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1. Network model of skeletal muscle cell signalling predicts differential responses to endurance and resistance exercise training.

Author

Fowler, Annabelle, Knaus, Katherine, Khuu, Stephanie, Khalilimeybodi, Ali, Schenk, Simon, Ward, Samuel, Fry, Andrew, Rangamani, Padmini, and McCulloch, Andrew

Subjects
computational model, endurance exercise, exercise, resistance exercise, signalling network, skeletal muscle, Humans, Signal Transduction, Muscle, Skeletal, Resistance Training, Physical Endurance, Animals, Adaptation, Physiological, Exercise, Models, Biological
Abstract

Exercise-induced muscle adaptations vary based on exercise modality and intensity. We constructed a signalling network model from 87 published studies of human or rodent skeletal muscle cell responses to endurance or resistance exercise in vivo or simulated exercise in vitro. The network comprises 259 signalling interactions between 120 nodes, representing eight membrane receptors and eight canonical signalling pathways regulating 14 transcriptional regulators, 28 target genes and 12 exercise-induced phenotypes. Using this network, we formulated a logic-based ordinary differential equation model predicting time-dependent molecular and phenotypic alterations following acute endurance and resistance exercises. Compared with nine independent studies, the model accurately predicted 18/21 (85%) acute responses to resistance exercise and 12/16 (75%) acute responses to endurance exercise. Detailed sensitivity analysis of differential phenotypic responses to resistance and endurance training showed that, in the model, exercise regulates cell growth and protein synthesis primarily by signalling via mechanistic target of rapamycin, which is activated by Akt and inhibited in endurance exercise by AMP-activated protein kinase. Endurance exercise preferentially activates inflammation via reactive oxygen species and nuclear factor κB signalling. Furthermore, the expected preferential activation of mitochondrial biogenesis by endurance exercise was counterbalanced in the model by protein kinase C in response to resistance training. This model provides a new tool for investigating cross-talk between skeletal muscle signalling pathways activated by endurance and resistance exercise, and the mechanisms of interactions such as the interference effects of endurance training on resistance exercise outcomes.

Published
2024

3. Börjeson–Forssman–Lehmann syndrome: delineating the clinical and allelic spectrum in 14 new families

Author

Jain, Vani, Foo, Seow Hoong, Chooi, Stephen, Moss, Celia, Goodwin, Richard, Berland, Siren, Clarke, Angus J., Davies, Sally J., Corrin, Sian, Murch, Oliver, Doyle, Samantha, Graham, Gail E., Greenhalgh, Lynn, Holder, Susan E., Johnson, Diana, Kumar, Ajith, Ladda, Roger L., Sell, Susan, Begtrup, Amber, Lynch, Sally A., McCann, Emma, Østern, Rune, Pottinger, Caroline, Splitt, Miranda, and Fry, Andrew E.

Published
2023
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4. Clinical and functional consequences of GRIA variants in patients with neurological diseases

Author

XiangWei, Wenshu, Perszyk, Riley E., Liu, Nana, Xu, Yuchen, Bhattacharya, Subhrajit, Shaulsky, Gil H., Smith-Hicks, Constance, Fatemi, Ali, Fry, Andrew E., Chandler, Kate, Wang, Tao, Vogt, Julie, Cohen, Julie S., Paciorkowski, Alex R., Poduri, Annapurna, Zhang, Yuehua, Wang, Shuang, Wang, Yuping, Zhai, Qiongxiang, Fang, Fang, Leng, Jie, Garber, Kathryn, Myers, Scott J., Jauss, Robin-Tobias, Park, Kristen L., Benke, Timothy A., Lemke, Johannes R., Yuan, Hongjie, Jiang, Yuwu, and Traynelis, Stephen F.

Published
2023
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9. Biallelic CRELD1 variants cause a multisystem syndrome, including neurodevelopmental phenotypes, cardiac dysrhythmias, and frequent infections

