Cellular energy stress induces AMPK-mediated regulation of YAP and the Hippo pathway.

YAP (Yes-associated protein) is a transcription co-activator in the Hippo tumour suppressor pathway and controls cell growth, tissue homeostasis and organ size. YAP is inhibited by the kinase Lats, which phosphorylates YAP to induce its cytoplasmic localization and proteasomal degradation. YAP induces gene expression by binding to the TEAD family transcription factors. Dysregulation of the Hippo-YAP pathway is frequently observed in human cancers. Here we show that cellular energy stress induces YAP phosphorylation, in part due to AMPK-dependent Lats activation, thereby inhibiting YAP activity. Moreover, AMPK directly phosphorylates YAP Ser 94, a residue essential for the interaction with TEAD, thus disrupting the YAP-TEAD interaction. AMPK-induced YAP inhibition can suppress oncogenic transformation of Lats-null cells with high YAP activity. Our study establishes a molecular mechanism and functional significance of AMPK in linking cellular energy status to the Hippo-YAP pathway

Rag GTPases are cardioprotective by regulating lysosomal function.

The Rag family proteins are Ras-like small GTPases that have a critical role in amino-acid-stimulated mTORC1 activation by recruiting mTORC1 to lysosome. Despite progress in the mechanistic understanding of Rag GTPases in mTORC1 activation, little is known about the physiological function of Rag GTPases in vivo. Here we show that loss of RagA and RagB (RagA/B) in cardiomyocytes results in hypertrophic cardiomyopathy and phenocopies lysosomal storage diseases, although mTORC1 activity is not substantially impaired in vivo. We demonstrate that despite upregulation of lysosomal protein expression by constitutive activation of the transcription factor EB (TFEB) in RagA/B knockout mouse embryonic fibroblasts, lysosomal acidification is compromised owing to decreased v-ATPase level in the lysosome fraction. Our study uncovers RagA/B GTPases as key regulators of lysosomal function and cardiac protection

MAP4K family kinases act in parallel to MST1/2 to activate LATS1/2 in the Hippo pathway.

The Hippo pathway plays a central role in tissue homoeostasis, and its dysregulation contributes to tumorigenesis. Core components of the Hippo pathway include a kinase cascade of MST1/2 and LATS1/2 and the transcription co-activators YAP/TAZ. In response to stimulation, LATS1/2 phosphorylate and inhibit YAP/TAZ, the main effectors of the Hippo pathway. Accumulating evidence suggests that MST1/2 are not required for the regulation of YAP/TAZ. Here we show that deletion of LATS1/2 but not MST1/2 abolishes YAP/TAZ phosphorylation. We have identified MAP4K family members--Drosophila Happyhour homologues MAP4K1/2/3 and Misshapen homologues MAP4K4/6/7-as direct LATS1/2-activating kinases. Combined deletion of MAP4Ks and MST1/2, but neither alone, suppresses phosphorylation of LATS1/2 and YAP/TAZ in response to a wide range of signals. Our results demonstrate that MAP4Ks act in parallel to and are partially redundant with MST1/2 in the regulation of LATS1/2 and YAP/TAZ, and establish MAP4Ks as components of the expanded Hippo pathway

Inter- and Intra-observer Reliability of MRI for Lumbar Lateral Disc Herniation

Background: The authors analyzed inter- and intra-observer agreement with respect to interpretation of simple magnetic resonance T1- and T2-weighted axial and sagittal images for the diagnosis of lumbar lateral disc herniation, including foraminal and extraforaminal disc herniations.Methods: Forty-two patients in whom lumbar lateral disc herniation was suspected or confirmed by simple magnetic resonance imaging at one institute between May 2003 and December 2004 were included. The magnetic resonance images consisting of T1- and T2-weighted axial and sagittal images, and these were reviewed blindly and independently by three orthopaedic spine surgeons in a random manner. The images were interpreted as positive or negative for lateral disc herniation on 2 different occasions 3 months apart. Results were analyzed using Cohens kappa statistic, and strengths of agreements were determined using the Landis and Koch criteria.Results: The kappa values for inter-observer agreement averaged 0.234 (0.282, 0.111, and 0.308 respectively) on the first occasion, and 0.166 (0.249, 0.111, and 0.137 respectively) on the second occasion, with an overall mean value of 0.200. Thus, the strength of agreement was only slight-to-fair according to the Landis and Koch criteria. Kappa values for intra-observer agreement averaged 0.479 (0.488, 0.491, and 0.459 respectively), indicating moderate agreement.Conclusions: The present study indicates that simple magnetic resonance imaging is not a reliable imaging modality for diagnosing lumbar lateral disc herniation. Another imaging study with improved diagnostic values should be developed to diagnose this pathologic finding.Keywords: Lumbar lateral disc herniation, Inter-observer reliability, Intra-observer reliability, Magnetic resonance imagingOAIID:oai:osos.snu.ac.kr:snu2009-01/102/0000004226/1SEQ:1PERF_CD:SNU2009-01EVAL_ITEM_CD:102USER_ID:0000004226EMP_ID:A076317DEPT_CD:801FILENAME:E019T_CiOS-2009_Kim_Inter-and Intra-observer Reliability of MRI for Lumbar.pdfDEPT_NM:의학과EMAIL:[email protected]_YN:NCONFIRM:YCONFIRM:

