The polarity protein Yurt associates with the plasma membrane via basic and hydrophobic motifs embedded in its FERM domain.

The subcellular distribution of the polarity protein Yurt (Yrt) is subjected to a spatio-temporal regulation in Drosophila melanogaster embryonic epithelia. After cellularization, Yrt binds to the lateral membrane of ectodermal cells and maintains this localization throughout embryogenesis. During terminal differentiation of the epidermis, Yrt accumulates at septate junctions and is also recruited to the apical domain. Although the mechanisms through which Yrt associates with septate junctions and the apical domain have been deciphered, how Yrt binds to the lateral membrane remains as an outstanding puzzle. Here, we show that the FERM domain of Yrt is necessary and sufficient for membrane localization. Our data also establish that the FERM domain of Yrt directly binds negatively charged phospholipids. Moreover, we demonstrate that positively charged amino acid motifs embedded within the FERM domain mediates Yrt membrane association. Finally, we provide evidence suggesting that Yrt membrane association is functionally important. Overall, our study highlights the molecular basis of how Yrt associates with the lateral membrane during the developmental time window where it is required for segregation of lateral and apical domains.

Clinical outcome of exercise therapy and early post-operative rehabilitation for treatment of neglected Achilles tendon rupture: a randomized study.

PURPOSE: Treatment of neglected Achilles tendon rupture is very challenging. This randomized study aimed to compare the clinical outcome of early post-operative rehabilitation (EPR) with post-operative cast immobilization (PCI). METHODS: Fifty-seven patients with neglected Achilles tendon rupture were randomized to receive EPR (n = 26) or PCI (n = 31) management following surgery. Clinical outcome was monitored by follow-up at weeks 8, 12, 18 and 26 and year 2. The significance of intergroup differences from the Leppilahti scoring system (LSS), ultrasonography, multislice spiral computerized tomography (MSCT) and electromyography was assessed. RESULTS: Ultrasonography and MSCT revealed no occurrence of tendon elongation or adhesion. Four patients could perform sustained single-leg heel-raise exercise for 60 s at post-operative day 40. The PCI group also showed increased post-operative LSS score, but recovery was slower. Post-operative complications, such as ankle joint ankylosis and osteoporosis, only occurred in the PCI group. CONCLUSIONS: Compared with cast immobilization, early post-operative rehabilitation results in better clinical outcome and faster overall tendon regeneration of neglected Achilles tendon rupture. LEVEL OF EVIDENCE: II.

A YAP/TAZ-ARHGAP29-RhoA Signaling Axis Regulates Podocyte Protrusions and Integrin Adhesions.

Glomerular disease due to podocyte malfunction is a major factor in the pathogenesis of chronic kidney disease. Identification of podocyte-specific signaling pathways is therefore a prerequisite to characterizing relevant disease pathways and developing novel treatment approaches. Here, we employed loss of function studies for EPB41L5 (Yurt) as a central podocyte gene to generate a cell type-specific disease model. Loss of Yurt in fly nephrocytes caused protein uptake and slit diaphragm defects. Transcriptomic and proteomic analysis of human EPB41L5 knockout podocytes demonstrated impaired mechanotransduction via the YAP/TAZ signaling pathway. Further analysis of specific inhibition of the YAP/TAZ-TEAD transcription factor complex by TEADi led to the identification of ARGHAP29 as an EPB41L5 and YAP/TAZ-dependently expressed podocyte RhoGAP. Knockdown of ARHGAP29 caused increased RhoA activation, defective lamellipodia formation, and increased maturation of integrin adhesion complexes, explaining similar phenotypes caused by loss of EPB41L5 and TEADi expression in podocytes. Detection of increased levels of ARHGAP29 in early disease stages of human glomerular disease implies a novel negative feedback loop for mechanotransductive RhoA-YAP/TAZ signaling in podocyte physiology and disease.

Pak1 and PP2A antagonize aPKC function to support cortical tension induced by the Crumbs-Yurt complex.

The Drosophila polarity protein Crumbs is essential for the establishment and growth of the apical domain in epithelial cells. The protein Yurt limits the ability of Crumbs to promote apical membrane growth, thereby defining proper apical/lateral membrane ratio that is crucial for forming and maintaining complex epithelial structures such as tubes or acini. Here, we show that Yurt also increases Myosin-dependent cortical tension downstream of Crumbs. Yurt overexpression thus induces apical constriction in epithelial cells. The kinase aPKC phosphorylates Yurt, thereby dislodging the latter from the apical domain and releasing apical tension. In contrast, the kinase Pak1 promotes Yurt dephosphorylation through activation of the phosphatase PP2A. The Pak1-PP2A module thus opposes aPKC function and supports Yurt-induced apical constriction. Hence, the complex interplay between Yurt, aPKC, Pak1, and PP2A contributes to the functional plasticity of Crumbs. Overall, our data increase our understanding of how proteins sustaining epithelial cell polarization and Myosin-dependent cell contractility interact with one another to control epithelial tissue architecture.

