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1. Atomistic simulations reveal impacts of missense mutations on the structure and function of SynGAP1.

Author

Ali, Aliaa E, Li, Li-Li, Courtney, Michael J, Pentikäinen, Olli T, and Postila, Pekka A

Subjects
MISSENSE mutation, DRUG discovery, ALZHEIMER'S disease, MOLECULAR dynamics, MUTAGENESIS
Abstract

De novo mutations in the synaptic GTPase activating protein (SynGAP) are associated with neurological disorders like intellectual disability, epilepsy, and autism. SynGAP is also implicated in Alzheimer's disease and cancer. Although pathogenic variants are highly penetrant in neurodevelopmental conditions, a substantial number of them are caused by missense mutations that are difficult to diagnose. Hence, in silico mutagenesis was performed for probing the missense effects within the N-terminal region of SynGAP structure. Through extensive molecular dynamics simulations, encompassing three 150-ns replicates for 211 variants, the impact of missense mutations on the protein fold was assessed. The effect of the mutations on the folding stability was also quantitatively assessed using free energy calculations. The mutations were categorized as potentially pathogenic or benign based on their structural impacts. Finally, the study introduces wild-type-SynGAP in complex with RasGTPase at the inner membrane, while considering the potential effects of mutations on these key interactions. This study provides structural perspective to the clinical assessment of SynGAP missense variants and lays the foundation for future structure-based drug discovery. [ABSTRACT FROM AUTHOR]

Published
2024
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6. Preoperative risk factors for conversion from laparoscopic to open cholecystectomy: a validated risk score derived from a prospective U.K. database of 8820 patients

Author

Fenwick, Stephen, Elmasry, Mohamed, Nunes, Quentin, Kennedy, David, Khan, Raja B., Khan, Muhammad A.S., Magee, Conor J., Jones, Steven M., Mason, Denise, Parappally, Ciny P., Mathur, Pawan, Saunders, Michael, Jamel, Sara, Haque, Samer U.l., Zafar, Sara, Shiwani, Muhammad H., Samuel, Nehemiah, Dar, Farooq, Jackson, Andrew, Lovett, Bryony, Dindyal, Shiva, Winter, Hannah, Rahman, Saquib, Wheatley, Kevin, Nieto, Tom, Ayaani, Soofiyah, Youssef, Haney, Nijjar, Rajwinder S., Watkin, Helen, Naumann, David, Emeshi, Sophie, Sarmah, Piyush B., Lee, Kathryn, Joji, Nikita, Heath, Jonathan, Teasdale, Rebecca L., Weerasinghe, Chamindri, Needham, Paul J., Welbourn, Hannah, Forster, Luke, Finch, David, Blazeby, Jane M., Robb, William, McNair, Angus G.K., Hrycaiczuk, Alex, Charalabopoulos, Alexandros, Kadirkamanathan, Sritharan, Tang, Cheuk-Bong, Jayanthi, Naga V.G., Noor, Nigel, Dobbins, Brian, Cockbain, Andrew J., Nilsen-Nunn, April, de Siqueira, Jonathan, Pellen, Mike, Cowley, Jonathan B., Ho, Wei-Min, Miu, Victor, White, Timothy J., Hodgkins, Kathryn A., Kinghorn, Alison, Tutton, Matthew G., Al-Abed, Yahya A., Menzies, Donald, Ahmad, Anwar, Reed, Joanna, Khan, Shabuddin, Monk, David, Vitone, Louis J., Murtaza, Ghulam, Joel, Abraham, Brennan, Stephen, Shier, David, Zhang, Catherine, Yoganathan, Thusidaran, Robinson, Steven J., McCallum, Iain J.D., Jones, Michael J., Elsayed, Mohammed, Tuck, Liz, Wayman, John, Carney, Kate, Aroori, Somaiah, Hosie, Kenneth B., Kimble, Adam, Bunting, David M., Fawole, Adeshina S., Basheer, Mohammed, Dave, Rajiv V., Sarveswaran, Janahan, Jones, Elinor, Kendal, Chris, Tilston, Michael P., Gough, Martin, Wallace, Tom, Singh, Shailendra, Downing, Justine, Mockford, Katherine A., Issa, Eyad, Shah, Nayab, Chauhan, Neal, Wilson, Timothy R., Forouzanfar, Amir, Wild, Jonathan R.L., Nofal, Emma, Bunnell, Catherine, Madbak, Khaliel, Rao, Sudhindra T.V., Devoto, Laurence, Siddiqi, Najaf, Khawaja, Zechan, Hewes, James C., Gould, Laura, Chambers, Alice, Rodriguez, Daniel U., Sen, Gourab, Robinson, Stuart, Bartlett, Francis, Rae, David M., Stevenson, Thomas E.J., Sarvananthan, Kas, Dwerryhouse, Simon J., Higgs, Simon M., Old, Oliver J., Hardy, Thomas J., Shah, Reena, Hornby, Steve T., Keogh, Ken, Frank, Lucinda, Al-Akash, Musallam, Upchurch, Emma A., Frame, Richard J., Hughes, Michael, Jelley, Clare, Weaver, Simon, Roy, Sudipta, Sillo, Toritseju O., Galanopoulos, Giorgios, Cuming, Tamzin, Cunha, Pedro, Tayeh, Salim, Kaptanis, Sarantos, Heshaishi, Mohamed, Eisawi, Abdalla, Abayomi, Michael, Ngu, Wee S., Fleming, Katie, Bajwa, Dalvir S., Chitre, Vivek, Aryal, Kamal, Ferris, Paul, Silva, Michael, Lammy, Simon, Mohamed, Sarah, Khawaja, Amir, Hussain, Adnan, Ghazanfar, Mudassar A., Bellini, Maria I., Ebdewi, Hamdi, Elshaer, Mohamed, Gravante, Gianpiero, Drake, Benjamin, Ogedegbe, Arikoge, Mukherjee, Dipankar, Arhi, Chanpreet, Giwa, Lola, Iqbal, Nusrat, Watson, Nicholas F., Aggarwal, Smeer K., Orchard, Philippa, Villatoro, Eduardo, Willson, Peter D., Mok, Kam W.J., Woodman, Thomas, Deguara, Jean, Garcea, Giuseppe, Babu, Benoy I., Dennison, Alistair R., Malde, Deep, Lloyd, David, Slavin, John P., Jones, Robert P., Ballance, Laura, Gerakopoulos, Stratos, Jambulingam, Periyathambi, Mansour, Sami, Sakai, Naomi, Acharya, Vikas, Sadat, Mohammed M., Karim, Lawen, Larkin, David, Amin, Khalid, Khan, Amarah, Law, Jennifer, Jamdar, Saurabh, Smith, Stella R., Sampat, Keerthika, O'shea, Kathryn M., Manu, Mangta, Asprou, Fotini M., Malik, Nabeela S., Chang, Jessica, Johnstone, Marianne, Lewis, Michael, Roberts, Geoffrey P., Karavadra, Babu, Photi, Evangelos, Hewes, James, Rodriguez, Dan, O'Reilly, Derek A., Rate, Anthony J., Sekhar, Hema, Henderson, Lucy T., Starmer, Benjamin Z., Coe, Peter O., Tolofari, Sotonye, Barrie, Jenifer, Bashir, Gareth, Sloane, Jake, Madanipour, Suroosh, Halkias, Constantine, Trevatt, Alexander E.J., Borowski, David W., Hornsby, Jane, Courtney, Michael J., Virupaksha, Suvi, Seymour, Keith, Robinson, Sarah, Hawkins, Helen, Bawa, Sadiq, Gallagher, Paul V., Reid, Alistair, Wood, Peter, Finch, Jonathan G., Finch, J.Guy, Parmar, Jitesh, Stirland, Euan, Gardner-Thorpe, James, Al-Muhktar, Ahmed, Peterson, Mark, Majeed, Ali, Bajwa, Farrukh M., Martin, Jack, Choy, Alfred, Tsang, Andrew, Pore, Naresh, Andrew, David R., Al-Khyatt, Waleed, Santosh Bhandari, Christopher Taylor, Chambers, Adam, Subramanium, Dhivya, Toh, Simon K.C., Carter, Nicholas C., Mercer, Stuart J., Knight, Benjamin, Vijay, Vardhini, Alagaratnam, Swethan, Sinha, Sidhartha, Khan, Shahab, El-Hasani, Shamsi S., Hussain, Abdulzahra A., Bhattacharya, Vish, Kansal, Nisheeth, Fasih, Tani, Jackson, Claire, Siddiqui, Midhat N., Chishti, Imran A., Fordham, Imogen J., Siddiqui, Zohaib, Bausbacher, Harald, Geogloma, Ileana, Gurung, Kabita, Tsavellas, George, Basynat, Pradeep, Shrestha, Ashish K., Basu, Sanjoy, Chhabra, Alok, Harilingam, Mohan, Rabie, Mohamed, Akhtar, Mansoor, Kumar, Pradeep, Jafferbhoy, Sadaf F., Hussain, Najam, Raza, Soulat, Haque, Manzarul, Alam, Imran, Aseem, Rabiya, Patel, Shakira, Asad, Mehek, Booth, Michael I., Ball, William R., Wood, Christopher P.J., Pinho-Gomes, Ana C., Kausar, Ambareen, Obeidallah, Mohammed, Varghase, Joseph, Lodhia, Joshil, Bradley, Donal, Rengifo, Carla, Lindsay, David, Gopalswamy, Sivakumar, Finlay, Ian, Wardle, Stacy, Bullen, Naomi, Iftikhar, Syed Y., Awan, Altaf, Ahmed, Javed, Leeder, Paul, Fusai, Guiseppe, Bond-Smith, Giles, Psica, Alicja, Puri, Yogesh, Hou, David, Noble, Fergus, Szentpali, Karoly, Broadhurst, Jack, Date, Ravindra, Hossack, Martin R., Goh, Yan L., Turner, Paul, Shetty, Vinutha, Riera, Manel, Macano, Christina A.W., Sukha, Anisha, Preston, Shaun R., Hoban, Jennifer R., Puntis, Daniel J., Williams, Sophie V., Krysztopik, Richard, Kynaston, James, Batt, Jeremy, Doe, Matthew, Goscimski, Andrzej, Jones, Gareth H., Hall, Claire, Carty, Nick, Ahmed, Jamil, Panteleimonitis, Sofoklis, Gunasekera, Rohan T., Sheel, Andrea R.G., Lennon, Hannah, Hindley, Caroline, Reddy, Marcus, Kenny, Ross, Elkheir, Natalie, McGlone, Emma R., Rajaganeshan, Rajasundaram, Hancorn, Kate, Hargreaves, Anita, Prasad, Raj, Longbotham, David A., Vijayanand, Dhakshinamoorthy, Wijetunga, Imeshi, Ziprin, Paul, Nicolay, Christopher R., Yeldham, Geoffrey, Read, Edward, Gossage, James A., Rolph, Rachel C., Ebied, Husam, Phull, Manraj, Khan, Mohammad A., Popplewell, Matthew, Kyriakidis, Dimitrios, Hussain, Anwar, Henley, Natasha, Packer, Jessica R., Derbyshire, Laura, Porter, Jonathan, Appleton, Shaun, Farouk, Marwan, Basra, Melvinder, Jennings, Neil A., Ali, Shahda, Kanakala, Venkatesh, Ali, Haythem, Lane, Risha, Dickson-Lowe, Richard, Zarsadias, Prizzi, Mirza, Darius, Puig, Sonia, Al Amari, Khalid, Vijayan, Deepak, Sutcliffe, Robert, Marudanayagam, Ravi, Hamady, Zayed, Prasad, Abheesh R., Patel, Abhilasha, Durkin, Damien, Kaur, Parminder, Bowen, Laura, Byrne, James P., Pearson, Katherine L., Delisle, Theo G., Davies, James, Tomlinson, Mark A., Johnpulle, Michelle A., Slawinski, Corinna, Macdonald, Andrew, Nicholson, James, Newton, Katy, Mbuvi, James, Farooq, Ansar, Mothe, Bhavani S., Zafrani, Zakhi, Brett, Daniel, Francombe, James, Spreadborough, Philip, Barnes, James, Cheung, Melanie, Al-Bahrani, Ahmed Z., Preziosi, Giuseppe, Urbonas, Tomas, Alberts, Justin, Mallik, Mekhlola, Patel, Krashna, Segaran, Ashvina, Doulias, Triantafyllos, Sufi, Pratik A., Yao, Caroline, Pollock, Sarah, Manzelli, Antonio, Wajed, Saj, Kourkulos, Michail, Pezzuto, Roberto, Wadley, Martin, Hamilton, Emma, Jaunoo, Shameen, Padwick, Robert, Sayegh, Mazin, Newton, Richard C., Hebbar, Madhusoodhana, Farag, Sameh F., Hebbar, Madhu, Spearman, John, Hamdan, Mohammed F., D'Costa, Conrad, Blane, Christine, Giles, Mathew, Peter, Mark B., Hirst, Natalie A., Hossain, Tanvir, Pannu, Arslan, El-Dhuwaib, Yesar, Morrison, Tamsin E.M., Taylor, Greg W., Thompson, Ronald L.E., McCune, Ken, Loughlin, Paula, Lawther, Roger, Byrnes, Colman K., Simpson, Duncan J., Mawhinney, Abi, Warren, Conor, McKay, Damian, McIlmunn, Colin, Martin, Serena, MacArtney, Matthew, Diamond, Tom, Davey, Phil, Jones, Claire, Clements, Joshua M., Digney, Ruairi, Chan, Wei M., McCain, Stephen, Gull, Sadaf, Janeczko, Adam, Dorrian, Emmet, Harris, Andrew, Dawson, Suzanne, Johnston, Dorothy, McAree, Barry, Ghareeb, Essam, Thomas, George, Connelly, Martin, McKenzie, Stephen, Cieplucha, Krzysztos, Spence, Gary, Campbell, William, Hooks, Gareth, Bradley, Neil, Hill, Arnold D.K., Cassidy, John T., Boland, Michael, Burke, Paul, Nally, Deirdre M., Khogali, Elmoataz, Shabo, Wael, Iskandar, Edrin, McEntee, Gerry P., O'Neill, Maeve A., Peirce, Colin, Lyons, Emma M., O'Sullivan, Adrian W., Thakkar, Rohan, Carroll, Paul, Ivanovski, Ivan, Balfe, Paul, Lee, Matthew, Winter, Des C., Kelly, Michael E., Hoti, Emir, Maguire, Donal, Karunakaran, Priyadarssini, Geoghegan, Justin G., Martin, Sean T., Cross, Keith S., Cooke, Fiachra, Zeeshan, Saquib, Murphy, James O., Mealy, Ken, Mohan, Helen M., Nedujchelyn, Yuwaraja, Ullah, Muhammad F., Ahmed, Irfan, Giovinazzo, Francesco, Milburn, James, Prince, Sarah, Brooke, Eleanor, Buchan, Joanna, Khalil, Ahmed M., Vaughan, Elizabeth M., Ramage, Michael I., Aldridge, Roland C., Gibson, Simon, Nicholson, Gary A., Vass, David G., Grant, Alan J., Holroyd, David J., Jones, Angharad, Sutton, Cherith M.L.R., O'Dwyer, Patrick, Nilsson, Frida, Weber, Beatrix, Williamson, Tracey K., Lalla, Kushik, Bryant, Alice, Carter, Ross, Forrest, Craig R., Hunter, David I., Nassar, Ahmad H., Orizu, Mavis N., Knight, Katrina, Qandeel, Haitham, Suttie, Stuart, Belding, Rowena, McClarey, Andrew, Boyd, Alan T., Guthrie, Graeme J.K., Lim, Pei J., Luhmann, Andreas, Watson, Angus J.M., Richards, Colin H., Nicol, Laura, Madurska, Marta, Harrison, Ewen, Boyce, Kathryn M., Roebuck, Amanda, Ferguson, Graeme, Pati, Pradeep, Wilson, Michael S.J., Dalgaty, Faith, Fothergill, Laura, Driscoll, Peter J., Mozolowski, Kirsty L., Banwell, Victoria, Bennett, Stephen P., Rogers, Paul N., Skelly, Brendan L., Rutherford, Claire L., Mirza, Ahmed K., Lazim, Taha, Lim, Henry C.C., Duke, Diana, Ahmed, Talat, Beasley, William D., Wilkinson, Marc D., Maharaj, Geta, Malcolm, Cathy, Brown, Timothy H., Shingler, Guy M., Mowbray, Nicholas, Radwan, Rami, Morcous, Paul, Wood, Simon, Kadhim, Abbas, Stewart, Duncan J., Baker, Andrew L., Tanner, Nicola, Shenoy, Hrishikesh, Sutcliffe, Robert P., Hollyman, Marianne, Hodson, James, Bonney, Glenn, Vohra, Ravi S., and Griffiths, Ewen A.

