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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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10. Reductions in social anxiety during treatment predict lower levels of loneliness during follow-up among individuals with social anxiety disorder.

Author

ODay, Emily, Butler, Rachel, Morrison, Amanda, Gross, James, Heimberg, Richard, and goldin, philippe

Subjects
CBGT, Loneliness, MBSR, Social anxiety, Anxiety, Follow-Up Studies, Humans, Loneliness, Phobia, Social, Psychotherapy, Group, Treatment Outcome
Abstract

INTRODUCTION: Individuals with social anxiety disorder (SAD) are at elevated risk of loneliness, yet little research has examined loneliness in this population. Cognitive-behavioral group therapy (CBGT) and mindfulness-based stress reduction (MBSR) have demonstrated efficacy in treating SAD, yet research has not examined whether they lead to reductions in loneliness. METHODS: This sample comprised 108 individuals with SAD who were randomized to CBGT, MBSR, or a waitlist control (WL); WL participants were re-randomized to CBGT or MBSR following WL. Assessments were completed pre- and post-treatment, and 3-, 6-, 9-, and 12-month follow-up assessments. RESULTS: Compared to WL, individuals in CBGT and MBSR were less lonely at post-treatment; there was no difference between treatments after treatment or during follow-up. Greater reductions in social anxiety from pre- to post-treatment predicted lower levels of loneliness during follow-up. Greater reductions in loneliness from pre- to post-treatment also predicted lower levels of social anxiety during follow-up. DISCUSSION: Individuals who experience reductions in their social anxiety during treatment may also feel less lonely following treatment. Reductions in loneliness also lead to improvements in social anxiety. Future research should continue to examine the relationship between social anxiety and loneliness and how interventions for SAD may help reduce loneliness.

Published
2021

11. Recruiting and Retaining School Psychologists: The Experiences of District Level Administrative Supervisors

Author

Young, Ellie L., Butler, Rachel, Smith, Timothy B., Hilton, Sterling C., and Smith, Alivia

Abstract

A shortage of school psychologists has been evident since the profession was initially recognized as a distinct field, and there is insufficient research on what current administrative supervisors are doing to address this problem. This qualitative study examined the perceptions of district level administrative supervisors regarding recruitment and retention of school psychologists. Participants reported the following: (a) school psychology graduate programs do not producing enough school psychologists, (b) administrators are challenged to find enough school psychologists to hire, (c) neighboring school districts compete to hire candidates, and (d) administrators recruit and retain in a worker's market that favors the school psychologist. These administrative supervisors also communicated a sense that they had little influence over the shortage. Actions within the administrators' control included developing close relationships with graduate programs for successful recruiting, creating appealing workloads that matched salaries, being responsive to the needs of their current school psychologists, and offering job flexibility.

Published
2021
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12. Retention and Job Satisfaction of School Psychologists

Author

Young, Ellie L., Moulton, Sara E., Julian, Alexander, Smith, Alivia, and Butler, Rachel

Abstract

Retention of current school psychologists is a vital strategy for addressing shortages in the field. Understanding what contributes to why school psychologists stay in the field has the potential to influence leaders and administrators to ensure that they are targeting what matters most to school psychologists. Survey results from 134 school psychologists indicated that they stay in the field because they enjoy working with children and believe their work makes a difference. These generally satisfied school psychologists also shared that they work with teams that facilitate effective and creative problem solving and were acknowledged for their contributions. For the few school psychologists who expressed dissatisfaction, their responses communicated a lack of professional self-efficacy: their opinions were not valued, they did not believe they were effective in their roles, administrators did not value their contributions, and they did not believe they could make a difference for students. Implications for practice highlight the need for district and building administrators to ensure that school psychologists have manageable caseloads that allow them to work directly with children and to be a part of teams that solve problems.

Published
2021
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13. Do sudden gains predict treatment outcome in social anxiety disorder? Findings from two randomized controlled trials.

