Cells can sense and respond to various mechanical stimuli from their surrounding environment. One of the explanations for mechanosensitivity, a lipidbilayer model, suggests that a stretch of the membrane induced by mechanical force alters the physical state of the lipid bilayer, driving mechanosensors to assume conformations better matched to the altered membrane. However, mechanosensors of this class are restricted to ion channels. Here, we reveal that integrin aIIbb3, a prototypic adhesion receptor, can be activated by various mechanical stimuli including stretch, shear stress, and osmotic pressure. The force-induced integrin activation was not dependent on its known intracellular activation signaling events and was even observed in reconstituted cell-free liposomes. Instead, these mechanical stimuli were found to alter the lipid embedding of the integrin b3 transmembrane domain (TMD) and subsequently weaken the aIIb-b3 TMD interaction, which results in activation of the receptor. Moreover, artificial modulation of the membrane curvature near integrin aIIbb3 can induce its activation in cells as well as in lipid nanodiscs, suggesting that physical deformation of the lipid bilayer, either by mechanical force or curvature, can induce integrin activation. Thus, our results establish the adhesion receptor as a bona fide mechanosensor that directly senses and responds to the force-modulated lipid environment. Furthermore, this study expands the lipidbilayer model by suggesting that the force-induced topological change of TMDs and subsequent alteration in the TMD interactome is a molecular basis of sensing mechanical force transmitted via the lipid bilayer. (D) The degrees of fibrinogen binding in THD-transfected cells. Error bars in (C) and (D) represent SD (n = 3). (E) Diagram of 33FLAG-aIIb(TMD-tail)-TAP and Tac-b3(TMD-tail). Abbreviation is as follows: TAP, tandem affinity purification. (F) CHO cells transfected with a and b TMD-tail constructs were stretched and maintained for 0, 1, or 5 min before their lysis. The TMD interaction was measured by detecting Tac-b3(TMD-tail) in precipitates of aIIb(TMD-tail)-TAP. Relative TMD interaction compared with nonstretched control is shown. *p < 0.05 (one-way ANOVA followed by Tukey multiple-comparison post hoc test). (G and H) Effect of Y747A mutation (G) or cytochalasin D (H) on stretch-induced disruption of aIIb-b3 TMD interaction. Error bars in (F)-(H) represent SE (n = 3). *p < 0.05, **p < 0.001, ***p < 0.0001. See also Figure S1.
Hip fractures, including femoral neck and intertrochanteric fractures, are considered serious fractures due to high patient mortality and fatality rates. [1,2] The latest hip fracture incidence data depends on the study area, subject, or method, [3,4] but the absolute number of fractures seem to be rise in aging populations. [5] Therefore, the socioeconomic burden of these fractures is expected to be a challenge. [6] Currently, the general treatment principle for hip fracture is urgent operative treatment, such as osteosynthesis and arthroplasty. [7] This is because operative treatment helps to restore function, return to daily life, [8] improve quality of life, [9] and shortens hospital stay. [10] However, in the clinical field, there are situations in which non-operative treatments should be considered due to the patients' general condition, [7,11] other comorbid diseases, refusal of operative treatment by patients and their families, or burden of medical Objectives: In this study, we aimed to analyze patient mortality rate after non-operative treatment of hip fractures to determine the distribution of causes of death and to compare factors affecting mortality.Patients and methods: Between January 2013 and March 2019, a total of 93 patients (17 males, 76 females; mean age: 86.0±7.4 years; range, 64 to 98 years) who had hip fractures and were treated non-operatively were analyzed retrospectively. Survival, date of death, and cause of death were collected and analyzed. Baseline demographics, pre-trauma ambulation, pre-and post-trauma residence status, American Society of Anesthesiologists Physical Status (ASA PS) classification, and Parker's mobility score were compared with one-year mortality rates. Results:The mean follow-up of survivors was 16.1±11.9 (range, 6.3 to 79.6) months. The mean survival of non-survivors was 4.9±6.1 (range, 0.007 to 27.3) months. The 3-, 6-, 12-, and 24-month mortality rates were 40.9%, 53.3%, 74.4%, and 87.5%, respectively. Respiratory diseases (33.3%) and cardiovascular diseases (13.6%) were the main causes of death among the patients. There was no statistically significant difference between the patients' age, sex, fracture site, pre-trauma ambulation, pre-and post-trauma residence status, ASA PS classification, Parker's mobility score, and one-year mortality. Conclusion:A significant number of patients are still treated non-operatively after hip fractures, and they have a high mortality rate. Efforts and research are needed to reduce mortality and improve the quality of life.
Despite the known importance of the transmembrane domain (TMD) of syndecan receptors in cell adhesion and signaling, the molecular basis for syndecan TMD function remains unknown. Using in vivo invertebrate models, we found that mammalian syndecan-2 rescued both the guidance defects in C. elegans hermaphrodite-specific neurons and the impaired development of the midline axons of Drosophila caused by the loss of endogenous syndecan. These compensatory effects, however, were reduced significantly when syndecan-2 dimerization-defective TMD mutants were introduced. To further investigate the role of the TMD, we generated a chimera, 2eTPC, comprising the TMD of syndecan-2 linked to the cytoplasmic domain of platelet-derived growth factor receptor (PDGFR). This chimera exhibited SDS-resistant dimer formation that was lost in the corresponding dimerization-defective syndecan-2 TMD mutant, 2eT(GL)PC. Moreover, 2eTPC specifically enhanced Tyr 579 and Tyr 857 phosphorylation in the PDGFR cytoplasmic domain, while the TMD mutant failed to support such phosphorylation. Finally, 2eTPC, but not 2eT(GL)PC, induced phosphorylation of Src and PI3 kinase (known downstream effectors of Tyr 579 phosphorylation) and promoted Src-mediated migration of NIH3T3 cells. Taken together, these data suggest that the TMD of a syndecan-2 specifically regulates receptor cytoplasmic domain function and subsequent downstream signaling events controlling cell behavior.
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