25 research outputs found
Regulation of death receptor signaling by the autophagy protein TP53INP2
TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in deathâreceptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptorâinduced apoptosis. TP53INP2 binds caspaseâ8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspaseâ8 by TRAF6. We have defined a TRAF6âinteracting motif (TIM) and a ubiquitinâinteracting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspaseâ8 to TRAF6 for further polyubiquitination of caspaseâ8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspaseâ8, and subsequently reduce levels of death receptorâinduced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAILâinduced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspaseâ8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway
J-PLUS:Searching for very metal-poor star candidates using the SPEEM pipeline
We explore the stellar content of the Javalambre Photometric Local Universe Survey (J-PLUS) Data Release 2 and show its potential to identify low-metallicity stars using the Stellar Parameters Estimation based on Ensemble Methods (SPEEM) pipeline. SPEEM is a tool to provide determinations of atmospheric parameters for stars and separate stellar sources from quasars, using the unique J-PLUS photometric system. The adoption of adequate selection criteria allows the identification of metal-poor star candidates suitable for spectroscopic follow-up. SPEEM consists of a series of machine learning models which uses a training sample observed by both J-PLUS and the SEGUE spectroscopic survey. The training sample has temperatures Teff between 4\,800 K and 9\,000 K; between 1.0 and 4.5, and $-3.
Taking the pulse of Earth's tropical forests using networks of highly distributed plots
Tropical forests are the most diverse and productive ecosystems on Earth. While better understanding of these forests is critical for our collective future, until quite recently efforts to measure and monitor them have been largely disconnected. Networking is essential to discover the answers to questions that transcend borders and the horizons of funding agencies. Here we show how a global community is responding to the challenges of tropical ecosystem research with diverse teams measuring forests tree-by-tree in thousands of long-term plots. We review the major scientific discoveries of this work and show how this process is changing tropical forest science. Our core approach involves linking long-term grassroots initiatives with standardized protocols and data management to generate robust scaled-up results. By connecting tropical researchers and elevating their status, our Social Research Network model recognises the key role of the data originator in scientific discovery. Conceived in 1999 with RAINFOR (South America), our permanent plot networks have been adapted to Africa (AfriTRON) and Southeast Asia (T-FORCES) and widely emulated worldwide. Now these multiple initiatives are integrated via ForestPlots.net cyber-infrastructure, linking colleagues from 54 countries across 24 plot networks. Collectively these are