Published
2016
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10. Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Author

Griffiths, Ewen A, Hodson, James, Vohra, Ravi S, Marriott, Paul, Katbeh, Tarek, Zino, Samer, Nassar, Ahmad HM, Vohra, Ravinder S, Kirkham, Amanda J, Pasquali, Sandro, Johnstone, Marianne, Spreadborough, Philip, Alderson, Derek, Fenwick, Stephen, Elmasry, Mohamed, Nunes, Quentin M, Kennedy, David, Khan, Raja Basit, Khan, Muhammad AS, Magee, Conor J, Jones, Steven M, Mason, Denise, Parappally, Ciny P, Mathur, Pawan, Saunders, Michael, Jamel, Sara, Haque, Samer Ul, Zafar, Sara, Shiwani, Muhammad Hanif, Samuel, Nehemiah, Dar, Farooq, Jackson, Andrew, Lovett, Bryony, Dindyal, Shiva, Winter, Hannah, Fletcher, Ted, Rahman, Saquib, Wheatley, Kevin, Nieto, Tom, Ayaani, Soofiyah, Youssef, Haney, Nijjar, Rajwinder S, Watkin, Helen, Naumann, David, Emesih, Sophie, Sarmah, Piyush B, Lee, Kathryn, Joji, Nikita, Lambert, Joel, Heath, Jonathan, Teasdale, Rebecca L, Weerasinghe, Chamindri, Needham, Paul J, Welbourn, Hannah, Forster, Luke, Finch, David, Blazeby, Jane M, Robb, William, McNair, Angus GK, Hrycaiczuk, Alex, Charalabopoulos, Alexandros, Kadirkamanathan, Sritharan, Tang, Cheuk-Bong, Jayanthi, Naga VG, Noor, Nigel, Dobbins, Brian, Cockbain, Andrew J, Nilsen-Nunn, April, de Siqueira, Jonathan, Pellen, Mike, Cowley, Jonathan B, Ho, Wei-Min, Miu, Victor, White, Timothy J, Hodgkins, Kathryn A, Kinghorn, Alison, Tutton, Matthew G, Al-Abed, Yahya A, Menzies, Donald, Ahmad, Anwar, Reed, Joanna, Khan, Shabuddin, Monk, David, Vitone, Louis J, Murtaza, Ghulam, Joel, Abraham, Brennan, Stephen, Shier, David, Zhang, Catherine, Yoganathan, Thusidaran, Robinson, Steven J, McCallum, Iain JD, Jones, Michael J, Elsayed, Mohammed, Tuck, Liz, Wayman, John, Carney, Kate, Aroori, Somaiah, Hosie, Kenneth B, Kimble, Adam, Bunting, David M, Fawole, Adeshina S, Basheer, Mohammed, Dave, Rajiv V, Sarveswaran, Janahan, Jones, Elinor, Kendal, Chris, Tilston, Michael P, Gough, Martin, Wallace, Tom, Singh, Shailendra, Downing, Justine, Mockford, Katherine A, Issa, Eyad, Shah, Nayab, Chauhan, Neal, Wilson, Timothy R, Forouzanfar, Amir, Wild, Jonathan RL, Nofal, Emma, Bunnell, Catherine, Madbak, Khaliel, Rao, Sudhindra TV, Devoto, Laurence, Siddiqi, Najaf, Khawaja, Zechan, Hewes, James C, Gould, Laura, Chambers, Alice, Rodriguez, Daniel Urriza, Sen, Gourab, Robinson, Stuart, Bartlett, Francis, Rae, David M, Stevenson, Thomas EJ, Sarvananthan, Kas, Dwerryhouse, Simon J, Higgs, Simon M, Old, Oliver J, Hardy, Thomas J, Shah, Reena, Hornby, Steve T, Keogh, Ken, Frank, Lucinda, Al-Akash, Musallam, Upchurch, Emma A, Frame, Richard J, Hughes, Michael, Jelley, Clare, Weaver, Simon, Roy, Sudipta, Sillo, Toritseju O, Galanopoulos, Giorgios, Cuming, Tamzin, Cunha, Pedro, Tayeh, Salim, Kaptanis, Sarantos, Heshaishi, Mohamed, Eisawi, Abdalla, Abayomi, Michael, Ngu, Wee Sing, Fleming, Katie, Bajwa, Dalvi S, Chitre, Vivek, Aryal, Kamal, Ferris, Paul, Silva, Michael, Lammy, Simon, Mohamed, Sarah, Khawaja, Amir, Hussain, Adnan, Ghazanfar, Mudassar A, Bellini, Maria Irene, Ebdewi, Hamdi, Elshaer, Mohamed, Gravante, Gianpiero, Drake, Benjamin, Ogedegbe, Arikoge, Mukherjee, Dipankar, Arhi, Chanpreet, Giwa, Lola, Iqbal, Nusrat, Watson, Nicholas F, Aggarwal, Smeer Kumar, Orchard, Philippa, Villatoro, Eduardo, Willson, Peter D, Mok, Kam Wa Jessica, Woodman, Thomas, Deguara, Jean, Garcea, Giuseppe, Babu, Benoy I, Dennison, AR, Malde, Deep, Lloyd, David, Satheesan, Steve, Al-Taan, Omer, Boddy, Alexander, Slavin, John P, Jones, Robert P, Ballance, Laura, Gerakopoulos, Stratos, Jambulingam, Periyathambi, Mansour, Sami, Sakai, Naomi, Acharya, Vikas, Sadat, Mohammed M, Karim, Lawen, Larkin, David, Amin, Khalid, Khan, Amarah, Law, Jennifer, Jamdar, Saurabh, Smith, Stella R, Sampat, Keerthika, O'shea, Kathryn M, Manu, Mangta, Asprou, Fotini M, Malik, Nabeela S, Chang, Jessica, Lewis, Michael, Roberts, Geoffrey P, Karavadra, Babu, Photi, Evangelos, Hewes, James, Rodriguez, Dan, O'Reilly, Derek A, Rate, Anthony J, Sekhar, Hema, Henderson, Lucy T, Starmer, Benjamin Z, Coe, Peter O, Tolofari, Sotonye, Barrie, Jenifer, Bashir, Gareth, Sloane, Jake, Madanipour, Suroosh, Halkias, Constantine, Trevatt, Alexander EJ, Borowski, David W, Hornsby, Jane, Courtney, Michael J, Virupaksha, Suvi, Seymour, Keith, Robinson, Sarah, Hawkins, Helen, Bawa, Sadiq, Gallagher, Paul V, Reid, Alistair, Wood, Peter, Finch, JG, Finch, J Guy, Parmar, J, Stirland, E, Gardner-Thorpe, James, Al-Muhktar, Ahmed, Peterson, Mark, Majeed, Ali, Bajwa, Farrukh M, Martin, Jack, Choy, Alfred, Tsang, Andrew, Pore, Naresh, Andrew, David R, Al-Khyatt, Waleed, Bhandari, Christopher Taylor Santosh, Chambers, Adam, Subramanium, Dhivya, Toh, Simon KC, Carter, Nicholas C, Tate, Sophie, Pearce, Belinda, Wainwright, Denise, Mercer, Stuart J, Knight, Benjamin, Vijay, Vardhini, Alagaratnam, Swethan, Sinha, Sidhartha, Khan, Shahab, El-Hasani, Shamsi S, Hussain, Abdulzahra A, Bhattacharya, Vish, Kansal, Nisheeth, Fasih, Tani, Jackson, Claire, Siddiqui, Midhat N, Chishti, Imran A, Fordham, Imogen J, Siddiqui, Zohaib, Bausbacher, Harald, Geogloma, Ileana, Gurung, Kabita, Tsavellas, George, Basynat, Pradeep, Shrestha, Ashish Kiran, Basu, Sanjoy, Harilingam, Alok Chhabra Mohan, Rabie, Mohamed, Akhtar, Mansoor, Kumar, Pradeep, Jafferbhoy, Sadaf F, Hussain, Najam, Raza, Soulat, Haque, Manzarul, Alam, Imran, Aseem, Rabiya, Patel, Shakira, Asad, Mehek, Booth, Michael I, Ball, William R, Wood, Christopher PJ, Pinho-Gomes, Ana C, Kausar, Ambareen, Obeidallah, Moh'd Rami, Varghase, Joseph, Lodhia, Joshil, Bradley, Donal, Rengifo, Carla, Lindsay, David, Gopalswamy, Sivakumar, Finlay, Ian, Wardle, Stacy, Bullen, Naomi, Iftikhar, Syed Yusuf, Awan, Altaf, Ahmed, Javed, Leeder, Paul, Fusai, Guiseppe, Bond-Smith, Giles, Psica, Alicja, Puri, Yogesh, Hou, David, Noble, Fergus, Szentpali, Karoly, Broadhurst, Jack, Date, Ravindra, Hossack, Martin R, Goh, Yan Li, Turner, Paul, Shetty, Vinutha, Riera, Manel, Macano, Christina AW, Sukha, Anisha, Preston, Shaun R, Hoban, Jennifer R, Puntis, Daniel J, Williams, Sophie V, Krysztopik, Richard, Kynaston, James, Batt, Jeremy, Doe, Matthew, Goscimski, Andrzej, Jones, Gareth H, Hall, Claire, Carty, Nick, Ahmed, Jamil, Panteleimonitis, Sofoklis, Gunasekera, Rohan T, Sheel, Andrea RG, Lennon, Hannah, Hindley, Caroline, Reddy, Marcus, Kenny, Ross, Elkheir, Natalie, McGlone, Emma R, Rajaganeshan, Rajasundaram, Hancorn, Kate, Hargreaves, Anita, Prasad, Raj, Longbotham, David A, Vijayanand, Dhakshinamoorthy, Wijetunga, Imeshi, Ziprin, Paul, Nicolay, Christopher R, Yeldham, Geoffrey, Read, Edward, Gossage, James A, Rolph, Rachel C, Ebied, Husam, Phull, Manraj, Khan, Mohammad A, Popplewell, Matthew, Kyriakidis, Dimitrios, Hussain, Anwar, Henley, Natasha, Packer, Jessica R, Derbyshire, Laura, Porter, Jonathan, Appleton, Shaun, Farouk, Marwan, Basra, Melvinder, Jennings, Neil A, Ali, Shahda, Kanakala, Venkatesh, Ali, Haythem, Lane, Risha, Dickson-Lowe, Richard, Zarsadias, Prizzi, Mirza, Darius, Puig, Sonia, Al Amari, Khalid, Vijayan, Deepak, Sutcliffe, Robert, Marudanayagam, Ravi, Hamady, Zayed, Prasad, Abheesh R, Patel, Abhilasha, Durkin, Damien, Kaur, Parminder, Bowen, Laura, Byrne, James P, Pearson, Katherine L, Delisle, Theo G, Davies, James, Tomlinson, Mark A, Johnpulle, Michelle A, Slawinski, Corinna, Macdonald, Andrew, Nicholson, James, Newton, Katy, Mbuvi, James, Farooq, Ansar, Mothe, Bhavani Sidhartha, Zafrani, Zakhi, Brett, Daniel, Francombe, James, Barnes, James, Cheung, Melanie, Al-Bahrani, Ahmed Z, Preziosi, Giuseppe, Urbonas, Tomas, Alberts, Justin, Mallik, Mekhlola, Patel, Krashna, Segaran, Ashvina, Doulias, Triantafyllos, Sufi, Pratik A, Yao, Caroline, Pollock, Sarah, Manzelli, Antonio, Wajed, Saj, Kourkulos, Michail, Pezzuto, Roberto, Wadley, Martin, Hamilton, Emma, Jaunoo, Shameen, Padwick, Robert, Sayegh, Mazin, Newton, Richard C, Hebbar, Madhusoodhana, Farag, Sameh F, Spearman, John, Hamdan, Mohammed F, D'Costa, Conrad, Blane, Christine, Giles, Mathew, Peter, Mark B, Hirst, Natalie A, Hossain, Tanvir, El-Dhuwaib, Arslan Pannu Yesar, Morrison, Tamsin EM, Taylor, Greg W, Thompson, Ronald LE, McCune, Ken, Loughlin, Paula, Lawther, Roger, Byrnes, Colman K, Simpson, Duncan J, Mawhinney, Abi, Warren, Conor, McKay, Damian, McIlmunn, Colin, Martin, Serena, MacArtney, Matthew, Diamond, Tom, Davey, Phil, Jones, Claire, Clements, Joshua M, Digney, Ruairi, Chan, Wei Ming, McCain, Stephen, Gull, Sadaf, Janeczko, Adam, Dorrian, Emmet, Harris, Andrew, Dawson, Suzanne, Johnston, Dorothy, McAree, Barry, Ghareeb, Essam, Thomas, George, Connelly, Martin, McKenzie, Stephen, Cieplucha, Krzysztos, Spence, Gary, Campbell, William, Hooks, Gareth, Bradley, Neil, Hill, Arnold DK, Cassidy, John T, Boland, Michael, Burke, Paul, Nally, Deirdre M, Khogali, Elmoataz, Shabo, Wael, Iskandar, Edrin, McEntee, Gerry P, O'Neill, Maeve A, Peirce, Colin, Lyons, Emma M, O'Sullivan, Adrian W, Thakkar, Rohan, Carroll, Paul, Ivanovski, Ivan, Balfe, Paul, Lee, Matthew, Winter, Des C, Kelly, Michael E, Hoti, Emir, Maguire, Donal, Karunakaran, Priyadarssini, Geoghegan, Justin G, McDermott, Frank, Martin, Sean T, Cross, Keith S, Cooke, Fiachra, Zeeshan, Saquib, Murphy, James O, Mealy, Ken, Mohan, Helen M, Nedujchelyn, Yuwaraja, Ullah, Muhammad Fahad, Ahmed, Irfan, Giovinazzo, Francesco, Milburn, James, Prince, Sarah, Brooke, Eleanor, Buchan, Joanna, Khalil, Ahmed M, Vaughan, Elizabeth M, Ramage, Michael I, Aldridge, Roland C, Gibson, Simon, Nicholson, Gary A, Vass, David G, Grant, Alan J, Holroyd, David J, Jones, M Angharad, Sutton, Cherith MLR, O'Dwyer, Patrick, Nilsson, Frida, Weber, Beatrix, Williamson, Tracey K, Lalla, Kushik, Bryant, Alice, Carter, C Ross, Forrest, Craig R, Hunter, David I, Nassar, Ahmad H, Orizu, Mavis N, Knight, Katrina, Qandeel, Haitham, Suttie, Stuart, Belding, Rowena, McClarey, Andrew, Boyd, Alan T, Guthrie, Graeme JK, Lim, Pei J, Luhmann, Andreas, Watson, Angus JM, Richards, Colin H, Nicol, Laura, Madurska, Marta, Harrison, Ewen, Boyce, Kathryn M, Roebuck, Amanda, Ferguson, Graeme, Pati, Pradeep, Wilson, Michael SJ, Dalgaty, Faith, Fothergill, Laura, Driscoll, Peter J, Mozolowski, Kirsty L, Banwell, Victoria, Bennett, Stephen P, Rogers, Paul N, Skelly, Brendan L, Rutherford, Claire L, Mirza, Ahmed K, Lazim, Taha, Lim, Henry CC, Duke, Diana, Ahmed, Talat, Beasley, William D, Wilkinson, Marc D, Maharaj, Geta, Malcolm, Cathy, Brown, Timothy H, Al-Sarireh, Bilal, Shingler, Guy M, Mowbray, Nicholas, Radwan, Rami, Morcous, Paul, Wood, Simon, Kadhim, Abbas, Stewart, Duncan J, Baker, Andrew L, Tanner, Nicola, Shenoy, Hrishikesh, Hafiz, Shazia, De Marchi, Joshua A, Singh-Ranger, Deepak, Hisham, Elzanati, Ainley, Paul, O'Neill, Stephen, Terrace, John, Napetti, Sara, Hopwood, Benjamin, Rhys, Thomas, Kanavati, Osama, Coats, Maria, Aleksandrov, Danail, Kallaway, Charlotte, Yahya, Salama, Templeton, Alexa, Trotter, Martin, Lo, Christina, Dhillon, Ajit, Heywood, Nick, Aawsaj, Yousif, Hamdan, Alhafidz, Reece-Bolton, Obuobi, McGuigan, Andrew, Shahin, Yousef, Aymon, Luther, Ali Alison, Nicholson, James A, Rajendran, Ilayaraja, Boal, Matthew, Ritchie, Judith, Grp, CholeS Study, Collaborative, West Midlands Res, Segaran, A, and Collaborative, West Midlands Research

