind mAβ42 and potently inhibit Aβ42 polymerization, suggesting a potential role for soluble sTREM2 in preventing AD pathogenesis. Discussion: These findings demonstrate that TREM2 has at least two ligand‐binding surfaces that might be therapeutic targets and uncovers a potential function for sTREM2 in directly inhibiting Aβ polymerization. [ABSTRACT FROM AUTHOR]