transforming understanding of tropical forests and their biospheric role. Together we have discovered how, where and why forest carbon and biodiversity are responding to climate change, and how they feedback on it. This long-term pan-tropical collaboration has revealed a large long-term carbon sink and its trends, as well as making clear which drivers are most important, which forest processes are affected, where they are changing, what the lags are, and the likely future responses of tropical forests as the climate continues to change. By leveraging a remarkably old technology, plot networks are sparking a very modern revolution in tropical forest science. In the future, humanity can benefit greatly by nurturing the grassroots communities now collectively capable of generating unique, long-term understanding of Earth's most precious forests.Additional co-authors: Susan Laurance, William Laurance, Francoise Yoko Ishida, Andrew Marshall, Catherine Waite, Hannsjoerg Woell, Jean-Francois Bastin, Marijn Bauters, Hans Beeckman, Pfascal Boeckx, Jan Bogaert, Charles De Canniere, Thales de Haulleville, Jean-Louis Doucet, Olivier Hardy, Wannes Hubau, Elizabeth Kearsley, Hans Verbeeck, Jason Vleminckx, Steven W. Brewer, Alfredo AlarcĂłn, Alejandro Araujo-Murakami, Eric Arets, Luzmila Arroyo, Ezequiel Chavez, Todd Fredericksen, RenĂ© GuillĂ©n Villaroel, Gloria Gutierrez Sibauty, Timothy Killeen, Juan Carlos Licona, John Lleigue, Casimiro Mendoza, Samaria Murakami, Alexander Parada Gutierrez, Guido Pardo, Marielos Peña-Claros, Lourens Poorter, Marisol Toledo, Jeanneth Villalobos Cayo, Laura Jessica Viscarra, Vincent Vos, Jorge Ahumada, Everton Almeida, Jarcilene Almeida, Edmar Almeida de Oliveira, Wesley Alves da Cruz, Atila Alves de Oliveira, FabrĂcio Alvim Carvalho, FlĂĄvio Amorim Obermuller, Ana Andrade, Fernanda Antunes Carvalho, Simone Aparecida Vieira, Ana Carla Aquino, Luiz AragĂŁo, Ana Claudia AraĂșjo, Marco Antonio Assis, Jose Ataliba Mantelli Aboin Gomes, FabrĂcio Baccaro, PlĂnio Barbosa de Camargo, Paulo Barni, Jorcely Barroso, Luis Carlos Bernacci, Kauane Bordin, Marcelo Brilhante de Medeiros, Igor Broggio, JosĂ© LuĂs Camargo, Domingos Cardoso, Maria Antonia Carniello, Andre Luis Casarin Rochelle, Carolina Castilho, Antonio Alberto Jorge Farias Castro, Wendeson Castro, Sabina Cerruto Ribeiro, FlĂĄvia Costa, Rodrigo Costa de Oliveira, Italo Coutinho, John Cunha, Lola da Costa, Lucia da Costa Ferreira, Richarlly da Costa Silva, Marta da Graça Zacarias Simbine, Vitor de Andrade Kamimura, Haroldo Cavalcante de Lima, Lia de Oliveira Melo, Luciano de Queiroz, JosĂ© Romualdo de Sousa Lima, MĂĄrio do EspĂrito Santo, Tomas Domingues, Nayane Cristina dos Santos Prestes, Steffan Eduardo Silva Carneiro, Fernando Elias, Gabriel Eliseu, Thaise Emilio, Camila LaĂs Farrapo, LetĂcia Fernandes, Gustavo Ferreira, Joice Ferreira, Leandro Ferreira, Socorro Ferreira, Marcelo Fragomeni Simon, Maria Aparecida Freitas, Queila S. GarcĂa, Angelo Gilberto Manzatto, Paulo Graça, Frederico Guilherme, Eduardo Hase, Niro Higuchi, Mariana Iguatemy, Reinaldo Imbrozio Barbosa, Margarita Jaramillo, Carlos