Author

Gross, James, Heimberg, Richard, Butler, Rachel, ODay, Emily, Kaplan, Simona, Swee, Michaela, Horenstein, Arielle, Morrison, Amanda, and goldin, philippe

Subjects
Cognitive behavioral therapy, Mindfulness-based stress reduction, Social anxiety, Sudden gains, Adult, Cognitive Behavioral Therapy, Female, Humans, Male, Mindfulness, Phobia, Social, Psychotherapy, Group, Treatment Outcome, Young Adult
Abstract

OBJECTIVE: Sudden gains (SGs) have been found to occur during randomized controlled trials (RCTs) for social anxiety disorder (SAD). Evidence is mixed whether SGs relate to treatment outcome in SAD. We examined SGs in two RCTs for SAD. METHOD: Study 1 (N = 68) examined SGs in individual cognitive-behavioral therapy (CBT), and Study 2 (N = 100) compared SGs in group CBT and Mindfulness-Based Stress Reduction (MBSR). Weekly ratings of social anxiety were used to calculate SGs. The Liebowitz Social Anxiety Scale-Self-Report and the Social Interaction Anxiety Scale were completed at pretreatment, posttreatment, and follow-up to assess outcome. RESULTS: In Study 1, 17.6% of participants experienced a SG. Participants with SGs started and ended treatment with lower social anxiety. SGs were not associated with greater decreases in social anxiety from pre-to posttreatment or 12-month follow-up. In Study 2, SGs occurred in 27% of participants and at comparable rates in MBSR and group CBT. SGs were not associated with changes in social anxiety during treatment in either condition. CONCLUSION: SGs occurred during treatment for SAD. In both RCTs, participants improved regardless of experiencing a SG, suggesting that SGs are not predictive of greater improvement during treatment for SAD.

Published
2019

15. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive, HER2-negative breast cancer (FAKTION): overall survival, updated progression-free survival, and expanded biomarker analysis from a randomised, phase 2 trial

Author

Howell, Sacha J, Casbard, Angela, Carucci, Margherita, Ingarfield, Kate, Butler, Rachel, Morgan, Sian, Meissner, Magdalena, Bale, Catherine, Bezecny, Pavel, Moon, Sarah, Twelves, Chris, Venkitaraman, Ramachandran, Waters, Simon, de Bruin, Elza C, Schiavon, Gaia, Foxley, Andrew, and Jones, Robert H

Published
2022
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16. Social anxiety and weight interact with body salience to affect experiences of social exclusion.

Author

Butler, Rachel M., Kaplan, Simona C., and Heimberg, Richard G.

Subjects
*SOCIAL anxiety, *AFFECT (Psychology), *SOCIAL marginality, *BODY mass index, *BODY weight, *BODY image, *SELF-esteem
Abstract

BackgroundMethodsResultsConclusionsIndividuals at a higher weight experience greater victimization and exclusion by peers, and limited research suggests that the salience of one’s body image may increase negative emotional reactions to social rejection. Additionally, social exclusion is related to higher levels of social anxiety (SA). We examined how body salience interacts with SA and weight to predict anxiety, self-esteem, and negative affect following social rejection.Participants were undergraduate women (N = 186). We explored the interactive effects of SA, body mass index (BMI), and body salience (i.e., face versus body photo condition) on emotional response to exclusion in a social ostracism paradigm, Cyberball. BMI and self-reported SA were collected at baseline. One week later, participants played Cyberball and reported state affect, anxiety, and self-esteem before and after the game.The 3-way interaction of BMI, SA, and photo condition did not significantly predict post-exclusion state measures. Photo condition moderated the relationship between SA and post-exclusion anxiety and between BMI and post-exclusion anxiety.Those with higher SA were particularly anxious following exclusion if their bodies were visible to others. Additionally, those with lower BMI experienced greater anxiety after exclusion when their body was visible than those with higher BMI. [ABSTRACT FROM AUTHOR]

Published
2024
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17. Emotional clarity and attention to emotions in cognitive behavioral group therapy and mindfulness-based stress reduction for social anxiety disorder.