Author

Borras, Silvia, Clark, Caroline, Dean, John, Miedzybrodzka, Zosia, Ross, Alison, Tennant, Stephen, Dabir, Tabib, Donnelly, Deirdre, Humphreys, Mervyn, Magee, Alex, McConnell, Vivienne, McKee, Shane, McNerlan, Susan, Morrison, Patrick J., Rea, Gillian, Stewart, Fiona, Cole, Trevor, Cooper, Nicola, Cooper-Charles, Lisa, Cox, Helen, Islam, Lily, Jarvis, Joanna, Keelagher, Rebecca, Lim, Derek, McMullan, Dominic, Morton, Jenny, Naik, Swati, O’Driscoll, Mary, Ong, Kai-Ren, Osio, Deborah, Ragge, Nicola, Turton, Sarah, Vogt, Julie, Williams, Denise, Bodek, Simon, Donaldson, Alan, Hills, Alison, Low, Karen, Newbury-Ecob, Ruth, Norman, Andrew M., Roberts, Eileen, Scurr, Ingrid, Smithson, Sarah, Tooley, Madeleine, Abbs, Steve, Armstrong, Ruth, Dunn, Carolyn, Holden, Simon, Park, Soo-Mi, Paterson, Joan, Raymond, Lucy, Reid, Evan, Sandford, Richard, Simonic, Ingrid, Tischkowitz, Marc, Woods, Geoff, Bradley, Lisa, Comerford, Joanne, Green, Andrew, Lynch, Sally, McQuaid, Shirley, Mullaney, Brendan, Berg, Jonathan, Goudie, David, Mavrak, Eleni, McLean, Joanne, McWilliam, Catherine, Reavey, Eleanor, Azam, Tara, Cleary, Elaine, Jackson, Andrew, Lam, Wayne, Lampe, Anne, Moore, David, Porteous, Mary, Baple, Emma, Baptista, Júlia, Brewer, Carole, Castle, Bruce, Kivuva, Emma, Owens, Martina, Rankin, Julia, Shaw-Smith, Charles, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Bradley, Therese, Davidson, Rosemarie, Gardiner, Carol, Joss, Shelagh, Kinning, Esther, Longman, Cheryl, McGowan, Ruth, Murday, Victoria, Pilz, Daniela, Tobias, Edward, Whiteford, Margo, Williams, Nicola, Barnicoat, Angela, Clement, Emma, Faravelli, Francesca, Hurst, Jane, Jenkins, Lucy, Jones, Wendy, Ajith Kumar, V.K., Lees, Melissa, Loughlin, Sam, Male, Alison, Morrogh, Deborah, Rosser, Elisabeth, Scott, Richard, Wilson, Louise, Beleza, Ana, Deshpande, Charu, Flinter, Frances, Holder, Muriel, Irving, Melita, Izatt, Louise, Josifova, Dragana, Mohammed, Shehla, Molenda, Aneta, Robert, Leema, Roworth, Wendy, Ruddy, Deborah, Ryten, Mina, Yau, Shu, Bennett, Christopher, Blyth, Moira, Campbell, Jennifer, Coates, Andrea, Dobbie, Angus, Hewitt, Sarah, Hobson, Emma, Jackson, Eilidh, Jewell, Rosalyn, Kraus, Alison, Prescott, Katrina, Sheridan, Eamonn, Thomson, Jenny, Bradshaw, Kirsty, Dixit, Abhijit, Eason, Jacqueline, Haines, Rebecca, Harrison, Rachel, Mutch, Stacey, Sarkar, Ajoy, Searle, Claire, Shannon, Nora, Sharif, Abid, Suri, Mohnish, Vasudevan, Pradeep, Canham, Natalie, Ellis, Ian, Greenhalgh, Lynn, Howard, Emma, Stinton, Victoria, Swale, Andrew, Weber, Astrid, Banka, Siddharth, Breen, Catherine, Briggs, Tracy, Burkitt-Wright, Emma, Chandler, Kate, Clayton-Smith, Jill, Donnai, Dian, Douzgou, Sofia, Gaunt, Lorraine, Jones, Elizabeth, Kerr, Bronwyn, Langley, Claire, Metcalfe, Kay, Smith, Audrey, Wright, Ronnie, Bourn, David, Burn, John, Fisher, Richard, Hellens, Steve, Henderson, Alex, Montgomery, Tara, Splitt, Miranda, Straub, Volker, Wright, Michael, Zwolinski, Simon, Allen, Zoe, Bernhard, Birgitta, Brady, Angela, Brooks, Claire, Busby, Louise, Clowes, Virginia, Ghali, Neeti, Holder, Susan, Ibitoye, Rita, Wakeling, Emma, Blair, Edward, Carmichael, Jenny, Cilliers, Deirdre, Clasper, Susan, Gibbons, Richard, Kini, Usha, Lester, Tracy, Nemeth, Andrea, Poulton, Joanna, Price, Sue, Shears, Debbie, Stewart, Helen, Wilkie, Andrew, Albaba, Shadi, Baker, Duncan, Balasubramanian, Meena, Johnson, Diana, Parker, Michael, Quarrell, Oliver, Stewart, Alison, Willoughby, Josh, Crosby, Charlene, Elmslie, Frances, Homfray, Tessa, Jin, Huilin, Lahiri, Nayana, Mansour, Sahar, Marks, Karen, McEntagart, Meriel, Saggar, Anand, Tatton-Brown, Kate, Butler, Rachel, Clarke, Angus, Corrin, Sian, Fry, Andrew, Kamath, Arveen, McCann, Emma, Mugalaasi, Hood, Pottinger, Caroline, Procter, Annie, Sampson, Julian, Sansbury, Francis, Varghese, Vinod, Baralle, Diana, Callaway, Alison, Cassidy, Emma