Introduction-The History


Control of processes with multiple steady states using MPC and RBF neural networks


Improving the Energy Management of a Building Complex through Utility System Modelling

Michal Touš, Vítězslav Máša, Martin Pavlas, Valentýn Avramov


Contributors

Advances in Space Science and Technology


Copyright


Determination of Rates, Orders, and Rate Coefficients


Author Index to Volume VII


Preface


Chapter 32 Surficial characterization of dioxin in Midland, Michigan, using non-euclidean geostatistics


An Enzyme Immuno Assay for the Detection of Basic Myelin Protein and Antibodies to BMP in CSF

G.J. VAN KAMP, J.C. KOETSIER, L. LUYENDIJK, J. O. MISPELBLOM BEIJER, C.L. VERWEY


Contributors


Index


Maintainability Considerations

Practical Machinery Management for Process Plants


Posterity's Judgment of Regiomontanus

Studies in the History and Philosophy of Mathematics


Approximate Multi-Parametric Programming based B&B Algorithm for MINLPs


Preface

International Review of Research in Mental Retardation


Economic Plantwide Control of C4 Isomerization Process

Rahul Jagtap, Sonam Goenka, Nitin Kaistha


F


Quellen


Serum Beta-2 Microglobulin in the Follow-Up of Chronic Lymphocytic Leukemia

J.C. RENVERSEZ, M.F. SOTTO, D. HOLLARD, J.J. SOTTO


Miscellaneous maps

Developments in Structural Geology and Tectonics


Many-body Effects in Photoemission


Author Index


The maintenance environment


Copyright page

Handbook of Petroleum Exploration and Production


A Comparative Analysis of Actual Dutch Macroeconomic Models

G. d'Alcantara, P.-A. Muet, H.N. Weddepohl


An Evaluation of the Effects of Commodity-Price Indexation on Developed and Developing Economies: An Application of the Rempis Model


Contributors


Appendix B


Hybrid Methods

Studies in Computer Science and Artificial Intelligence


Contributors

Advances in Child Development and Behavior


Scaling integrated cardiovascular–kidney–metabolic care through primary health care in the Americas: a health policy analysis of HEARTS 2.0 implementation levers and architecture


Not as information, but as a trigger: recurrent climate trauma after the 2024 Rio Grande do Sul floods


Modelling gestational weight gain trajectories and risk of adverse birth outcomes using super imposition by translation and rotation: findings from two Brazilian cohort studies

Audêncio Victor, Liania A. Luzia, Tamiris Ramos Silva, Aldaisa Pereira Lopes, Rebecca E. Penzias, Isabel Oliveira Aires, Patrícia Helen Rondó, Eric O. Ohuma


Methadone treatment and associated health and social outcomes after a national manufacturing closure in Mexico: a longitudinal observational cohort study in Tijuana

Jesse Lloyd Goldshear, Alicia Harvey-Vera, Gudelia Rangel, Daniela Abramovitz, Natasha K. Martin, Steffanie A. Strathdee, Joseph Friedman, Maria Elena Medina-Mora, Annick Bórquez

National Institute on Drug Abuse, Center for AIDS Research, University of California, San Diego, National Institutes of Health


Economic evaluation of dapagliflozin added to standard therapy in chronic heart failure in Argentina: a cost-utility analysis

Javier Santiago Araujo, Francisco Moioni, Diego Sebastián Novielli, Germán Andrés Jelusic, Sofía Inés Lucini, Jeremías Augusto Zabalo, José Alberto Spala, María Celeste Piervincenzi


Data-driven subclassification of type 2 diabetes in Mexico: a conceptual framework to improve diabetes care

Mario Cesar Torres-Chávez, Jaretzy García-Manteca, Jacqueline A. Seiglie, Omar Yaxmehen Bello-Chavolla, Neftali Eduardo Antonio-Villa


Crossing the divides: integrated services for youth at risk of homelessness

Manasi Kumar, Deborah Padgett, Kelsey Louie, Sarah Narendorf


Spatiotemporal analysis and socioeconomic determinants of pediatric lymphoid leukemias mortality in Brazil from 2000 to 2021: an ecological study

Bárbara Sarni Sanches, Isadora Lima Oliveira, Ciana Duque Estrada Botelho, Nathalia Lopez Duarte, Ursula Berger, Marcelo Gerardin Poirot Land

Society for Industrial and Organizational Psychology, National Council for Scientific and Technological Development, Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State, Coordination for the improvement of Higher Education Personnel


Global and regional inequalities in dairy recommendations: a natural language processing analysis of food-based dietary guidelines across income groups

Ayleen Bertini, Hugo Cáceres-Ozimica, Rodrigo Valenzuela, Samuel Durán-Agüero


Socioeconomic dynamics and tuberculosis mortality in São Paulo: a population-level analysis using spatial modeling

Yan Mathias Alves, Reginaldo Bazon Vaz Tavares, Nathalia Zini, Tatiana Pestana Barbosa, Maria Eduarda Pagano Pelodan, Antônio Carlos Vieira Ramos, Tatiana Ferraz de Araújo Alecrim, Jaqueline Garcia de Almeida Ballestero, Bruno de Bezerril Andrade, Jason Edward Farley, Ricardo Alexandre Arcêncio

Coordination for the improvement of Higher Education Personnel, State of Sao Paulo Research Foundation


Association between drought and adverse birth outcomes: a nationwide cohort study with 29.8 million live births in Brazil

Aline dos Santos Rocha, Leydson Galvíncio Dantas, Andrêa J.F. Ferreira, Paulo Victor Maciel da Costa, Danielson J.D. Neves, Enny S. Paixao, Julia M. Pescarini, Rosemeire Fiaccone, Ismael H. Silveira, Priscila Ribas de Farias Costa, Rita de Cássia Ribeiro-Silva, Otavio Ranzani, Mauricio L. Barreto

Wellcome Trust, Spain Ministry of Science Innovation and Universities


Racial inequities in cervical cancer mortality and the role of the Bolsa Família conditional cash transfer programme: results from the 100 Million Brazilian Cohort

Joanna M.N. Guimarães, Julia M. Pescarini, Ana L. Moncayo, Peter Craig, Samuel Araujo Gomes da Silva, Francine de Souza Dias, Ronal Ruiz Grijalva, Ligia Gabrielli, Isabel dos-Santos-Silva, M. da Conceição C. de Almeida, Sheila M. Alvim Matos, Ana Luísa Patrão, Gustavo Matta, Mauricio L. Barreto, Estela M.L. Aquino, Pablo Alvarez, Cristiana Almeida, Cristina Elizabeth Aldaz Barreno, Roberto F.S. Andrade, Diego Oswaldo Andrade Ortiz, E.F. Anjos, Luiz Gustavo Araújo da Cruz Casais e Silva, Pamela Alejandra Arcos Garcia, Mauricio L. Barreto, R.T.I. Bernal, Mercy Julia Borbor Cordova, Elizabeth Brickley, Claire Burke, Brenda Butler, Nina Micaela Calderon Huachi, Desmond D. Campbell, Mhairi Campbell, Roberto Carrero, Laís S.M. Cardoso, Jose L. Cerezo, Irina Chis Ster, Annabel del Rocio Constatine Tigua, Philip J. Cooper, Marianne Costa, Gustavo Correa Matta, Peter Craig, Enny Paixao Cruz, Bethânia de Araujo Almeida, Edgar Marcelino de Carvalho Neto, Felix de Jesus Neves, Dandara de Oliveira Ramos, Francine de Souza Dias, Ruth Dundas, A.B.N. Einloft, Lucas Emanuel da Silva, A.A. Fonseca, Roberto Fernandes Silva Andrade, Rosemeire Fiaccone Leovigildo, María del Pilar Flores-Quispe, Ligia Franco Sansigolo Kerr, Gervásio Ferreira dos Santos, Emmanuelle Goes, Marcos Gonzaga, Monsermin Gualan, J.M.N. Guimarães, Sally Hargreaves, Katie Harron, Évelin Angélica Herculano de Morais, Maria Yury Ichihara, Vittal Katikireddi, Carl Kendall, A.H. Leyland, R.J. Lilford, Luz Marina Llangari Arizo, David Lopes, Rachel Lowe, Daniela Lugo, Sara Macdonald, D.C. Malta, Adelyne Mendes Pereira, Adriana Mendoza Ruiz, Ana Lucía Moncayo Benalcazar, Denise Moraes Pimenta, Grace Navarrete Chavez, Erica Miranda Nascimento, Rumão Batista Nunes de Carvalho, Sara Caroline Oliveira Junker, Samila Oliveira Lima Sena, Jonathan R. Olsen, Suelen Oliveira, Naiá Ortelan, E.P. Pinto Junior, Robespierre Pita, Julia M. Pescarini, Rita Ribeiro, Rodrigo Alejandro Rodriguez Alvarado, Batul Rojeab Bravo, Natalia Cristina Romero Sandoval, Fernanda Revoredo, Maria Alejandra Ruano, Nai Rui Chng, Ronal Ruiz, Raphael Sande, T. Santos de Jesus, Paula M. Santucci, Katie Ellen Scandrett, Mariana Sebastiao, Viviane Silva de Jesus, Michal Shimonovich, Maira Lima Souza, J.F. Sousa Filho, Raiza Tourinho Lima, Cleônidas Tavares de Souza Junior, Carlos Teles, David Gonzalo Vera Alcivar, Cristiani Vieira Machado, Valerie Wells, Daniel Zurita

National Council for Scientific and Technological Development, National Institute for Health and Care Research, Wellcome Trust


Modernizing renal eligibility in oncology trials

Harold Nathan Tan, Sreedhar Mandayam, Prabir Roy-Chaudhury, Timothy A. Yap


Health-care provider compliance with a revised Plasmodium vivax radical cure algorithm incorporating tafenoquine and quantitative G6PD testing in the Peruvian Amazon: a prospective observational study

Elisa Vidal-Cardenas, Catharine I. De Freitas-Vidal, Veronica Soto-Calle, Hugo Rodríguez-Ferrucci, Wilma Casanova, Ivan Condori-Lizarraga, Stephan Duparc, Elodie Jambert, Melanie Larson, Heike Huegel, Thy Do, Paula Alejandra Burela, Marcus Lacerda, Alejandro Llanos-Cuentas


Economic burden of adult mild traumatic brain injury in the United States: a scoping review of healthcare-related charges and costs

Kathleen R. Ran, David J. Caldwell, Phiroz E. Tarapore, Cathra Halabi, Alexander A. Aabedi, Maria C.V. Velasco, Rajiv Saigal, Anthony M. DiGiorgio, Michael C. Huang, H.E. Hinson, Geoffrey T. Manley, John K. Yue


Measuring the health benefits and costs of antimicrobial-resistant gonorrhea surveillance in the United States: an agent-based model and cost-effectiveness analysis

Marcy S. Ekanayake-Weber, Minttu M. Rönn, Xuecheng Yin, Katherine Hsu, Yunfei Li, Thomas L. Gift, Harrell Chesson, Rebekah Frankson, Joshua A. Salomon, Yonatan H. Grad, Reza Yaesoubi

National Institute of Allergy and Infectious Diseases, Centers for Disease Control and Prevention


Implementation of a specialized inpatient HIV care model and in-hospital mortality in South Brazil: a before-after study

Pedro M. Fonseca, Andressa Noal, Gisele O. Boff, Ana Elize Barin, Eduardo Teixeira, Frederico DC. Abbott, Christopher J. Hernandez, Irajane Albuquerque, Omar Sued, Nicole Reis, Freddy Perez

Pan American Health Organization, Centers for Disease Control and Prevention, Universidade Federal de Ciências da Saúde de Porto Alegre


The burden of noncommunicable and injury-related nervous system disorders in the Americas, 1990–2023: an analysis of the Global Burden of Disease Study 2023

Ramon Martinez, Kiran T. Thakur, Luisa F. Alviz, William M. Gardner, Francisco J. Varela, Anselm J.M. Hennis, Renato Oliveira e Souza

Institute for Health Metrics and Evaluation


Inequities in HIV/AIDS mortality in 315 Latin American cities: a population-based cross-sectional analysis

Sebastián Genero, Andrés Trotta, Laio Magno, Mónica Serena Perner, Tania Alfaro, Diana Higuera-Mendieta, Usama Bilal, Marcio Alazraqui


Ultra-processed food intake and risk of renal cell carcinoma in the NIH-AARP Diet and health study: a prospective cohort analysis

Kaelyn F. Burns, Mark P. Purdue, Neha Khandpur, Euridice Martinez-Steele, Rashmi Sinha, Hyokyoung G. Hong, Erikka Loftfield

NIH National Cancer Institute, AARP, National Institutes of Health


Late childhood and adolescent health outcomes in preterm–born infants during 2004–2012: a population-based cohort study in British Columbia, Canada