Subjects
medicine.medical_specialty, medicine.medical_treatment, 030230 surgery, Article, 03 medical and health sciences, 0302 clinical medicine, Case mix index, Laparoscopic, length of stay, male, middle aged, postoperative complications, Medicine, Cholecystectomy, Prospective cohort study, Grading (education), humans, Laparoscopic cholecystectomy, business.industry, General surgery, adult, cholecystectomy, difficulty grading, laparoscopic, operative difficulty, surgery, aged, cholecystectomy, laparoscopic, conversion to open surgery, female, multivariate analysis, prospective studies, ROC curve, Difficulty grading, Cohort, 030211 gastroenterology & hepatology, Surgery, business, Operative difficulty, Grading scale, Abdominal surgery
Abstract

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p p Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty.

Published
2018

11. JNK1 phosphorylation of SCG10 determines microtubule dynamics and axodendritic length

Author

Tararuk, Tatsiana, Ostman, Nina, Li, Wenrui, Bjorkblom, Benny, Padzik, Artur, Zdrojewska, Justyna, Hongisto, Vesa, Herdegen, Thomas, Konopka, Witold, Courtney, Michael J., and Coffey, Eleanor T.

Subjects
Microtubules -- Research, Morphogenesis -- Research, Biological sciences
Abstract

C-Jun N[H.sub.2]-terminal kinases (JNKs) are essential during brain development, when they regulate morphogenic changes involving cell movement and migration. In the adult, JNK determines neuronal cyto-architecture. To help uncover the molecular effectors for JNKs in these events, we affinity purified JNK-interacting proteins from brain. This revealed that the stathmin family microtubule-destabilizing proteins SCG10, SCLIP, RB3, and RB3' interact tightly with JNK. Furthermore, SCG10 is also phosphorylated by JNK in vivo on sites that regulate its microtubule depolymerizing activity, serines 62 and 73. SCG10-S73 phosphorylation is significantly decreased in JNK1-/- cortex, indicating that JNK1 phosphorylates SCG10 in developing forebrain. JNK phosphorylation of SCG10 determines axodendritic length in cerebrocortical cultures, and JNK site-phosphorylated SCG10 colocalizes with active JNK in embryonic brain regions undergoing neurite elongation and migration. We demonstrate that inhibition of cytoplasmic JNK and expression of SCG10-62A/73A both inhibited fluorescent tubulin recovery after photobleaching. These data suggest that JNK1 is responsible for regulation of SCG10 depolymerizing activity and neurite elongation during brain development.

Published
2006

19. Preoperative risk factors for conversion from laparoscopic to open cholecystectomy: a validated risk score derived from a prospective U.K. database of 8820 patients