J., Daniels, Stacey, Douglas, Andrew, Foulds, Nicola, Hunt, David, Kharbanda, Mira, Lachlan, Katherine, Mercer, Catherine, Side, Lucy, Temple, I. Karen, Wellesley, Diana, Ambrose, J.C., Arumugam, P., Baple, E.L., Bleda, M., Boardman-Pretty, F., Boissiere, J.M., Boustred, C.R., Caulfield, M.J., Chan, G.C., Craig, C.E.H., Daugherty, L.C., de Burca, A., Devereau, A., Elgar, G., Foulger, R.E., Fowler, T., FurióTarí, P., Hackett, J.M., Halai, D., Hamblin, A., Henderson, S., Holman, J.E., Hubbard, T.J.P., Ibáñez, K., Jackson, R., Jones, L.J., Kasperaviciute, D., Kayikci, M., Lahnstein, L., Lawson, K., Leigh, S.E.A., Leong, I.U.S., Lopez, F.J., MaleadyCrowe, F., Mason, J., McDonagh, E.M., Moutsianas, L., Mueller, M., Murugaesu, N., Need, A.C., Odhams, C.A., Patch, C., Perez-Gil, D., Polychronopoulos, D., Pullinger, J., Rahim, T., Rendon, A., Riesgo-Ferreiro, P., Rogers, T., Ryten, M., Savage, K., Sawant, K., Scott, R.H., Siddiq, A., Sieghart, A., Smedley, D., Smith, K.R., Sosinsky, A., Spooner, W., Stevens, H.E., Stuckey, A., Sultana, R., Thomas, E.R.A., Thompson, S.R., Tucci, A., Walsh, E., Watters, S.A., Welland, M.J., Williams, E., Witkowska, K., Acosta, Maria T., Adam, Margaret, Adams, David R., Agrawal, Pankaj B., Alejandro, Mercedes E., Alvey, Justin, Amendola, Laura, Andrews, Ashley, Ashley, Euan A., Azamian, Mahshid S., Bacino, Carlos A., Bademci, Guney, Baker, Eva, Balasubramanyam, Ashok, Baldridge, Dustin, Bale, Jim, Bamshad, Michael, Barbouth, Deborah, Bayrak-Toydemir, Pinar, Beck, Anita, Beggs, Alan H., Behrens, Edward, Bejerano, Gill, Bennet, Jimmy, Berg-Rood, Beverly, Bernstein, Jonathan A., Berry, Gerard T., Bican, Anna, Bivona, Stephanie, Blue, Elizabeth, Bohnsack, John, Bonnenmann, Carsten, Bonner, Devon, Botto, Lorenzo, Boyd, Brenna, Briere, Lauren C., Brokamp, Elly, Brown, Gabrielle, Burke, Elizabeth A., Burrage, Lindsay C., Butte, Manish J., Byers, Peter, Byrd, William E., Carey, John, Carrasquillo, Olveen, Peter Chang, Ta Chen, Chanprasert, Sirisak, Chao, Hsiao-Tuan, Clark, Gary D., Coakley, Terra R., Cobban, Laurel A., Cogan, Joy D., Coggins, Matthew, Cole, F. Sessions, Colley, Heather A., Cooper, Cynthia M., Craigen, William J., Crouse, Andrew B., Cunningham, Michael, D'Souza, Precilla, Dai, Hongzheng, Dasari, Surendra, Davids, Mariska, Dayal, Jyoti G., Deardorff, Matthew, Dell'Angelica, Esteban C., Dhar, Shweta U., Dipple, Katrina, Doherty, Daniel, Dorrani, Naghmeh, Douine, Emilie D., Draper, David D., Duncan, Laura, Earl, Dawn, Eckstein, David J., Emrick, Lisa T., Eng, Christine M., Esteves, Cecilia, Estwick, Tyra, Falk, Marni, Fernandez, Liliana, Ferreira, Carlos, Fieg, Elizabeth L., Findley, Laurie C., Fisher, Paul G., Fogel, Brent L., Forghani, Irman, Fresard, Laure, Gahl, William A., Glass, Ian, Godfrey, Rena A., Golden-Grant, Katie, Goldman, Alica M., Goldstein, David B., Grajewski, Alana, Groden, Catherine A., Gropman, Andrea L., Gutierrez, Irma, Hahn, Sihoun, Hamid, Rizwan, Hanchard, Neil A., Hassey, Kelly, Hayes, Nichole, High, Frances, Hing, Anne, Hisama, Fuki M., Holm, Ingrid A., Hom, Jason, Horike-Pyne, Martha, Huang, Alden, Huang, Yong, Isasi, Rosario, Jamal, Fariha, Jarvik, Gail P., Jarvik, Jeffrey, Jayadev, Suman, Johnston, Jean