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5. Social and moral psychology of COVID-19 across 69 countries

Author

Azevedo, Flavio, Pavlović, Tomislav, Rêgo, Gabriel G., Ay, F. Ceren, Gjoneska, Biljana, Etienne, Tom W., Ross, Robert M., Schönegger, Philipp, Riaño-Moreno, Julián C., Cichocka, Aleksandra, Capraro, Valerio, Cian, Luca, Longoni, Chiara, Chan, Ho Fai, Van Bavel, Jay J., Sjåstad, Hallgeir, Nezlek, John B., Alfano, Mark, Gelfand, Michele J., Birtel, Michèle D., Cislak, Aleksandra, Lockwood, Patricia L., Abts, Koen, Agadullina, Elena, Aruta, John Jamir Benzon, Besharati, Sahba Nomvula, Bor, Alexander, Choma, Becky L., Crabtree, Charles David, Cunningham, William A., De, Koustav, Ejaz, Waqas, Elbaek, Christian T., Findor, Andrej, Flichtentrei, Daniel, Franc, Renata, Gruber, June, Gualda, Estrella, Horiuchi, Yusaku, Huynh, Toan Luu Duc, Ibanez, Agustin, Imran, Mostak Ahamed, Israelashvili, Jacob, Jasko, Katarzyna, Kantorowicz, Jaroslaw, Kantorowicz-Reznichenko, Elena, Krouwel, André, Laakasuo, Michael, Lamm, Claus, Leygue, Caroline, Lin, Ming-Jen, Mansoor, Mohammad Sabbir, Marie, Antoine, Mayiwar, Lewend, Mazepus, Honorata, McHugh, Cillian, Minda, John Paul, Mitkidis, Panagiotis, Olsson, Andreas, Otterbring, Tobias, Packer, Dominic J., Perry, Anat, Petersen, Michael Bang, Puthillam, Arathy, Rothmund, Tobias, Santamaría-García, Hernando, Schmid, Petra C., Stoyanov, Drozdstoy, Tewari, Shruti, Todosijević, Bojan, Tsakiris, Manos, Tung, Hans H., Umbres, Radu G., Vanags, Edmunds, Vlasceanu, Madalina, Vonasch, Andrew, Yucel, Meltem, Zhang, Yucheng, Abad, Mohcine, Adler, Eli, Akrawi, Narin, Mdarhri, Hamza Alaoui, Amara, Hanane, Amodio, David M., Antazo, Benedict G., Apps, Matthew, Ba, Mouhamadou Hady, Barbosa, Sergio, Bastian, Brock, Berg, Anton, Bernal-Zárate, Maria P., Bernstein, Michael, Białek, Michał, Bilancini, Ennio, Bogatyreva, Natalia, Boncinelli, Leonardo, Booth, Jonathan E., Borau, Sylvie, Buchel, Ondrej, Cameron, C. Daryl, Carvalho, Chrissie F., Celadin, Tatiana, Cerami, Chiara, Chalise, Hom Nath, Cheng, Xiaojun, Cockcroft, Kate, Conway, Jane, Córdoba-Delgado, Mateo Andres, Crespi, Chiara, Crouzevialle, Marie, Cutler, Jo, Cypryańska, Marzena, Dabrowska, Justyna, Daniels, Michael A., Davis, Victoria H., Dayley, Pamala N., Delouvée, Sylvain, Denkovski, Ognjan, Dezecache, Guillaume, Dhaliwal, Nathan A., Diato, Alelie B., Di Paolo, Roberto, Drosinou, Marianna, Dulleck, Uwe, Ekmanis, Jānis, Ertan, Arhan S., Farhana, Hapsa