Sumera Aziz Ali, Ye Shen, Jeffrey N. Bone, Lindsay L. Richter, Sarka Lisonkova, Faith Gette, Emily Kieran, Edmond S. Chan, Cherry Mammen, Carol Lam, Ashley Roberts, Kristopher T. Kang, Dax G. Rumsey, Tara McGrath, Kevin C. Harris, Connie L. Yang, Jonathan Wong, Natalie H. Chan, James Lee, Shahrad R. Rassekh, Anthony KC. Chan, Joseph Y. Ting

Women and Children's Health Research Institute, Canadian Institutes of Health Research


Shaping the neurological health agenda in the Americas: from mortality to chronic disability


The cost-effectiveness of vitamin D supplementation for the prevention of type 2 diabetes in the United States: a microsimulation modelling study

Jonathan Briody, Anastassios G. Pittas, Ping Zhang, Yixue Shao, Edward Gregg


Breast cancer mortality in Argentina, 1991–2023: a nationwide ecological study of spatiotemporal patterns and regional inequalities

Figueroa Marcelo Isidro, Andrade Lautaro Daniel, Llera Andrea, Alfaro Emma, Dopazo Hernán, Fachini Ana Sol, Dipierri José Edgardo

National Scientific and Technical Research Council


Age-related differences in the presentation, management, and outcomes of lower gastrointestinal bleeding: a retrospective multinational cohort study

Francisco Vara-Luiz, Carolina Palma, Paulo Mascarenhas, Tony C. Tham, Marianna Arvanitakis, Enrique Rodriguez-de-Santiago, Isabel Pedroto, Diogo Simas, Franco Radaelli, Marine Camus, Paraskevas Gkolfakis, Konstantinos Triantafyllou, Carlo Fabbri, Marta Patita, Erica Tan, Ellen Campbell, Michael Smyth, Hannah Beattie, Ravish Seeruthun, Alia Hadefi, Gabriela Rodríguez-Francisco, João Pedro Paulo, Luísa Gonçalves, Isabel Caetano, Alberto Savino, Marie Goudot, Antonia Panagaki, Eleni Koukoulioti, Maroulla Nikolaki, Giulia Gibiino, Alberto Gattuso, Ivo Mendes, Francisco Piçarra, Jorge Fonseca


Health service utilization by people with psychosis during Peru's mental health reform and the COVID-19 pandemic: a population-based study

Ruben Valle, Juan P. Murillo, Peiyuan Huang, Cesar Gutierrez, Srividya N. Iyer

Canadian Institutes of Health Research, Canada Research Chairs Program


Long COVID symptom profiles, workforce participation, and working hours among adults in England: a population-based cohort study

Chiara Di Gravio, Viveka Guzmán, Shuang Wu, Emily Cooper, Clare Bambra, Nikki Smith, Alex Piper, Matthew Whitaker, Joshua Elliott, Christina J. Atchison, Graham Cooke, Marc Chadeau-Hyam, Paul Elliott, Helen Ward


Ropeginterferon alfa-2b-njft treatment in essential thrombocythemia across different driver mutations: results from a North American, single-arm, multicentre study (EXCEED-ET)

Brandi N. Reeves, Firas El Chaer, Lynda Foltz, Tsewang Tashi, Ghaith Abu-Zeinah, Albert Qin, Jennifer Lucas, Anna B. Halpern, Dawn Maze, Hana Safah, Casey L. O’Connell, Swati Goel, Lindsay Rein, Bruno Fang, Joan How, Sunil Babu, Zhuoyan Li, Sonia Cerquozzi, Stephen T. Oh, Anthony M. Hunter, Nikolai Podoltsev, Pankit Vachhani, Julia M. Cunningham, Christopher Hillis, Prithviraj Bose, Abdulraheem Yacoub, John Mascarenhas, Oleh Zagrijtschuk, Henry Castro, Ruben A. Mesa, Lucia Masarova


Persistent behavioral, biological, and physiological sequelae in active-duty treatment-seeking U.S. special operations forces personnel: a cross-sectional study

Shane W. Adams, B. Christopher Frueh, Jerome Sabangan, Carey A. Pawlowski, Robert C. Oh, Cameron P. Pugach, QiLiang Chen, Odette A. Harris

Biomedical Laboratory Research and Development, VA Office of Research and Development, National Institute of Mental Health, National Institute of Mental Health


The obesity-related chronic disease index (ORCDi), a novel composite metric to quantify ORCD burden: an ecological study across U.S. census tracts

Md Roungu Ahmmad, Fazlay Faruque, Xiaoli Zhang

U.S. Department of Agriculture, University of South Florida, Centers for Disease Control and Prevention, Agency for Toxic Substances and Disease Registry


Genomic epidemiology of dengue virus serotype 3 lineage 3III_B.3.2 in Brazil: insights into its spread and dengue severity amid co-circulation of multiple dengue serotypes

Caroline do Nascimento Ferreira, Carla Adriane Royer, Camila Confortin, Nelson Fernando Quallio Marques, Mayra Marinho Presibella, Aline Andrade Freund, Karoline Rodrigues Campos, Claudio Tavares Sacchi, Adriano Abbud, Gustavo Barbosa de Lima, Clarice Neuenschwander Lins de Morais, Veronica Gomes da Silva, Keilla Maria Paz e Silva, Mayara Matias de Oliveira Marques da Costa, Sabrina Gonçalves, Sofia Isabel Rótulo Araújo, Darcita Buerger Rovaris, Edson Delatorre, Rodrigo Ribeiro-Rodrigues, Pedro Augusto Alves, Daisy Maria Strottmann, Camila Zanluca, Claudia Nunes Duarte dos Santos, Felipe Gomes Naveca, Gabriel da Luz Wallau, Daniel Maximo Correa Alcantara, Zoraida del Carmen Fernandez Grillo, Hellen Geremias Gatica Santos, Gonzalo Bello, Tiago Gräf, Suzana Harue Umeo, Juan Gabriel Carvalheiro de Araújo, Lavinia Nery Villa Stangler Arend, Celia Fagundes da Cruz, Claudia Regina Gonçalves, Fernanda Modesto Tolentino Binharde, Adriana Yurika Maeda, Camila Maria dos Santos, Camila Aoyama Vieira, Gislene Garcia de Castro Lichs, Luiz Henrique Ferraz Demarchi, Marina Castilhos Souza Umaki Zardin, Alexandre Freitas da Silva, Filipe Zimmer Dezordi, Marcelo Henrique Santos Paiva, Matheus Filgueira Bezerra, Bartolomeu Acioli-Santos, Clintiano Curvêlo da Silva, Elisa de Almeida Neves Azevedo, Tulio de Lima Campos, Andreza Pâmela Vasconcelos, Diego Arruda Falcão, Senele Ana de Alcantara Belettini, Vanessa Pecini da Cunha, Mariza Hoffmann Machado, Marcio Pacheco de Andrade, Felipe Donateli Gatti, Gabriela Mendonça de Colombo, Joana Zorzal Nodari, Thiago de Jesus Sousa, Ana Paula Moreira Franco Luiz, Thaís Bárbara de Souza Silva

Universidade Federal de Pernambuco, Ministry of Health, Uganda, Ministério da Saúde, Fundação Oswaldo Cruz, Fundação de Amparo à Pesquisa e Inovação do Espírito Santo, Fundação de Amparo à Pesquisa e Inovação do Espírito Santo, Instituto Oswaldo Cruz, National Council for Scientific and Technological Development, National Council for Scientific and Technological Development, National Council for Scientific and Technological Development, National Council for Scientific and Technological Development


Epidemiology and severity of pediatric influenza hospitalizations before and during the COVID-19 pandemic: a surveillance study of the Canadian immunization monitoring program (IMPACT), 2012–2023

Costanza Di Chiara, Jesse Papenburg, Julie A. Bettinger, Daniel S. Farrar, Waison Wong, Catherine Burton, Scott A. Halperin, Taj Jadavji, Kescha Kazmi, Manish Sadarangani, Shaun K. Morris

BC Children’s Hospital Foundation, Société Canadienne de Pédiatrie, Public Health Agency of Canada


Free speech exceptions in professional medical associations and schools


Food-environment policies for child nutrition in Ecuador and Latin America: beyond front-of-package labels and advertising restrictions

José Francisco López-Gil, Fiorella Quiroz-Cárdenas, Miguel López-Moreno


Incidence, survival, and prevalence trends for myocardial infarction, stroke, hip fracture, and cancer across Swedish birth cohorts: a population-based register study

Anna-Kathleen Piereth, Katharina Schmidt-Mende, Karin Modig, Marcus Ebeling


Female sex: beyond risk prediction in mental health

Júlia Pasqualini Genro, Sofia de Lima Silva, Patrícia P. Bado, Cibele Edom Bandeira


Health factors, stigma, and psychosocial resources associated with self-rated health: a cross-sectional analysis of the People Living with HIV Stigma Index 2.0 in Bolivia

Jason M. Lo Hog Tian, Mary Anne E. Roach, Carrie Lyons, Katherine Rucinski, Amrita Rao, John Mark Wiginton, Sarah M. Murray, Kaitlyn Atkins, Gnilane Turpin, Virginia Hilaquita Soto, Julio César Aguilera Hurtado, José Willan Montaño Ferrel, Martin Negrete, Keren Dunaway, Stefan D. Baral

National Institute of Nursing Research, National Institute of Mental Health, National Institute of Mental Health, The Global Fund to Fight AIDS Tuberculosis and Malaria, Joint United Nations Programme on HIV/AIDS, National Institute of Allergy and Infectious Diseases


Developmental predictors of suicide attempts from childhood to early adulthood: a 15-year prospective cohort study

Rodolfo Furlan Damiano, Daniel M. Low, Lucas Toshio Ito, Marcos Leite Santoro, Síntia Belangero, Pedro Mario Pan, Caio Casella, Julia Luiza Schäfer, Rudolf Uher, Peter Szatmari, Craig J. Bryan, Hilary P. Blumberg, Eurípedes Constantino Miguel, Luis Augusto Rohde, Giovanni Abrahão Salum

National Council for Scientific and Technological Development, National Council for Scientific and Technological Development, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, State of Sao Paulo Research Foundation, H2020 European Research Council, H2020 European Research Council, European Research Council, Canada Research Chairs Program, UK Research and Innovation Medical Research Council


Development and validation of a miRNA-based prognostic model for high-grade serous ovarian cancer: a retrospective cohort study

Cristiane Esteves Teixeira, Nayara Gusmão Tessarollo, Glenerson Baptista, Alessandra Freitas Serain, Helena Zancanaro, Diego José Gomes de Paula, Luciana Castro Moreeuw, Cláudia Bessa Pereira Chaves, João P.B. Viola, Alexandre Dias Porto Chiavegatto Filho, Mariana Boroni

National Cancer Institute, National Institute on Drug Abuse, National Heart, Lung, and Blood Institute, Carlos Chagas Filho Foundation for Research Support of Rio de Janeiro State, Ministério da Saúde, National Institute of Mental Health, National Institute of Neurological Disorders and Stroke, Conselho Nacional de Desenvolvimento Científico e Tecnológico, National Institutes of Health, National Human Genome Research Institute


TP53 p.Arg337His in Brazilian lung cancer: when tumour profiling should trigger germline evaluation


The burden of childhood cancers in the South Asian Association for Regional Cooperation (SAARC) Region: a population-based, cross-sectional GLOBOCAN 2022 analysis

The Lancet Regional Health - Southeast Asia

Tara Pattilachan Menon, Jazlyn Selvasingh, Taral K. Jella, C.S. Pramesh, Sanjeeva Gunasekera, Venkatraman Radhakrishnan, Maya Prasad, Swati Goel, Shakeel Modak, Suzanne L. Wolden, Christopher B. Jackson, Bishal Gyawali, Edward Christopher Dee

Prostate Cancer Foundation, National Cancer Center


Clinical and Cost-Effectiveness of the “UCL Live Well With Parkinson's” Toolkit: A Randomised Controlled Trial

Anette Schrag, Kumud Kantilal, Tasmin Rookes, Benjamin Gardner, Gareth Ambler, Rachael Hunter, Nathan Davies, Catherine Atkinson, Patricia Schartau, Mariam Adeleke, Lina Gonzalez, Jiunn Wang, Maria Carmody, Kate Walters

National Institute on Handicapped Research, Department of Health and Social Care, National Institute for Health Research Programme Grants for Applied Research


Endolymphatic duct blockage for Ménière’s disease: a double-blind, randomised controlled trial

Annejet A. Schenck, Raymond van de Berg, Thomas T.A. Peters, Yvette E. Smulders, Stephanie M. Winters, Stefan Böhringer, Adriaan F. Holm, Jérôme J. Waterval, Sebastiaan Hammer, Susan P.M. Hombergen, Milou R. Munting, Peter Paul G. van Benthem, Josephina M. Kruyt, Hendrikus M. Blom

National Institute for Public Health and the Environment, ZonMw, Leids Universitair Medisch Centrum


Synthetic opioid contamination in Brazil’s illicit drug market: an emerging and underdetected risk

