These authors contributed equally to this work. SUMMARYSalicylic acid (SA) is a small phenolic molecule with hormonal properties, and is an essential component of the immune response. SA exerts its functions by interacting with protein targets; however, the specific cellular components modulated by SA and critical for immune signal transduction are largely unknown. To uncover cellular activities targeted by SA, we probed Arabidopsis protein microarrays with a functional analog of SA. We demonstrate that thimet oligopeptidases (TOPs) constitute a class of SA-binding enzymes. Biochemical evidence demonstrated that SA interacts with TOPs and inhibits their peptidase activities to various degrees both in vitro and in plant extracts. Functional characterization of mutants with altered TOP expression indicated that TOP1 and TOP2 mediate SA-dependent signaling and are necessary for the immune response to avirulent pathogens. Our results support a model whereby TOP1 and TOP2 act in separate pathways to modulate SA-mediated cellular processes.

Pharmaceuticals targeting the pathogenesis of diabetic distal symmetric polyneuropathy have all failed in clinical trials, limiting recourse to palliative treatments. The American Diabetes Association regards the effectiveness of glycemic control and lifestyle modification therapies on diabetic neuropathies as inconclusive. The objective of this research was to determine if and how physical exercise influences distal symmetric polyneuropathic severity in type 2 diabetes patients. Embase, MEDLINE, and Google Scholar were searched to collect randomized and controlled studies published between January 1, 2012 and April 20, 2020. Titles had to mention diabetes, physical exercise of any type or lifestyle interventions in general, and neuropathy. Abstracts had to indicate satisfaction of PICOS criteria, whereas full-text reviews had to be fully confirmatory. Extracted data was thematically synthesized based primarily on relationships between exercise interventions and effects on distal symmetric polyneuropathic severity outcomes in type 2 diabetes patients. Qualitative analysis scoring criteria objectively mirrored PICO except for the bias and limitation score component, which assessed common markers of validity for randomized trials (as specified in the PRISMA statement). Database searches yielded 379 unique records, 15 of which passed eligibility screening. Thematic synthesis supported exercise as an ameliorative treatment of type 2 diabetes distal symmetric polyneuropathy through improved Michigan Diabetic Neuropathy Scores and increased sural sensory nerve conduction velocity, though efficacy may be limited by neuropathic severity. This is the first systematic review to acquire these results, and to do so within the context How to cite this paper: Zampogna, G.

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