Hossain, Farkhari, Fahima, Farmer, Harry, Fenwick, Ali, Fidanovski, Kristijan, Flew, Terry, Fraser, Shona, Frempong, Raymond Boadi, Fugelsang, Jonathan A., Gale, Jessica, Garcia-Navarro, E. Begoña, Garladinne, Prasad, Ghajjou, Oussama, Gkinopoulos, Theofilos, Gray, Kurt, Griffin, Siobhán M., Gronfeldt, Bjarki, Gümren, Mert, Gurung, Ranju Lama, Halperin, Eran, Harris, Elizabeth, Herzon, Volo, Hruška, Matej, Huang, Guanxiong, Hudecek, Matthias F. C., Isler, Ozan, Jangard, Simon, Jorgensen, Frederik J., Kachanoff, Frank, Kahn, John, Dangol, Apsara Katuwal, Keudel, Oleksandra, Koppel, Lina, Koverola, Mika, Kubin, Emily, Kunnari, Anton, Kutiyski, Yordan, Laguna, Oscar Moreda, Leota, Josh, Lermer, Eva, Levy, Jonathan, Levy, Neil, Li, Chunyun, Long, Elizabeth U., Maglić, Marina, McCashin, Darragh, Metcalf, Alexander L., Mikloušić, Igor, El Mimouni, Soulaimane, Miura, Asako, Molina-Paredes, Juliana, Monroy-Fonseca, César, Morales-Marente, Elena, Moreau, David, Muda, Rafał, Myer, Annalisa, Nash, Kyle, Nesh-Nash, Tarik, Nitschke, Jonas P., Nurse, Matthew S., Ohtsubo, Yohsuke, de Mello, Victoria Oldemburgo, O’Madagain, Cathal, Onderco, Michal, Palacios-Galvez, M. Soledad, Palomöki, Jussi, Pan, Yafeng, Papp, Zsófia, Pärnamets, Philip, Paruzel-Czachura, Mariola, Pavlović, Zoran, Payán-Gómez, César, Perander, Silva, Pitman, Michael Mark, Prasad, Rajib, Pyrkosz-Pacyna, Joanna, Rathje, Steve, Raza, Ali, Rhee, Kasey, Robertson, Claire E., Rodríguez-Pascual, Iván, Saikkonen, Teemu, Salvador-Ginez, Octavio, Santi, Gaia C., Santiago-Tovar, Natalia, Savage, David, Scheffer, Julian A., Schultner, David T., Schutte, Enid M., Scott, Andy, Sharma, Madhavi, Sharma, Pujan, Skali, Ahmed, Stadelmann, David, Stafford, Clara Alexandra, Stanojević, Dragan, Stefaniak, Anna, Sternisko, Anni, Stoica, Augustin, Stoyanova, Kristina K., Strickland, Brent, Sundvall, Jukka, Thomas, Jeffrey P., Tinghög, Gustav, Torgler, Benno, Traast, Iris J., Tucciarelli, Raffaele, Tyrala, Michael, Ungson, Nick D., Uysal, Mete S., Van Lange, Paul A. M., van Prooijen, Jan-Willem, van Rooy, Dirk, Västfjäll, Daniel, Verkoeijen, Peter, Vieira, Joana B., von Sikorski, Christian, Walker, Alexander Cameron, Watermeyer, Jennifer, Wetter, Erik, Whillans, Ashley, White, Katherine, Habib, Rishad, Willardt, Robin, Wohl, Michael J. A., Wójcik, Adrian Dominik, Wu, Kaidi, Yamada, Yuki, Yilmaz, Onurcan, Yogeeswaran, Kumar, Ziemer, Carolin-Theresa, Zwaan, Rolf A., Boggio, Paulo S., and Sampaio, Waldir M.