Author

Sutcliffe, Robert P., primary, Hollyman, Marianne, additional, Hodson, James, additional, Bonney, Glenn, additional, Vohra, Ravi S., additional, Griffiths, Ewen A., additional, Fenwick, Stephen, additional, Elmasry, Mohamed, additional, Nunes, Quentin, additional, Kennedy, David, additional, Khan, Raja B., additional, Khan, Muhammad A.S., additional, Magee, Conor J., additional, Jones, Steven M., additional, Mason, Denise, additional, Parappally, Ciny P., additional, Mathur, Pawan, additional, Saunders, Michael, additional, Jamel, Sara, additional, Haque, Samer U.l., additional, Zafar, Sara, additional, Shiwani, Muhammad H., additional, Samuel, Nehemiah, additional, Dar, Farooq, additional, Jackson, Andrew, additional, Lovett, Bryony, additional, Dindyal, Shiva, additional, Winter, Hannah, additional, Rahman, Saquib, additional, Wheatley, Kevin, additional, Nieto, Tom, additional, Ayaani, Soofiyah, additional, Youssef, Haney, additional, Nijjar, Rajwinder S., additional, Watkin, Helen, additional, Naumann, David, additional, Emeshi, Sophie, additional, Sarmah, Piyush B., additional, Lee, Kathryn, additional, Joji, Nikita, additional, Heath, Jonathan, additional, Teasdale, Rebecca L., additional, Weerasinghe, Chamindri, additional, Needham, Paul J., additional, Welbourn, Hannah, additional, Forster, Luke, additional, Finch, David, additional, Blazeby, Jane M., additional, Robb, William, additional, McNair, Angus G.K., additional, Hrycaiczuk, Alex, additional, Charalabopoulos, Alexandros, additional, Kadirkamanathan, Sritharan, additional, Tang, Cheuk-Bong, additional, Jayanthi, Naga V.G., additional, Noor, Nigel, additional, Dobbins, Brian, additional, Cockbain, Andrew J., additional, Nilsen-Nunn, April, additional, de Siqueira, Jonathan, additional, Pellen, Mike, additional, Cowley, Jonathan B., additional, Ho, Wei-Min, additional, Miu, Victor, additional, White, Timothy J., additional, Hodgkins, Kathryn A., additional, Kinghorn, Alison, additional, Tutton, Matthew G., additional, Al-Abed, Yahya A., additional, Menzies, Donald, additional, Ahmad, Anwar, additional, Reed, Joanna, additional, Khan, Shabuddin, additional, Monk, David, additional, Vitone, Louis J., additional, Murtaza, Ghulam, additional, Joel, Abraham, additional, Brennan, Stephen, additional, Shier, David, additional, Zhang, Catherine, additional, Yoganathan, Thusidaran, additional, Robinson, Steven J., additional, McCallum, Iain J.D., additional, Jones, Michael J., additional, Elsayed, Mohammed, additional, Tuck, Liz, additional, Wayman, John, additional, Carney, Kate, additional, Aroori, Somaiah, additional, Hosie, Kenneth B., additional, Kimble, Adam, additional, Bunting, David M., additional, Fawole, Adeshina S., additional, Basheer, Mohammed, additional, Dave, Rajiv V., additional, Sarveswaran, Janahan, additional, Jones, Elinor, additional, Kendal, Chris, additional, Tilston, Michael P., additional, Gough, Martin, additional, Wallace, Tom, additional, Singh, Shailendra, additional, Downing, Justine, additional, Mockford, Katherine A., additional, Issa, Eyad, additional, Shah, Nayab, additional, Chauhan, Neal, additional, Wilson, Timothy R., additional, Forouzanfar, Amir, additional, Wild, Jonathan R.L., additional, Nofal, Emma, additional, Bunnell, Catherine, additional, Madbak, Khaliel, additional, Rao, Sudhindra T.V., additional, Devoto, Laurence, additional, Siddiqi, Najaf, additional, Khawaja, Zechan, additional, Hewes, James C., additional, Gould, Laura, additional, Chambers, Alice, additional, Rodriguez, Daniel U., additional, Sen, Gourab, additional, Robinson, Stuart, additional, Bartlett, Francis, additional, Rae, David M., additional, Stevenson, Thomas E.J., additional, Sarvananthan, Kas, additional, Dwerryhouse, Simon J., additional, Higgs, Simon M., additional, Old, Oliver J., additional, Hardy, Thomas J., additional, Shah, Reena, additional, Hornby, Steve T., additional, Keogh, Ken, additional, Frank, Lucinda, additional, Al-Akash, Musallam, additional, Upchurch, Emma A., additional, Frame, Richard J., additional, Hughes, Michael, additional, Jelley, Clare, additional, Weaver, Simon, additional, Roy, Sudipta, additional, Sillo, Toritseju O., additional, Galanopoulos, Giorgios, additional, Cuming, Tamzin, additional, Cunha, Pedro, additional, Tayeh, Salim, additional, Kaptanis, Sarantos, additional, Heshaishi, Mohamed, additional, Eisawi, Abdalla, additional, Abayomi, Michael, additional, Ngu, Wee S., additional, Fleming, Katie, additional, Bajwa, Dalvir S., additional, Chitre, Vivek, additional, Aryal, Kamal, additional, Ferris, Paul, additional, Silva, Michael, additional, Lammy, Simon, additional, Mohamed, Sarah, additional, Khawaja, Amir, additional, Hussain, Adnan, additional, Ghazanfar, Mudassar A., additional, Bellini, Maria I., additional, Ebdewi, Hamdi, additional, Elshaer, Mohamed, additional, Gravante, Gianpiero, additional, Drake, Benjamin, additional, Ogedegbe, Arikoge, additional, Mukherjee, Dipankar, additional, Arhi, Chanpreet, additional, Giwa, Lola, additional, Iqbal, Nusrat, additional, Watson, Nicholas F., additional, Aggarwal, Smeer K., additional, Orchard, Philippa, additional, Villatoro, Eduardo, additional, Willson, Peter D., additional, Mok, Kam W.J., additional, Woodman, Thomas, additional, Deguara, Jean, additional, Garcea, Giuseppe, additional, Babu, Benoy I., additional, Dennison, Alistair R., additional, Malde, Deep, additional, Lloyd, David, additional, Slavin, John P., additional, Jones, Robert P., additional, Ballance, Laura, additional, Gerakopoulos, Stratos, additional, Jambulingam, Periyathambi, additional, Mansour, Sami, additional, Sakai, Naomi, additional, Acharya, Vikas, additional, Sadat, Mohammed M., additional, Karim, Lawen, additional, Larkin, David, additional, Amin, Khalid, additional, Khan, Amarah, additional, Law, Jennifer, additional, Jamdar, Saurabh, additional, Smith, Stella R., additional, Sampat, Keerthika, additional, O'shea, Kathryn M., additional, Manu, Mangta, additional, Asprou, Fotini M., additional, Malik, Nabeela S., additional, Chang, Jessica, additional, Johnstone, Marianne, additional, Lewis, Michael, additional, Roberts, Geoffrey P., additional, Karavadra, Babu, additional, Photi, Evangelos, additional, Hewes, James, additional, Rodriguez, Dan, additional, O'Reilly, Derek A., additional, Rate, Anthony J., additional, Sekhar, Hema, additional, Henderson, Lucy T., additional, Starmer, Benjamin Z., additional, Coe, Peter O., additional, Tolofari, Sotonye, additional, Barrie, Jenifer, additional, Bashir, Gareth, additional, Sloane, Jake, additional, Madanipour, Suroosh, additional, Halkias, Constantine, additional, Trevatt, Alexander E.J., additional, Borowski, David W., additional, Hornsby, Jane, additional, Courtney, Michael J., additional, Virupaksha, Suvi, additional, Seymour, Keith, additional, Robinson, Sarah, additional, Hawkins, Helen, additional, Bawa, Sadiq, additional, Gallagher, Paul V., additional, Reid, Alistair, additional, Wood, Peter, additional, Finch, Jonathan G., additional, Finch, J.Guy, additional, Parmar, Jitesh, additional, Stirland, Euan, additional, Gardner-Thorpe, James, additional, Al-Muhktar, Ahmed, additional, Peterson, Mark, additional, Majeed, Ali, additional, Bajwa, Farrukh M., additional, Martin, Jack, additional, Choy, Alfred, additional, Tsang, Andrew, additional, Pore, Naresh, additional, Andrew, David R., additional, Al-Khyatt, Waleed, additional, Santosh Bhandari, Christopher Taylor, additional, Chambers, Adam, additional, Subramanium, Dhivya, additional, Toh, Simon K.C., additional, Carter, Nicholas C., additional, Mercer, Stuart J., additional, Knight, Benjamin, additional, Vijay, Vardhini, additional, Alagaratnam, Swethan, additional, Sinha, Sidhartha, additional, Khan, Shahab, additional, El-Hasani, Shamsi S., additional, Hussain, Abdulzahra A., additional, Bhattacharya, Vish, additional, Kansal, Nisheeth, additional, Fasih, Tani, additional, Jackson, Claire, additional, Siddiqui, Midhat N., additional, Chishti, Imran A., additional, Fordham, Imogen J., additional, Siddiqui, Zohaib, additional, Bausbacher, Harald, additional, Geogloma, Ileana, additional, Gurung, Kabita, additional, Tsavellas, George, additional, Basynat, Pradeep, additional, Shrestha, Ashish K., additional, Basu, Sanjoy, additional, Chhabra, Alok, additional, Harilingam, Mohan, additional, Rabie, Mohamed, additional, Akhtar, Mansoor, additional, Kumar, Pradeep, additional, Jafferbhoy, Sadaf F., additional, Hussain, Najam, additional, Raza, Soulat, additional, Haque, Manzarul, additional, Alam, Imran, additional, Aseem, Rabiya, additional, Patel, Shakira, additional, Asad, Mehek, additional, Booth, Michael I., additional, Ball, William R., additional, Wood, Christopher