技术资料

We recently demonstrated that the sympathetic nervous system can be voluntarily activated following a training program consisting of cold exposure,breathing exercises,and meditation. This resulted in profound attenuation of the systemic inflammatory response elicited by lipopolysaccharide (LPS) administration. Herein,we assessed whether this training program affects the plasma metabolome and if these changes are linked to the immunomodulatory effects observed. A total of 224 metabolites were identified in plasma obtained from 24 healthy male volunteers at six timepoints,of which 98 were significantly altered following LPS administration. Effects of the training program were most prominent shortly after initiation of the acquired breathing exercises but prior to LPS administration,and point towards increased activation of the Cori cycle. Elevated concentrations of lactate and pyruvate in trained individuals correlated with enhanced levels of anti-inflammatory interleukin (IL)-10. In vitro validation experiments revealed that co-incubation with lactate and pyruvate enhances IL-10 production and attenuates the release of pro-inflammatory IL-1$\beta$ and IL-6 by LPS-stimulated leukocytes. Our results demonstrate that practicing the breathing exercises acquired during the training program results in increased activity of the Cori cycle. Furthermore,this work uncovers an important role of lactate and pyruvate in the anti-inflammatory phenotype observed in trained subjects. View Publication

Endogenous repair of osteochondral defect is usually limited by the insufficient number of cells in the early stage and incomplete cell differentiation in the later stage. The development of drug delivery systems for sequential release of pro-migratory and pro-chondrogenic molecules to induce endogenous bone marrow-derived mesenchymal stem cells (BMSCs) recruitment and chondrogenic differentiation is highly desirable for in situ osteochondral regeneration. In this study,a novel,all-silk-derived sequential delivery system was fabricated by incorporating the tunable drug-loaded silk fibroin (SF) nanospheres into a SF porous matrix. The loading efficiency and release kinetics of biomolecules depended on the initial SF/polyvinyl alcohol (PVA) concentrations (0.2{\%},1{\%} and 5{\%}) of the nanospheres,as well as the hydrophobicity of the loaded molecules,resulting in controllable and programmed delivery profiles. Our findings indicated that the 5{\%} nanosphere-incorporated matrix showed a rapid release of E7 peptide during the first 120 h,whereas the 0.2{\%} nanosphere-incorporated matrix provided a slow and sustained release of Kartogenin (KGN) longer than 30 days. During in vitro culture of BMSCs,this functional SF matrix incorporated with E7/KGN nanospheres showed good biocompatibility,as well as enhanced BMSCs migration and chondrogenic differentiation through the release of E7 and KGN. Furthermore,when implanted into rabbit osteochondral defect,the SF nanosphere matrix with sequential E7/KGN release promoted the regeneration of both cartilage and subchondral bone. This work not only provided a novel all-silk-derived drug delivery system for sequential release of molecules,but also a functional tissue-engineered scaffold for osteochondral regeneration. View Publication

Stress granules (SGs) are non-membrane-bound RNA-protein granules that assemble through phase separation in response to cellular stress. Disturbances in SG dynamics have been implicated as a primary driver of neurodegenerative diseases,including amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD),suggesting the hypothesis that these diseases reflect an underlying disturbance in the dynamics and material properties of SGs. However,this concept has remained largely untestable in available models of SG assembly,which require the confounding variable of exogenous stressors. Here we introduce a light-inducible SG system,termed OptoGranules,based on optogenetic multimerization of G3BP1,which is an essential scaffold protein for SG assembly. In this system,which permits experimental control of SGs in living cells in the absence of exogenous stressors,we demonstrate that persistent or repetitive assembly of SGs is cytotoxic and is accompanied by the evolution of SGs to cytoplasmic inclusions that recapitulate the pathology of ALS-FTD. Editorial note This article has been through an editorial process in which the authors decide how to respond to the issues raised during peer review. The Reviewing Editor's assessment is that all the issues have been addressed (see decision letter). View Publication