Published
2023
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11. National identity predicts public health support during a global pandemic

Author

Van Bavel, Jay J., Cichocka, Aleksandra, Capraro, Valerio, Sjåstad, Hallgeir, Nezlek, John B., Pavlović, Tomislav, Alfano, Mark, Gelfand, Michele J., Azevedo, Flavio, Birtel, Michèle D., Cislak, Aleksandra, Lockwood, Patricia L., Ross, Robert Malcolm, Abts, Koen, Agadullina, Elena, Aruta, John Jamir Benzon, Besharati, Sahba Nomvula, Bor, Alexander, Choma, Becky L., Crabtree, Charles David, Cunningham, William A., De, Koustav, Ejaz, Waqas, Elbaek, Christian T., Findor, Andrej, Flichtentrei, Daniel, Franc, Renata, Gjoneska, Biljana, Gruber, June, Gualda, Estrella, Horiuchi, Yusaku, Huynh, Toan Luu Duc, Ibanez, Augustin, Imran, Mostak Ahamed, Israelashvili, Jacob, Jasko, Katarzyna, Kantorowicz, Jaroslaw, Kantorowicz-Reznichenko, Elena, Krouwel, André, Laakasuo, Michael, Lamm, Claus, Leygue, Caroline, Lin, Ming-Jen, Mansoor, Mohammad Sabbir, Marie, Antoine, Mayiwar, Lewend, Mazepus, Honorata, McHugh, Cillian, Minda, John Paul, Mitkidis, Panagiotis, Olsson, Andreas, Otterbring, Tobias, Packer, Dominic J., Perry, Anat, Petersen, Michael Bang, Puthillam, Arathy, Riaño-Moreno, Julián C., Rothmund, Tobias, Santamaría-García, Hernando, Schmid, Petra C., Stoyanov, Drozdstoy, Tewari, Shruti, Todosijević, Bojan, Tsakiris, Manos, Tung, Hans H., Umbreș, Radu G., Vanags, Edmunds, Vlasceanu, Madalina, Vonasch, Andrew, Yucel, Meltem, Zhang, Yucheng, Abad, Mohcine, Adler, Eli, Akrawi, Narin, Mdarhri, Hamza Alaoui, Amara, Hanane, Amodio, David M., Antazo, Benedict G., Apps, Matthew, Ay, F. Ceren, Ba, Mouhamadou Hady, Barbosa, Sergio, Bastian, Brock, Berg, Anton, Bernal-Zárate, Maria P., Bernstein, Michael, Białek, Michał, Bilancini, Ennio, Bogatyreva, Natalia, Boncinelli, Leonardo, Booth, Jonathan E., Borau, Sylvie, Buchel, Ondrej, Cameron, C. Daryl, Carvalho, Chrissie F., Celadin, Tatiana, Cerami, Chiara, Chalise, Hom Nath, Cheng, Xiaojun, Cian, Luca, Cockcroft, Kate, Conway, Jane, Córdoba-Delgado, Mateo Andres, Crespi, Chiara, Crouzevialle, Marie, Cutler, Jo, Cypryańska, Marzena, Dabrowska, Justyna, Daniels, Michael A., Davis, Victoria H., Dayley, Pamala N., Delouvee, Sylvain, Denkovski, Ognjan, Dezecache, Guillaume, Dhaliwal, Nathan A., Diato, Alelie B., Di Paolo, Roberto, Drosinou, Marianna, Dulleck, Uwe, Ekmanis, Jānis, Ertan, Arhan S., Etienne, Tom W., Farhana, Hapsa