Author

Butler, Rachel, Boden, Matthew, Olino, Thomas, Morrison, Amanda, goldin, philippe, Gross, James, and Heimberg, Richard

Subjects
Attention, CBT, Emotional clarity, MBSR, Social anxiety, Adult, Attention, Cognitive Behavioral Therapy, Emotions, Female, Humans, Male, Mindfulness, Phobia, Social, Psychotherapy, Group, Stress, Psychological, Treatment Outcome, Young Adult
Abstract

We examined (1) differences between controls and patients with social anxiety disorder (SAD) in emotional clarity and attention to emotions; (2) changes in emotional clarity and attention to emotions associated with cognitive-behavioral group therapy (CBGT), mindfulness-based stress reduction (MBSR), or a waitlist (WL) condition; and (3) whether emotional clarity and attention to emotions moderated changes in social anxiety across treatment. Participants were healthy controls (n = 37) and patients with SAD (n = 108) who were assigned to CBGT, MBSR, or WL in a randomized controlled trial. At pretreatment, posttreatment, and 12-month follow-up, patients with SAD completed measures of social anxiety, emotional clarity, and attention to emotions. Controls completed measures at baseline only. At pretreatment, patients with SAD had lower levels of emotional clarity than controls. Emotional clarity increased significantly among patients receiving CBGT, and changes were maintained at 12-month follow-up. Emotional clarity at posttreatment did not differ between CBGT and MBSR or between MBSR and WL. Changes in emotional clarity predicted changes in social anxiety, but emotional clarity did not moderate treatment outcome. Analyses of attention to emotions were not significant. Implications for the role of emotional clarity in the treatment of SAD are discussed.

Published
2018

20. Molecular basis for DarT ADP-ribosylation of a DNA base

Author

Schuller, Marion, Butler, Rachel E., Ariza, Antonio, Tromans-Coia, Callum, Jankevicius, Gytis, Claridge, Tim D. W., Kendall, Sharon L., Goh, Shan, Stewart, Graham R., and Ahel, Ivan

Subjects
DNA -- Physiological aspects, Transferases -- Physiological aspects -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

ADP-ribosyltransferases use NAD.sup.+ to catalyse substrate ADP-ribosylation.sup.1, and thereby regulate cellular pathways or contribute to toxin-mediated pathogenicity of bacteria.sup.2-4. Reversible ADP-ribosylation has traditionally been considered a protein-specific modification.sup.5, but recent in vitro studies have suggested nucleic acids as targets.sup.6-9. Here we present evidence that specific, reversible ADP-ribosylation of DNA on thymidine bases occurs in cellulo through the DarT-DarG toxin-antitoxin system, which is found in a variety of bacteria (including global pathogens such as Mycobacterium tuberculosis, enteropathogenic Escherichia coli and Pseudomonas aeruginosa).sup.10. We report the structure of DarT, which identifies this protein as a diverged member of the PARP family. We provide a set of high-resolution structures of this enzyme in ligand-free and pre- and post-reaction states, which reveals a specialized mechanism of catalysis that includes a key active-site arginine that extends the canonical ADP-ribosyltransferase toolkit. Comparison with PARP-HPF1, a well-established DNA repair protein ADP-ribosylation complex, offers insights into how the DarT class of ADP-ribosyltransferases evolved into specific DNA-modifying enzymes. Together, our structural and mechanistic data provide details of this PARP family member and contribute to a fundamental understanding of the ADP-ribosylation of nucleic acids. We also show that thymine-linked ADP-ribose DNA adducts reversed by DarG antitoxin (functioning as a noncanonical DNA repair factor) are used not only for targeted DNA damage to induce toxicity, but also as a signalling strategy for cellular processes. Using M. tuberculosis as an exemplar, we show that DarT-DarG regulates growth by ADP-ribosylation of DNA at the origin of chromosome replication. Structural and mechanistic data of the ADP-ribosyltransferase DarT demonstrate the role of ADP-ribosylation of DNA by this enzyme in generating toxicity and regulating cellular signalling processes in bacteria., Author(s): Marion Schuller [sup.1] , Rachel E. Butler [sup.2] , Antonio Ariza [sup.1] , Callum Tromans-Coia [sup.1] , Gytis Jankevicius [sup.1] [sup.3] , Tim D. W. Claridge [sup.4] , Sharon [...]