Mariana Campello de Oliveira, João Maurício Castaldelli-Maia


Risk of stillbirth among pregnant women with anaemia in India: secondary analysis of multiple cohorts from the ICMR-SPIC consortium

Prerna Gopal, Charles Opondo, Debarati Mukherjee, Ayushi, Rukman Manapurath, John Michael Raj, Ramachandran Thiruvengadam, Ranadip Chowdhury, Pratibha Dwarkanath, Nitya Wadhwa, Kalpana Basany, Giridhara Rathnaiah Babu, Saswati Sanyal Choudhury, Shivaprasad S. Goudar, Archana Patel, Chittaranjan S. Yajnik, Sadhana Joshi, Sunita Taneja, Reema Mukherjee, Manisha Nair, Pratibha Dwarkanath, John Michael Raj, Anura V. Kurpad, Tinku Thomas, Rahul Jain, Nitya Wadhwa, Shinjini Bhatnagar, Kalpana Basany, Shailendra Dandge, Catherine L. Haggerty, Cleareann H. Bunker, P.S. Reddy, Giridhara R. Babu, Deepa R, Suganya Rajendran, Yamuna Ana, Manisha Nair, Saswati Sanyal Choudhury, Farzana Zahir, Carolin Solomi V, Ashok Verma, Sereesha Rao, Gitanjali Deka, Pranabika Mahanta, Swapna Kakoty, Robin Medhi, Shakuntala Chhabra, Anjali Rani, Amrit Bora, Indrani Roy, Bina Minz, Omesh Kumar Bharti, Rupanjali Deka, Shivaprasad S. Goudar, Manjunath S. Somannavar, Sangappa M. Dhaded, Avinash Kavi, Deepthy M. Sadanandan, Archana Patel, Kunal Kurhe, Prabir Kumar Das, Vaishali Khedikar, Alka Dafare, Chittaranjan S. Yajnik, Urmila Deshmukh, Onkar Deshmukh, Sadhana Joshi, Girija Wagh, Sanjay Lalwani, Sanjay Gupte, Juhi Nema, Sunita Taneja


Stillbirths at 22- and 28-weeks’ gestation or longer for the states in India: findings from the Global Burden of Disease Study 2023

Rakhi Dandona, G Anil Kumar, Haley Comfort, Theresa A. McHugh, Bhoomadevi A, Rizwan Suliankatchi Abdulkader, Anirudh Balakrishna Acharya, Gaurav Acharya, Swetha Acharya, Usha Adiga, Mohd Adnan, Dhiraj Motilal Agarwal, Vaishali Aggarwal, Aqeel Ahmad, Danish Ahmad, Naved Ahmad, Saheem Ahmad, Mehrunnisha Sharif Ahmed, Saif Ahmed, Syed Anees Ahmed, Mohd Akbar, Mohammad Jahoor Alam, Irfan Ali, Mohammad Daud Ali, Rafat Ali, Margret Beaula Alocious Sukumar, AH Sruthi Anil Kumar, Prapti Anjana, Kabilan Annadurai, Sadaf Anwar, Razique Anwer, Gururaj Arakeri, Jesu Arockiaraj, Syed Mohammed Basheeruddin Asdaq, Mohammad Saquib Ashraf, Syed Amir Ashraf, Ashish Awasthi, Sheeba B, Prasad Hanmantrao Babar, Giridhara Rathnaiah Babu, Raju Balaji, Senthilkumar Balakrishnan, Altaf Bandy, Bhavik Bansal, Hansi Bansal, Narasimha M. Beeraka, Gulam Saidunnisa Begum, Shahina Begum, Samir Bele, Uzma Iqbal Belgaumi, Om Prakash Prakash Bera, Ajeet Singh Bhadoria, Anuradha Bhardwaj, Nikha Bhardwaj, Pankaj Bhardwaj, Sonu Bhaskar, Shahnawaz Ali Bhat, Arushee Bhatnagar, Priyadarshini Bhattacharjee, Sudip Bhattacharya, Gurjit Kaur Bhatti, Jasvinder Singh Bhatti, Bijit Biswas, Monirujjaman Biswas, Trupti Bodhare, Jyoti Brahmaiah, Sravana Deepthi C, Sanjay C. J, Joshua Chadwick, Rama Mohan Chandika, Baskaran Chandrasekaran, Vijay Kumar Chattu, Anis Ahmad Chaudhary, Sirshendu Chaudhuri, Waseem Chauhan, Akhilanand Chaurasia, Snehal Prakash Chavhan, Saravanan Chinnaiyan, Shivani Chopra, Devasahayam J. Christopher, Mayank Dalakoti, P Vineeth Daniel, Roy Arokiam Daniel, Aso Mohammad Darwesh, Dhruva Dave, Vinoth Gnana Chellaiyan Devanbu, Devananda Devegowda, Sagnik Dey, Arkadeep Dhali, Kuldeep Dhama, Amol S. Dhane, Redolen Rose Dhar, Winniecia Dkhar, S Siva Prasad Dora, Ojas Prakashbhai Doshi, Rajkumar Prakashbhai Doshi, Viola Savy Dsouza, Siddhartha Dutta, Sulagna Dutta, Venkata Ravikanth Eddula, Balisa Mosisa Ejeta, Devaraj Ezhilarasan, Mohammad Fareed, Aisha Farhana, Rohit Ganduboina, Balasankar Ganesan, Balasubramanian Ganesh, Ezhilkugan Ganessane, Shivaprakash Gangachannaiah, Vinod Kumar Garg, Rupesh K. Gautam, Vikram Jeet Singh Gill, Bikash Ranjan Giri, Archit Goel, Rajesh Kumar Goel, Mahaveer Golechha, Sameer Vali Gopalani, Amit Gulati, Sheffali Gulati, Anish Kumar Gupta, Lalit Gupta, Abdul Hafiz, Pritam Halder, Mohd Anul Haq, Shamimul Hasan, Md Saquib Hasnain, Md Imtaiyaz Hassan, Omed Hassan Ahmed, Simon I. Hay, Ramesh Holla, Mehdi Hosseinzadeh, Talib Hussain, Mohammad Tarique Imam, Mohd Imran, Leeberk Raja Inbaraj, Danish Iqbal, C.V. Irshad, Mustafa Alhaji Isa, Jaison Jacob, Vennila Jaganathan, Qazi Mohammad Sajid Jamal, Jerin James, Rajiv Janardhanan, Krishna Mahendrabhai Jasani, Shubha Jayaram, Felix K. Jebasingh, Bijay Mukesh Jeswani, Jobin Jose, Jobinse Jose, Nitin Joseph, Krupal Joshi, Hema Shree K, Vidya Kadashetti, Sanjay Kalra, Mehnaz Kamal, Rajesh Kamath, Suthanthira Kannan S, Subham Kansal, Sunil Kumar Kar, Reddy Praneeth Karnam, Faizan Zaffar Kashoo, Manoj Kumar Kashyap, Ramya Kateel, Avleen Kaur, Harleen Kaur, Sandeep Kaur, Mohd Adnan Kausar, Kanica Kaushal, Abida Khan, Maseer Khan, Mohammad Idreesh Khan, Mohd Faheem Khan, Mohd Wajid Ali Khan, Sumaiya Khan, Wasif Ali Khan, Yusuf Saleem Khan, Parisa Khoshvaght, Samira Khoshvaght, Jagdish Khubchandani, P Ratan Khuman, Sanjay Kini B, Ladli Kishore, Shivakumar KM, Archana Koul, Sindhura Lakshmi Koulmane Laxminarayana, Kewal Krishan, Bindu Krishnan, Nitya Krishnasamy, Ananya Kuanar, Mohammed Kuddus, Anit Kujur, Ashwini Kumar, Chandan Kumar, Dewesh Kumar, Jogender Kumar, Kamal Kumar, Manoj Kumar, Mukesh Kumar, Nithin Kumar, Pawan Kumar, Pradeep Kumar, Radha Kumar, Rakesh Kumar, Sandeep Kumar, Sumit Kumar, Tushar Kumar, Subramanian Kumaran, Senthil Kumaran D, Nisha Kumari, Sajeetha Kumari R, Jibin Kunjavara, Krishna Prasad Kurpad, Pramod Kumar Kushawaha, Pallavi L. C, Chandrakant Lahariya, Anita Lakhani, Dharmesh Kumar Lal, Savita Lasrado, Virendra S. Ligade, Surbala Devi Lourembam, Abhilash Ludhiadch, Abdul Majid, Moutushi Majumder, Bhagabat Malik, Shahid Malik, Tabarak Malik, Lokesh Manjani, Kamaruddeen Mannethodi, Sahana Manoharan, Shaista Manzoor, Vijaya Marakala, J Jenifer Florence Mary, Madhumitha Masilamani, Mansi Mathur, Medha Mathur, Jitendra Meena, Satish Melwani, Godfred Antony Menezes, Ritesh G. Menezes, Giuseppe Minervini, G.K. Mini, Kumar Guru Mishra, Vinaytosh Mishra, Sayan Mitra, Tridip Mitra, Chaitanya Mittal, Dhruti Modi, Taj Mohammad, Omer Mohammed, Syam Mohan, Itismita Mohanty, Siba Sankar Mohanty, Shibani Mohapatra, Afrasim Moin, Ali H. Mokdad, Himel Mondal, Rohith Motappa, Shiv Kumar Mudgal, Reema Mukherjee, Sumoni Mukherjee, B.V. Murlimanju, Satta Muthu Murugan, Sathish Muthu, Raman Muthusamy, Karikalan Nagarajan, Dhayanithi Nagarajan Balachandran, Ganesh R. Naik, Gurudatta Naik, Prasad Nalabothu, Girish Nandakumar, Dhruva Nandi, Vinay Nangia, Sanghamitra Nayak, Mahesh P. A, Jagadish Rao Padubidri, Dimpal Manilal Paija, Debkumar Pal, Vijayakumar Palaniswamy, Sarika Palepu, Sujogya Kumar Panda, Deepshikha Pande Katare, Anuj Kumar Pandey, Romil R. Parikh, Arpit Parmar, Pragnesh Parmar, Bhargav U. Umeshchandra Patel, Kunal Nitinkumar Patel, Mehali Lalitbhai Patel, Mitesh Patel, Neel Navinkumar Patel, Niki Rut Patel, Sangram Kishor Patel, Satyananda Patel, Shivani Patel, Ashlesh Patil, Sandip Shripati Patil, Shankargouda Patil, Sourav S. Patnaik, Mohamed Anas Patni, Apurba Patra, Shrikant Pawar, Arun Mitra Peddireddy, Bala Ganesh Pichamuthu, Ramesh Poluru, Akila Prashant, Pooja Puri, Surabhi Puri, Manas Pustake, Shuby Puthussery, Jagadeesh Puvvula, Shahazad Niwazi Qurashi, Safia Obaidur Rab, Navid Rabiee, Venkatraman Radhakrishnan, Yashpal Singh Raghav, Pracheth Raghuveer, Mohammad Hifz Ur Rahman, Amita Rai, Sunil Kumar Raina, Jeffrey Pradeep Raj, Gunaseelan Rajendran, Judah Rajendran, Pushp Lata Rajpoot, Prashant Rajput, Chitra Ramasamy, Shakthi Kumaran Ramasamy, Balaji Ramraj, Lokesh Rana, Chythra R. Rao, Priyanka Rao, Rajath Rao, Suchetha S. Rao, Shree Rath, Isha Rathi, Lokesh Ravi, Ramya Kundayi Ravi, Renju Ravi, Karthik Rayapureddi, Bhagwan Narayan Rekadwad, Moattar Raza Rizvi, Syed Mohd Danish Rizvi, Hannah Elizabeth Robinson-Oden, Ravi Rohilla, Himanshu Sekhar Rout, Parameswari Royapuram Parthasarathy, Manjula S, Chandan S. N, Mohd Saeed, Rajesh Sagar, Ashok Kumar Sah, Indranil Saha, Amirhossein Sahebkar, Vaibhav Sahni, Ambika Sahoo, Harihar Sahoo, Soumya Swaroop Sahoo, Binaya Krushna Sahu, Kirti Sundar Sahu, Mahesh Chandra Sahu, Sandeep G. Sangle, Rama Krishna Sanjeev, Sathish Sankar, Senthilkumar Sankararaman, Prasanna K. Santhekadur, Sivan Yegnanarayana Iyer Saraswathy, Siddaram Shivaji Sarate, Aswini Saravanan, Sachin C. Sarode, Mukesh Kumar Sathya Narayanan, Maheswar Satpathy, Shakta Mani Satyam, Jennifer Saulam, Ganesh Kumar Saya, Durairaj Sekar, Siddharthan Selvaraj, Vimalraj Selvaraj, Pallav Sengupta, Subramanian Senthilkumaran, Muhammed Shabil, Disha Sanjivkumar Shah, Shipraa Arpan Shah, Sweni Shah, Uzma Shahab, Syed Monowar Alam Shahid, Muhammad Aaqib Shamim, Mohd Shanawaz, Devika Shanmugasundaram, Mohammed Shannawaz, Amit Baran Sharangi, Ankita Sharma, Arkansh Sharma, Avimanu Sharma, Bhoopesh Kumar Sharma, Bunty Sharma, Dolly Sharma, Kamlesh Sharma, Manoj Sharma, Ravi Kumar Sharma, Ujjawal Sharma, Vishal Sharma, Rekha Raghuveer Shenoy, Subuhi Sherwani, Adithi Shetty, B Suresh Kumar Shetty, Mahabalesh Shetty, Premalatha K. Shetty, Shiran Shetty, Suraj S. Shetty, Arun Shirali, Priyanka Arun Shirali, Dharmsheel Shrivastav, Samra Siddiqui, Akanksha Singh, Amit Singh, Baljinder Singh, Brij Pal Singh, Harmanjit Singh, Harpreet Singh, Jasvinder A. Singh, Jawahar Singh, Kalpana Singh, Mitasha Singh, Paramdeep Singh, Poornima Suryanath Singh, Puneetpal Singh, Samer Singh, Satwinder Singh, Shilpy Singh, Siddharth Singh, Surendra Singh, Vanshika Singh, Yadvinder Singh, Abhijeet Prasad Sinha, Mukesh Kumar Sinha, Indra Sivakumar, Farrukh Sobia, Suha Soni, Prashant Sood, Chandrashekhar T. Sreeramareddy, Kannan Sridharan, Vignes Anand Srinivasalu, Shyamkumar Sriram, Vipul Srivastava, Vetriselvan Subramaniyan, Meenakshi Sundari Subramaniyan Natarajan, Alisha Suhag, Thanigaivel Sundaram, Chandan Kumar Swain, Shreya P. Swami, Azharuddin Sajid Syed Khaja, Jabeen Taiba, Jay Tewari, Lakshmi Thangavelu, Kavumpurathu Raman Thankappan, Rekha Thapar, Suresh Thareja, Mahalakshmi Thayumana Sundaram, Jeevarathinam Thirumalai, Muthu Thiruvengadam, Rekha Thiruvengadam, Nihal Thomas, Nikhil Kenny Thomas, Vikas Kumar Tiwari, Marcos Roberto Tovani-Palone, Santhosh Kumar Tumkur Narayanappa, Shadab Uddin, Srikanth Umakanthan, Bhaskaran Unnikrishnan, Era Upadhyay, Dipan Uppal, Rakesh V. R, Asokan Govindaraj Vaithinathan, Sai Mahesh Vajjala, Joe Varghese, Pavani Varma, Sampara Vasishta, Vishnu Priya Veeraraghavan, Anoop Velayudhan, U. Venkatesh, Baskar Venkidasamy, Akshaya Kumar Verma, Poonam Verma, Ramesh Vidavalur, Sharath Chaitanya Vipparthy, Athul Vivek, Hai Nam Vu, Megha Walia, Tanveer A.A. Wani, Dharmveer Yadav, Suresh Yadav, Vikas Yadav, Saba Yahoo, S. Yogeshkumar, Ghazala Yunus, Seema Zargar, Sanjay Zodpey, Christopher J.L. Murray, Lalit Dandona, Austin E. Schumacher, Nicholas J. Kassebaum