Hossain, Farkhari, Fahima, Farmer, Harry, Fenwick, Ali, Fidanovski, Kristijan, Flew, Terry, Fraser, Shona, Frempong, Raymond Boadi, Fugelsang, Jonathan A., Gale, Jessica, Garcia-Navarro, E. Begoña, Garladinne, Prasad, Ghajjou, Oussama, Gkinopoulos, Theofilos, Gray, Kurt, Griffin, Siobhán M., Gronfeldt, Bjarki, Gümren, Mert, Gurung, Ranju Lama, Halperin, Eran, Harris, Elizabeth, Herzon, Volo, Hruška, Matej, Huang, Guanxiong, Hudecek, Matthias F. C., Isler, Ozan, Jangard, Simon, Jørgensen, Frederik J., Kachanoff, Frank, Kahn, John, Dangol, Apsara Katuwal, Keudel, Oleksandra, Koppel, Lina, Koverola, Mika, Kubin, Emily, Kunnari, Anton, Kutiyski, Yordan, Laguna, Oscar, Leota, Josh, Lermer, Eva, Levy, Jonathan, Levy, Neil, Li, Chunyun, Long, Elizabeth U., Longoni, Chiara, Maglić, Marina, McCashin, Darragh, Metcalf, Alexander L., Mikloušić, Igor, El Mimouni, Soulaimane, Miura, Asako, Molina-Paredes, Juliana, Monroy-Fonseca, César, Morales-Marente, Elena, Moreau, David, Muda, Rafał, Myer, Annalisa, Nash, Kyle, Nesh-Nash, Tarik, Nitschke, Jonas P., Nurse, Matthew S., Ohtsubo, Yohsuke, Oldemburgo de Mello, Victoria, O’Madagain, Cathal, Onderco, Michal, Palacios-Galvez, M. Soledad, Palomäki, Jussi, Pan, Yafeng, Papp, Zsófia, Pärnamets, Philip, Paruzel-Czachura, Mariola, Pavlović, Zoran, Payán-Gómez, César, Perander, Silva, Pitman, Michael Mark, Prasad, Rajib, Pyrkosz-Pacyna, Joanna, Rathje, Steve, Raza, Ali, Rêgo, Gabriel G., Rhee, Kasey, Robertson, Claire E., Rodríguez-Pascual, Iván, Saikkonen, Teemu, Salvador-Ginez, Octavio, Sampaio, Waldir M., Santi, Gaia C., Santiago-Tovar, Natalia, Savage, David, Scheffer, Julian A., Schönegger, Philipp, Schultner, David T., Schutte, Enid M., Scott, Andy, Sharma, Madhavi, Sharma, Pujan, Skali, Ahmed, Stadelmann, David, Stafford, Clara Alexandra, Stanojević, Dragan, Stefaniak, Anna, Sternisko, Anni, Stoica, Augustin, Stoyanova, Kristina K., Strickland, Brent, Sundvall, Jukka, Thomas, Jeffrey P., Tinghög, Gustav, Torgler, Benno, Traast, Iris J., Tucciarelli, Raffaele, Tyrala, Michael, Ungson, Nick D., Uysal, Mete S., Van Lange, Paul A. M., van Prooijen, Jan-Willem, van Rooy, Dirk, Västfjäll, Daniel, Verkoeijen, Peter, Vieira, Joana B., von Sikorski, Christian, Walker, Alexander Cameron, Watermeyer, Jennifer, Wetter, Erik, Whillans, Ashley, Willardt, Robin, Wohl, Michael J. A., Wójcik, Adrian Dominik, Wu, Kaidi, Yamada, Yuki, Yilmaz, Onurcan, Yogeeswaran, Kumar, Ziemer, Carolin-Theresa, Zwaan, Rolf A., and Boggio, Paulo S.