Joly, Joice Klipel, IĂȘda LeĂŁo do Amaral, Carolina Levis, Antonio S. Lima, MaurĂcio Lima Dan, Aline Lopes, Herison Madeiros, William E. Magnusson, Rubens Manoel dos Santos, Beatriz Marimon, Ben Hur Marimon Junior, Roberta Marotti Martelletti Grillo, Luiz Martinelli, Simone Matias Reis, SalomĂŁo Medeiros, Milton Meira-Junior, Thiago Metzker, Paulo Morandi, Natanael Moreira do Nascimento, Magna Moura, Sandra Cristina MĂŒller, Laszlo Nagy, Henrique Nascimento, Marcelo Nascimento, Adriano Nogueira Lima, Raimunda Oliveira de AraĂșjo, Jhonathan Oliveira Silva, Marcelo Pansonato, Gabriel Pavan Sabino, Karla Maria Pedra de Abreu, Pablo JosĂ© Francisco Pena Rodrigues, Maria Piedade, Domingos Rodrigues, JosĂ© Roberto Rodrigues Pinto, Carlos Quesada, Eliana Ramos, Rafael Ramos, Priscyla Rodrigues, Thaiane Rodrigues de Sousa, Rafael SalomĂŁo, FlĂĄvia Santana, Marcos Scaranello, Rodrigo Scarton Bergamin, Juliana Schietti, Jochen Schöngart, Gustavo Schwartz, Natalino Silva, Marcos Silveira, Cristiana SimĂŁo Seixas, Marta Simbine, Ana Claudia Souza, Priscila Souza, Rodolfo Souza, Tereza Sposito, Edson Stefani Junior, Julio Daniel do Vale, Ima CĂ©lia GuimarĂŁes Vieira, Dora Villela, Marcos Vital, Haron Xaud, Katia Zanini, Charles Eugene Zartman, Nur Khalish Hafizhah Ideris, Faizah binti Hj Metali, Kamariah Abu Salim, Muhd Shahruney Saparudin, Rafizah Mat Serudin, Rahayu Sukmaria Sukri, Serge Begne, George Chuyong, Marie Noel Djuikouo, Christelle Gonmadje, Murielle Simo-Droissart, Bonaventure SonkĂ©, Hermann Taedoumg, Lise Zemagho, Sean Thomas, FidĂšle Baya, Gustavo Saiz, Javier Silva Espejo, Dexiang Chen, Alan Hamilton, Yide Li, Tushou Luo, Shukui Niu, Han Xu, Zhang Zhou, Esteban Ălvarez-DĂĄvila, Juan Carlos AndrĂ©s Escobar, Henry Arellano-Peña, Jaime Cabezas Duarte, Jhon CalderĂłn, Lina Maria Corrales Bravo, Borish Cuadrado, Hermes Cuadros, Alvaro Duque, Luisa Fernanda Duque, Sandra Milena Espinosa, Rebeca Franke-Ante, Hernando GarcĂa, Alejandro GĂłmez, Roy GonzĂĄlez-M., Ălvaro IdĂĄrraga-PiedrahĂta, Eliana Jimenez, RubĂ©n Jurado, Wilmar LĂłpez Oviedo, RenĂ© LĂłpez-Camacho, Omar Aurelio Melo Cruz, Irina Mendoza Polo, Edwin Paky, Karen PĂ©rez, Angel Pijachi, Camila Pizano, Adriana Prieto, Laura Ramos, Zorayda Restrepo Correa, James Richardson, Elkin RodrĂguez, Gina M. Rodriguez M., AgustĂn Rudas, Pablo Stevenson, MarkĂ©ta ChudomelovĂĄ, Martin Dancak, Radim HĂ©dl, Stanislav Lhota, Martin Svatek, Jacques Mukinzi, Corneille Ewango, Terese Hart, Emmanuel Kasongo Yakusu, Janvier Lisingo, Jean-Remy Makana, Faustin Mbayu, Benjamin Toirambe, John Tshibamba Mukendi, Lars Kvist, Gustav Nebel, Selene BĂĄez, Carlos CĂ©ron, Daniel M. Griffith, Juan Ernesto Guevara Andino, David Neill, Walter Palacios, Maria Cristina Peñuela-Mora, Gonzalo Rivas-Torres, Gorky Villa, Sheleme Demissie, Tadesse Gole, Techane Gonfa, Kalle Ruokolainen, Michel Baisie, Fabrice BĂ©nĂ©det, Wemo Betian, Vincent Bezard, Damien Bonal, JerĂŽme Chave, Vincent Droissart, Sylvie Gourlet-Fleury, Annette Hladik, Nicolas LabriĂšre, PĂ©trus Naisso, Maxime RĂ©jou-MĂ©chain, Plinio Sist, Lilian Blanc, Benoit Burban, GĂ©raldine Derroire, AurĂ©lie