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Karakose E.,Max Planck Institute of Biochemistry | Geiger T.,Max Planck Institute of Biochemistry | Flynn K.,Max Planck Institute of Biochemistry | Lorenz-Baath K.,Max Planck Institute of Biochemistry | And 4 more authors.
Journal of Cell Science | Year: 2015

PINCH-1 is a LIM-only domain protein that forms a ternary complex with integrin-linked kinase (ILK and parvin (to form the IPP complex) downstream of integrins Here, we demonstrate that PINCH-1 (also known as Lims1) gene ablation in the epidermis of mice caused epidermal detachment from the basement membrane, epidermal hyperthickening and progressive hair loss. PINCH-1- deficient keratinocytes also displayed profound adhesion, spreading and migration defects in vitro that were substantially more severe than those of ILK-deficient keratinocytes indicating that PINCH-1 also exerts functions in an ILK-independent manner. By isolating the PINCH-1 interactome, the LIM-domain-containing and actin-binding protein epithelial protein lost in neoplasm (EPLIN, also known as LIMA1) was identified as a new PINCH-1-associated protein. EPLIN localized, in a PINCH-1-dependent manner, to integrin adhesion sites of keratinocytes in vivo and in vitro and its depletion severely attenuated keratinocyte spreading and migration on collagen and fibronectin without affecting PINCH-1 levels in focal adhesions. Given that the low PINCH-1 levels in ILK-deficient keratinocytes were sufficient to recruit EPLIN to integrin adhesions, our findings suggest that PINCH-1 regulates integrin-mediated adhesion of keratinocytes through the interactions with ILK as well as EPLIN. © 2015. Published by The Company of Biologists Ltd. Source


Pandharipande P.P.,Vanderbilt University | Pandharipande P.P.,Nashville Veterans Affairs Medical Center | Patel M.B.,Nashville Veterans Affairs Medical Center | Patel M.B.,Vanderbilt University | And 2 more authors.
Polskie Archiwum Medycyny Wewnetrznej | Year: 2014

Pain, agitation, and delirium (PAD) are common in critically ill patients. Consequently, analgesic and sedative medications are frequently administered to critically ill patients to treat PAD, to improve synchrony with mechanical ventilation, and to decrease the physiological stress response. However, prolonged, continuous deep sedation of intensive care unit (ICU) patients is associated with numerous adverse outcomes, including longer durations of mechanical ventilation, prolonged ICU stays, acute brain dysfunction, and an increased risk of death. The 2013 ICU PAD Guidelines were developed to provide a clear, evidence-based road map for clinicians to better manage PAD in critically ill patients. Significant knowledge gaps in these areas still remain, but if widely adopted, the PAD Guidelines can help bridge these gaps and will be transformative in terms of their impact on ICU care. Strong evidence indicates that linking PAD management strategies with ventilator weaning, early mobility, and sleep hygiene in ICU patients will result in significant synergistic benefits to patient care and reductions in costs. An interdisciplinary team-based approach, using proven process improvement strategies, and ICU patient and family activation and engagement, will help ensure successful implementation of the ICU PAD Care Bundle in ICUs. This paper highlights the major recommendations of the 2013 ICU PAD Guidelines. We hope this review will help ICU physicians and other health care providers advance the management of PAD in critically ill patients, and improve patients' clinical outcomes. Source


Cheng H.,Vanderbilt University | Fan X.,Vanderbilt University | Moeckel G.W.,Yale University | Harris R.C.,Vanderbilt University | Harris R.C.,Nashville Veterans Affairs Medical Center
Journal of the American Society of Nephrology | Year: 2011

Diabetic nephropathy (DN) increases podocyte cyclooxygenase-2 (COX-2) expression, and COX-2 inhibition reduces proteinuria and glomerular injury in animal models of diabetes. To investigate the role of podocyte COX-2 in development of diabetic nephropathy, we employed a streptozotocin model of diabetic mellitus in wild-type and transgenic mice expressing COX-2 selectively in podocytes. Progressive albuminuria developed only in diabetic COX-2 transgenic mice despite hyperglycemia, BP, and GFR being similar to those in wild-type mice. Transgenic mice also manifested significant foot-process effacement, moderate mesangial expansion, and segmental thickening of the glomerular basement membrane. In cultured podocytes overexpressing COX-2, high glucose induced cell injury and increased both expression of the pro(renin) receptor and activation of the renin-angiotensin system. Downregulation of the (pro)renin receptor attenuated the injury induced by high glucose. In vivo, podocyte pro(renin) receptor expression increased in diabetic COX-2-transgenic mice, and treatment with a COX-2 inhibitor abrogated the upregulation of (pro)renin receptor and reduced albuminuria, footprocess effacement, and mesangial matrix expansion. In summary, these results demonstrate that increased expression of podocyte COX-2 predisposes to diabetic glomerular injury and that the (pro)-renin receptor may be one mediator for this increased susceptibility to injury. Copyright © 2011 by the American Society of Nephrology. Source