Distribution and antimicrobial resistance profiles of bacterial species in stray cats, hospital-admitted cats, and veterinary staff in South Korea

Antimicrobial resistance is becoming increasingly important in both human and veterinary medicine. According to the One Health concept, an important step is to monitor the resistance patterns of pathogenic bacteria. In this study, the antimicrobial susceptibility patterns and trends of bacteria isolated from stray cats, hospital-admitted cats, and veterinary staff in South Korea between 2017 and 2018 were investigated. The minimum inhibitory concentrations of different antibiotics for Staphylococcus spp., Enterobacteriaceae, and Enterococcus spp. were determined to establish representatives of different antibiotic classes relevant for treatment or surveillance. For Coagulase-positive and Coagulase-negative Staphylococci, resistance to fluoroquinolones was below 13%, but resistance to ampicillin and penicillin was high (20–88%). A total of 9.5, 12.1, and 40.3% of staphylococcal isolates from stray cats, hospital-admitted cats, and veterinary staff, respectively, were confirmed to be mecA positive. For Enterobacteriaceae, resistance to carbapenems, fluoroquinolones, and 3rd generation cephalosporins was low (0–11.1%). The Enterococcus spp. isolates showed no resistance to vancomycin. The antimicrobial resistance rates of the Staphylococcus spp. and Enterobacteriaceae isolates from stray cats were usually lower than those of isolates from hospital-admitted cats and veterinary staff, but the Enterococcus spp. isolates revealed the opposite. Thus, the antimicrobial resistance varied across bacterial species according to the source from which they were isolated. Resistance to critically important compounds were low. However, the presence of antimicrobial resistance in cat isolates is of both public health and animal health concern.This work was supported by a grant from the Animal and Plant Quarantine Agency, Ministry of Agriculture and Forestry (Z-1543081-2017-18-03) and the Cooperative Research Program of Center for Companion Animal Research Jung et al. BMC Veterinary Research (2020) 16:109 Page 12 of 14 (Project No. PJ013985022019) of Rural Development Administration, South Korea. The funding bodies played no role in the design of the study, the collection, analysis, and interpretation of data and in writing the manuscript

Use of Allograft in Skeletally Immature Patients for Calcaneal Neck Lengthening Osteotomy

PURPOSE: To date, there have been no studies evaluating the usefulness of allograft as a substitute for autograft in calcaneal neck lengthening osteotomy. This retrospective study examined the results of calcaneal neck lengthening osteotomy using allograft for pathologic flatfoot deformity in children and adolescents with various neuromuscular diseases. MATERIALS AND METHODS: 118 feet in 79 children treated surgically between Mar 2000 and July 2005 were reviewed. The mean age at the time of the operation was 9+3 years (range, 3-17 years) and follow-up averaged 15.4 months (range, 13-21 months) postoperatively. Talo-1st metatarsal angle, talo-calcaneal angle, calcaneal pitch were measured before and after operation and bony union was estimated. RESULTS: Bony union was noted at the latest follow-up and there were no postoperative complications such as reduction loss, infection, nonunion, delayed union or graft loss during the follow-up period in all but one foot. All radiographic indices were improved postoperatively in all cases. CONCLUSION: Our results indicate that use of allograft in calcaneal neck lengthening osteotomy is a useful option for correction of the planovalgus deformity in skeletally immature patients whose enough autobone can not be obtained.ope