Published
2022
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22. Qualitative emphysema and risk of COPD hospitalization in a multicenter CT lung cancer screening cohort study

Author

Gazourian, Lee, Thedinger, William B., Regis, Shawn M., Pagura, Elizabeth J., Price, Lori Lyn, Gawlik, Melissa, Stefanescu, Cristina F., Lamb, Carla, Rieger-Christ, Kimberly M., Singh, Harpreet, Casasola, Marcel, Walker, Alexander R., Rupal, Arashdeep, Patel, Avignat S., Come, Carolyn E., Sanayei, Ava M., Long, William P., Rizzo, Giulia S., McKee, Andrea B., Washko, George R., San Jose Estepar, Raul, Wald, Christoph, McKee, Brady J., Thomson, Carey C., and Liesching, Timothy N.

Published
2021
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26. Semiparametric Allocation of Subjects to Cohort Strata.

Author

Walker, Alexander M., Russo, Massimiliano, Schneeweiss, Maria C., and Glynn, Robert J.

Abstract

Background: We illustrate a method for stratum assignment in small cohort studies that avoids modeling assumptions. Methods: Off-the-shelf software (rgenoud) made stratum assignments to minimize a loss function built on within-stratum and populationadjusted Euclidean distances. Results: In 100 trials using simulated data of 300 records with a binary treatment and four dissimilar covariate treatment predictors, minimizing a loss based on Euclidean distance reduced covariate imbalance by a median of 99%. Stratification by propensity score and weighting records by the inverse of their probability of treatment reduced imbalance by 76%-89% and 83%-94%, respectively. Loss minimization applied to a cohort of 361 children undergoing immunotherapy achieved nearly complete elimination of covariate differences for important treatment predictors. Conclusion: With the availability of semiparametric stratumassignment algorithms, analysts can tailor loss functions to meet design goals. Here, a loss function that emphasized covariate balance performed well under limited testing. [ABSTRACT FROM AUTHOR]

Published
2024
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27. Host ANP32A mediates the assembly of the influenza virus replicase

Author

Carrique, Loïc, Fan, Haitian, Walker, Alexander P., Keown, Jeremy R., Sharps, Jane, Staller, Ecco, and Barclay, Wendy S.

Subjects
RNA polymerases -- Physiological aspects, Influenza viruses -- Physiological aspects -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Aquatic birds represent a vast reservoir from which new pandemic influenza A viruses can emerge.sup.1. Influenza viruses contain a negative-sense segmented RNA genome that is transcribed and replicated by the viral heterotrimeric RNA polymerase (FluPol) in the context of viral ribonucleoprotein complexes.sup.2,3. RNA polymerases of avian influenza A viruses (FluPolA) replicate viral RNA inefficiently in human cells because of species-specific differences in acidic nuclear phosphoprotein 32 (ANP32), a family of essential host proteins for FluPol activity.sup.4. Host-adaptive mutations, particularly a glutamic-acid-to-lysine mutation at amino acid residue 627 (E627K) in the 627 domain of the PB2 subunit, enable avian FluPolA to overcome this restriction and efficiently replicate viral RNA in the presence of human ANP32 proteins. However, the molecular mechanisms of genome replication and the interplay with ANP32 proteins remain largely unknown. Here we report cryo-electron microscopy structures of influenza C virus polymerase (FluPolC) in complex with human and chicken ANP32A. In both structures, two FluPolC molecules form an asymmetric dimer bridged by the N-terminal leucine-rich repeat domain of ANP32A. The C-terminal low-complexity acidic region of ANP32A inserts between the two juxtaposed PB2 627 domains of the asymmetric FluPolA dimer, suggesting a mechanism for how the adaptive PB2(E627K) mutation enables the replication of viral RNA in mammalian hosts. We propose that this complex represents a replication platform for the viral RNA genome, in which one of the FluPol molecules acts as a replicase while the other initiates the assembly of the nascent replication product into a viral ribonucleoprotein complex. Structural and biochemical studies of influenza virus RNA polymerase in complex with host acidic nuclear phosphoprotein 32 (ANP32) show how ANP32-mediated polymerase dimerization enables the replication of influenza viral RNA in a host-dependent manner., Author(s): Loïc Carrique [sup.1] , Haitian Fan [sup.2] , Alexander P. Walker [sup.2] , Jeremy R. Keown [sup.1] , Jane Sharps [sup.2] , Ecco Staller [sup.3] [sup.5] , Wendy S. [...]

Published
2020
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28. Structures of influenza A virus RNA polymerase offer insight into viral genome replication

Author

Fan, Haitian, Walker, Alexander P., Carrique, Loïc, Keown, Jeremy R., Serna Martin, Itziar, Karia, Dimple, and Sharps, Jane

