We thank the editor for allowing us to respond to the comments by Akshara et al. The authors concur with us on unpreparedness and goes on to highlight how female doctors are over-worked during the pandemic. In this response, we also discuss why providing free data will not bring about significant change in students' perception of online classes. We then advise how students can learn basic examination skills during the pandemic. Finally, we express our views on government and universities and finish with a recommendation that would help future doctors in times like the COVID-19 pandemic.
WOS: 000417141100007 ; PubMed ID: 29058690 ; Steroid-resistant nephrotic syndrome (SRNS) is a frequent cause of chronic kidney disease. Here, we identified recessive mutations in the gene encoding the actin-binding protein advillin (AVIL) in 3 unrelated families with SRNS. While all AVIL mutations resulted in a marked loss of its actin-bundling ability, truncation of AVIL also disrupted colocalization with F-actin, thereby leading to impaired actin binding and severing. Additionally, AVIL colocalized and interacted with the phospholipase enzyme PLCE1 and with the ARP2/3 actin-modulating complex. Knockdown of AVIL in human podocytes reduced actin stress fibers at the cell periphery, prevented recruitment of PLCE1 to the ARP3-rich lamellipodia, blocked EGF-induced generation of diacylglycerol (DAG) by PLCE1, and attenuated the podocyte migration rate (PMR). These effects were reversed by overexpression of WT AVIL but not by overexpression of any of the 3 patient-derived AVIL mutants. The PMR was increased by overexpression of WT Avil or PLCE1, or by EGF stimulation; however, this increased PMR was ameliorated by inhibition of the ARP2/3 complex, indicating that ARP-dependent lamellipodia formation occurs downstream of AVIL and PLCE1 function. Together, these results delineate a comprehensive pathogenic axis of SRNS that integrates loss of AVIL function with alterations in the action of PLCE1, an established SRNS protein. ; Yale Center for Mendelian Genomics [U54HG006504]; NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [DK076683]; Young Scholars Program of Children's Hospital of Fudan University; Basic Science Research Program through the National Research Foundation of Korea [2015R1D1A1A01056685]; DFG fellowships [VE 196/1-1, Jo 1324/1-1, HE 7456/1-1]; German National Academy of Sciences Leopoldina [LPDS-2015-07]; Egyptian Group for Orphan Renal Diseases (EGORD); Department of Science and Technology, Government of India (DST-SERB); National Institute of Diabetes and Digestive and Kidney DiseasesUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USANIH National Institute of Diabetes & Digestive & Kidney Diseases (NIDDK) [DK-98120]; Public Health ServiceUnited States Public Health Service [DK-56338] ; We are grateful to the families and study participants for their contributions. We thank the Yale Center for Mendelian Genomics (U54HG006504) for WES analysis. FH is a William E. Harmon Professor of Pediatrics. This research was supported by the NIH (DK076683, to FH); the Young Scholars Program of Children's Hospital of Fudan University (to JR); Basic Science Research Program through the National Research Foundation of Korea 2015R1D1A1A01056685 (to HYG); DFG fellowships (VE 196/1-1, to ATvdV; Jo 1324/1-1, to TJS; and HE 7456/1-1, to TH); the German National Academy of Sciences Leopoldina (LPDS-2015-07, to EW); the Egyptian Group for Orphan Renal Diseases (EGORD) (to NAS); the Department of Science and Technology, Government of India (DST-SERB, to MAJ); the National Institute of Diabetes and Digestive and Kidney Diseases (DK-98120, to SK); and the Public Health Service (DK-56338, to SK).