Published
2021
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27. Fulvestrant plus capivasertib versus placebo after relapse or progression on an aromatase inhibitor in metastatic, oestrogen receptor-positive breast cancer (FAKTION): a multicentre, randomised, controlled, phase 2 trial

Author

Jones, Robert H, Casbard, Angela, Carucci, Margherita, Cox, Catrin, Butler, Rachel, Alchami, Fouad, Madden, Tracie-Ann, Bale, Catherine, Bezecny, Pavel, Joffe, Johnathan, Moon, Sarah, Twelves, Chris, Venkitaraman, Ramachandran, Waters, Simon, Foxley, Andrew, and Howell, Sacha J

Published
2020
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28. Temporal genome-wide fitness analysis of Mycobacterium marinum during infection reveals the genetic requirement for virulence and survival in amoebae and microglial cells

Author

Lefrançois, Louise H., primary, Nitschke, Jahn, additional, Wu, Huihai, additional, Panis, Gaël, additional, Prados, Julien, additional, Butler, Rachel E., additional, Mendum, Tom A., additional, Hanna, Nabil, additional, Stewart, Graham R., additional, and Soldati, Thierry, additional

Published
2024
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30. Hidden mysteries and open secrets : negotiating age in seventeenth and eighteenth century culture

Author

Butler, Rachel

Subjects
941.06, DA Great Britain
Abstract

Since the study of aging merged out of Second-wave feminism during the 1960’s, aging has been associated exclusively with the time of old age. In this study I will revisit the assumptions which have underpinned the exclusive nature of this relationship in recent historiography through an analysis of a wide-range of primary sources addressing aging as a physiological and psychic process. Whilst aging was a much contested concept; a matter for speculation and fundamentally unquantifiable, it was also in the final analysis an unregulated process which could begin at any time of life. Whilst ideas of aging were constituted in a number of contexts: medical, theological and philosophical dominate this study, I will also illustrate ways in which practices and discourses of age were interrelated, each informing the other. Historians of age have in their own ways paraphrased Joan Scott’s definition of gender, statements have however been qualified by the prefix that a certain age; either childhood or old age is a useful category of analysis. My study eschews such an approach, arguing instead that for age to become a useful category of analysis we must firstly attempt to fully understand the process which gives rise to the value judgements that certain ages are a more useful category of analysis than others. Understanding aging will make are per se a useful category of analysis in the same way that studies of masculinity, in addition to studies of femininity, have made studies of gender a useful category o analysis.