Subjects
RNA polymerases -- Structure, Influenza viruses -- Analysis -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Influenza A viruses are responsible for seasonal epidemics, and pandemics can arise from the transmission of novel zoonotic influenza A viruses to humans.sup.1,2. Influenza A viruses contain a segmented negative-sense RNA genome, which is transcribed and replicated by the viral-RNA-dependent RNA polymerase (FluPol.sub.A) composed of PB1, PB2 and PA subunits.sup.3-5. Although the high-resolution crystal structure of FluPol.sub.A of bat influenza A virus has previously been reported.sup.6, there are no complete structures available for human and avian FluPol.sub.A. Furthermore, the molecular mechanisms of genomic viral RNA (vRNA) replication--which proceeds through a complementary RNA (cRNA) replicative intermediate, and requires oligomerization of the polymerase.sup.7-10--remain largely unknown. Here, using crystallography and cryo-electron microscopy, we determine the structures of FluPol.sub.A from human influenza A/NT/60/1968 (H3N2) and avian influenza A/duck/Fujian/01/2002 (H5N1) viruses at a resolution of 3.0-4.3 Å, in the presence or absence of a cRNA or vRNA template. In solution, FluPol.sub.A forms dimers of heterotrimers through the C-terminal domain of the PA subunit, the thumb subdomain of PB1 and the N1 subdomain of PB2. The cryo-electron microscopy structure of monomeric FluPol.sub.A bound to the cRNA template reveals a binding site for the 3' cRNA at the dimer interface. We use a combination of cell-based and in vitro assays to show that the interface of the FluPol.sub.A dimer is required for vRNA synthesis during replication of the viral genome. We also show that a nanobody (a single-domain antibody) that interferes with FluPol.sub.A dimerization inhibits the synthesis of vRNA and, consequently, inhibits virus replication in infected cells. Our study provides high-resolution structures of medically relevant FluPol.sub.A, as well as insights into the replication mechanisms of the viral RNA genome. In addition, our work identifies sites in FluPol.sub.A that could be targeted in the development of antiviral drugs. Structures of RNA polymerase of human and avian influenza A viruses reveal that the interface of the RNA polymerase dimer is required to initiate viral RNA synthesis in viral genome replication., Author(s): Haitian Fan [sup.1] , Alexander P. Walker [sup.1] , Loïc Carrique [sup.2] , Jeremy R. Keown [sup.2] , Itziar Serna Martin [sup.1] [sup.2] [sup.6] , Dimple Karia [sup.2] , [...]

Published
2019
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34. Stratified analysis in comparative effectiveness studies that emulate randomized trials.

Author

Htoo, Phyo T., Glynn, Robert J., Wang, Shirley, Paik, Julie M., Schneeweiss, Sebastian, Walker, Alexander M., and Patorno, Elisabetta

Abstract

Purpose: For observational cohort studies that employ matching by propensity scores (PS), preliminary stratification by consequential predictors of outcome better emulates stratified randomization and potentially reduces variance and bias through relaxed dependence on modeling assumptions. We assessed the impact of pre‐stratification in two real‐life examples. For both, prior evidence from placebo‐controlled randomized clinical trials (RCTs) suggested small or no risk reduction, but observational analysis suggested protection, presumably the result of confounding bias. Study Design and Setting: The study populations consisted of Medicare beneficiaries (2014‐18) with type 2 diabetes initiating either (i) empagliflozin versus dipeptidyl peptidase‐4 inhibitors (DPP‐4i) or (ii) empagliflozin versus glucagon‐like peptide‐1 receptor agonists (GLP‐1RA). The outcome was myocardial infarction or stroke. We estimated hazard ratios (HR) and rate differences (RD) after controlling for 143 pre‐exposure covariates via 1:1 PS matching after (1) PS estimation in the total cohort (total‐cohort PS‐matching) and (2) PS estimation separately by baseline cardiovascular disease (stratified PS matching). Results: Stratified PS matching resulted in HRs that exceeded those from total‐cohort PS‐matching by 13% and 9%, respectively, for the comparisons of empagliflozin to DPP‐4i and GLP‐1RA. Against both comparators, HRs and RDs after stratified PS matching were closer to the null, with slightly higher variances (2%–3%) than those after total‐cohort PS matching. Conclusion: Stratified PS matching produced effect estimates closer to the expected trial findings than total‐cohort PS matching. The price paid in increased variance was minimal. [ABSTRACT FROM AUTHOR]

Published
2024
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46. Tutors' Responses to Student Disclosures: From "Suicidal Ideation" to "Feeling a Little Stressed".