Whole genome sequencing in cerebral palsy: a UK paediatric pilot study

Thiloka E. Ratnaike, Heather H. Pierce, Alison J. Coffey, Joao M.L. Dias, Iain R.L. Kean, Emily Li, Ravi P. More, Dulika S. Sumathipala, Maya Bajracharya, Zoya Kingsbury, Taksina Newington, Anthony S. Rogers, Isabelle Delon, Kate Downes, Yasmin de Alwis, Anna P. Basu, Manal Issa, Catherine Kearney, Amjad H. Khan, Benjamin P. Marlow, Alison Sansome, JooWook Ahn, A Yee Than, Tracy Lau, David R. Bentley, Sarah Bowdin, Evan Reid, Henry Houlden, Sean Humphray, David H. Rowitch

Wellcome Trust, Rosetrees Trust, Isaac Newton Trust, NIHR Cambridge Biomedical Research Centre


Healthcare utilisation, expenditure, and admission-based mortality associated with paediatric hepatobiliary diseases in Thailand: a national database analysis (2015–2023)

Songpon Getsuwan, Busara Charoenwat, Chatmanee Lertudomphonwanit, Kaewjai Thepsuthammarat, Suporn Treepongkaruna, Sumitr Sutra


Prolonged CD38 targeting with felzartamab in antibody-mediated kidney transplant rejection: a biomarker-guided open-label phase 2 extension

Katharina A. Mayer, Matthias Diebold, Eva V. Schrezenmeier, Philip F. Halloran, Susanne Haindl, Martina Schatzl, Aylin Akifova, Daniela M. Allmer, Sabine Schranz, Nicolas Kozakowski, Johannes Kläger, Kerstin Amann, Julia Beck, Ekkehard Schütz, Maarten Naesens, Alexandre Loupy, Marc Raynaud, Irene Görzer, Hannes Vietzen, Gordon Ingle, Donna L. Flesher, Uptal D. Patel, Fabian Halleck, Irene Graf, Bernd Jilma, Klemens Budde, Georg A. Böhmig


Hospital acquisitions and 30-day mortality after acute myocardial infarction and stroke in Germany: a quasi-experimental cohort study

Esra Eren Bayindir, Reinhard Busse, Jonas Schreyögg


Modulating the microbiome as an approach to anticancer drug development

Proceedings of the National Academy of Sciences

Jemma Arakelyan, Ho-Jung Choe, Chengnan Wu, Daniil A. Rusanov, Elena E. Bardina, Anna A. Kirsanova, Yuliya V. Zakalyukina, Nikita Y. Shmelev, Anton P. Tyurin, Vladislav Y. Komarov, Vladimir Kushnarev, Nikolay S. Karnaukhov, Gerald D’Cruz, Eugene S. Vasilyev, Eunice Dotse, Kwan T. Chow, William C. Cho, Alexey V. Tkachev, Artem L. Gushchin, Maria V. Babak

Department of Chemistry, Drug Discovery Lab, City University of Hong Kong

Pneumoconiosis Compensation Fund Board of Hong Kong, Russian Science Foundation, the Ministry of Science and Higher Education of the Russian Federation, the Ministry of Science and Higher Education of the Russian Federation, Russian Science Foundation, Croucher Foundation, Croucher Foundation, Hong Kong Research Grants Council, Hong Kong Research Grants Council

Abstract: Recent studies have suggested that the commensal microbiome positively affects cancer prognosis and treatment outcomes. However, only a few strategies for regulating the microbiome composition have been reported. In this study, we identified gold(I) complexes that selectively inhibited nonbeneficial bacterial strains in vitro without affecting commensal Lactobacillus strains. In contrast, clinically used drugs demonstrated comparable effects on both commensal and noncommensal strains. Consistent with the in vitro results, the selected gold(I) complex induced favorable changes in the intratumoral and gastrointestinal microbiomes in vivo. Furthermore, its anticancer efficacy was found to be dependent on the composition of microbiome and correlated with the production of short-chain fatty acid bacterial metabolites. Structure–activity relationship studies have dissected the contribution of each structural component in both the in vivo efficacy and microbiome-modulating properties. Transcriptomic analysis of tumors revealed microbiome-associated gene signaling pathways. These findings provide valuable insights for future research on microbiome-modulating anticancer drugs, presenting potential avenues to optimize cancer treatment outcomes and mitigate side effects such as gastrointestinal dysbiosis. Furthermore, our study provides insights into the involvement of microbiome in the mechanism of action of metal-based chemotherapeutics.


Crystal structure of an anticoagulant protein in complex with the Gla domain of factor X

Hiroshi Mizuno, Zui Fujimoto, Hideko Atoda, Takashi Morita

Department of Biotechnology, National Institute of Agrobiological Resources, Tsukuba, Ibaraki 305-8602, Japan; and Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo 204-8588, Japan

Abstract: The γ-carboxyglutamic acid (Gla) domain of blood coagulation factors is responsible for Ca 2+ -dependent phospholipid membrane binding. Factor X-binding protein (X-bp), an anticoagulant protein from snake venom, specifically binds to the Gla domain of factor X. The crystal structure of X-bp in complex with the Gla domain peptide of factor X at 2.3-Å resolution showed that the anticoagulation is based on the fact that two patches of the Gla domain essential for membrane binding are buried in the complex formation. The Gla domain thus is expected to be a new target of anticoagulant drugs, and X-bp provides a basis for designing them. This structure also provides a membrane-bound model of factor X.


The RNA demethylase FTO is required for maintenance of bone mass and functions to protect osteoblasts from genotoxic damage

Qian Zhang, Ryan C. Riddle, Qian Yang, Clifford R. Rosen, Denis C. Guttridge, Naomi Dirckx, Marie-Claude Faugere, Charles R. Farber, Thomas L. Clemens

Department of Orthopaedic Surgery, The Johns Hopkins University, Baltimore, MD 21287;

Abstract: Significance Like other complex disorders, such as diabetes and obesity, osteoporosis is strongly influenced by genetic factors. In this study, we explored the function of the fat mass and obesity-associated gene (FTO), an RNA demethyase that has been strongly linked by genome-wide association studies to obesity and bone density. We show that loss of Fto in mouse osteoblasts leads to age-related bone loss with increased susceptibility of osteoblasts to cell death. RNA profiling of osteoblasts lacking Fto prioritized FTO targets that are members of the DNA repair pathway, which are activated in response to genotoxic stimuli. Our results identify an epigenetic pathway in which FTO normally functions in bone to enhance the stability of mRNA-encoding proteins that protect osteoblasts from genotoxic damage.


Subspace partitioning in the human prefrontal cortex resolves cognitive interference

Jan Weber, Gabriela Iwama, Anne-Kristin Solbakk, Alejandro O. Blenkmann, Pal G. Larsson, Jugoslav Ivanovic, Robert T. Knight, Tor Endestad, Randolph Helfrich

Hertie Institute for Clinical Brain Research, Center for Neurology, University Medical Center Tübingen, 72076 Tübingen, Germany

Deutsche Forschungsgemeinschaft, Research Council Norway, Research Council Norway, Research Council Norway, Research Council Norway, Research Council Norway, Research Council Norway, Research Council Norway, HHS | NIH | National Institute of Mental Health, HHS | NIH | National Institute of Neurological Disorders and Stroke

Abstract: The human prefrontal cortex (PFC) constitutes the structural basis underlying flexible cognitive control, where mixed-selective neural populations encode multiple task features to guide subsequent behavior. The mechanisms by which the brain simultaneously encodes multiple task–relevant variables while minimizing interference from task-irrelevant features remain unknown. Leveraging intracranial recordings from the human PFC, we first demonstrate that competition between coexisting representations of past and present task variables incurs a behavioral switch cost. Our results reveal that this interference between past and present states in the PFC is resolved through coding partitioning into distinct low-dimensional neural states; thereby strongly attenuating behavioral switch costs. In sum, these findings uncover a fundamental coding mechanism that constitutes a central building block of flexible cognitive control.


A proline-rich motif in p53 is required for transactivation- independent growth arrest as induced by Gas1

Elisabetta M. Ruaro, Licio Collavin, Giannino Del Sal, Rebecca Haffner, Moshe Oren, Arnold J. Levine, Claudio Schneider

Laboratorio Nazionale Consorzio Interuniversitario per le Biotecnologie and International Centre for Genetic Engineering and Biotechnology, Area Science Park Padriciano 99, 34012 Trieste, Italy; Dipartimento di Biochimica Biofisica e Chimica delle Macromolecole, Via L. Giorgeri 1, Universita’degli Studi 34100 Trieste, Italy; Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot 76100, Israel; and Department of Molecular Biology, Lewis Thomas Building, Washington Road,...

Abstract: The involvement of p53 in regulating diverse cellular processes dictates that it must respond to multiple signaling mechanisms, thus coordinating the response to various “stress conditions.” Genotoxic stress has served as a paradigm to dissect the transactivation-dependent branch of the pathway by which p53 can induce growth arrest. Alternate mechanisms have been invoked to explain transactivation-independent effects of p53, especially in the context of apoptosis. We have identified a p53-dependent pathway initiated by the gas1 product, a plasma membrane protein highly expressed during G0, which activates a transactivation-independent p53 growth arrest function. Through a detailed deletional analysis and site-specific mutagenesis of p53 we show that the Gas1-dependent signal transduction relies on a proline-rich region (amino acids 63–85) of murine p53. In vivo competition experiments using combinations of such mutants implicate this functional domain of p53 as a docking site in the transmission of antiproliferative signals.