P.J., additional, Pinho-Gomes, Ana C., additional, Kausar, Ambareen, additional, Obeidallah, Mohammed, additional, Varghase, Joseph, additional, Lodhia, Joshil, additional, Bradley, Donal, additional, Rengifo, Carla, additional, Lindsay, David, additional, Gopalswamy, Sivakumar, additional, Finlay, Ian, additional, Wardle, Stacy, additional, Bullen, Naomi, additional, Iftikhar, Syed Y., additional, Awan, Altaf, additional, Ahmed, Javed, additional, Leeder, Paul, additional, Fusai, Guiseppe, additional, Bond-Smith, Giles, additional, Psica, Alicja, additional, Puri, Yogesh, additional, Hou, David, additional, Noble, Fergus, additional, Szentpali, Karoly, additional, Broadhurst, Jack, additional, Date, Ravindra, additional, Hossack, Martin R., additional, Goh, Yan L., additional, Turner, Paul, additional, Shetty, Vinutha, additional, Riera, Manel, additional, Macano, Christina A.W., additional, Sukha, Anisha, additional, Preston, Shaun R., additional, Hoban, Jennifer R., additional, Puntis, Daniel J., additional, Williams, Sophie V., additional, Krysztopik, Richard, additional, Kynaston, James, additional, Batt, Jeremy, additional, Doe, Matthew, additional, Goscimski, Andrzej, additional, Jones, Gareth H., additional, Hall, Claire, additional, Carty, Nick, additional, Ahmed, Jamil, additional, Panteleimonitis, Sofoklis, additional, Gunasekera, Rohan T., additional, Sheel, Andrea R.G., additional, Lennon, Hannah, additional, Hindley, Caroline, additional, Reddy, Marcus, additional, Kenny, Ross, additional, Elkheir, Natalie, additional, McGlone, Emma R., additional, Rajaganeshan, Rajasundaram, additional, Hancorn, Kate, additional, Hargreaves, Anita, additional, Prasad, Raj, additional, Longbotham, David A., additional, Vijayanand, Dhakshinamoorthy, additional, Wijetunga, Imeshi, additional, Ziprin, Paul, additional, Nicolay, Christopher R., additional, Yeldham, Geoffrey, additional, Read, Edward, additional, Gossage, James A., additional, Rolph, Rachel C., additional, Ebied, Husam, additional, Phull, Manraj, additional, Khan, Mohammad A., additional, Popplewell, Matthew, additional, Kyriakidis, Dimitrios, additional, Hussain, Anwar, additional, Henley, Natasha, additional, Packer, Jessica R., additional, Derbyshire, Laura, additional, Porter, Jonathan, additional, Appleton, Shaun, additional, Farouk, Marwan, additional, Basra, Melvinder, additional, Jennings, Neil A., additional, Ali, Shahda, additional, Kanakala, Venkatesh, additional, Ali, Haythem, additional, Lane, Risha, additional, Dickson-Lowe, Richard, additional, Zarsadias, Prizzi, additional, Mirza, Darius, additional, Puig, Sonia, additional, Al Amari, Khalid, additional, Vijayan, Deepak, additional, Sutcliffe, Robert, additional, Marudanayagam, Ravi, additional, Hamady, Zayed, additional, Prasad, Abheesh R., additional, Patel, Abhilasha, additional, Durkin, Damien, additional, Kaur, Parminder, additional, Bowen, Laura, additional, Byrne, James P., additional, Pearson, Katherine L., additional, Delisle, Theo G., additional, Davies, James, additional, Tomlinson, Mark A., additional, Johnpulle, Michelle A., additional, Slawinski, Corinna, additional, Macdonald, Andrew, additional, Nicholson, James, additional, Newton, Katy, additional, Mbuvi, James, additional, Farooq, Ansar, additional, Mothe, Bhavani S., additional, Zafrani, Zakhi, additional, Brett, Daniel, additional, Francombe, James, additional, Spreadborough, Philip, additional, Barnes, James, additional, Cheung, Melanie, additional, Al-Bahrani, Ahmed Z., additional, Preziosi, Giuseppe, additional, Urbonas, Tomas, additional, Alberts, Justin, additional, Mallik, Mekhlola, additional, Patel, Krashna, additional, Segaran, Ashvina, additional, Doulias, Triantafyllos, additional, Sufi, Pratik A., additional, Yao, Caroline, additional, Pollock, Sarah, additional, Manzelli, Antonio, additional, Wajed, Saj, additional, Kourkulos, Michail, additional, Pezzuto, Roberto, additional, Wadley, Martin, additional, Hamilton, Emma, additional, Jaunoo, Shameen, additional, Padwick, Robert, additional, Sayegh, Mazin, additional, Newton, Richard C., additional, Hebbar, Madhusoodhana, additional, Farag, Sameh F., additional, Hebbar, Madhu, additional, Spearman, John, additional, Hamdan, Mohammed F., additional, D'Costa, Conrad, additional, Blane, Christine, additional, Giles, Mathew, additional, Peter, Mark B., additional, Hirst, Natalie A., additional, Hossain, Tanvir, additional, Pannu, Arslan, additional, El-Dhuwaib, Yesar, additional, Morrison, Tamsin E.M., additional, Taylor, Greg W., additional, Thompson, Ronald L.E., additional, McCune, Ken, additional, Loughlin, Paula, additional, Lawther, Roger, additional, Byrnes, Colman K., additional, Simpson, Duncan J., additional, Mawhinney, Abi, additional, Warren, Conor, additional, McKay, Damian, additional, McIlmunn, Colin, additional, Martin, Serena, additional, MacArtney, Matthew, additional, Diamond, Tom, additional, Davey, Phil, additional, Jones, Claire, additional, Clements, Joshua M., additional, Digney, Ruairi, additional, Chan, Wei M., additional, McCain, Stephen, additional, Gull, Sadaf, additional, Janeczko, Adam, additional, Dorrian, Emmet, additional, Harris, Andrew, additional, Dawson, Suzanne, additional, Johnston, Dorothy, additional, McAree, Barry, additional, Ghareeb, Essam, additional, Thomas, George, additional, Connelly, Martin, additional, McKenzie, Stephen, additional, Cieplucha, Krzysztos, additional, Spence, Gary, additional, Campbell, William, additional, Hooks, Gareth, additional, Bradley, Neil, additional, Hill, Arnold D.K., additional, Cassidy, John T., additional, Boland, Michael, additional, Burke, Paul, additional, Nally, Deirdre M., additional, Khogali, Elmoataz, additional, Shabo, Wael, additional, Iskandar, Edrin, additional, McEntee, Gerry P., additional, O'Neill, Maeve A., additional, Peirce, Colin, additional, Lyons, Emma M., additional, O'Sullivan, Adrian W., additional, Thakkar, Rohan, additional, Carroll, Paul, additional, Ivanovski, Ivan, additional, Balfe, Paul, additional, Lee, Matthew, additional, Winter, Des C., additional, Kelly, Michael E., additional, Hoti, Emir, additional, Maguire, Donal, additional, Karunakaran, Priyadarssini, additional, Geoghegan, Justin G., additional, Martin, Sean T., additional, Cross, Keith S., additional, Cooke, Fiachra, additional, Zeeshan, Saquib, additional, Murphy, James O., additional, Mealy, Ken, additional, Mohan, Helen M., additional, Nedujchelyn, Yuwaraja, additional, Ullah, Muhammad F., additional, Ahmed, Irfan, additional, Giovinazzo, Francesco, additional, Milburn, James, additional, Prince, Sarah, additional, Brooke, Eleanor, additional, Buchan, Joanna, additional, Khalil, Ahmed M., additional, Vaughan, Elizabeth M., additional, Ramage, Michael I., additional, Aldridge, Roland C., additional, Gibson, Simon, additional, Nicholson, Gary A., additional, Vass, David G., additional, Grant, Alan J., additional, Holroyd, David J., additional, Jones, Angharad, additional, Sutton, Cherith M.L.R., additional, O'Dwyer, Patrick, additional, Nilsson, Frida, additional, Weber, Beatrix, additional, Williamson, Tracey K., additional, Lalla, Kushik, additional, Bryant, Alice, additional, Carter, Ross, additional, Forrest, Craig R., additional, Hunter, David I., additional, Nassar, Ahmad H., additional, Orizu, Mavis N., additional, Knight, Katrina, additional, Qandeel, Haitham, additional, Suttie, Stuart, additional, Belding, Rowena, additional, McClarey, Andrew, additional, Boyd, Alan T., additional, Guthrie, Graeme J.K., additional, Lim, Pei J., additional, Luhmann, Andreas, additional, Watson, Angus J.M., additional, Richards, Colin H., additional, Nicol, Laura, additional, Madurska, Marta, additional, Harrison, Ewen, additional, Boyce, Kathryn M., additional, Roebuck, Amanda, additional, Ferguson, Graeme, additional, Pati, Pradeep, additional, Wilson, Michael S.J., additional, Dalgaty, Faith, additional, Fothergill, Laura, additional, Driscoll, Peter J., additional, Mozolowski, Kirsty L., additional, Banwell, Victoria, additional, Bennett, Stephen P., additional, Rogers, Paul N., additional, Skelly, Brendan L., additional, Rutherford, Claire L., additional, Mirza, Ahmed K., additional, Lazim, Taha, additional, Lim, Henry C.C., additional, Duke, Diana, additional, Ahmed, Talat, additional, Beasley, William D., additional, Wilkinson, Marc D., additional, Maharaj, Geta, additional, Malcolm, Cathy, additional, Brown, Timothy H., additional, Shingler, Guy M., additional, Mowbray, Nicholas, additional, Radwan, Rami, additional, Morcous, Paul, additional, Wood, Simon, additional, Kadhim, Abbas, additional, Stewart, Duncan J., additional, Baker, Andrew L., additional, Tanner, Nicola, additional, and Shenoy, Hrishikesh, additional