A novel minimally invasive surgery combined with early exercise therapy promoting tendon regeneration in the treatment of spontaneous Achilles tendon rupture.

OBJECTIVE: Acute closed spontaneous Achilles tendon rupture often occurs in elderly individuals and is usually accompanied with many complications. Conventional surgical approaches to remove the tendon lesions and enthesophytes are highly traumatic and cause complications. In this study, a previously established minimally invasive surgical approach was modified and combined with a Kazakh exercise therapy to reduce trauma, improve wound healing, and promote tendon regeneration in the management of acute closed spontaneous Achilles tendon rupture. METHODS: Fifty-two patients with acute closed spontaneous Achilles tendon rupture were randomly classified into 2 groups. Group A included 23 patients that were treated with the novel approach. Group B included 29 patients that were treated with a continuous medial oblique surgical approach. Follow-up examinations were performed at post-operative weeks 12 and 24, and year 2. Outcomes were assessed by Achilles tendon rupture score (ATRS), a heel-rise endurance test, and ultrasonographic and multislice spiral computerized tomography. RESULTS: Mean ATRS in Group A was 68.6 and 86.0 at post-operative week 12 and 24, respectively, significantly higher than that in Group B (55.9 and 72.0, respectively). Recovery of patients in Group A was significantly better compared to Group B (p < 0.01), allowing them to participate in early rehabilitating kinesiotherapy. Patients in Group A rarely experienced complications after surgery, such as infection and Achilles tendon exposure, while in Group B, the wound healing was slower, the inside flaps were prone to necrosis and infection, and Achilles tendon exposure occurred in 10% of patients. CONCLUSIONS: The novel minimally invasive surgery is more advantageous in the treatment of acute closed spontaneous Achilles tendon rupture over previous approaches by promoting wound healing and tendon regeneration.

The interdependence of the Rho GTPases and apicobasal cell polarity.

Signaling via the Rho GTPases provides crucial regulation of numerous cell polarization events, including apicobasal (AB) polarity, polarized cell migration, polarized cell division and neuronal polarity. Here we review the relationships between the Rho family GTPases and epithelial AB polarization events, focusing on the 3 best-characterized members: Rho, Rac and Cdc42. We discuss a multitude of processes that are important for AB polarization, including lumen formation, apical membrane specification, cell-cell junction assembly and maintenance, as well as tissue polarity. Our discussions aim to highlight the immensely complex regulatory mechanisms that encompass Rho GTPase signaling during AB polarization. More specifically, in this review we discuss several emerging common themes, that include: 1) the need for Rho GTPase activities to be carefully balanced in both a spatial and temporal manner through a multitude of mechanisms; 2) the existence of signaling feedback loops and crosstalk to create robust cellular responses; and 3) the frequent multifunctionality that exists among AB polarity regulators. Regarding this latter theme, we provide further discussion of the potential plasticity of the cell polarity machinery and as a result the possible implications for human disease.

Percutaneous Yurt-bone suture versus minimally invasive surgery for acute Achilles tendon rupture / 中华创伤骨科杂志

Objective To compare the clinical outcomes of percutaneous Yurt-bone suture versus minimally invasive surgery in the treatment of acute Achilles tendon rupture.Methods Between September 2011 and December 2015,31 patients with acute Achilles tendon rupture were treated at our department.Of them,14 received percutaneous Yurt-bone suture and 17 minimally invasive surgery.The 2 groups were compared in terms of hospital stay,intraoperative bleeding volume,surgery time,decrease in leg circumference,delayed healing of the incision,single heel rise test,rerupture rate,sural nerve lesion and Achilles tendon total rupture scores (ATRS) at the final follow-up.Results The average follow-up period was 17.6 months (range,from 9 to 27 months) for all the patients in the 2 groups.The percutaneous Yurt-bone suture group had significantly less intraoperative bleeding volume (8.5 ± 3.6 mL),shorter surgery time (41.4 ± 5.3 min) and shorter hospital stay (4.2 ± 0.8 days),than the minimally invasive surgery group (43.5 ± 7.6 mL,75.5 ±7.8 min and 5.8 ± 1.3 days,respectively) (P ＜ 0.05).There were no statistically significant differences between the 2 groups regarding decrease in leg circumference (1.9 ± 0.2 cm versus 2.0 ±0.2 cm),delayed healing of the incision(0 versus 2 cases),positive single heel rise test (both one case),sural nerve lesion(one versus 0) or ATRS score (91.2 ± 3.7 versus 90.4 ± 3.3) (P ＞ 0.05).No re-rupture was observed in either group.Conclusion In the treatment of acute Achilles tendon rupture,compared with minimally invasive surgery,percutaneous Yurt-bone suture has advantages of shorter hospital stay,shorter surgery time,less intraoperative bleeding but a similar rate of complications.