Transpupillary in vivo two-photon imaging reveals enhanced surveillance of retinal microglia in diabetic mice

Noriyuki Sotani, Sentaro Kusuhara, Ryuto Nishisho, Hiroto Kuno, Hidenori Shima, Koichiro Haruwaka, Yuka Mori, Maya Kishi, Tomoyuki Furuyashiki, Kenta Kobayashi, Hiroaki Wake, Toru Takumi, Makoto Nakamura, Yoshihisa Tachibana

Department of Physiology and Cell Biology, Kobe University

MEXT | Japan Science and Technology Agency, Japan Agency for Medical Research and Development, Japan Society for the Promotion of Science London, Japan Society for the Promotion of Science London, Japan Society for the Promotion of Science London, Japan Society for the Promotion of Science London

Abstract: The retina, located outside the cranium, serves as an ideal structure for investigating information processing within the central nervous system due to its well-organized neurovascular unit comprising diverse cell types, including neurons, glial cells (such as microglia, Müller glia, and astrocytes), pericytes, and vascular endothelial cells. Disrupted retinal homeostasis contributes to various ocular diseases such as diabetic retinopathy, age-related macular degeneration, glaucoma, and retinitis pigmentosa. However, noninvasive in vivo imaging methods to study the pathogenesis of these disorders remain limited. Here, we developed a two-photon microscopy technique for real-time, transpupillary in vivo visualization of the retinal neurovascular unit in mice. Our approach integrates systematic head fixation, a custom-made polymethyl methacrylate contact lens, and a glycerin immersion objective lens with an extended working distance and a higher numerical aperture, specifically designed for two-photon microscopy. This method enabled us to visualize dynamic microglial process activity around retinal blood vessels. Our results revealed that retinal microglia exhibit enhanced surveillance under diabetic conditions, which is undetectable by static confocal microscopy. Furthermore, we demonstrated that liraglutide, a glucagon-like peptide-1 receptor agonist commonly used for the treatment of diabetes and obesity, reversed the enhanced microglial behaviors in the diabetic retina. Our simple yet effective approach mitigates the need for advanced optical systems like adaptive optics, providing an effective tool for real-time imaging of the retina. This method offers a valuable resource for visual neuroscience research and holds great potential for clinical applications, particularly in the early diagnosis, intervention, and monitoring of retinal diseases.


Calpain drives pyroptotic vimentin cleavage, intermediate filament loss, and cell rupture that mediates immunostimulation

Michael A. Davis, Marian R. Fairgrieve, Andreas Den Hartigh, Olga Yakovenko, Bhargavi Duvvuri, Christian Lood, Wendy E. Thomas, Susan L. Fink, Michael Gale

Department of Immunology, University of Washington, Seattle, WA 98109;

HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, HHS | NIH | National Institute of Allergy and Infectious Diseases, Alliance for Lupus Research

Abstract: Significance Pyroptosis is a form of inflammatory cell death. It is driven by plasma membrane pore formation that is thought to rupture cells through osmotic influx, thereby releasing intracellular content that initiates an inflammatory response to fight acute infection and tissue damage. However, when chronic or unregulated, this process can drive autoimmune disease and cancer. Here, we show that pyroptotic cells do not undergo rupture in culture. Instead, the calcium-dependent protease calpain destroys intermediate filaments, which provide mechanical resilience to cells. As a result, cells are susceptible to rupture by mechanical disruption from shear stress or compression as occurs in the blood stream or within tissues. Thus, our data reveal potential targets for the therapeutic intervention of autoimmune diseases and cancer.


Genome-wide ancestry of 17th-century enslaved Africans from the Caribbean

Hannes Schroeder, María C. Ávila-Arcos, Anna-Sapfo Malaspinas, G. David Poznik, Marcela Sandoval-Velasco, Meredith L. Carpenter, José Víctor Moreno-Mayar, Martin Sikora, Philip L. F. Johnson, Morten Erik Allentoft, José Alfredo Samaniego, Jay B. Haviser, Michael W. Dee, Thomas W. Stafford, Antonio Salas, Ludovic Orlando, Eske Willerslev, Carlos D. Bustamante, M. Thomas P. Gilbert

Centre for Geogenetics, Natural History Museum of Denmark, University of Copenhagen, 1350 Copenhagen, Denmark;

European Commission Directorate-General for Research and Innovation, EC | European Research Council, European Commission Directorate-General for Research and Innovation, EC | European Research Council, Det Frie Forskningsråd, Lundbeckfonden, NSF | MPS | Division of Mathematical Sciences, NSF | EHR | Division of Graduate Education, Swiss National Science Foundation, HHS | National Institutes of Health, HHS | National Institutes of Health, Leverhulme Trust, Ministerio de Ciencia e Innovación, Danish National Research Foundation

Abstract: Significance The transatlantic slave trade resulted in the forced movement of over 12 million Africans to the Americas. Although many coastal shipping points are known, they do not necessarily reflect the slaves’ actual ethnic or geographic origins. We obtained genome-wide data from 17th-century remains of three enslaved individuals who died on the Caribbean island of Saint Martin and use them to identify their genetic origins in Africa, with far greater precision than previously thought possible. The study demonstrates that genomic data can be used to trace the genetic ancestry of long-dead individuals, a finding that has important implications for archeology, especially in cases where historical information is missing.


The two-dimensional IR nonlinear spectroscopy of a cyclic penta-peptide in relation to its three-dimensional structure

Peter Hamm, Manho Lim, William F. DeGrado, Robin M. Hochstrasser

Department of Chemistry and Department of
 Biochemistry and Biophysics, The Johnson Foundation for Research in
 Biophysics, University of Pennsylvania, Philadelphia, PA 19104

Abstract: A form of two-dimensional (2D) vibrational spectroscopy, which uses two ultrafast IR laser pulses, is used to examine the structure of a cyclic penta-peptide in solution. Spectrally resolved cross peaks occur in the off-diagonal region of the 2D IR spectrum of the amide I region, analogous to those in 2D NMR spectroscopy. These cross peaks measure the coupling between the different amide groups in the structure. Their intensities and polarizations relate directly to the three-dimensional structure of the peptide. With the help of a model coupling Hamiltonian, supplemented by density functional calculations, the spectra of this penta-peptide can be regenerated from the known solution phase structure. This 2D-IR measurement, with an intrinsic time resolution of less than 1 ps, could be used in all time regimes of interest in biology.


Disaggregation of Alzheimer β-amyloid by site-directed mAb

Beka Solomon, Rela Koppel, Dan Frankel, Eilat Hanan-Aharon

Department of Molecular Microbiology and Biotechnology, Tel Aviv University, Ramat Aviv 69978, Israel

Abstract: In Alzheimer disease, β-amyloid peptide accumulates in the brain as insoluble amyloid plaques. Amyloid filaments, similar to those found in amyloid plaques, can be assembled in vitro from chemically synthesized β-peptides. In this study, we report that antibodies raised against the N-terminal region (1–28) of the β-amyloid peptide bind to the in vitro -formed β-amyloid assemblies, leading to disaggregation of the fibrils and partial restoration of the peptide’s solubility. The concomitant addition of fibrillar β-amyloid with these antibodies to PC 12 cells leads to the inhibition of the neurotoxic effects of β-amyloid. Some of the mAbs raised against soluble β-peptide (1–28) have been found to prevent in vitro fibrillar aggregation of β-amyloid peptide. These experimental data suggest that site-directed mAbs interfere with the aggregation of β-amyloid and trigger reversal to its nontoxic, normal components. The above findings give hints on how to convert in vivo senile plaques into nontoxic, diffuse components and may have therapeutic interest for those studying Alzheimer disease and other human diseases related to amyloidogenic properties of physiological peptides and proteins.


Contrasted coevolutionary dynamics between a bacterial pathogen and its bacteriophages

Alex Betts, Oliver Kaltz, Michael E. Hochberg

Institut des Sciences de l'Evolution, Université Montpellier II, Unité Mixte de Recherche 5554, 34095 Montpellier Cedex 05, France;

Abstract: Significance Scientists have long debated the dynamic form of perpetual reciprocal adaptations, or coevolution, between hosts and their parasites. The two main types of antagonistic coevolution described to date are arms race dynamics, in which interaction traits escalate through time, and fluctuating selection dynamics, in which traits cycle through time. We used experimental evolution between Pseudomonas aeruginosa and a panel of its lytic phages and found the full known range of coevolutionary dynamics. We argue that the coevolutionary pattern is determined by whether phages typically adsorb directly to receptors on the bacterial outer membrane or instead use retractable type IV pili as a primary or alternative site. Our results have applications in the use of phages as therapeutics or disinfectants to control bacterial pathogens.


Substitutions near the HA receptor binding site explain the origin and major antigenic change of the B/Victoria and B/Yamagata lineages

Miruna E. Rosu, Pascal Lexmond, Theo M. Bestebroer, Blake M. Hauser, Derek J. Smith, Sander Herfst, Ron A. M. Fouchier

Department of Viroscience, Erasmus Medical Centre, Rotterdam 3015 CE, The Netherlands

EC | Horizon 2020 Framework Programme, HHS | NIH | National Institute of Allergy and Infectious Diseases

Abstract: Influenza B virus primarily infects humans, causing seasonal epidemics globally. Two antigenic variants—Victoria-like and Yamagata-like—were detected in the 1980s, of which the molecular basis of emergence is still incompletely understood. Here, the antigenic properties of a unique collection of historical virus isolates, sampled from 1962 to 2000 and passaged exclusively in mammalian cells to preserve antigenic properties, were determined with the hemagglutination inhibition assay and an antigenic map was built to quantify and visualize the divergence of the lineages. The antigenic map revealed only three distinct antigenic clusters—Early, Victoria, and Yamagata—with relatively little antigenic diversity in each cluster until 2000. Viruses with Victoria-like antigenic properties emerged around 1972 and diversified subsequently into two genetic lineages. Viruses with Yamagata-like antigenic properties evolved from one lineage and became clearly antigenically distinct from the Victoria-like viruses around 1988. Recombinant mutant viruses were tested to show that insertions and deletions (indels), as observed frequently in influenza B virus hemagglutinin, had little effect on antigenic properties. In contrast, amino-acid substitutions at positions 148, 149, 150, and 203, adjacent to the hemagglutinin receptor binding site, determined the main antigenic differences between the Early, Victoria-like, and Yamagata-like viruses. Surprisingly, substitutions at two of the four positions reverted in recent viruses of the Victoria lineage, resulting in antigenic properties similar to viruses circulating ∼50 y earlier. These data shed light on the antigenic diversification of influenza viruses and suggest there may be limits to the antigenic evolution of influenza B virus.


Noise differentially impacts phoneme representations in the auditory and speech motor systems

Yi Du, Bradley R. Buchsbaum, Cheryl L. Grady, Claude Alain

Rotman Research Institute, Baycrest Centre for Geriatric Care, Toronto, ON, Canada M6A 2E1; and

Abstract: Significance Contentious debate remains regarding the role of the redundant motor activation during speech perception. In this functional MRI study, multivariate pattern analysis revealed stronger multivoxel phoneme discrimination in speech motor regions than auditory cortices when the speech phonemes were moderately degraded by noise. Our findings provide neuroimaging evidence for the sensorimotor integration account. Preserved phoneme discrimination in speech motor areas may compensate for loss of specificity in noise-impoverished speech representations, which aids speech perception under adverse listening conditions.


ELL-associated factors 1 and 2 are positive regulators of RNA polymerase II elongation factor ELL

Stephanie E. Kong, Charles A. S. Banks, Ali Shilatifard, Joan Weliky Conaway, Ronald C. Conaway

Stowers Institute for Medical Research, Kansas City, MO 64110; Edward A. Doisy Department of Biochemistry and Molecular Biology, St. Louis University Health Sciences Center, St. Louis, MO 63104; Department of Biochemistry and Molecular Biology, Kansas University Medical Center, Kansas City, KS 66160; and Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190

Abstract: In human cells, the ELL family of transcription factors includes at least three members, which are all capable of stimulating the overall rate of elongation by RNA polymerase II by suppressing transient pausing by the enzyme at many sites along DNA. In this report, we identify the ELL-associated factors (EAF)1 and EAF2 as strong positive regulators of ELL elongation activity. Our findings provide insights into the structure and function of ELL family transcription factors, and they bring to light direct roles for the EAF proteins in regulation of RNA polymerase II transcription.