M., Karaviti, Lefkothea, Kelley, Emily G., Kennedy, Jennifer, Kiley, Dana, Kohane, Isaac S., Kohler, Jennefer N., Krakow, Deborah, Krasnewich, Donna M., Kravets, Elijah, Korrick, Susan, Koziura, Mary, Krier, Joel B., Lalani, Seema R., Lam, Byron, Lam, Christina, Lanpher, Brendan C., Lanza, Ian R., Lau, C. Christopher, LeBlanc, Kimberly, Lee, Brendan H., Lee, Hane, Levitt, Roy, Lewis, Richard A., Lincoln, Sharyn A., Liu, Pengfei, Liu, Xue Zhong, Longo, Nicola, Loo, Sandra K., Loscalzo, Joseph, Maas, Richard L., Macnamara, Ellen F., MacRae, Calum A., Maduro, Valerie V., Majcherska, Marta M., Mak, Bryan, Malicdan, May Christine V., Mamounas, Laura A., Manolio, Teri A., Mao, Rong, Maravilla, Kenneth, Markello, Thomas C., Marom, Ronit, Marth, Gabor, Martin, Beth A., Martin, Martin G., Martínez-Agosto, Julian A., Marwaha, Shruti, McCauley, Jacob, McCormack, Colleen E., McCray, Alexa T., McGee, Elisabeth, Mefford, Heather, Merritt, J. Lawrence, Might, Matthew, Mirzaa, Ghayda, Morava, Eva, Moretti, Paolo M., Morimoto, Marie, Mulvihill, John J., Murdock, David R., Nakano-Okuno, Mariko, Nath, Avi, Nelson, Stan F., Newman, John H., Nicholas, Sarah K., Nickerson, Deborah, Nieves-Rodriguez, Shirley, Novacic, Donna, Oglesbee, Devin, Orengo, James P., Pace, Laura, Pak, Stephen, Pallais, J. Carl, Papp, Jeanette C., Parker, Neil H., Phillips, John A., Posey, Jennifer E., Potocki, Lorraine, Pusey, Barbara N., Quinlan, Aaron, Raskind, Wendy, Raja, Archana N., Rao, Deepak A., Renteria, Genecee, Reuter, Chloe M., Rives, Lynette, Robertson, Amy K., Rodan, Lance H., Rosenfeld, Jill A., Rosenwasser, Natalie, Ruzhnikov, Maura, Sacco, Ralph, Sampson, Jacinda B., Samson, Susan L., Saporta, Mario, Scott, C. Ron, Schaechter, Judy, Schedl, Timothy, Scott, Daryl A., Sharma, Prashant, Shin, Jimann, Signer, Rebecca, Sillari, Catherine H., Silverman, Edwin K., Sinsheimer, Janet S., Sisco, Kathy, Smith, Edward C., Smith, Kevin S., Solem, Emily, Solnica-Krezel, Lilianna, Stoler, Joan M., Stong, Nicholas, Sullivan, Jennifer A., Sun, Angela, Sutton, Shirley, Sweetser, David A., Sybert, Virginia, Tabor, Holly K., Tamburro, Cecelia P., Tekin, Mustafa, Telischi, Fred, Thorson, Willa, Tifft, Cynthia J., Toro, Camilo, Tran, Alyssa A., Tucker, Brianna M., Urv, Tiina K., Vanderver, Adeline, Velinder, Matt, Viskochil, Dave, Vogel, Tiphanie P., Wahl, Colleen E., Wallace, Stephanie, Walley, Nicole M., Walsh, Chris A., Walker, Melissa, Wambach, Jennifer, Wan, Jijun, Wang, Lee-Kai, Wangler, Michael F., Ward, Patricia A., Wegner, Daniel, Wener, Mark, Wenger, Tara, Perry, Katherine Wesseling, Westerfield, Monte, Wheeler, Matthew T., Whitlock, Jordan, Wolfe, Lynne A., Woods, Jeremy D., Yamamoto, Shinya, Yang, John, Yu, Guoyun, Zastrow, Diane B., Zhao, Chunli, Zuchner, Stephan, Jeffries, Lauren, Mis, Emily K., McWalter, Kirsty, Donkervoort, Sandra, Brodsky, Nina N., Carpier, Jean-Marie, Ji, Weizhen, Ionita, Cristian, Roy, Bhaskar, Morrow, Jon S., Darbinyan, Armine, Iyer, Krishna, Aul, Ritu B., Chao, Katherine R., Cobbold, Laura, Cohen, Stacey, Custodio, Helena M., Drummond-Borg, Margaret, Finanger, Erika, Hainline, Bryan E., Helbig, Ingo, Hewson, Stacy, Hu, Ying, Jackson, Adam, Konstantino, Monica, Leach, Meganne E., McCormick, David, Nelson, Stanley, Nguyen, Joanne, Nugent, Kimberly, Ortega, Lucy, Goodkin, Howard P., Roeder, Elizabeth, Roy, Sani, Sapp, Katie, Saade, Dimah, Sisodiya, Sanjay M., Stals, Karen, Towner, Shelley, Wilson, William, Khokha, Mustafa K., Bönnemann, Carsten G., Lucas, Carrie L., and Lakhani, Saquib A.