Published
2015

40. Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme

Author

Lindsay, Colin R., Shaw, Emily C., Blackhall, Fiona, Blyth, Kevin G., Brenton, James D., Chaturvedi, Anshuman, Clarke, Noel, Dick, Craig, Evans, Thomas R.J., Hall, Geoff, Hanby, Andrew M., Harrison, David J., Johnston, Stephen R.D., Mason, Malcolm D., Morton, Dion, Newton-Bishop, Julia, Nicholson, Andrew G., Oien, Karin A., Popat, Sanjay, Rassl, Doris, Sharpe, Rowena, Taniere, Phillipe, Walker, Ian, Wallace, William A., West, Nicholas P., Butler, Rachel, Gonzalez de Castro, David, Griffiths, Mike, Johnson, Peter W.M., Rehal, Pauline, Butler, Samantha, Smith, Matthew, Doak, Rachel, Tanska, Anna, Halford, Graham, James, Lisa, Kotara, Chris, Masson, Gareth, Clokie, Sam, Bell, Jennie, Macdonald, Fiona, De Castro, David Gonzalez, Thompson, Lisa, Mair, Debbie, Lillis, Suzanne, Wren, Dorte, Hollifield, Robert, Dover, Keeda, Maurya, Manisha, Brooks, Damian, Gomez, Belen, Grady, Lisa, Jones, Thomas, Hooper, Chantal, Webster, Daphne, Travis, Jolyon, Ogwuru, Stephanie, Gazdova, Jana, Collins, Denise, Chapman, Elaine, Leavey, Lisa, Proszek, Paula, Hulkki, Sanna, Collins, V.Peter, Ibrahim, Ash, Brown, Kat, Burge, Jo, Burnett, Karen, Devonshire, Ginny, Moseley, Ellen, Haynes, Bev, Hodgkin, Charlotte, Jimenez-linan, Merche, Jones, Linda, Kenyon, Gilly, Mahler-araujo, Betania, Payne, Karen, Piper, Jo, Richardson, Sue, Rytina, Ed, Warren, Anne, Coker, Liz, Godsall, Gemma, Arends, Mark, O’Neill, Amanda, Rintoul, Katy, Goymer, Donna, Taylor, Julie, Matthews, Claire, Bhayani, Harshil, Osalador, Tina, Niwaz, Zakiya, Higgins, Anna, Bamsey, Olivia, Salter, Janine, Renouf, Louise, Noel-Storr, Glenn, Roberts, Helen, Gierejko, Kasia, Knapman, Paola, Wotherspoon, Andrew, Stamp, Gordon, Attygailye, Ayoma, Hazell, Steve, Osin, Peter, Nerurkar, Ash, Francis, Steven, Runde, Marion, Arch, Jo, Chitnis, Xavier, Siu, Bernard, Townsend, Debra, Hennelly, Laura, Taylor, Natalie, Johnson, Bernadette, Banerjee, Susie, Pyle, Lynda, Hamill, Monica, Gyertson, Jenny, George, Angela, Patel, Krishna, Pearce, Karla, Edmonds, Kim, Sarker, Sarah, Eeles, Rosalind, Bancroft, Liz, Thomas, Sarah, Kano, Yukie, Rowland, Lisa, Brooks, Karen, O’brien, Mary, Bhosle, Jaishree, Priest, Kathy, Ayite, Bee, Severn, Jo, Beedham, Helen, Lucas, Nicky, Tye, Kim, Lorentzos, Alison, Webb, Janine, Kerr, Sarah, Corestav, Lisa, Bottero, Diego, Jell, Laura, Thomas, Janet, Marriott, Cheryl, Rajah, Neil, Cole, Andy, Ly, Dieu, Taniere, Philippe, O’sullivan, Brendan, Swift, Clare, Hughes, Frances, Neil, Desley, Hanby, Andrew, Banks, Roz, Ajayi, Dolapo, Barclay, Alison, Bishop, Julia Newton, Beirne, Debbie, Bernard, Andrew, Berry, Maxine, Bentley, Jo, Bishop, Tim, Chambers, Amy, Clarke, Jude, Crossley, Anne, Gahir, Narinder, Gibson, Debbie, Good, Rona, Grosios, Konstantina, Harnden, Pat, Hasler, Kate, Hindmarch, Damien, Jackson, Sharon, Johnstone, Colin, Jones, Anne-marie, Lambert, Gil, Lane, Sally, Mcnicholas, Nicola, Millican-Slater, Rebecca, Moriaty, Cath, Newsham, Alex, O’connell, Kara, Ripley, Lisa, Sebag-Montefiore, David, Simpson, Mary, Speirs, Val, Sugden, Joh, Tate, Lauren, Tidswell, Emma, Twelves, Chris, Walker, Christy, Waterhouse, Barry, Waugh, Martin, White, Louise, Wright, Elizabeth, Rogan, Jane, Ashton, Garry, Abbey, Caron, Greenhalgh, Michelle, Nonaka, Daisuke, Shing, Elwyn, Gibbard, Carmen, Burton, Georgina, Fawkes, Naomi, Marsden, Angela, Waddington, Rachael, Harrison, Phil, Moghadam, Shahrzad, Murray, Kate, Brown, Sarah, Mitchinson, Christy, Booton, Richard, Shah, Rajesh, Harrison, David, Oniscu, Anca, Wallace, William, Rae, Frances, Marshall, Craig, Mcleod, Linda, Charles, Morag, Sutherland, Sarah Jane, Dawson, Carol, Mitchell, Paul, Maclellan, Alex, Muir, Sandra, Johnstone, Lynne, O’connor, John, Johnstone, Shirley, Mcpherson, Jim, Hair, Jane, Pignatelli, Massimo, Armstrong, Roma, Oien, Karin, Evans, Jeff, Burgoyne, Margaret, Blessing, Karen, Duthie, Fraser, Moyes, Colin, Mallon, Elizabeth, Millan, David, Roberts, Fiona, Seywright, Morag, Fraser, Siobhan, Ford, Ian, Kean, Sharon, Flood, Marion, Grant, David, Mcdonald, Claire, Moffat, Tom, Mclelland, Hugh, Kyle, Alistair, Cameron, Graham, Wright, Martin, Kenny, Stephen, Mcauslan, Karen, Jones, Andrew, Fitzsimons, Ted, Graham, Fiona, Bell, Alexandra, Duffy, Phil, Fisher, Alec, Smith, Alexis, Shannon, Elaine, Woods, Bryan, Hutchison, Colin, Booth, Angela, Duffy, Lyndsay, Mcculloch, Gillian, Sadiq, Hudda, Deakin, Susan, Haywood, Steven, Mason, Malcolm, Chester, John, Parry-jones, Alison, Macarthur, Abby, Williams, Suzanne, Griffiths, David, Morgan, Fiona, and Bailey, Hazel