Dourdain, Clement Stahl, Natacha Nssi Bengone, Eric Chezeaux, FidĂšle Evouna Ondo, Vincent Medjibe, Vianet Mihindou, Lee White, Heike Culmsee, Cristabel DurĂĄn Rangel, Viviana Horna, Florian Wittmann, Stephen Adu-Bredu, Kofi Affum-Baffoe, Ernest Foli, Michael Balinga, Anand Roopsind, James Singh, Raquel Thomas, Roderick Zagt, Indu K. Murthy, Kuswata Kartawinata, Edi Mirmanto, Hari Priyadi, Ismayadi Samsoedin, Terry Sunderland, Ishak Yassir, Francesco Rovero, Barbara Vinceti, Bruno HĂ©rault, Shin-Ichiro Aiba, Kanehiro Kitayama, Armandu Daniels, Darlington Tuagben, John T. Woods, Muhammad Fitriadi, Alexander Karolus, Kho Lip Khoon, Noreen Majalap, Colin Maycock, Reuben Nilus, Sylvester Tan, Almeida Sitoe, Indiana Coronado G., Lucas Ojo, Rafael de Assis, Axel Dalberg Poulsen, Douglas Sheil, Karen ArĂ©valo Pezo, Hans Buttgenbach Verde, Victor Chama Moscoso, Jimmy Cesar Cordova Oroche, Fernando Cornejo Valverde, Massiel Corrales Medina, Nallaret Davila Cardozo, Jano de Rutte Corzo, Jhon del Aguila Pasquel, Gerardo Flores Llampazo, Luis Freitas, Darcy Galiano Cabrera, Roosevelt GarcĂa Villacorta, Karina Garcia Cabrera, Diego GarcĂa Soria, Leticia Gatica Saboya, Julio Miguel Grandez Rios, Gabriel Hidalgo Pizango, EurĂdice Honorio Coronado, Isau Huamantupa-Chuquimaco, Walter Huaraca Huasco, Yuri Tomas Huillca Aedo, Jose Luis Marcelo Peña, Abel Monteagudo Mendoza, Vanesa Moreano Rodriguez, Percy NĂșñez Vargas, Sonia Cesarina Palacios Ramos, Nadir Pallqui Camacho, Antonio Peña Cruz, Freddy Ramirez Arevalo, JosĂ© Reyna Huaymacari, Carlos Reynel Rodriguez, Marcos Antonio RĂos Paredes, Lily Rodriguez Bayona, Rocio del Pilar Rojas Gonzales, Maria Elena Rojas Peña, Norma Salinas Revilla, Yahn Carlos Soto Shareva, Raul Tupayachi Trujillo, Luis Valenzuela Gamarra, Rodolfo Vasquez Martinez, Jim Vega Arenas, Christian Amani, Suspense Averti Ifo, Yannick Bocko, Patrick Boundja, Romeo Ekoungoulou, Mireille Hockemba, Donatien Nzala, Alusine Fofanah, David Taylor, Guillermo Bañares-de Dios, Luis Cayuela, Ăñigo Granzow-de la Cerda, Manuel MacĂa, Juliana Stropp, Maureen Playfair, Verginia Wortel, Toby Gardner, Robert Muscarella, Hari Priyadi, Ervan Rutishauser, Kuo-Jung Chao, Pantaleo Munishi, Olaf BĂĄnki, Frans Bongers, Rene Boot, Gabriella Fredriksson, Jan Reitsma, Hans ter Steege, Tinde van Andel, Peter van de Meer, Peter van der Hout, Mark van Nieuwstadt, Bert van Ulft, Elmar Veenendaal, Ronald Vernimmen, Pieter Zuidema, Joeri Zwerts, Perpetra Akite, Robert Bitariho, Colin Chapman, Eilu Gerald, Miguel Leal, Patrick Mucunguzi, Miguel Alexiades, Timothy R. Baker, Karina Banda, Lindsay Banin, Jos Barlow, Amy Bennett, Erika Berenguer, Nicholas Berry, Neil M. Bird, George A. Blackburn, Francis Brearley, Roel Brienen, David Burslem, Lidiany Carvalho, Percival Cho, Fernanda Coelho, Murray Collins, David Coomes, Aida Cuni-Sanchez, Greta Dargie, Kyle Dexter, Mat Disney, Freddie Draper, Muying Duan, Adriane Esquivel-Muelbert, Robert Ewers, Belen Fadrique, Sophie Fauset, Ted R. Feldpausch, Filipe França, David Galbraith, Martin Gilpin, Emanuel Gloor, John Grace, Keith Hamer, David Harris, Tommaso Jucker, Michelle