Spatiotemporal trends of hemorrhagic fever with renal syndrome (HFRS) in China under climate variation

Yuchen Wang, Chutian Zhang, Jing Gao, Ziqi Chen, Zhao Liu, Jianbin Huang, Yidan Chen, Zhichao Li, Nan Chang, Yuxin Tao, Hui Tang, Xuejie Gao, Ying Xu, Can Wang, Dong Li, Xiaobo Liu, Jingxiang Pan, Wenjia Cai, Peng Gong, Yong Luo, Wannian Liang, Qiyong Liu, Nils Chr. Stenseth, Ruifu Yang, Lei Xu

Vanke School of Public Health, Tsinghua University, Beijing 100084, China

Abstract: Hemorrhagic fever with renal syndrome (HFRS) is a zoonotic disease caused by the rodent-transmitted orthohantaviruses (HVs), with China possessing the most cases globally. The virus hosts in China are Apodemus agrarius and Rattus norvegicus , and the disease spread is strongly influenced by global climate dynamics. To assess and predict the spatiotemporal trends of HFRS from 2005 to 2098, we collected historical HFRS data in mainland China (2005–2020), historical and projected climate and population data (2005–2098), and spatial variables including biotic, environmental, topographical, and socioeconomic. Spatiotemporal predictions and mapping were conducted under 27 scenarios incorporating multiple integrated representative concentration pathway models and population scenarios. We identify the type of magistral HVs host species as the best spatial division, including four region categories. Seven extreme climate indices associated with temperature and precipitation have been pinpointed as key factors affecting the trends of HFRS. Our predictions indicate that annual HFRS cases will increase significantly in 62 of 356 cities in mainland China. Rattus regions are predicted to be the most active, surpassing Apodemus and Mixed regions. Eighty cities are identified as at severe risk level for HFRS, each with over 50 reported cases annually, including 22 new cities primarily located in East China and Rattus regions after 2020, while 6 others develop new risk. Our results suggest that the risk of HFRS will remain high through the end of this century, with Rattus norvegicus being the most active host, and that extreme climate indices are significant risk factors. Our findings can inform evidence-based policymaking regarding future risk of HFRS.


A pair of native fungal pathogens drives decline of a new invasive herbivore

Eric H. Clifton, Louela A. Castrillo, Andrii Gryganskyi, Ann E. Hajek

Department of Entomology, Cornell University, Ithaca, NY 14853-2601;

USDA | Animal and Plant Health Inspection Service, USDA | U.S. Forest Service

Abstract: Two North American fungal pathogens caused a coepizootic leading to localized collapse of an outbreak population of the newly invasive planthopper pest, the spotted lanternfly ( Lycorma delicatula ), in the eastern United States. The pathogens partitioned the habitat, with the majority of L. delicatula on tree trunks killed by Batkoa major , while cadavers of L. delicatula killed by Beauveria bassiana were usually on the ground. The future will show whether these pathogens will be drivers in boom–bust cycles or will result in recurrent low population densities of this new invasive species.


Fossil fuel methane emissions likely underestimated in a model based on atmospheric δ 13 C trends

Benjamin T. Uveges, Robert W. Howarth, Jed P. Sparks

Department of Ecology and Evolutionary Biology, Cornell University


Distinct early and late neural mechanisms regulate feature-specific sensory adaptation in the human visual system

Reuben Rideaux, Rebecca K. West, Dragan Rangelov, Jason B. Mattingley

Queensland Brain Institute, The University of Queensland, St. Lucia 4072, Australia

Department of Education and Training | Australian Research Council, DHAC | National Health and Medical Research Council, DHAC | National Health and Medical Research Council

Abstract: A canonical feature of sensory systems is that they adapt to prolonged or repeated inputs, suggesting the brain encodes the temporal context in which stimuli are embedded. Sensory adaptation has been observed in the central nervous systems of many animal species, using techniques sensitive to a broad range of spatiotemporal scales of neural activity. Two competing models have been proposed to account for the phenomenon. One assumes that adaptation reflects reduced neuronal sensitivity to sensory inputs over time (the “fatigue” account); the other posits that adaptation arises due to increased neuronal selectivity (the “sharpening” account). To adjudicate between these accounts, we exploited the well-known “tilt aftereffect”, which reflects adaptation to orientation information in visual stimuli. We recorded whole-brain activity with millisecond precision from human observers as they viewed oriented gratings before and after adaptation, and used inverted encoding modeling to characterize feature-specific neural responses. We found that both fatigue and sharpening mechanisms contribute to the tilt aftereffect, but that they operate at different points in the sensory processing cascade to produce qualitatively distinct outcomes. Specifically, fatigue operates during the initial stages of processing, consistent with tonic inhibition of feedforward responses, whereas sharpening occurs ~200 ms later, consistent with feedback or local recurrent activity. Our findings reconcile two major accounts of sensory adaptation, and reveal how this canonical process optimizes the detection of change in sensory inputs through efficient neural coding.


CCAAT displacement protein/ <i>cut</i> homolog recruits G9a histone lysine methyltransferase to repress transcription

Department of Pediatrics, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029

Abstract: CCAAT displacement protein/ cut homolog (CDP/ cut ) is a highly conserved homeodomain protein that contains three cut repeat sequences. CDP/ cut is a transcriptional factor for many diverse cellular and viral genes that are involved in most cellular processes, including differentiation, development, and proliferation. Here, we report that CDP/ cut interacts with a histone lysine methyltransferase (HKMT), G9a, in vivo and in vitro . The deletion of the cut repeats within CDP/ cut abrogates the interaction with G9a. The transcriptional repressor function of CDP/ cut is mediated through HKMT activity of G9a associated with CDP/ cut . We show that the recruitment of G9a to the human p21 waf1/cdi1 promoter is contingent on the interaction with CDP/ cut , and CDP/ cut is directly associated with an increase in the methylation in vivo of Lys-9 in histone H3 within the CDP/ cut -regulatory region of the p21 waf1/cdi1 promoter. The endogenous level of p21 waf1/cdi1 expression is repressed through CDP/ cut and mediated by HKMT activity of G9a. Furthermore, we report the identification of G9a as a component of CDP/ cut complex. G9a colocalizes with CDP/ cut in the nucleus. These results indicate that G9a functions as a transcriptional corepressor in association with a CDP/ cut complex. These studies now reveal the interaction of G9a with a sequence-specific transcription factor that regulates gene repression through CDP/ cut .


Rapid β-lactam-induced lysis requires successful assembly of the cell division machinery

Hak Suk Chung, Zhizhong Yao, Nathan W. Goehring, Roy Kishony, Jon Beckwith, Daniel Kahne

Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA 02138; and

Abstract: β-lactam antibiotics inhibit penicillin binding proteins (PBPs) involved in peptidoglycan synthesis. Although inhibition of peptidoglycan biosynthesis is generally thought to induce cell lysis, the pattern and mechanism of cell lysis can vary substantially. β-lactams that inhibit FtsI, the only division specific PBP, block cell division and result in growth as filaments. These filaments ultimately lyse through a poorly understood mechanism. Here we find that one such β-lactam, cephalexin, can, under certain conditions, lead instead to rapid lysis at nascent division sites through a process that requires the complete and ordered assembly of the divisome, the essential machinery involved in cell division. We propose that this assembly process (in which the localization of cell wall hydrolases depends on properly targeted FtsN, which in turn depends on the presence of FtsI) ensures that the biosynthetic machinery to form new septa is in place before the machinery to degrade septated daughter cells is enabled. β-lactams that target FtsI subvert this mechanism by inhibiting FtsI without perturbing the normal assembly of the cell division machinery and the consequent activation of cell wall hydrolases. One seemingly paradoxical implication of our results is that β-lactam therapy may be improved by promoting active cell division.


Gaucher disease protects against tuberculosis

Jingwen Fan, Victoria L. Hale, Lindsey T. Lelieveld, Laura J. Whitworth, Elisabeth M. Busch-Nentwich, Mark Troll, Paul H. Edelstein, Timothy M. Cox, Francisco J. Roca, Johannes M. F. G. Aerts, Lalita Ramakrishnan

Molecular Immunity Unit, Cambridge Institute of Therapeutic Immunology and Infectious Diseases, Department of Medicine, University of Cambridge, Cambridge CB2 0QH, UK

Wellcome Trust, HHS | NIH | NIAID | Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, NWO | Nationaal Regieorgaan Onderwijsonderzoek, NIHR | NIHR Cambridge Biomedical Research Centre

Abstract: Biallelic mutations in the glucocerebrosidase ( GBA1 ) gene cause Gaucher disease, characterized by lysosomal accumulation of glucosylceramide and glucosylsphingosine in macrophages. Gaucher and other lysosomal diseases occur with high frequency in Ashkenazi Jews. It has been proposed that the underlying mutations confer a selective advantage, in particular conferring protection against tuberculosis. Here, using a zebrafish Gaucher disease model, we find that the mutation GBA1 N370S, predominant among Ashkenazi Jews, increases resistance to tuberculosis through the microbicidal activity of glucosylsphingosine in macrophage lysosomes. Consistent with lysosomal accumulation occurring only in homozygotes, heterozygotes remain susceptible to tuberculosis. Thus, our findings reveal a mechanistic basis for protection against tuberculosis by GBA1 N370S and provide biological plausibility for its selection if the relatively mild deleterious effects in homozygotes were offset by significant protection against tuberculosis, a rampant killer of the young in Europe through the Middle Ages into the 19th century.


TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 with <i>TPL2</i> mRNA

Alejandra Escós, José Martín-Gómez, Diego González-Romero, Ester Díaz-Mora, Rosario Francisco-Velilla, Cesar Santiago, José M. Cuezva, Sonia Domínguez-Zorita, Encarnación Martínez-Salas, Nahum Sonenberg, Juan José Sanz-Ezquerro, Seyed Mehdi Jafarnejad, Ana Cuenda

Department of Immunology and Oncology, Centro Nacional de Biotecnología-Consejo Superior de Investigaciones Científicas (CNB/CSIC) Campus Universidad Autónoma de Madrid (UAM), Madrid, 28049 Spain

Ministerio de Ciencia e Innovación, Ministerio de Ciencia e Innovación, Ministerio de Ciencia e Innovación

Abstract: p38γ and p38δ (p38γ/p38δ) regulate inflammation, in part by controlling tumor progression locus 2 (TPL2) expression in myeloid cells. Here, we demonstrate that TPL2 protein levels are dramatically reduced in p38γ/p38δ-deficient (p38γ/δ −/− ) cells and tissues without affecting TPL2 messenger ribonucleic acid (mRNA) expression. We show that p38γ/p38δ posttranscriptionally regulates the TPL2 amount at two different levels. p38γ/p38δ interacts with the TPL2/A20 Binding Inhibitor of NF-κB2 (ABIN2)/Nuclear Factor κB1p105 (NF-κB1p105) complex, increasing TPL2 protein stability. Additionally, p38γ/p38δ regulates TPL2 mRNA translation by modulating the repressor function of TPL2 3′ Untranslated region (UTR) mediated by its association with aconitase-1 (ACO1). ACO1 overexpression in wild-type cells increases the translational repression induced by TPL2 3′UTR and severely decreases TPL2 protein levels. p38δ binds to ACO1, and p38δ expression in p38γ/δ −/− cells fully restores TPL2 protein to wild-type levels by reducing the translational repression of TPL2 mRNA. This study reveals a unique mechanism of posttranscriptional regulation of TPL2 expression, which given its central role in innate immune response, likely has great relevance in physiopathology.


A new Eocene archaeocete (Mammalia, Cetacea) from India and the time of origin of whales

Department of Earth Sciences, University of Roorkee, Roorkee 247667, Uttar Pradesh, India; and Museum of Paleontology and Department of Geological Sciences, University of Michigan, Ann Arbor, MI 48019-1079

Abstract: Himalayacetus subathuensis is a new pakicetid archaeocete from the Subathu Formation of northern India. The type dentary has a small mandibular canal indicating a lack of auditory specializations seen in more advanced cetaceans, and it has Pakicetus -like molar teeth suggesting that it fed on fish. Himalayacetus is significant because it is the oldest archaeocete known and because it was found in marine strata associated with a marine fauna. Himalayacetus extends the fossil record of whales about 3.5 million years back in geological time, to the middle part of the early Eocene [≈53.5 million years ago (Ma)]. Oxygen in the tooth-enamel phosphate has an isotopic composition intermediate between values reported for freshwater and marine archaeocetes, indicating that Himalayacetus probably spent some time in both environments. When the temporal range of Archaeoceti is calibrated radiometrically, comparison of likelihoods constrains the time of origin of Archaeoceti and hence Cetacea to about 54–55 Ma (beginning of the Eocene), whereas their divergence from extant Artiodactyla may have been as early as 64–65 Ma (beginning of the Cenozoic).