Published
2018
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43. Transposon libraries identify novel Mycobacterium bovis BCG genes involved in the dynamic interactions required for BCG to persist during in vivo passage in cattle

Author

Mendum, Tom A., Chandran, Aneesh, Williams, Kerstin, Vordermeier, H. Martin, Villarreal-Ramos, Bernardo, Wu, H., Singh, Albel, Smith, Alex A., Butler, Rachel E., Prasad, Aravind, Bharti, Neeraj, Banerjee, Ruma, Kasibhatla, Sunitha M., Bhatt, Apoorva, Stewart, Graham R., and McFadden, Johnjoe

Published
2019
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50. Experiences of running a stratified medicine adaptive platform trial: Challenges and lessons learned from 10 years of the FOCUS4 trial in metastatic colorectal cancer

Author

Brown, Louise C, Graham, Janet, Fisher, David, Adams, Richard, Seligmann, Jenny, Seymour, Matthew, Kaplan, Richard, Yates, Emma, Parmar, Mahesh, Richman, Susan D, Quirke, Philip, Butler, Rachel, Shiu, Kaikeen, Middleton, Gary, Samuel, Leslie, Wilson, Richard H., and Maughan, Timothy S

Subjects
Pharmacology, Class I Phosphatidylinositol 3-Kinases, Rectal Neoplasms, Colonic Neoplasms, Humans, General Medicine, Colorectal Neoplasms
Abstract

Background: Complex innovative design trials are becoming increasingly common and offer potential for improving patient outcomes in a faster time frame. FOCUS4 was the first molecularly stratified trial in metastatic colorectal cancer and it remains one of the first umbrella trial designs to be launched globally. Here, we aim to describe lessons learned from delivery of the trial over the last 10 years. Methods: FOCUS4 was a Phase II/III molecularly stratified umbrella trial testing the safety and efficacy of targeted therapies in metastatic colorectal cancer. It used adaptive statistical methodology to decide which sub-trial should close early, and new therapies were added as protocol amendments. Patients with newly diagnosed metastatic colorectal cancer were registered, and central laboratory testing was used to stratify their tumour into molecular subtypes. Following 16 weeks of first-line therapy, patients with stable or responding disease were eligible for randomisation into either a molecularly stratified sub-trial (FOCUS4-B, C or D) or non-stratified FOCUS4-N. The primary outcome for all studies was progression-free survival comparing the intervention with active monitoring/placebo. At the close of the trial, feedback was elicited from all investigators through surveys and interviews and consolidated into a series of recommendations and lessons learned for the delivery of similar future trials. Results: Between January 2014 and October 2020, 1434 patients were registered from 88 UK hospitals. Of the 20 drug combinations that were explored for inclusion in the platform trial, three molecularly targeted sub-trials were activated: FOCUS4-D (February 2014–March 2016) evaluated AZD8931 in the BRAF-PIK3CA-RAS wildtype subgroup; FOCUS4-B (February 2016–July 2018) evaluated aspirin in the PIK3CA mutant subgroup and FOCUS4-C (June 2017–October 2020) evaluated adavosertib in the RAS+TP53 double mutant subgroup. FOCUS4-N was active throughout and evaluated capecitabine monotherapy versus a treatment break. A total of 361 (25%) registered patients were randomised into a sub-trial. Feedback on the experiences of delivery of FOCUS4 could be grouped into three main areas of challenge: funding/infrastructure, biomarker testing procedures and trial design efficiencies within which 20 recommendations are summarised. Conclusion: Adaptive stratified medicine platform studies are feasible in common cancers but present challenges. Our stakeholder feedback has helped to inform how these trial designs can succeed and answer multiple questions efficiently, providing resource is adequate.

Published
2022

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