Published
2016
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20. ZLc002, a putative small-molecule inhibitor of nNOS interaction with NOSI AP, suppresses inflammatory nociception and chemotherapy-induced neuropathic pain and synergizes with paclitaxel to reduce tumor cell viability.

Author

Wan-Hung Lee, Hohmann, Andrea G., Carey, Lawrence M., Zhili Xu, Lai, Yvonne Y., Li-Li Li, and Courtney, Michael J.

Subjects
METHYL aspartate receptors, PROTEIN-protein interactions, NITRIC oxide, POSTSYNAPTIC density protein, DRUG development
Abstract

Elevated N-methyl-D-aspartate receptor activity contributes to central sensitization. Our laboratories and others recently reported that disrupting protein-protein interactions downstream of N-methyl-D-aspartate receptors suppresses pain. Specifically, disrupting binding between the enzyme neuronal nitric oxide synthase and either its upstream (postsynaptic density 95 kDa, PSD95) or downstream (e.g. nitric oxide synthase 1 adaptor protein, NOS1AP) protein partners suppressed inflammatory and/or neuropathic pain. However, the lack of a small-molecule neuronal nitric oxide synthase-NOS1AP inhibitor has hindered efforts to validate the therapeutic utility of disrupting the neuronal nitric oxide synthase-NOS1AP interface as an analgesic strategy. We, therefore, evaluated the ability of a putative small-molecule neuronal nitric oxide synthase-NOS1AP inhibitor ZLc002 to disrupt binding between neuronal nitric oxide synthase and NOS1AP using ex vivo, in vitro, and purified recombinant systems and asked whether ZLc002 would suppress inflammatory and neuropathic pain in vivo. In vitro, ZLc002 reduced co-immunoprecipitation of full-length NOS1AP and neuronal nitric oxide synthase in cultured neurons and in HEK293T cells co-expressing full-length neuronal nitric oxide synthase and NOS1AP. However, using a cellfree biochemical binding assay, ZLc002 failed to disrupt the in vitro binding between His-neuronal nitric oxide synthase1-299 and glutathione S-transferase-NOS1AP400-506, protein sequences containing the required binding domains for this protein-protein interaction, suggesting an indirect mode of action in intact cells. ZLc002 (4-10mg/kg i.p.) suppressed formalinevoked inflammatory pain in rats and reduced Fos protein-like immunoreactivity in the lumbar spinal dorsal horn. ZLc002 also suppressed mechanical and cold allodynia in a mouse model of paclitaxel-induced neuropathic pain. Anti-allodynic efficacy was sustained for at least four days of once daily repeated dosing. ZLc002 also synergized with paclitaxel when administered in combination to reduce breast (4T1) or ovarian (HeyA8) tumor cell line viability but did not alter tumor cell viability without paclitaxel. Our results verify that ZLc002 disrupts neuronal nitric oxide synthase-NOS1AP interaction in intact cells and demonstrate, for the first time, that systemic administration of a putative small-molecule inhibitor of neuronal nitric oxide synthase-NOS1AP suppresses inflammatory and neuropathic pain. [ABSTRACT FROM AUTHOR]

Published
2018
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21. Unexpected Heterodivalent Recruitment of NOS1AP to nNOS Reveals Multiple Sites for Pharmacological Intervention in Neuronal Disease Models

Author

Li, Lili, De Mera, Raquel M. Melero-Fernandez, Chen, Jia, Ba, Wei, Kasri, Nael Nadif, Zhang, Mingjie, Courtney, Michael J., Li, Lili, De Mera, Raquel M. Melero-Fernandez, Chen, Jia, Ba, Wei, Kasri, Nael Nadif, Zhang, Mingjie, and Courtney, Michael J.