<i>Klebsiella oxytoca</i> enterotoxins tilimycin and tilivalline have distinct host DNA-damaging and microtubule-stabilizing activities

Katrin Unterhauser, Lisa Pöltl, Georg Schneditz, Sabine Kienesberger, Ronald A. Glabonjat, Maksym Kitsera, Jakob Pletz, Fernando Josa-Prado, Elisabeth Dornisch, Christian Lembacher-Fadum, Sandro Roier, Gregor Gorkiewicz, Daniel Lucena, Isabel Barasoain, Wolfgang Kroutil, Marc Wiedner, Joanna I. Loizou, Rolf Breinbauer, José Fernando Díaz, Stefan Schild, Christoph Högenauer, Ellen L. Zechner

Institute of Molecular Biosciences, University of Graz, A-8010 Graz, Austria;

Austrian Science Fund, BioTechMed-Graz, Ministerio de Economica y Competitividad, BioTechMed-Graz

Abstract: Significance Human gut microbes form a complex community with vast biosynthetic potential. Microbial products and metabolites released in the gut impact human health and disease. However, defining causative relationships between specific bacterial products and disease initiation and progression remains an immense challenge. This study advances understanding of the functional capacity of the gut microbiota by determining the presence, concentration, and spatial and temporal variability of two enterotoxic metabolites produced by the gut-resident Klebsiella oxytoca . We present a detailed mode of action for the cytotoxins and recapitulate their functionalities in disease models in vivo. The findings provide distinct molecular mechanisms for the enterotoxicity of the metabolites allowing them to act in tandem to damage the intestinal epithelium and cause colitis.


Ecological modulation of plant defense via phytochrome control of jasmonate sensitivity

Javier E. Moreno, Yi Tao, Joanne Chory, Carlos L. Ballaré

Ifeva, Consejo Nacional de Investigaciones Científicas y Técnicas, and Universidad de Buenos Aires, Avenida San Martín 4453 C1417DSE Buenos Aires, Argentina; and

Abstract: For plants, the tradeoff between resource investment in defense and increased growth to out-compete neighbors creates an allocation dilemma. How plants resolve this dilemma, at the mechanistic level, is unclear. We found that Arabidopsis plants produced an attenuated defense phenotype under conditions of crowding and when exposed to far-red (FR) radiation, a light signal that plants use to detect the proximity of neighbors via the photoreceptor phytochrome. This phenotype was detectable through standard bioassays that measured the growth of Spodoptera frugiperda caterpillars. Two possible explanations for the effect of FR are: ( i ) a simple by-product of the diversion of resources to competition, and ( ii ) a specific effect of phytochrome on defense signaling. The first possibility was ruled out by the fact that the auxin-deficient sav3 mutant, which fails to induce growth responses to FR, still responded to FR with an attenuated defense phenotype. In support of the second hypothesis, we found that phytochrome inactivation by FR caused a strong reduction of plant sensitivity to jasmonates, which are key regulators of plant immunity. The effects of FR on jasmonate sensitivity were restricted to certain elements of the pathway. Supporting the idea that the FR effects on jasmonate signaling are functionally significant, we found that FR failed to increase tissue quality in jar1 , a mutant impaired in jasmonate response. We conclude that the plant modulates its investment in defense as a function of the perceived risk of competition, and that this modulation is effected by phytochrome via selective desensitization to jasmonates.


Genetic and molecular analysis of trichome development in <i>Arabis alpina</i>

Divykriti Chopra, Mona Mapar, Lisa Stephan, Maria C. Albani, Anna Deneer, George Coupland, Eva-Maria Willing, Swen Schellmann, Korbinian Schneeberger, Christian Fleck, Andrea Schrader, Martin Hülskamp

Botanical Institute, Biocenter, University of Cologne, 50674 Cologne, Germany;

Abstract: Significance Typically, comparative developmental studies focus on the question whether key genes are conserved over large evolutionary distances. How the gene regulatory network of a whole developmental process evolves is virtually unknown. This requires a functional comparison of homologous processes in species closely related enough to find similarities and distant enough to see functional changes. We approach this question by genetically and molecularly comparing trichome development in Arabidopsis thaliana with that in Arabis alpina . We show which steps are regulated similarly and which are different. A closer analysis of trichome patterning revealed fascinating changes in the gene regulatory network; in particular, the finding that overexpression of one key regulator leads to opposite phenotypes in the two species suggested fundamental changes.


Stabilization of a β-hairpin in monomeric Alzheimer's amyloid-β peptide inhibits amyloid formation

Wolfgang Hoyer, Caroline Grönwall, Andreas Jonsson, Stefan Ståhl, Torleif Härd

*Department of Medical Biochemistry and Swedish Nuclear Magnetic Resonance Center, University of Gothenburg, Box 440, SE-405 30 Göteborg, Sweden;

Abstract: According to the amyloid hypothesis, the pathogenesis of Alzheimer's disease is triggered by the oligomerization and aggregation of the amyloid-β (Aβ) peptide into protein plaques. Formation of the potentially toxic oligomeric and fibrillar Aβ assemblies is accompanied by a conformational change toward a high content of β-structure. Here, we report the solution structure of Aβ(1–40) in complex with the phage-display selected affibody protein Z Aβ3 , a binding protein of nanomolar affinity. Bound Aβ(1–40) features a β-hairpin comprising residues 17–36, providing the first high-resolution structure of Aβ in β conformation. The positions of the secondary structure elements strongly resemble those observed for fibrillar Aβ. Z Aβ3 stabilizes the β-sheet by extending it intermolecularly and by burying both of the mostly nonpolar faces of the Aβ hairpin within a large hydrophobic tunnel-like cavity. Consequently, Z Aβ3 acts as a stoichiometric inhibitor of Aβ fibrillation. The selected Aβ conformation allows us to suggest a structural mechanism for amyloid formation based on soluble oligomeric hairpin intermediates.


A chemical approach for identifying <i>O</i> -GlcNAc-modified proteins in cells

David J. Vocadlo, Howard C. Hang, Eun-Ju Kim, John A. Hanover, Carolyn R. Bertozzi

Center for New Directions in Organic Synthesis,
 Department of Chemistry, and Department of
 Molecular and Cell Biology, Material Sciences Division, Lawrence Berkeley
 National Laboratory, and Howard Hughes Medical Institute, University of
 California, Berkeley, CA 94720; and Laboratory
 of Biochemistry and Metabolism, National Institute of Diabetes and Digestive
 and Kidney Diseases, National Institutes of Health, Bethesda, MD
 20892-0851

Abstract: The glycosylation of serine and threonine residues with a single GlcNAc moiety is a dynamic posttranslational modification of many nuclear and cytoplasmic proteins. We describe a chemical strategy directed toward identifying O -GlcNAc-modified proteins from living cells or proteins modified in vitro . We demonstrate, in vitro , that each enzyme in the hexosamine salvage pathway, and the enzymes that affect this dynamic modification (UDP-GlcNAc:polypeptidtyltransferase and O -GlcNAcase), tolerate analogues of their natural substrates in which the N -acyl side chain has been modified to bear a bio-orthogonal azide moiety. Accordingly, treatment of cells with N -azidoacetylglucosamine results in the metabolic incorporation of the azido sugar into nuclear and cytoplasmic proteins. These O -azidoacetylglucosamine-modified proteins can be covalently derivatized with various biochemical probes at the site of protein glycosylation by using the Staudinger ligation. The approach was validated by metabolic labeling of nuclear pore protein p62, which is known to be posttranslationally modified with O -GlcNAc. This strategy will prove useful for both the identification of O -GlcNAc-modified proteins and the elucidation of the specific residues that bear this saccharide.


Cryo-EM structure of the prohibitin complex in open conformation

Sixing Hong, Zeyuan Guan, Liying Zhang, Jinjin Zhuang, Ling Yan, Yanjun Liu, Zhu Liu, Qiang Wang, Ping Yin

National Key Laboratory of Crop Genetic Improvement, Hubei Hongshan Laboratory, Huazhong Agricultural University

Abstract: Prohibitin 1 (PHB1) and Prohibitin 2 (PHB2), two conserved prohibitin members, are primarily localized to the mitochondrial inner membrane (MIM) to form a nanoscale macromolecular prohibitin complex. This prohibitin complex can facilitate the spatial organization of proteins and lipids, thus maintaining cellular metabolism and homeostasis, but its architecture remains largely unknown. Here, we report the cryo-EM structure of a prohibitin complex at 2.8 Å resolution, which contains 11 PHB1–PHB2 heterodimers. This complex displays a bell-like cage, consisting of a lid and a wall, which creates an intermembrane space-facing compartment for the MIM. The lid of the cage is stably assembled, and it is responsible for the prohibitin complex formation. In contrast, the wall of the cage is flexible and exhibits lateral openings, providing a channel for intramembrane exchange of proteins and lipids. These findings provide a structural basis for understanding the scaffold role of the prohibitin complex in organizing intramembrane proteins and lipids.


Eicosanoid regulation of debris-stimulated metastasis

Jianjun Deng, Haixia Yang, Victoria M. Haak, Jun Yang, Franciele C. Kipper, Chantal Barksdale, Sung Hee Hwang, Allison Gartung, Diane R. Bielenberg, Selvakumar Subbian, Koc-Kan Ho, Xiang Ye, Daidi Fan, Yongkui Sun, Bruce D. Hammock, Dipak Panigrahy

Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;

HHS | NIH | National Institute of Environmental Health Sciences, HHS | NIH | National Institute of Environmental Health Sciences, Credit Unions Kids at Heart, Joe Andruzzi Foundation, CJ Buckley Pediatric Brain Tumor Fund

Abstract: Significance Cancer therapy, such as chemotherapy, induces tumor cell death (“debris”), which can stimulate metastasis. Chemotherapy-generated debris upregulates soluble epoxide hydrolase (sEH) and the prostaglandin E 2 receptor 4 (EP4), which triggers a macrophage-derived storm of proinflammatory and proangiogenic lipid autacoid and cytokine mediators. Although sEH inhibitors and EP4 antagonists are in clinical development for multiple inflammatory diseases, their combined role in cancer is unknown. Here, we show that the synergistic antitumor activity of sEH and EP4 inhibition suppresses hepato-pancreatic tumor growth, without overt toxicity, via macrophage phagocytosis of debris and counterregulation of a debris-stimulated cytokine storm. Thus, stimulating the resolution of inflammation via combined inhibition of sEH and EP4 may be an approach for preventing metastatic progression driven by cancer therapy.


Therapeutic IGF-I receptor inhibition alters fibrocyte immune phenotype in thyroid-associated ophthalmopathy

Roshini Fernando, Oshadi Caldera, Terry J. Smith

Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, Division of Metabolism, Endocrinology, and Diabetes, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105

Abstract: Significance Teprotumumab, a therapeutic IGF-I receptor inhibitor, dramatically alters the clinical course of thyroid-associated ophthalmopathy (TAO) and has recently become the only medical therapy for TAO thus far approved by the US FDA. Introduction of teprotumumab has resulted in a paradigm shift in the clinical management of TAO. Here, we demonstrate that teprotumumab and other IGF-I inhibitors attenuate MHC II and B7 expression in fibrocytes in TAO, both in vitro and in patients treated with the drug in vivo. This inhibition is associated with substantial reductions in two key inflammatory cytokines implicated in TAO. Thus, the current findings provide a plausible mechanism underlying the therapeutic responses to teprotumumab.