Kalamandeen, Bente Klitgaard, Aurora Levesley, Simon L. Lewis, Jeremy Lindsell, Gabriela Lopez-Gonzalez, Jon Lovett, Yadvinder Malhi, Toby Marthews, Emma McIntosh, Karina Melgaço, William Milliken, Edward Mitchard, Peter Moonlight, Sam Moore, Alexandra Morel, Julie Peacock, Kelvin Peh, Colin Pendry, R. Toby Pennington, Luciana de Oliveira Pereira, Carlos Peres, Oliver L. Phillips, Georgia Pickavance, Thomas Pugh, Lan Qie, Terhi Riutta, Katherine Roucoux, Casey Ryan, Tiina Sarkinen, Camila Silva Valeria, Dominick Spracklen, Suzanne Stas, Martin Sullivan, Michael Swaine, Joey Talbot, James Taplin, Geertje van der Heijden, Laura Vedovato, Simon Willcock, Mathew Williams, Luciana Alves, Patricia Alvarez Loayza, Gabriel Arellano, Cheryl Asa, Peter Ashton, Gregory Asner, Terry Brncic, Foster Brown, Robyn Burnham, Connie Clark, James Comiskey, Gabriel Damasco, Stuart Davies, Tony Di Fiore, Terry Erwin, William Farfan-Rios, Jefferson Hall, David Kenfack, Thomas Lovejoy, Roberta Martin, Olga Martha Montiel, John Pipoly, Nigel Pitman, John Poulsen, Richard Primack, Miles Silman, Marc Steininger, Varun Swamy, John Terborgh, Duncan Thomas, Peter Umunay, Maria Uriarte, Emilio Vilanova Torre, Ophelia Wang, Kenneth Young, Gerardo A. Aymard C., Lionel HernĂĄndez, Rafael Herrera FernĂĄndez, Hirma RamĂrez-Angulo, Pedro Salcedo, Elio Sanoja, Julio Serrano, Armando Torres-Lezama, Tinh Cong Le, Trai Trong Le, Hieu Dang Tra
Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries
Abstract
Background
Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres.
Methods
This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and lowâmiddle-income countries.
Results
In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of âsingle-useâ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for lowâmiddle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia.
Conclusion
This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both highâ and lowâmiddleâincome countries
Review of the Quality of YouTube Videos Recommending Exercises for the COVID-19 Lockdown
Background: The world is experiencing a pandemic caused by COVID-19. Insufficient phys ical activity can increase the risk of illness. Trying to replicate a normal search that any user/patient
could do in YouTube, the objective of this study was to evaluate the quality of YouTube videos
related to home exercises during lockdown and their adherence to World Health Organization (WHO)
recommendations. Methods: A simple search was carried out on YouTube. The first 150 videos were
selected. After applying exclusion criteria, 68 videos were analyzed and evaluated. Two statistical
analyses based on machine learning techniques were carried out. Videos were classified according
to principal component analysis (PCA) models as âRelevantâ and âNon-Relevantâ. Popularity was
assessed using the video power index (VPI). Informationâs quality and accuracy were gauged using
the DISCERN scale and global quality score (GQS). Reliability and credibility of information that can
be found on health-related websites was assessed using the Health On the Net Code (HONCode).