Author

Walker, Alexander, Tait-McCutcheon, Sandi L., and Gilbert, Amanda

Subjects
LONELINESS, SUICIDAL ideation, UNIVERSITIES & colleges, DISCLOSURE, TUTORS & tutoring, THEMATIC analysis
Abstract

Tutors in higher education are receiving and responding to student disclosures that include racism, anxiety, loneliness, legal disputes, family upheavals, physical, emotional, and mental health, bereavement, legal battles, and harassment. In many cases, this caring aspect of the tutor role is not acknowledged, allocated time in job descriptions, or accurately remunerated. This qualitative study explored how tutors experienced and managed student disclosures, the personal and professional impact of responding to disclosures, and how tutors believed they could be better supported. Data was collected from two cohorts of participants tutoring at a University in Aotearoa New Zealand. using interviews and questionnaires and analysed by reflexive thematic analysis. Our findings showed that our participants believed they were positioned vulnerably between a rock and a hard place. At the rock, tutors were told to follow university guidelines and refer distressed students to over-loaded course coordinators or over-subscribed support services. At the hard place, tutors were often the first to be disclosed to, because of their front-facing positioning at the university and once they had heard the disclosure felt it was unethical not to try and help. Tutors believed they could assist students with personal challenges if their precarious positioning within the university was protected and strengthened and if appropriate support was provided by their university through training, time, and remuneration. Findings have implications for higher education providers to reconsider how tutors are supported to support students. [ABSTRACT FROM AUTHOR]

Published
2023
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47. A TGFβ-ECM-integrin signaling axis drives structural reconfiguration of the bile duct to promote polycystic liver disease.

Author

Waddell, Scott H., Yao, Yuelin, Olaizola, Paula, Walker, Alexander, Jarman, Edward J., Gournopanos, Konstantinos, Gradinaru, Andreea, Christodoulou, Ersi, Gautier, Philippe, Boerrigter, Melissa M., Cadamuro, Massimiliano, Fabris, Luca, Drenth, Joost PH, Kendall, Timothy J., Banales, Jesus M., Khamseh, Ava, Mill, Pleasantine, and Boulter, Luke

Subjects
POLYCYSTIC kidney disease, BILE ducts, LIVER diseases, EDEMA, CHOLANGITIS, BILIARY tract, CYST rupture
Abstract

The formation of multiple cysts in the liver occurs in a number of isolated monogenic diseases or multisystemic syndromes, during which bile ducts develop into fluid-filled biliary cysts. For patients with polycystic liver disease (PCLD), nonsurgical treatments are limited, and managing life-long abdominal swelling, pain, and increasing risk of cyst rupture and infection is common. We demonstrate here that loss of the primary cilium on postnatal biliary epithelial cells (via the deletion of the cilia gene Wdr35) drives ongoing pathological remodeling of the biliary tree, resulting in progressive cyst formation and growth. The development of cystic tissue requires the activation of transforming growth factor–β (TGFβ) signaling, which promotes the expression of a procystic, fibronectin-rich extracellular matrix and which itself is perceived by a changing profile of integrin receptors on the cystic epithelium. This signaling axis is conserved in liver cysts from patients with either autosomal dominant polycystic kidney disease or autosomal dominant polycystic liver disease, indicating that there are common cellular mechanisms for liver cyst growth regardless of the underlying genetic cause. Cyst number and size can be reduced by inhibiting TGFβ signaling or integrin signaling in vivo. We suggest that our findings represent a therapeutic route for patients with polycystic liver disease, most of whom would not be amenable to surgery. Editor's summary: Polycystic liver disease can result in severely reduced quality of life but has few available treatments. Waddell et al. show that loss of primary cilia in adult mouse biliary epithelia produces an integrin-rich cellular microenvironment that promotes pathological bile duct remodeling, resulting in the formation of morphologically abnormal cyst growth and fission-induced polycystic structures. Pharmacological inhibition of a specific integrin or TGFβ signaling reduced cyst size and number in the animals. Analysis of human liver samples suggested that this pathway may be a target in polycystic liver disease of varying genetic etiologies. —Catherine Charneski [ABSTRACT FROM AUTHOR]

Published
2023
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