The inflammatory pathways that drive the development of intimai hyperplasia (IH) following arterial injury are not fully understood. We hypothesized that the lysosomal cysteine protease cathepsin L activates processes leading to IH after arterial injury. Using a mouse model of wire-induced carotid artery injury, we showed that cathepsin L activity peaks at d 7 and remains elevated for 28 d. Genetic deletion of cathepsin L prevented IH and monocyte recruitment in the carotid wall. The injury-induced increases in cathepsin L mRNA and activity were mitigated in mice with myeloid-specific deletion of toll-like receptor 4 (TLR4) or myeloid differentiation primary response gene 88 (MyD88). We further discovered that the HIV protease inhibitor saquinavir (SQV), which is known to block recombinant mouse cathepsin L activity in vitro, prevented IH after arterial injury. SQV also suppressed LPS (TLR4 agonist)-induced monocyte adhesion to endothelial monolayers. These findings establish cathepsin L as a critical regulator of the inflammation that leads to IH and that the TLR4-MyD88 pathway in myeloid lineages regulates cathepsin L expression in the vessel wall following wire injury. The Food and Drug Administration-approved drug SQV blocks IH though mechanisms that may include the suppression of cathepsin L.

tsThe loss mechanisms of irreversible Li in electrolytes with various salts (e.g., lithium hexafluorophosphate (LiPF6), lithium difluoro(oxalato)borate (LiDFOB), and lithium bis(fluorosulfonyl)amide (LiFSI)) are systemically revealed.A universal procedure for the electrolyte design of Li metal batteries is proposed: (i) decouple and find the main reason for the irreversible Li loss; (ii) add the corresponding electrolyte additive.

BackgroundLow-molecular-weight glutenin subunits (LMW-GS), encoded by Glu-3 complex loci in hexaploid wheat, play important roles in the processing quality of wheat flour. To date, the molecular characteristics and effects on dough quality of individual Glu-3 alleles and their encoding proteins have been poorly studied. We used a Glu-A3 deletion line of the Chinese Spring (CS-n) wheat variety to conduct the first comprehensive study on the molecular characteristics and functional properties of the LMW-GS allele Glu-A3a.ResultsThe Glu-A3a allele at the Glu-A3 locus in CS and its deletion in CS-n were identified and characterized by proteome and molecular marker methods. The deletion of Glu-A3a had no significant influence on plant morphological and yield traits, but significantly reduced the dough strength and breadmaking quality compared to CS. The complete sequence of the Glu-A3a allele was cloned and characterized, which was found to encode a B-subunit with longer repetitive domains and an increased number of α-helices. The Glu-A3a-encoded B-subunit showed a higher expression level and accumulation rate during grain development. These characteristics of the Glu-A3a allele could contribute to achieving superior gluten quality and demonstrate its potential application to wheat quality improvement. Furthermore, an allele-specific polymerase chain reaction (AS-PCR) marker for the Glu-A3a allele was developed and validated using different bread wheat cultivars, including near-isogenic lines (NILs) and recombinant inbred lines (RILs), which could be used as an effective molecular marker for gluten quality improvement through marker-assisted selection.ConclusionsThis work demonstrated that the LMW-GS allele Glu-A3a encodes a specific LMW-i type B-subunit that significantly affects wheat dough strength and breadmaking quality. The Glu-A3a-encoded B-subunit has a long repetitive domain and more α-helix structures as well as a higher expression level and accumulation rate during grain development, which could facilitate the formation of wheat with a stronger dough structure and superior breadmaking quality.