Published
2024
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12. Atypical hemolytic uremic syndrome in the era of terminal complement inhibition: an observational cohort study

Author

Holt, Richard, Jones, Caroline, Ashman, Neil, Fan, Stanley, Forbes, Suzanne, Rajakariar, Ravindra, De Freitas, Declan, Magee, Colm, Hanko, Jennifer, Milford, David, Muorah, Mordi, Howie, Alexander J., Baharani, Jyoti, Dasgupta, Indranil, Roberts, Russell, MacDiarmaid-Gordon, Adam, Fry, Andrew, Torpey, Nicholas, Waldron, Mary, Awan, Atif, Raftery, Tara, Ratcliffe, Laura, Vilar, Enric, Newman, Joel, Seviar, Dale, Marks, Stephen D., Rees, Lesley, Veligratli, Faidra, Waters, Aoife, Chowdhury, Paramit, Pattison, James, Booth, Caroline, Williams, Nicole, Corbett, Richard, Amin, Beena, Pickering, Matthew, Bramham, Kate, Al-Hamed, Mohamed, Hill, Anita, Mooney, Andrew, Finlay, Eric, Newnham, Amanda, Yadav, Pallavi, Kaur, Amrit, Plant, Nicholas, Shenoy, Mohan, Choong, Lye Wai, Helps, Aileen, McLemon, Robert, Muniraju, Thalakunte, Khan, Izhar, Kidder, Dana, Padmanabhan, Neal, Cousland, Zoe, Price, Jonathan, Taylor, Alison, Jennings, Claudine, Ahmad, Sohail, Mead, Paul, Aslam, Mona, Bebb, Charlotte, Byrne, Catherine, Ferraro, Alastair, Christian, Martin, Evans, Jonathan, Kim, Jon Jin, Lunn, Andrew, Mallik, Meeta, Mason, Phil, Mole, David, Craze, Janet, Sangala, Nicholas, Uniacke, Mark, McGregor, Ellon, Lambie, Stewart, Bhandary, Nitin, Flossmann, Oliver, Mohteshamzadeh, Mobin, Abeyaratne, Asanga, Bingham, Coralie, Clissold, Rhian, Smyth, Lucy, Connolly, John, Reynolds, Ben, Neary, John, Bell, Joanne, Roxburgh, Sarah, Popoola, Joyce, Donne, Rosie, Fardon, Nicholas, Khwaja, Arif, Siddiqi, Shareen, Kumar, Gurinder, Kardasz, Steve, Moore, Iain, Tez, Didem, Willows, Jamie, Davison, Rachel, Harty, John, Wong, William, Williams, Andrew J., Gale, Daniel, Coward, Richard, Inward, Carol, Mraz, Martin, Ayub, Waqar, Short, Andrew, Lappin, David, Baines, Richard, Bommayya, Girish, Houlberg, Kris, Saif, Imran, Gilbert, Rodney, Griffin, Sian, Smith, Graham, Van Der Voort, Judith, Chandar, Jayanthi, Freundlich, Michael, McCarroll, Frank, Wong, Germaine, Laboi, Paul, Molyneux, Rebekah, Brocklebank, Vicky, Walsh, Patrick R., Smith-Jackson, Kate, Hallam, Thomas M., Marchbank, Kevin J., Wilson, Valerie, Bigirumurame, Theophile, Dutt, Tina, Montgomery, Emma K., Malina, Michal, Wong, Edwin K. S., Johnson, Sally, Sheerin, Neil S., and Kavanagh, David

Published
2023
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15. PSMC5 insufficiency and P320R mutation impair proteasome function

Author

Yu, Zhong-Qiu, primary, Carmichael, Jenny, additional, Collins, Galen A, additional, D'Agostino, Maria Daniela, additional, Lessard, Mathieu, additional, Firth, Helen V, additional, Harijan, Pooja, additional, Fry, Andrew E, additional, Dean, John, additional, Zhang, Jiuchun, additional, Kini, Usha, additional, Goldberg, Alfred L, additional, and Rubinsztein, David C, additional

Published
2024
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21. Genomic discovery of an evolutionarily programmed modality for small-molecule targeting of an intractable protein surface

Author

Shigdel, Uddhav K, Lee, Seung-Joo, Sowa, Mathew E, Bowman, Brian R, Robison, Keith, Zhou, Minyun, Pua, Khian Hong, Stiles, Dylan T, Blodgett, Joshua AV, Udwary, Daniel W, Rajczewski, Andrew T, Mann, Alan S, Mostafavi, Siavash, Hardy, Tara, Arya, Sukrat, Weng, Zhigang, Stewart, Michelle, Kenyon, Kyle, Morgenstern, Jay P, Pan, Ende, Gray, Daniel C, Pollock, Roy M, Fry, Andrew M, Klausner, Richard D, Townson, Sharon A, and Verdine, Gregory L