Cates J.M.M.,Vanderbilt University | Friedman D.B.,Vanderbilt University | Seeley E.H.,Vanderbilt University | Dupont W.D.,Vanderbilt University | And 5 more authors.
International Journal of Experimental Pathology | Year: 2010

Summary A significant proportion of patients with osteogenic sarcoma die from lung metastasis within 5 years of diagnosis. Molecular signatures that predict pulmonary metastasis from primary osteogenic sarcoma and identify those patients at risk would be clinically useful as prognostic markers. Protein expression profiles of two clonally related murine osteogenic sarcoma cell lines with low (K12) and high (K7M2) metastatic potential were compared using two different proteomic technologies, two-dimensional difference gel electrophoresis and cell profiling by matrix-assisted laser desorption/ionization mass spectrometry. Interrogation of a molecular pathways network database suggested several additional candidate molecules that potentially predict metastatic potential of primary osteogenic sarcoma. Two such proteins, macrophage migration inhibitory factor and tumour necrosis factor were selected for further validation studies. Western blots confirmed increased expression of both cytokines in K7M2 cells compared to K12 cells. Levels of migration inhibitory factor and tumour necrosis factor were semi-quantitatively measured in human osteogenic sarcoma samples by immunohistochemistry and were correlated with clinicopathologic parameters and patient outcomes. Multivariate survival analysis demonstrated that tumour necrosis factor expression in chemotherapy naïve osteogenic sarcoma is an independent prognostic factor for overall and metastasis-free survival. No significant differences in adverse outcomes were observed based on macrophage migration inhibitory factor expression. © 2010 The Authors. Source


Schafer J.C.,Vanderbilt University | Baetz N.W.,Vanderbilt University | Lapierre L.A.,Vanderbilt University | Mcrae R.E.,Vanderbilt University | And 4 more authors.
Traffic | Year: 2014

A tripartite association of Rab11a with both Rab11-FIP2 and MYO5B regulates recycling endosome trafficking. We sought to define the intermolecular interactions required between Rab11-FIP2 and MYO5B. Using a random mutagenesis strategy, we identified point mutations at S229P or G233E in Rab11-FIP2 that caused loss of interaction with MYO5B in yeast two-hybrid assays as well as loss of interaction of Rab11-FIP2(129-356) with MYO5B tail when expressed in HeLa cells. Single mutations or the double S229P/G233E mutation failed to alter the association of full-length Rab11-FIP2 with MYO5B tail in HeLa cells. While EGFP-Rab11-FIP2 wild type colocalized with endogenous MYO5B staining in MDCK cells, EGFP-Rab11-FIP2(S229P/G233E) showed a significant decrease in localization with endogenous MYO5B. Analysis of Rab11a-containing vesicle movement in live HeLa cells demonstrated that when the MYO5B/Rab11-FIP2 association is perturbed by mutation or by Rab11-FIP2 knockdown, vesicle movement is increased in both speed and track length, consistent with an impairment of MYO5B tethering at the cytoskeleton. These results support a critical role for the interaction of MYO5B with Rab11-FIP2 in stabilizing the functional complex with Rab11a, which regulates dynamic movements of membrane recycling vesicles. The interaction between MYO5B and Rab11-FIP2 impacts MYO5B tethering and subsequent movement of Rab11a vesicles. When the tripartite complex of MYO5B, Rab11-FIP2 and Rab11a is intact, MYO5B is tethered to F actin and Rab11a-containing vesicles travel relatively slowly. When the interaction between MYO5B and Rab11-FIP2 is disturbed by mutation of Rab11-FIP2 at S229P/G233E (SPGE), MYO5B tethering to F actin is compromised and Rab11a-containing vesicles travel relatively rapidly. © 2013 John Wiley & Sons A/S. Source

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