Abstract

The protein NOS1AP/CAPON mediates signaling from a protein complex of NMDA receptor, PSD95 and nNOS. The only stroke trial for neuroprotectants that showed benefit to patients targeted this ternary complex. NOS1AP/nNOS interaction regulates small GTPases, iron transport, p38MAPK-linked excitotoxicity, and anxiety. Moreover, the nos1ap gene is linked to disorders from schizophrenia, post-traumatic stress disorder, and autism to cardiovascular disorders and breast cancer. Understanding protein interactions required for NOS1AP function, therefore, has broad implications for numerous diseases. Here we show that the interaction of NOS1AP with nNOS differs radically from the classical PDZ docking assumed to be responsible. The NOS1AP PDZ motif does not bind nNOS as measured by multiple methods. In contrast, full-length NOS1AP forms an unusually stable interaction with nNOS. We mapped the discrepancy between full-length and C-terminal PDZ motif to a novel internal region we call the ExF motif. The C-terminal PDZ motif, although neither sufficient nor necessary for binding, nevertheless promotes the stability of the complex. It therefore potentially affects signal transduction and suggests that functional interaction of nNOS with NOS1AP might be targetable at two distinct sites. We demonstrate that excitotoxic pathways can be regulated, in cortical neuron and organotypic hippocampal slice cultures from rat, either by the previously described PDZ ligand TAT-GESV or by the ExF motif-bearing region of NOS1AP, even when lacking the critical PDZ residues as long as the ExF motif is intact and not mutated. This previously unrecognized heterodivalent interaction of nNOS with NOS1AP may therefore provide distinct opportunities for pharmacological intervention in NOS1AP-dependent signaling and excitotoxicity.

Published
2015

25. Phosphorylation of SCG10/stathmin-2 determines multipolar stage exit and neuronal migration rate

Author

Westerlund, Nina, Zdrojewska, Justyna, Padzik, Artur, Komulainen, Emilia, Björkblom, Benny, Rannikko, Emmy, Tararuk, Tanya, Garcia-Frigola, Cristina, Sandholm, Jouko, Nguyen, Laurent, Kallunki, Tuula, Courtney, Michael J, Coffey, Eleanor T, Westerlund, Nina, Zdrojewska, Justyna, Padzik, Artur, Komulainen, Emilia, Björkblom, Benny, Rannikko, Emmy, Tararuk, Tanya, Garcia-Frigola, Cristina, Sandholm, Jouko, Nguyen, Laurent, Kallunki, Tuula, Courtney, Michael J, and Coffey, Eleanor T

Abstract

Cell migration is the consequence of the sum of positive and negative regulatory mechanisms. Although appropriate migration of neurons is a principal feature of brain development, the negative regulatory mechanisms remain obscure. We found that JNK1 was highly active in developing cortex and that selective inhibition of JNK in the cytoplasm markedly increased both the frequency of exit from the multipolar stage and radial migration rate and ultimately led to an ill-defined cellular organization. Moreover, regulation of multipolar-stage exit and radial migration in Jnk1−/− (also known as Mapk8) mice, resulted from consequential changes in phosphorylation of the microtubule regulator SCG10 (also called stathmin-2). Expression of an SCG10 mutant that mimics the JNK1-phosphorylated form restored normal migration in the brains of Jnk1−/− mouse embryos. These findings indicate that the phosphorylation of SCG10 by JNK1 is a fundamental mechanism that governs the transition from the multipolar stage and the rate of neuronal cell movement during cortical development.

Published
2011
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26. Concurrent protective and destructive signaling of JNK2 in neuroblastoma cells

Author

Waetzig, Vicki, Wacker, Ute, Haeusgen, Wiebke, Björkblom, Benny, Courtney, Michael J., Coffey, Eleanor T., Herdegen, Thomas, Waetzig, Vicki, Wacker, Ute, Haeusgen, Wiebke, Björkblom, Benny, Courtney, Michael J., Coffey, Eleanor T., and Herdegen, Thomas

Abstract

Investigation of the c-Jun N-terminal kinases (JNKs) has mainly focused on their response to stress and their pro-apoptotic effects. In this regard, JNKs are crucial mediators of chemotherapy-induced killing of tumor cells. Importantly, however, JNKs also have physiological functions in cancer involving cell cycle regulation or oncogenesis. Hypothetically, the composition of JNK signalosomes determines the signaling outcome which, in turn, implies a multitude of different, sometimes opposing and interfering functions. In the present study, the well-characterized human neuroblastoma cell line SH-SY5Y served as a model system to separate physiological and pro-apoptotic JNK actions in the response to the cytoskeleton-interfering substances colchicine, cytochalasin D and taxol. Basically, JNKs mediated both cell death and proliferation. Using the chemical JNK inhibitor SP600125 as well as compartment-specific JNK-inhibiting constructs and dominant-negative isoform mutants, we show that the nuclear subgroup of JNK2 is the dominant effector in colchicine- and taxol-induced apoptosis, while cell cycle promotion is mediated by both cytoplasmic and nuclear JNK2. In contrast, cytochalasin D-triggered apoptosis is independent of JNK signaling. Interestingly, the data of the present study demonstrate for the first time that both cell protective (cell cycle progression) and destructive mechanisms (apoptosis) are simultaneously controlled by a single JNK isoform in the same cell system even under the influence of one stimulus. This has implications for the therapeutic application of JNK inhibitors and cytoskeleton-interfering substances in oncologic disorders.

Published
2009
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27. Constitutively Active Cytoplasmic c-Jun N-Terminal Kinase 1 Is a Dominant Regulator of Dendritic Architecture: Role of Microtubule-Associated Protein 2 as an Effector

Author

Björkblom, Benny, Östman, Nina, Hongisto, Vesa, Komarovski, Vladislav, Filén, Jan-Jonas, Nyman, Tuula A., Kallunki, Tuula, Courtney, Michael J., Coffey, Eleanor T., Björkblom, Benny, Östman, Nina, Hongisto, Vesa, Komarovski, Vladislav, Filén, Jan-Jonas, Nyman, Tuula A., Kallunki, Tuula, Courtney, Michael J., and Coffey, Eleanor T.

Abstract

Normal functioning of the nervous system requires precise regulation of dendritic shape and synaptic connectivity. Here, we report a severe impairment of dendritic structures in the cerebellum and motor cortex of c-Jun N-terminal kinase 1 (JNK1)-deficient mice. Using an unbiased screen for candidate mediators, we identify the dendrite-specific high-molecular-weight microtubule-associated protein 2 (MAP2) as a JNK substrate in the brain. We subsequently show that MAP2 is phosphorylated by JNK in intact cells and that MAP2 proline-rich domain phosphorylation is decreased in JNK1-/- brain. We developed compartment-targeted JNK inhibitors to define whether a functional relationship exists between the physiologically active, cytosolic pool of JNK and dendritic architecture. Using these, we demonstrate that cytosolic, but not nuclear, JNK determines dendritic length and arbor complexity in cultured neurons. Moreover, we confirm that MAP2-dependent process elongation is enhanced after activation of JNK. Using JNK1-/- neurons, we reveal a dominant role for JNK1 over ERK in regulating dendritic arborization, whereas ERK only regulates dendrite shape under conditions in which JNK activity is low (JNK1-/- neurons). These results reveal a novel antagonism between JNK and ERK, potentially providing a mechanism for fine-tuning the dendritic arbor. Together, these data suggest that JNK phosphorylation of MAP2 plays an important role in defining dendritic architecture in the brain.

Published
2005
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28. c-Jun N-Terminal Kinase Phosphorylation of MARCKSL1 Determines Actin Stability and Migration in Neurons and in Cancer Cells

Author

Björkblom, Benny, primary, Padzik, Artur, additional, Mohammad, Hasan, additional, Westerlund, Nina, additional, Komulainen, Emilia, additional, Hollos, Patrik, additional, Parviainen, Lotta, additional, Papageorgiou, Anastassios C., additional, Iljin, Kristiina, additional, Kallioniemi, Olli, additional, Kallajoki, Markku, additional, Courtney, Michael J., additional, Mågård, Mats, additional, James, Peter, additional, and Coffey, Eleanor T., additional

Published
2012
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30. Tasks, talk and teaching : task-based language learning and the negotiation of meaning in oral interaction

Author

Courtney, Michael J. and Courtney, Michael J.

Abstract

Undergraduates in Hong Kong universities are taught in an English-medium environment but come from an educational background where classroom opportunities to practise speaking in English are limited. Stimulating and motivating oral materials are an essential tool to help students to practise in the classroom in meaningful ways. Interactive peer-group oral tasks not only provide a practical basis for oral development within a language syllabus, but they can also promote the essential skill of critical thinking. A theoretical justification for their use can be derived from second language acquisition research but the best justification is from learners themselves. This report explores the key theoretical issues surrounding the use of such pedagogy. The main issue is so-called “negotiated meaning”, specifically in relation to such classroom tasks. However, exploration of this theoretical area inevitably takes us into a general discussion of the role of interaction in discourse analysis – particularly in relation to developments in the fairly recent field of conversation analysis. Previous studies have made strong claims in relation to the potential of interactive communication tasks for language acquisition. However, researchers have based their claims on small samples and limited descriptions of task design and task performance. The present study used a much larger intact sample and a more detailed and inclusive task taxonomy. The first part of the investigation establishes a method for classifying the design of commonly used oral interactive tasks (the input). A method is developed to quantify the performance (the output) of such tasks statistically. Finally, the central performance activity of negotiated meaning is discussed in some detail in relation to task participant interaction and the theoretical question of language acquisition. The investigation concludes that statistically significant links between input and output were evident, thereby offering a principle

Published
2001

37. Voltage gated calcium channels potentiate muscarinic receptor-mediated calcium responses in SH-SY5Y human neuroblastoma cells

Author

Åkerman, Karl E. O., Shariatmadari, Ramin, Courtney, Michael J., Kukkonen, Jyrki P., Åkerman, Karl E. O., Shariatmadari, Ramin, Courtney, Michael J., and Kukkonen, Jyrki P.