Subjects
Biochemistry and Cell Biology, Chemical Sciences, Biological Sciences, Emerging Infectious Diseases, Rare Diseases, Vaccine Related, Biodefense, Prevention, Orphan Drug, Infectious Diseases, 2.1 Biological and endogenous factors, Aetiology, Development of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Actinobacteria, Amino Acid Sequence, Antiviral Agents, Autoantigens, Calcineurin, Cell Cycle Proteins, Evolution, Molecular, Genome, Bacterial, HEK293 Cells, Humans, Macrolides, Models, Molecular, Protein Conformation, Protein Interaction Domains and Motifs, Sequence Homology, Sirolimus, Small Molecule Libraries, TOR Serine-Threonine Kinases, Tacrolimus Binding Protein 1A, natural products, genome mining, FK506-binding protein
Abstract

The vast majority of intracellular protein targets are refractory toward small-molecule therapeutic engagement, and additional therapeutic modalities are needed to overcome this deficiency. Here, the identification and characterization of a natural product, WDB002, reveals a therapeutic modality that dramatically expands the currently accepted limits of druggability. WDB002, in complex with the FK506-binding protein (FKBP12), potently and selectively binds the human centrosomal protein 250 (CEP250), resulting in disruption of CEP250 function in cells. The recognition mode is unprecedented in that the targeted domain of CEP250 is a coiled coil and is topologically featureless, embodying both a structural motif and surface topology previously considered on the extreme limits of "undruggability" for an intracellular target. Structural studies reveal extensive protein-WDB002 and protein-protein contacts, with the latter being distinct from those seen in FKBP12 ternary complexes formed by FK506 and rapamycin. Outward-facing structural changes in a bound small molecule can thus reprogram FKBP12 to engage diverse, otherwise "undruggable" targets. The flat-targeting modality demonstrated here has the potential to expand the druggable target range of small-molecule therapeutics. As CEP250 was recently found to be an interaction partner with the Nsp13 protein of the SARS-CoV-2 virus that causes COVID-19 disease, it is possible that WDB002 or an analog may exert useful antiviral activity through its ability to form high-affinity ternary complexes containing CEP250 and FKBP12.

Published
2020

25. PlasmodiumNEK1 coordinates MTOC organisation and kinetochore attachment during rapid mitosis in male gamete formation

Author

Zeeshan, Mohammad, primary, Rashpa, Ravish, additional, Ferguson, David J., additional, Mckeown, George, additional, Nugmanova, Raushan, additional, Subudhi, Amit K., additional, Beyeler, Raphael, additional, Pashley, Sarah L., additional, Markus, Robert, additional, Brady, Declan, additional, Roques, Magali, additional, Bottrill, Andrew R., additional, Fry, Andrew M., additional, Pain, Arnab, additional, Vaughan, Sue, additional, Holder, Anthony A., additional, Tromer, Eelco C., additional, Brochet, Mathieu, additional, and Tewari, Rita, additional

Published
2024
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31. Between-rater reliability for using radar technology to quantify maximal horizontal deceleration performance in NCAA division 1 American football and female lacrosse athletes.

Author

Philipp, Nicolas M., McKay, Ben, Martin, Ethan, Cabarkapa, Dimitrije, Fry, Andrew C., and Troester, Jordan

Subjects
BASKETBALL players, NCAA Basketball Tournament, RADAR, ATHLETIC ability, CONFIDENCE intervals
Abstract

Introduction: With recent increases in the popularity of studying the physical construct of horizontal deceleration performance in team-sport athletes, the aim of the present study was to assess the inter-rater and intra-rater reliability of processing and quantifying horizontal deceleration ability using radar technology. Methods: Data from 92 NCAA Division 1 athletes from two different athletic teams (American football and Lacrosse) were used for the present investigation. All athletes performed two trials of the modified acceleration to deceleration assessment (ADA), which consisted of a maximal 10 m sprint acceleration, followed by a rapid deceleration. Four individual raters manually processed raw, radar-derived instantaneous velocity data for the ADA, and an automated script was used to calculate metrics of interest. Results: Primary study findings suggest moderate to excellent levels of agreement (ICC = 0.56-0.91) for maximal horizontal deceleration metrics between the four individual raters. The intra-rater analyses revealed poor to excellent consistency (ICC = 0.31-0.94) between ADA trials, with CV%'s ranging from 3.1% to 13.2%, depending on the respective metric and rater. Discussion: Our data suggests that if a foundational understanding and agreement of manual data processing procedures for radar-derived data is given between raters, metrics may be interpreted with moderate to excellent levels of confidence. However, when possible, and when using the Stalker ATS radar technology, authors recommend that practitioners use one trained individual to manually process raw data. Ideally, this process should become fully automated, based on selected filters or algorithms, rather than the subjectivity of the rater. [ABSTRACT FROM AUTHOR]

Published
2024
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32. Changes in Countermovement Vertical Jump Force-Time Metrics During a Game in Professional Male Basketball Players.

Author

Cabarkapa, Dimitrije, Johnson, Quincy R., Cabarkapa, Damjana V., Philipp, Nicolas M., Eserhaut, Drake A., and Fry, Andrew C.

