The nociceptive activity of peripheral sensory neurons is modulated by the neuronal membrane proteasome.

Proteasomes are critical for peripheral nervous system (PNS) function. Here, we investigate mammalian PNS proteasomes and reveal the presence of the neuronal membrane proteasome (NMP). We show that specific inhibition of the NMP on distal nerve fibers innervating the mouse hind paw leads to reduction in mechanical and pain sensitivity. Through investigating PNS NMPs, we demonstrate their presence on the somata and proximal and distal axons of a subset of dorsal root ganglion (DRG) neurons. Single-cell RNA sequencing experiments reveal that the NMP-expressing DRGs are primarily MrgprA3+ and Cysltr2+. NMP inhibition in DRG cultures leads to cell-autonomous and non-cell-autonomous changes in Ca2+ signaling induced by KCl depolarization, αß-meATP, or the pruritogen histamine. Taken together, these data support a model whereby NMPs are expressed on a subset of somatosensory DRGs to modulate signaling between neurons of distinct sensory modalities and indicate the NMP as a potential target for controlling pain.

Neuronal membrane proteasome-derived peptides modulate NMDAR-dependent neuronal signaling to promote changes in gene expression.

The neuronal membrane proteasome (NMP) degrades intracellular proteins into peptides that are released directly into the extracellular space, whereby they stimulate neurons to promote signaling mechanisms that remain unknown. Here, we demonstrate that neuronal stimulation promotes NMP activity and, subsequently, enhanced production of NMP peptides. We show that these neuronal activity-dependent NMP peptides can rapidly promote N-methyl-D-aspartate receptor (NMDAR)-dependent calcium influx in neurons. This leads to sustained phosphorylation of the well-defined stimulus-induced transcription factor, cyclic AMP response element (CRE)-binding protein (CREB). Downstream of these events, we identified changes to neuronal target genes which included increased expression of immediate early genes (e.g., Fos, Npas4, Egr4) and other genes known to have critical neuroregulatory roles. Further observations led to the discovery that NMP peptide-induced changes in gene expression is dependent on NMDARs and independent of AMPA receptors or voltage-gated sodium channels. These data demonstrate that NMP peptides are endogenous and selective activators of NMDA receptors and act as sufficient and novel stimuli within the context of neuronal activity-dependent signaling. This novel pathway is parallel to classic neuronal activity-dependent programs and points to NMP and its resulting peptides as potential modulators of neuronal function.

Regenerative potential and limitations in a zebrafish model of hyperglycemia-induced nerve degeneration.

BACKGROUND: Previous work from our lab has described a model of motor nerve degeneration in hyperglycemic zebrafish larvae which resembles mammalian models of diabetic peripheral neuropathy (DPN). Here, we optimized the hyperglycemic-induction protocol, characterized deficits in nerve structure and behavioral function, and then examined the regenerative potential following recovery from the hyperglycemic state. RESULTS: In agreement with our previous work, hyperglycemia induced motor nerve degeneration and behavioral deficits. However, the optimized protocol initiated disruption of tight junctions within the blood-nerve barrier, a phenotype apparent in mammalian models of DPN. Following a 10-day recovery period, regeneration of motor nerve components was apparent, but behavioral deficits persisted. We next examined the effect of hyperglycemia on the musculoskeletal system and found subtle deficits in muscle that resolved following recovery, and robust deficits in the skeletal system which persisted following recovery. CONCLUSION: Here we optimized our previous model of hyperglycemia-induced motor nerve degeneration to more closely align with that observed in mammalian models and then characterized the regenerative potential following recovery from hyperglycemia. Notably, we observed striking impairments to skeletal development, which underscores the global impact hyperglycemia has across systems, and provides a framework for elucidating molecular mechanisms responsible for regenerative events moving forward.

California Sexually Violent Predator (SVP) Evaluations in the Field: Static-99R and Diagnostic Field Reliability.

Tests and diagnoses used in sexually violent predator (SVP) evaluations must be reliable, as reliability is foundational to validity. The current study contained a stratified sample of evaluations of 395 individuals referred as potential SVPs between 2012 and 2017. Each individual was initially evaluated by at least two experts. The sample included three groups: individuals not meeting SVP criteria (N = 200, or 400 evaluations), individuals meeting SVP criteria (N = 95, with 190 evaluations), and individuals where evaluators disagreed (N = 100, with 200 evaluations). The sample also included 200 subsequent independent evaluations on these "disagree" cases. Static-99R score intraclass coefficient (ICC) interrater reliability was good to excellent within each group and overall. Evaluators scored the Static-99R within one point of each other 87% of the time. Cohen's kappa diagnostic agreement for Pedophilic Disorder was substantial. ASPD and substance abuse kappa were in the "fair" range, while OSPD diagnoses in the positive group were at the "moderate" level of agreement. Ethnic differences in diagnoses were consistent with other studies, with equivalent Static-99R ICC values across ethnic groups. There were no significant differences between state civil servants versus contracted experts in Static-99R ratings or final determinations. The results suggest that Static-99R scores have acceptable reliability in these evaluations, and Pedophilic Disorder (the most common paraphilic disorder in our study) and OSPD can be reliably diagnosed. We discuss limitations of the study, as well as the need for care in high-stakes evaluations given the imperfect reliability of psychological measurements.

Interpretative characteristics and case features associated with the performances of radiologists in reading mammograms: A study from a non-screening population in Asia.

AIMS: To explore radiologist characteristics and case features associated with diagnostic performances in cancer detection on mammograms in a South East Asian population. METHODS: Fifty-three radiologists reported 60 mammographic examinations which consisted of 40 normal and 20 cancer-containing cases at the BREAST workshops. Radiologists were asked to examine each mammogram using the BIRADS on diagnostic monitors. Differences in reader characteristics and case features between correct and incorrect decisions were assessed separately for cancer and normal cases. Univariate and multivariate logistic regressions were applied to generate odds ratios (OR) for significant factors related to correct decisions. RESULTS: Radiologists who spent ≥10 hours/week reporting mammograms had a higher possibility of detecting cancer lesions (OR = 1.6; P = 0.01). A higher rate of accuracy in reporting negative cases was associated with female radiologists (OR = 1.4; P = 0.002), radiologists who read ≤20 mammograms per week (OR = 1.5; P < 0.0001), had completed training course (OR = 1.7; P < 0.0001) or wore eyeglasses (OR = 1.4; P = 0.01). Cancer cases with breast density >50% (OR = 2.1; P < 0.0001), having abnormal lesions ≥9 mm (OR = 1.8; P < 0.0001), or displaying calcifications, a discrete mass or nonspecific density (OR = 1.6; P < 0.0001) were recorded with a higher detection rate by radiologists than other cases. Lesions located on the right breasts (OR = 1.8; P < 0.0001) or found in the lower inner, upper outer or mixed locations (OR = 2.7; P < 0.0001) were also recorded with a better diagnostic possibility compared with other lesions. CONCLUSION: This work identified key features related to diagnostic accuracy of breast cancer on mammograms in a nonscreening population, which is helpful for developing appropriate strategies to improve breast cancer detectability of radiologists.