Our incomplete understanding of osteoarthritis (OA) pathogenesis has significantly hindered the development of disease-modifying therapy. The functional relationship between subchondral bone (SB) and articular cartilage (AC) is unclear. Here, we found that the changes of SB architecture altered the distribution of mechanical stress on AC. Importantly, the latter is well aligned with the pattern of transforming growth factor beta (TGFβ) activity in AC, which is essential in the regulation of AC homeostasis. Specifically, TGFβ activity is concentrated in the areas of AC with high mechanical stress. A high level of TGFβ disrupts the cartilage homeostasis and impairs the metabolic activity of chondrocytes. Mechanical stress stimulates talin-centered cytoskeletal reorganization and the consequent increase of cell contractile forces and cell stiffness of chondrocytes, which triggers αV integrin–mediated TGFβ activation. Knockout of αV integrin in chondrocytes reversed the alteration of TGFβ activation and subsequent metabolic abnormalities in AC and attenuated cartilage degeneration in an OA mouse model. Thus, SB structure determines the patterns of mechanical stress and the configuration of TGFβ activation in AC, which subsequently regulates chondrocyte metabolism and AC homeostasis.

Significance: Septic shock commonly leads to multiorgan injury both directly via tissue inflammation and secondarily via hypoperfusion, but both can result in mitochondrialN-formyl peptide (mtFP) release into the circulation. However, no studies have evaluated the role of circulating mtFPs during septic shock. We found that a relatively high plasma nicotinamide adenine dinucleotide dehydrogenase subunit-6 (the most potent human mtFP) level was independently associated with the development of secondary infection in patients with septic shock and that the increased susceptibility to secondary infection is partly attributed to the suppression of polymorphonuclear leukocyte (PMN) chemotaxis by mtFP occupancy of formyl peptide receptor-1. Incorporation of these findings into therapeutic strategies may improve clinical outcomes in septic shock patients by preventing PMN chemotactic anergy.

Immune checkpoint blockade (ICB) has become a standard anti-cancer treatment, offering durable clinical benefits. However, the limited response rate of ICB necessitates biomarkers to predict and modulate the efficacy of the therapy. The gut microbiome’s influence on ICB efficacy is of particular interest due to its modifiability through various interventions. However, gut microbiome biomarkers for ICB response have been inconsistent across different studies. Here, we identify TANB77, an uncultured and distinct bacterial clade, as the most consistent responder-enriched taxon through meta-analysis of ten independent ICB recipient cohorts. Traditional taxonomy fails to distinguish TANB77 from unrelated taxa, leading to its oversight. Mice with higher gut TANB77 abundance, either naturally or through transplantation, show improved response to anti-PD-1 therapy. Additionally, mice injected with TANB77-derived pilin-like protein exhibit improved anti-PD-1 therapy response, providing in vivo evidence for the beneficial role of the pilin-like protein. These findings suggest that pilins from the TANB77 order may enhance responses to ICB therapy across diverse cohorts of cancer patients.

Physical interactions between cells and micro/nanometer-sized architecture presented in an extracellular matrix (ECM) environment significantly influence cell adhesion and morphology, often facilitating the incidence of diseases, such as cancer invasion and metastasis. Sensing and responding to the topographical cues are deeply associated with a physical interplay between integrins, ligands, and mechanical force transmission, ultimately determining diverse cell behavior. Thus, how the tension applied to the integrin-ligand bonds controls cells’ response to the topographical cues needs to be elucidated through quantitative analysis. Here, in this brief research report, we reported a novel platform, termed “topo-tension gauge tether (TGT),” to visualize single-molecule force applied to the integrin-ligand on the aligned anisotropic nanopatterns. Using the topo-TGT assay, first, topography-induced adhesion and morphology of cancerous and normal cells were compared with the pre-defined peak integrin tension. Next, spatial integrin tensions underneath cells were identified using reconstructed integrin tension maps. As a result, we characterized each cell’s capability to comply with nanotopographies and the magnitude of the spatial integrin tension. Altogether, the quantitative information on integrin tension will be a valuable basis for understanding the biophysical mechanisms underlying the force balance influencing adhesion to the topographical cues.