Subjects
BIOMECHANICS, VOLUNTEER service, MALE athletes, NEUROPHYSIOLOGY, FATIGUE (Physiology), NEUROMUSCULAR system, PROFESSIONAL athletes, DESCRIPTIVE statistics, ATHLETIC ability, JUMPING, BASKETBALL, COMPARATIVE studies, PSYCHOSOCIAL factors
Abstract

As technology within elite basketball advances and is more available to sporting organizations, novel approaches for assessing and addressing athletic performance during practice or competition are being continuously explored. The aim of this investigation was to examine changes in neuromuscular performance during live basketball play. Eight professional male basketball players volunteered to participate in this study. The testing procedures were conducted during a pre-tournament camp over a span of 2 days. During the first day, the athletes were familiarized with the testing procedures, and baseline measurements were obtained. Using a uniaxial force plate system sampling at 1,000 Hz, each athlete performed 3 countermovement vertical jumps (CVJ) without an arm swing before proceeding with their regular training activities. During the second day of the pre-tournament camp, the athletes repeated identical CVJ testing procedures before the start of the first quarter and post-first, second, third, and fourth quarter of a simulated 5- on-5 basketball game. Repeated-measures testing design was used to examine statistically significant differences in various forcetime metrics of interest in comparison to the baseline levels (p, 0.05). Besides a trivial decrease in eccentric mean force, the findings of this study revealed no statistically significant changes in any force-time metrics of interest within both eccentric and concentric phases of the CVJ (i.e., mean and peak force and power, jump height, impulse, velocity, and contraction time). Thus, we can conclude that these variables were not sensitive to acute fatigue, suggesting that the neuromuscular performances of professional male basketball players tend to remain unchanged throughout a 5-on-5 simulated game. [ABSTRACT FROM AUTHOR]

Published
2024
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33. Relationship between vertical jump performance and playing time and efficiency in professional male basketball players.

Author

Cabarkapa, Dimitrije, Cabarkapa, Damjana V., Aleksic, Jelena, Scott, Angeleau A., and Fry, Andrew C.

Subjects
VERTICAL jump, BASKETBALL players, BODY mass index, BASKETBALL coaches, STATISTICAL correlation
Abstract

With innovative force plate technology being available to many sports organizations worldwide that allow for time-efficient in-depth neuromuscular performance assessment, the purpose of the present study was to examine the relationship between some of the most commonly analyzed countermovement vertical jump (CVJ) force-time metrics and basketball playing time and efficiency. Twenty-four professional male basketball players volunteered to participate in the present study. The CVJ testing procedures were conducted within the first quarter of the competitive season span. Following a standardized warm-up protocol, each athlete stepped on a dual uni-axial force plate system sampling at 1,000 Hz and performed three maximum-effort CVJs with no arm swing. To minimize the possible influence of fatigue, each jump trial was separated by a 10–15 s rest interval and the average value across three jumps was used for performance analysis purposes. Basketball playing efficiency and average playing time were obtained at the end of the regular season competitive period from the coaching staff records and the official team records. Pearson product-moment correlation coefficients (r) were used to examine the strength of the relationships between force-time metrics and basketball playing time and efficiency, separately for each dependent variable (p < 0.05). A significant positive association was observed between playing efficiency and eccentric mean force and eccentric mean and peak power (r = 0.406–0.552). Similarly, an increase in eccentric mean power was positively correlated with the number of minutes played during the competitive season (r = 0.464). Moreover, the aforementioned relationship remained present even when eccentric mean power was expressed relative to the player’s body mass (r = 0.406). Thus, the findings of the present study indicate that, at the professional level of men’s basketball competition, CVJ eccentric strength and power have a positive impact on both playing time and efficiency. [ABSTRACT FROM AUTHOR]

Published
2024
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34. Dose-Response Relationship for External Workload and Neuromsuclar Performance Over a Female, Collegiate, Basketball Season.

Author

Philipp, Nicolas M., Cabarkapa, Dimitrije, Blackburn, Stryder D., and Fry, Andrew C.

Subjects
EXERCISE physiology, NEUROPHYSIOLOGY, UNIVERSITIES & colleges, PHYSICAL training & conditioning, EXERCISE intensity, NEUROMUSCULAR system, RETROSPECTIVE studies, DOSE-response relationship in biochemistry, SPORTS events, MEDICAL records, ACQUISITION of data, BASKETBALL, ATHLETIC ability, JUMPING, GROUND reaction forces (Biomechanics)
Abstract

