The podocyte protease web: uncovering the gatekeepers of glomerular disease.

Proteases regulate glomerular physiology. The last decade has revealed a multitude of podocyte proteases that govern the glomerular response to numerous chemical, mechanical, and metabolic cues. These proteases form a protein signaling web that integrates stress stimuli and serves as a key controller of the glomerular microenvironment. Both the extracellular and intracellular proteolytic networks are perturbed in focal segmental glomerulosclerosis, as well as hypertensive and diabetic nephropathy. Accordingly, the highly intertwined podocyte protease web is an integrative part of the podocyte's damage response. Novel mass spectrometry-based technologies will help to untangle this proteolytic network: functional readouts acquired from deep podocyte proteomics, single glomerular proteomics, and degradomics have exposed unanticipated protease activity in podocytes. Future efforts should characterize the interdependency and upstream regulation of key proteases, along with their role in promoting tissue heterogeneity in glomerular diseases. These efforts will not only illuminate the machinery of podocyte proteostasis but also reveal avenues for therapeutic intervention in the podocyte protease web.

Relative Retinal Blood Flow: A Novel and Informative Measure of Unilateral Retinal Vein Occlusion Severity.

Purpose: This study quantifies retinal vascular blood flow affected by unilateral central or branch retinal vein occlusion (CRVO or BRVO). We created a new, unitless metric for the severity of these diseases-relative blood flow (RBF)-and contextualized it with subject demographics, ocular presentation, and systemic conditions. Finally, we explored its efficacy as a predictor of future outcomes. Methods: Data were collected from 20 control subjects and 32 clinically diagnosed CRVO (n = 15) or BRVO (n = 17) patients. We used laser speckle flowgraphy to quantify blood flow as mean blur rate and present RBF as the ratio between the blood flow in a subject's diseased and undiseased eyes. Because of our demonstration that blood flow has high intrapatient (between eyes and over time) but low interpatient correlation in eyes of healthy subjects, any differences between eyes can be attributed to the disease. These data were correlated with subject demographics and disease characteristics. Results: In CRVO and BRVO eyes, average blood flow decreased by 26% and 7%, respectively. In CRVO, occlusion duration, central macular thickness, intraocular pressure, diabetes, previous laser and injection treatments, and injection within three months after measurement were significantly associated with RBF. In BRVO, no significant associations with RBF were found. Conclusions: Blood flow in CRVO and BRVO was reduced compared to the unaffected fellow eye in most patients. RBF was useful in determining the severity of RVOs and predicting future treatment needs. Translational Relevance: RBF is a promising new and informative metric for quantifying the severity of unilateral RVOs.

Auditory working memory predicts individual differences in absolute pitch learning.

Absolute pitch (AP) is typically defined as the ability to label an isolated tone as a musical note in the absence of a reference tone. At first glance the acquisition of AP note categories seems like a perceptual learning task, since individuals must assign a category label to a stimulus based on a single perceptual dimension (pitch) while ignoring other perceptual dimensions (e.g., loudness, octave, instrument). AP, however, is rarely discussed in terms of domain-general perceptual learning mechanisms. This is because AP is typically assumed to depend on a critical period of development, in which early exposure to pitches and musical labels is thought to be necessary for the development of AP precluding the possibility of adult acquisition of AP. Despite this view of AP, several previous studies have found evidence that absolute pitch category learning is, to an extent, trainable in a post-critical period adult population, even if the performance typically achieved by this population is below the performance of a "true" AP possessor. The current studies attempt to understand the individual differences in learning to categorize notes using absolute pitch cues by testing a specific prediction regarding cognitive capacity related to categorization - to what extent does an individual's general auditory working memory capacity (WMC) predict the success of absolute pitch category acquisition. Since WMC has been shown to predict performance on a wide variety of other perceptual and category learning tasks, we predict that individuals with higher WMC should be better at learning absolute pitch note categories than individuals with lower WMC. Across two studies, we demonstrate that auditory WMC predicts the efficacy of learning absolute pitch note categories. These results suggest that a higher general auditory WMC might underlie the formation of absolute pitch categories for post-critical period adults. Implications for understanding the mechanisms that underlie the phenomenon of AP are also discussed.