Exercises were evaluated according to WHO recommendations. Results: DISCERN, HONCode, and
GQS scored a mean of 2.29, 58.95, and 2.32, respectively. The PCA calculation allowed videos to
auto-classify into high- and low-quality videos. Conclusions: The quality of YouTube videos recom mending exercises during lockdown is low and doesnât reflect WHO recommendations. Effective
strategies and tools capable of indicating the quality of this information are needed to filter out
erroneous or non-rigorous information that may affect peopleâs health. These tools should help any
user/viewer to distinguish videos of high and low quality
Fasciola hepatica induces Foxp3 T cell, proinflammatory and regulatory cytokine overexpression in liver from infected sheep during early stages of infection
Abstract The expression of T regulatory cells (Foxp3), regulatory (interleukin [IL]-10 and transforming growth factor beta [TGF-ÎČ]) and proinflammatory (tumor necrosis factor alpha [TNF-α] and interleukin [IL]-1ÎČ) cytokines was quantified using real time polymerase chain reaction (qRT-PCR) in the liver of sheep during early stages of infection with Fasciola hepatica (1, 3, 9, and 18 days post-infection [dpi]). Portal fibrosis was also evaluated by Massonâs trichrome stain as well as the number of Foxp3+ cells by immunohistochemistry. Animals were divided into three groups: (a) group 1 was immunized with recombinant cathepsin L1 from F. hepatica (FhCL1) in Montanide adjuvant and infected; (b) group 2 was uniquely infected with F. hepatica; and (c) group 3 was the control group, unimmunized and uninfected. An overexpression of regulatory cytokines of groups 1 and 2 was found in all time points tested in comparison with group 3, particularly at 18 dpi. A significant increase of the number of Foxp3+ lymphocytes in groups 1 and 2 was found at 9 and 18 dpi relative to group 3. A progressive increase in portal fibrosis was found in groups 1 and 2 in comparison with group 3. In this regard, group 1 showed smaller areas of fibrosis than group 2. There was a significant positive correlation between Foxp3 and IL-10 expression (by immunohistochemistry and qRT-PCR) just as between portal fibrosis and TGF-ÎČ gene expression. The expression of proinflammatory cytokines increased gradually during the experience. These findings suggest the induction of a regulatory phenotype by the parasite that would allow its survival at early stages of the disease when it is more vulnerable
Regulation of death receptor signaling by the autophagy protein TP53INP2
TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in deathâreceptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptorâinduced apoptosis. TP53INP2 binds caspaseâ8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspaseâ8 by TRAF6. We have defined a TRAF6âinteracting motif (TIM) and a ubiquitinâinteracting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspaseâ8 to TRAF6 for further polyubiquitination of caspaseâ8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspaseâ8, and subsequently reduce levels of death receptorâinduced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAILâinduced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspaseâ8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway
Regulation of death receptor signaling by the autophagy protein TP53INP2
TP53INP2 positively regulates autophagy by binding to Atg8 proteins. Here, we uncover a novel role of TP53INP2 in deathâreceptor signaling. TP53INP2 sensitizes cells to apoptosis induced by death receptor ligands. In keeping with this, TP53INP2 deficiency in cultured cells or mouse livers protects against death receptorâinduced apoptosis. TP53INP2 binds caspaseâ8 and the ubiquitin ligase TRAF6, thereby promoting the ubiquitination and activation of caspaseâ8 by TRAF6. We have defined a TRAF6âinteracting motif (TIM) and a ubiquitinâinteracting motif in TP53INP2, enabling it to function as a scaffold bridging already ubiquitinated caspaseâ8 to TRAF6 for further polyubiquitination of caspaseâ8. Mutations of key TIM residues in TP53INP2 abrogate its interaction with TRAF6 and caspaseâ8, and subsequently reduce levels of death receptorâinduced apoptosis. A screen of cancer cell lines showed that those with higher protein levels of TP53INP2 are more prone to TRAILâinduced apoptosis, making TP53INP2 a potential predictive marker of cancer cell responsiveness to TRAIL treatment. These findings uncover a novel mechanism for the regulation of caspaseâ8 ubiquitination and reveal TP53INP2 as an important regulator of the death receptor pathway