Abstract

Muscarinic receptor-mediated Ca2+ elevations were investigated using the fura-2 method and image analysis. Typical responses consisted of an initial fast and transient phase followed by a sustained phase. Removal of external Ca2+ did not affect the magnitude of the initial phase of the signal whereas the sustained phase was abolished. Hence they may mainly consist of a release from intracellular stores and an influx, respectively. Depolarization of the cells with 30 mM KCl in the presence of external Ca2+ caused a small elevation of [Ca2+]i. In these conditions a considerable potentiation of the fast phase of muscarinic Ca2+ response was seen. The potentiation was dependent on the extracellular Ca2+ as it was abolished in the presence of antagonists of voltage-gated Ca2+ channels or by removal of external Ca2+ prior to KCl. Removal of external Ca2+ after the KCl-induced increase in [Ca2+]i partially inhibited the potentiation. If Ca2+ was readded together with the muscarinic stimulation a maximum potentiation was seen. The results suggest that the muscarinic response is potentiated by a Ca2+-mediated priming of both a fast and transient receptor associated Ca2+ influx pathway and release from the intracellular stores.

Published
1997
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38. Peer group discourse : description and causality

Author

Courtney, Michael J., Wong, Man-Yu, Courtney, Michael J., and Wong, Man-Yu

Abstract

There is little general agreement amongst language teachers about the value of getting students to talk to other students in the language class, apart from the assumption that getting students to speak is important in the same way that practice of any set of skills is intuitively regarded as necessary to reinforce and automatise those skills. Indeed, there are many who see such interlanguage exchanges as potentially harmful in terms of the manipulation of 'deviant' linguistic forms which it appears to encourage (Prabhu 1987). Pedagogic and evaluative tasks designed for oral practice and evaluation range from elaborate simulations, which might involve a whole class over an entire course, to the simpler discrete information-gap and jigsaw types. A common element in the design of such tasks is that they are intended to be performed by the learners themselves, with the teacher as facilitator rather than controller. The resulting performances from this type of peer-group communication task have already been the focus of a considerable amount of research as well as attracting the attention of materials writers. Current interest in task-based approaches to oral practice, self-access methodology and other more learner-centred approaches, have all directly and indirectly promoted the use of language activities which can be managed by the learner without teacher intervention. Other more practical considerations, such as large class sizes and the increasing realisation amongst teaching staff that oral practice in such environments cannot be given the focus it urgently requires, have meant that an increasing responsibility has been placed upon learners themselves.

Published
1997

40. Coupling of astroglial alpha 2-adrenoreceptors to second messenger pathways

Author

Enkvist, M. O. Kristian, Hamalainen, Heli, Jansson, Christian C., Kukkonen, Jyrki P., Hautala, Rasmus, Courtney, Michael J., Akerman, Karl E. O., Enkvist, M. O. Kristian, Hamalainen, Heli, Jansson, Christian C., Kukkonen, Jyrki P., Hautala, Rasmus, Courtney, Michael J., and Akerman, Karl E. O.

Published
1996

43. The nNOS-p38MAPK Pathway Is Mediated by NOS1AP during Neuronal Death.

Author

Li, Li-Li, Ginet, Vanessa, Xiaonan Liu, Vergun, Olga, Tuittila, Minna, Mathieu, Marc, Bonny, Christophe, Puyal, Julien, Truttmann, Anita C., and Courtney, Michael J.

Subjects
NITRIC-oxide synthases, CELL death, CELL-mediated cytotoxicity, DIABETES complications, STIMULUS & response (Biology), CELLULAR signal transduction, MITOGEN-activated protein kinases
Abstract

Neuronal nitric oxide synthase (nNOS) and p38MAPK are strongly implicated in excitotoxicity, a mechanism common to many neurodegenerative conditions, but the intermediary mechanism is unclear. NOS1AP is encoded by a gene recently associated with sudden cardiac death, diabetes-associated complications, and schizophrenia (Arking et al., 2006; Becker et al., 2008; Brzustowicz, 2008; Lehtinen et al, 2008). Here we find it interacts with p38MAPK-activating kinase MKK3. Excitotoxic stimulus induces recruitment of NOS1AP to nNOS in rat cortical neuron culture. Excitotoxic activation of p38MAPK and subsequent neuronal death are reduced by competing with the nNOS:NOSl AP interaction and by knockdown with NOSlAP-targeting siRNAs. We designed a cell-permeable peptide that competes for the unique PDZ domain of nNOS that interacts with NOS1 AP. This peptide inhibits NMDA-induced recruitment of NOS1 AP to nNOS and in vivo in rat, doubles surviving tissue in a severe model of neonatal hypoxia-ischemia, a major cause of neonatal death and pediatric disability. The highly unusual sequence specificity of the nNOS:NOSlAP interaction and involvement in excitotoxic signaling may provide future opportunities for generation of neuroprotectants with high specificity. [ABSTRACT FROM AUTHOR]

Published
2013
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44. Calpains Are Downstream Effectors of bax-Dependent Excitotoxic Apoptosis.

Author

D'Orsi, Beatrice, Bonner, Helena, Tuffy, Liam P., Düssmann, Heiko, Woods, Ina, Courtney, Michael J., Ward, Manus W., and Prehn, Jochen H. M.

Subjects
CALPAIN, GLUTAMATE receptors, APOPTOSIS, CALCIUM channels, METHYL aspartate receptors, MITOCHONDRIAL membranes, FLUORESCENCE microscopy
Abstract

Excitotoxicity resulting from excessive Ca2+ influx through glutamate receptors contributes to neuronal injury after stroke, trauma, and seizures. Increased cytosolic Ca2+ levels activate a family of calcium-dependent proteases with papain-like activity, the calpains. Here we investigated the role of calpain activation during NMDA-induced excitotoxic injury in embryonic (E16 -E18) murine cortical neurons that (1) underwent excitotoxic necrosis, characterized by immediate deregulation of Ca2+ homeostasis, a persistent depolarization of mitochondrial membrane potential (?Ψm), and insensitivity to bax-gene deletion, (2) underwent excitotoxic apoptosis, characterized by recovery of NMDA-induced cytosolic Ca2+ increases, sensitivity to bax gene deletion, and delayed ?Ψm depolarization and Ca2+ deregulation, or (3) that were tolerant to excitotoxic injury. Interestingly, treatment with the calpain inhibitor calpeptin, overexpression of the endogenous calpain inhibitor calpastatin, or gene silencing of calpain protected neurons against excitotoxic apoptosis but did not influence excitotoxic necrosis. Calpeptin failed to exert a protective effect in bax-deficient neurons but protected bid-deficient neurons similarly to wild-type cells. To identify when calpains became activated during excitotoxic apoptosis, we monitored calpain activation dynamics by time-lapse fluorescence microscopy using a calpain-sensitive Förster resonance energy transfer probe. We observed a delayed calpain activation that occurred downstream of mitochondrial engagement and directly preceded neuronal death. In contrast,we could not detect significant calpain activity during excitotoxic necrosis or in neurons that were tolerant to excitotoxic injury. Oxygen/ glucose deprivation-induced injury in organotypic hippocampal slice cultures confirmed that calpains were specifically activated during bax-dependent apoptosis and in this setting function as downstream cell-death executioners. [ABSTRACT FROM AUTHOR]

Published
2012
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45. Fellowships in general practice in the St Thomas' district.

Author

Courtney, Michael J., McNell, David C., and Watson, Christopher J.

Subjects
*MEDICAL fellowships, *HOSPITALS
Abstract

Examines fellowships in general practice at the Saint Thomas Hospital in London, England. Types of fellowships in the facility; Purpose and aim of the fellowships; Benefits of the fellowships to general practitioners.

Published
1986

46. Constitutively active cytoplasmic c-Jun N-terminal kinase 1 is a dominant regulator of dendritic architecture: role of microtubule-associated protein 2 as an effector.

Author

Björkblom B, Ostman N, Hongisto V, Komarovski V, Filén JJ, Nyman TA, Kallunki T, Courtney MJ, and Coffey ET

Subjects
Animals, COS Cells, Cell Differentiation, Cell Nucleus enzymology, Cells, Cultured enzymology, Cells, Cultured ultrastructure, Cerebellar Cortex cytology, Cerebellar Cortex enzymology, Cerebellar Cortex growth & development, Chlorocebus aethiops, Mice, Mice, Knockout, Mitogen-Activated Protein Kinase 1 metabolism, Mitogen-Activated Protein Kinase 3 metabolism, Mitogen-Activated Protein Kinase 8 antagonists & inhibitors, Mitogen-Activated Protein Kinase 8 deficiency, Mitogen-Activated Protein Kinase 8 genetics, Motor Cortex cytology, Motor Cortex enzymology, Neurons ultrastructure, Phosphorylation, Prosencephalon cytology, Prosencephalon enzymology, Protein Processing, Post-Translational, Rats, Rats, Sprague-Dawley, Recombinant Fusion Proteins physiology, Transfection, Cytosol enzymology, Dendrites ultrastructure, Microtubule-Associated Proteins physiology, Mitogen-Activated Protein Kinase 8 physiology
Abstract

Normal functioning of the nervous system requires precise regulation of dendritic shape and synaptic connectivity. Here, we report a severe impairment of dendritic structures in the cerebellum and motor cortex of c-Jun N-terminal kinase 1 (JNK1)-deficient mice. Using an unbiased screen for candidate mediators, we identify the dendrite-specific high-molecular-weight microtubule-associated protein 2 (MAP2) as a JNK substrate in the brain. We subsequently show that MAP2 is phosphorylated by JNK in intact cells and that MAP2 proline-rich domain phosphorylation is decreased in JNK1-/- brain. We developed compartment-targeted JNK inhibitors to define whether a functional relationship exists between the physiologically active, cytosolic pool of JNK and dendritic architecture. Using these, we demonstrate that cytosolic, but not nuclear, JNK determines dendritic length and arbor complexity in cultured neurons. Moreover, we confirm that MAP2-dependent process elongation is enhanced after activation of JNK. Using JNK1-/- neurons, we reveal a dominant role for JNK1 over ERK in regulating dendritic arborization, whereas ERK only regulates dendrite shape under conditions in which JNK activity is low (JNK1-/- neurons). These results reveal a novel antagonism between JNK and ERK, potentially providing a mechanism for fine-tuning the dendritic arbor. Together, these data suggest that JNK phosphorylation of MAP2 plays an important role in defining dendritic architecture in the brain.

Published
2005
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