The aim of this study was to investigate the relationship between external workload exposure and changes in countermovement jump force-time characteristics over the course of an entire basketball season, in a sample of National Collegiate Athletic Association Division I, female, basketball players. Data for 12 players were retrospectively analyzed, with external workload being quantified by means of an exponentially weighted, acute, and chronic workload, as well as an acute:chronic workload ratio derived from an inertial measurement unit--based system worn by athletes for all practices and games during the regular season. Countermovement jumps were performed on a total of 26 test days over the span of the in-season competitive period. To statistically analyze these relationships, and to account for multiple observations of the same athletes in a data set, linear mixed-effects models with athlete identity (ID) intercept as the random effect were used. Study findings suggested that associations between external workload exposure and respective force-time characteristics after controlling for the random effect of athlete ID were dependent on the specific metric or metric subgroup used, as well as the type of workload exposure (e.g., acute vs. chronic). Force-time signatures from the braking phase (e.g., average braking force) seemed to be particularly associated with higher degrees of acute workload exposure, whereas strategy-based metrics such as countermovement depth showed significant associations with chronic workload exposure. Furthermore, model results suggested the importance of analyzing neuromuscular responses to external workload on an individual basis, rather than across an entire team. Findings might help practitioners in their selection process related to metrics of interest in monitoring neuromuscular fatigue and readiness. [ABSTRACT FROM AUTHOR]

Published
2024
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39. Clinical delineation, sex differences, and genotype–phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Author

Faundes, Víctor, Goh, Stephanie, Akilapa, Rhoda, Bezuidenhout, Heidre, Bjornsson, Hans T., Bradley, Lisa, Brady, Angela F., Brischoux-Boucher, Elise, Brunner, Han, Bulk, Saskia, Canham, Natalie, Cody, Declan, Dentici, Maria Lisa, Digilio, Maria Cristina, Elmslie, Frances, Fry, Andrew E., Gill, Harinder, Hurst, Jane, Johnson, Diana, Julia, Sophie, Lachlan, Katherine, Lebel, Robert Roger, Byler, Melissa, Gershon, Eric, Lemire, Edmond, Gnazzo, Maria, Lepri, Francesca Romana, Marchese, Antonia, McEntagart, Meriel, McGaughran, Julie, Mizuno, Seiji, Okamoto, Nobuhiko, Rieubland, Claudine, Rodgers, Jonathan, Sasaki, Erina, Scalais, Emmanuel, Scurr, Ingrid, Suri, Mohnish, van der Burgt, Ineke, Matsumoto, Naomichi, Miyake, Noriko, Benoit, Valérie, Lederer, Damien, and Banka, Siddharth

Published
2021
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40. Comprehensive study of 28 individuals with SIN3A-related disorder underscoring the associated mild cognitive and distinctive facial phenotype

Author

Balasubramanian, Meena, Dingemans, Alexander J. M., Albaba, Shadi, Richardson, Ruth, Yates, Thabo M., Cox, Helen, Douzgou, Sofia, Armstrong, Ruth, Sansbury, Francis H., Burke, Katherine B., Fry, Andrew E., Ragge, Nicola, Sharif, Saba, Foster, Alison, De Sandre-Giovannoli, Annachiara, Elouej, Sahar, Vasudevan, Pradeep, Mansour, Sahar, Wilson, Kate, Stewart, Helen, Heide, Solveig, Nava, Caroline, Keren, Boris, Demirdas, Serwet, Brooks, Alice S., Vincent, Marie, Isidor, Bertrand, Küry, Sebastien, Schouten, Meyke, Leenders, Erika, Chung, Wendy K., Haeringen, Arie van, Scheffner, Thomas, Debray, Francois-Guillaume, White, Susan M., Palafoll, Maria Irene Valenzuela, Pfundt, Rolph, Newbury-Ecob, Ruth, and Kleefstra, Tjitske

Published
2021
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42. International consensus recommendations on the diagnostic work-up for malformations of cortical development

Author

Oegema, Renske, Barakat, Tahsin Stefan, Wilke, Martina, Stouffs, Katrien, Amrom, Dina, Aronica, Eleonora, Bahi-Buisson, Nadia, Conti, Valerio, Fry, Andrew E., Geis, Tobias, Andres, David Gomez, Parrini, Elena, Pogledic, Ivana, Said, Edith, Soler, Doriette, Valor, Luis M., Zaki, Maha S., Mirzaa, Ghayda, Dobyns, William B., Reiner, Orly, Guerrini, Renzo, Pilz, Daniela T., Hehr, Ute, Leventer, Richard J., Jansen, Anna C., Mancini, Grazia M. S., and Di Donato, Nataliya

Published
2020
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43. Impaired eIF5A function causes a Mendelian disorder that is partially rescued in model systems by spermidine

Author

Faundes, Víctor, Jennings, Martin D., Crilly, Siobhan, Legraie, Sarah, Withers, Sarah E., Cuvertino, Sara, Davies, Sally J., Douglas, Andrew G. L., Fry, Andrew E., Harrison, Victoria, Amiel, Jeanne, Lehalle, Daphné, Newman, William G., Newkirk, Patricia, Ranells, Judith, Splitt, Miranda, Cross, Laura A., Saunders, Carol J., Sullivan, Bonnie R., Granadillo, Jorge L., Gordon, Christopher T., Kasher, Paul R., Pavitt, Graham D., and Banka, Siddharth

Published
2021
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