Phylogenetic classification of the world’s tropical forests

J. W. Ferry Slik, Janet Franklin, Víctor Arroyo-Rodríguez, Richard Field, Salomon Aguilar, Nikolay Aguirre, Jorge Ahumada, Shin-Ichiro Aiba, Luciana F. Alves, Anitha K, Andres Avella, Francisco Mora, Gerardo A. Aymard C., Selene Báez, Patricia Balvanera, Meredith L. Bastian, Jean-François Bastin, Peter J. Bellingham, Eduardo van den Berg, Polyanna da Conceição Bispo, Pascal Boeckx, Katrin Boehning-Gaese, Frans Bongers, Brad Boyle, Fabian Brambach, Francis Q. Brearley, Sandra Brown, Shauna-Lee Chai, Robin L. Chazdon, Shengbin Chen, Phourin Chhang, George Chuyong, Corneille Ewango, Indiana M. Coronado, Jurgi Cristóbal-Azkarate, Heike Culmsee, Kipiro Damas, H. S. Dattaraja, Priya Davidar, Saara J. DeWalt, Hazimah Din, Donald R. Drake, Alvaro Duque, Giselda Durigan, Karl Eichhorn, Eduardo Schmidt Eler, Tsutomu Enoki, Andreas Ensslin, Adandé Belarmain Fandohan, Nina Farwig, Kenneth J. Feeley, Markus Fischer, Olle Forshed, Queila Souza Garcia, Satish Chandra Garkoti, Thomas W. Gillespie, Jean-Francois Gillet, Christelle Gonmadje, Iñigo Granzow-de la Cerda, Daniel M. Griffith, James Grogan, Khalid Rehman Hakeem, David J. Harris, Rhett D. Harrison, Andy Hector, Andreas Hemp, Jürgen Homeier, M. Shah Hussain, Guillermo Ibarra-Manríquez, I. Faridah Hanum, Nobuo Imai, Patrick A. Jansen, Carlos Alfredo Joly, Shijo Joseph, Kuswata Kartawinata, Elizabeth Kearsley, Daniel L. Kelly, Michael Kessler, Timothy J. Killeen, Robert M. Kooyman, Yves Laumonier, Susan G. Laurance, William F. Laurance, Michael J. Lawes, Susan G. Letcher, Jeremy Lindsell, Jon Lovett, Jose Lozada, Xinghui Lu, Anne Mette Lykke, Khairil Bin Mahmud, Ni Putu Diana Mahayani, Asyraf Mansor, Andrew R. Marshall, Emanuel H. Martin, Darley Calderado Leal Matos, Jorge A. Meave, Felipe P. L. Melo, Zhofre Huberto Aguirre Mendoza, Faizah Metali, Vincent P. Medjibe, Jean Paul Metzger, Thiago Metzker, D. Mohandass, Miguel A. Munguía-Rosas, Rodrigo Muñoz, Eddy Nurtjahy, Eddie Lenza de Oliveira, Onrizal, Pia Parolin, Marc Parren, N. Parthasarathy, Ekananda Paudel, Rolando Perez, Eduardo A. Pérez-García, Ulf Pommer, Lourens Poorter, Lan Qie, Maria Teresa F. Piedade, José Roberto Rodrigues Pinto, Axel Dalberg Poulsen, John R. Poulsen, Jennifer S. Powers, Rama Chandra Prasad, Jean-Philippe Puyravaud, Orlando Rangel, Jan Reitsma, Diogo S. B. Rocha, Samir Rolim, Francesco Rovero, Andes Rozak, Kalle Ruokolainen, Ervan Rutishauser, Gemma Rutten, Mohd. Nizam Mohd. Said, Felipe Z. Saiter, Philippe Saner, Braulio Santos, João Roberto dos Santos, Swapan Kumar Sarker, Christine B. Schmitt, Jochen Schoengart, Mark Schulze, Douglas Sheil, Plinio Sist, Alexandre F. Souza, Wilson Roberto Spironello, Tereza Sposito, Robert Steinmetz, Tariq Stevart, Marcio Seiji Suganuma, Rahayu Sukri, Aisha Sultana, Raman Sukumar, Terry Sunderland, Supriyadi, H. S. Suresh, Eizi Suzuki, Marcelo Tabarelli, Jianwei Tang, Ed V. J. Tanner, Natalia Targhetta, Ida Theilade, Duncan Thomas, Jonathan Timberlake, Márcio de Morisson Valeriano, Johan van Valkenburg, Tran Van Do, Hoang Van Sam, John H. Vandermeer, Hans Verbeeck, Ole Reidar Vetaas, Victor Adekunle, Simone A. Vieira, Campbell O. Webb, Edward L. Webb, Timothy Whitfeld, Serge Wich, John Williams, Susan Wiser, Florian Wittmann, Xiaobo Yang, C. Yves Adou Yao, Sandra L. Yap, Rakan A. Zahawi, Rahmad Zakaria, Runguo Zang

Environmental and Life Sciences, Faculty of Science, Universiti Brunei Darussalam, Gadong BE1410, Brunei Darussalam;

Abstract: Significance Identifying and explaining regional differences in tropical forest dynamics, structure, diversity, and composition are critical for anticipating region-specific responses to global environmental change. Floristic classifications are of fundamental importance for these efforts. Here we provide a global tropical forest classification that is explicitly based on community evolutionary similarity, resulting in identification of five major tropical forest regions and their relationships: ( i ) Indo-Pacific, ( ii ) Subtropical, ( iii ) African, ( iv ) American, and ( v ) Dry forests. African and American forests are grouped, reflecting their former western Gondwanan connection, while Indo-Pacific forests range from eastern Africa and Madagascar to Australia and the Pacific. The connection between northern-hemisphere Asian and American forests is confirmed, while Dry forests are identified as a single tropical biome.


Chromatographically isolated CD63 + CD81 + extracellular vesicles from mesenchymal stromal cells rescue cognitive impairments after TBI

Dong-ki Kim, Hidetaka Nishida, Su Yeon An, Ashok K. Shetty, Thomas J. Bartosh, Darwin J. Prockop

Institute for Regenerative Medicine at Scott & White, College of Medicine, Texas A&M Health Science Center, Temple, TX 76502

Abstract: Significance It has gradually been recognized that the vesicles secreted by cells are a major means by which cells communicate with each other. This recognition has stimulated interest in using vesicles to deliver therapeutic agents. The results presented here address several limitations to progress in the field by developing protocols to produce and isolate large numbers of extracellular vesicles (EVs) from stem-like cells found in the bone marrow. The isolated EVs were found to reduce the adverse effects of traumatic injury to the brain in mice.


Fructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington’s disease

Anirban Chakraborty, Sravan Gopalkrishnashetty Sreenivasmurthy, Wyatt Miller, Weihan Huai, Tapan Biswas, Santi Mohan Mandal, Lisardo Boscá, Balaji Krishnan, Gourisankar Ghosh, Tapas Hazra

Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555

HHS | NIH | National Institute of Neurological Disorders and Stroke, HHS | NIH | National Institute of Neurological Disorders and Stroke

Abstract: Huntington’s disease (HD) and spinocerebellar ataxia type 3 (SCA3) are the two most prevalent polyglutamine (polyQ) neurodegenerative diseases, caused by CAG (encoding glutamine) repeat expansion in the coding region of the huntingtin (HTT) and ataxin-3 (ATXN3) proteins, respectively. We have earlier reported that the activity, but not the protein level, of an essential DNA repair enzyme, polynucleotide kinase 3′-phosphatase (PNKP), is severely abrogated in both HD and SCA3 resulting in accumulation of double-strand breaks in patients’ brain genome. While investigating the mechanistic basis for the loss of PNKP activity and accumulation of DNA double-strand breaks leading to neuronal death, we observed that PNKP interacts with the nuclear isoform of 6-phosphofructo-2-kinase fructose-2,6-bisphosphatase 3 (PFKFB3). Depletion of PFKFB3 markedly abrogates PNKP activity without changing its protein level. Notably, the levels of both PFKFB3 and its product fructose-2,6 bisphosphate (F2,6BP), an allosteric modulator of glycolysis, are significantly lower in the nuclear extracts of postmortem brain tissues of HD and SCA3 patients. Supplementation of F2,6BP restored PNKP activity in the nuclear extracts of patients’ brain. Moreover, intracellular delivery of F2,6BP restored both the activity of PNKP and the integrity of transcribed genome in neuronal cells derived from the striatum of the HD mouse. Importantly, supplementing F2,6BP rescued the HD phenotype in Drosophila, suggesting F2,6BP to serve in vivo as a cofactor for the proper functionality of PNKP and thereby, of brain health. Our results thus provide a compelling rationale for exploring the therapeutic use of F2,6BP and structurally related compounds for treating polyQ diseases.


Human methionine synthase reductase is a molecular chaperone for human methionine synthase

Kazuhiro Yamada, Roy A. Gravel, Tetsuo Toraya, Rowena G. Matthews

*Life Sciences Institute and Department of Biological Chemistry, University of Michigan, Ann Arbor, MI 48109-2216;

Abstract: Sustained activity of mammalian methionine synthase (MS) requires MS reductase (MSR), but there have been few studies of the interactions between these two proteins. In this study, recombinant human MS (hMS) and MSR (hMSR) were expressed in baculovirus-infected insect cells and purified to homogeneity. hMSR maintained hMS activity at a 1:1 stoichiometric ratio with a K act value of 71 nM. Escherichia coli MS, however, was not activated by hMSR. Moreover, hMS was not significantly active in the presence of E. coli flavodoxin and flavodoxin reductase, which maintain the activity of E. coli MS. These results indicate that recognition of MS by their reductive partners is very strict, despite the high homology between MS from different species. The effects of hMSR on the formation of hMS holoenzyme also were examined by using crude extracts of baculovirus-infected insect cells containing hMS apoenzyme (apoMS). In the presence of MSR and NADPH, holoenzyme formation from apoMS and methylcobalamin was significantly enhanced. The observed stimulation is shown to be due to stabilization of human apoMS in the presence of MSR. Apoenzyme alone is quite unstable at 37°C. MSR also is able to reduce aquacobalamin to cob(II)alamin in the presence of NADPH, and this reduction leads to stimulation of the conversion of apoMS and aquacobalamin to MS holoenzyme. Based on these findings, we propose that MSR serves as a special chaperone for hMS and as an aquacobalamin reductase, rather than acting solely in the reductive activation of MS.


Cloning, baculovirus expression, and characterization of a second mouse prolyl 4-hydroxylase alpha-subunit isoform: formation of an alpha 2 beta 2 tetramer with the protein disulfide-isomerase/beta subunit.

T Helaakoski, P Annunen, K Vuori, I A MacNeil, T Pihlajaniemi, K I Kivirikko

Collagen Research Unit, University of Oulu, Finland.

Abstract: Prolyl 4-hydroxylase (EC 1.14.11.2) catalyzes the posttranslational formation of 4-hydroxyproline in collagens. The vertebrate enzyme is an alpha 2 beta 2 tetramer, the beta subunit of which is a highly unusual multifunctional polypeptide, being identical to protein disulfide-isomerase (EC 5.3.4.1). We report here the cloning of a second mouse alpha subunit isoform, termed the alpha (II) subunit. This polypeptide consists of 518 aa and a signal peptide of 19 aa. The processed polypeptide is one residue longer than the mouse alpha (I) subunit (the previously known type), the cloning of which is also reported here. The overall amino acid sequence identity between the mouse alpha (II) and alpha (I) subunits is 63%. The mRNA for the alpha (II) subunit was found to be expressed in a variety of mouse tissues. When the alpha (II) subunit was expressed together with the human protein disulfide-isomerase/beta subunit in insect cells by baculovirus vectors, an active prolyl 4-hydroxylase was formed, and this protein appeared to be an alpha (II) 2 beta 2 tetramer. The activity of this enzyme was very similar to that of the human alpha (I) 2 beta 2 tetramer, and most of its catalytic properties were also highly similar, but it differed distinctly from the latter in that it was inhibited by poly(L-proline) only at very high concentrations. This property may explain why the type II enzyme was not recognized earlier, as an early step in the standard purification procedure for prolyl 4-hydroxylase is affinity chromatography on a poly(L-proline) column.


Coupling between dynamic 3D tissue architecture and BMP morphogen signaling during <i>Drosophila</i> wing morphogenesis

Jinghua Gui, Yunxian Huang, Martin Montanari, Daniel Toddie-Moore, Kenji Kikushima, Stephanie Nix, Yukitaka Ishimoto, Osamu Shimmi

Institute of Biotechnology, University of Helsinki, 00014 Helsinki, Finland;

Suomen Akatemia, Suomen Akatemia, Suomen Akatemia, Suomen Akatemia, Sigrid Juséliuksen Säätiö, MEXT | Japan Society for the Promotion of Science, MEXT | Japan Society for the Promotion of Science, Finnish Cultural Foundation | Etelä-Karjalan Rahasto, University of Helsinki | Helsingin Yliopiston Tiedesäätiö

Abstract: Significance Tissue morphogenesis is a dynamic process often accompanied by cell patterning and differentiation. Although how conserved growth factor signaling affects cell and tissue shapes has been actively studied, much less is known about how signaling and dynamic morphogenesis are mutually coordinated. Our study shows that BMP signaling and 3D morphogenesis of the Drosophila pupal wing are tightly coupled. These findings are highlighted by the fact that the directionality of BMP signal is changed from lateral planar during the inflation stage to interplanar after re-apposition of the dorsal and ventral wing epithelia. We suspect that the dynamic interplay between planar and interplanar signaling linked to tissue shape changes is likely to be used across species in many developing organs.


Glycosylation-dependent galectin–receptor interactions promote <i>Chlamydia trachomatis</i> infection

Agustin L. Lujan, Diego O. Croci, Julián A. Gambarte Tudela, Antonella D. Losinno, Alejandro J. Cagnoni, Karina V. Mariño, María T. Damiani, Gabriel A. Rabinovich

Laboratorio de Fagocitosis, Instituto de Histología y Embriología de Mendoza, Consejo Nacional de Investigaciones Científicas y Técnicas, Facultad de Ciencias Médicas, Universidad Nacional de Cuyo, C5500 Mendoza, Argentina;

MINCyT | Agencia Nacional de Promoción Científica y Tecnológica, MINCyT | Agencia Nacional de Promoción Científica y Tecnológica

Abstract: Significance Chlamydia trachomatis ( Ct ) is the most common bacterium responsible for sexually transmitted infections. It constitutes a major public health burden, with the greatest clinical impact occurring in women of reproductive age. A vast proportion of Ct infections are underestimated because they are asymptomatic in nature. This leads to chronic infections with severe consequences, such as ectopic pregnancy, tubal obstruction, infertility, and blindness. Ct is an obligate intracellular pathogen that completes its entire developmental cycle in humans. Here, we demonstrate that galectin-1 (Gal1), an endogenous glycan-binding protein, promotes Ct –host adhesion and invasion. Through glycosylation-dependent mechanisms, Gal1 enhances chlamydial infection by favoring Ct –host cell interactions. Thus, novel therapeutic approaches aimed at disrupting Gal1– N -glycan interactions may reduce the severity of Ct infections.