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1. Durable cross-protective neutralizing antibody responses elicited by lipid nanoparticle-formulated SARS-CoV-2 mRNA vaccines

Author

Ki Hyun Bae, Bhuvaneshwari Shunmuganathan, Li Zhang, Andrew Lim, Rashi Gupta, Yanming Wang, Boon Lin Chua, Yang Wang, Yue Gu, Xinlei Qian, Isabelle Siang Ling Tan, Kiren Purushotorman, Paul A. MacAry, Kevin P. White, and Yi Yan Yang

Subjects
Immunologic diseases. Allergy, RC581-607, Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract The advent of SARS-CoV-2 variants with defined mutations that augment pathogenicity and/or increase immune evasiveness continues to stimulate global efforts to improve vaccine formulation and efficacy. The extraordinary advantages of lipid nanoparticles (LNPs), including versatile design, scalability, and reproducibility, make them ideal candidates for developing next-generation mRNA vaccines against circulating SARS-CoV-2 variants. Here, we assess the efficacy of LNP-encapsulated mRNA booster vaccines encoding the spike protein of SARS-CoV-2 for variants of concern (Delta, Omicron) and using a predecessor (YN2016C isolated from bats) strain spike protein to elicit durable cross-protective neutralizing antibody responses. The mRNA-LNP vaccines have desirable physicochemical characteristics, such as small size (~78 nm), low polydispersity index (90%). We employ in vivo bioluminescence imaging to illustrate the capacity of our LNPs to induce robust mRNA expression in secondary lymphoid organs. In a BALB/c mouse model, a three-dose subcutaneous immunization of mRNA-LNPs vaccines achieved remarkably high levels of cross-neutralization against the Omicron B1.1.529 and BA.2 variants for extended periods of time (28 weeks) with good safety profiles for all constructs when used in a booster regime, including the YN2016C bat virus sequences. These findings have important implications for the design of mRNA-LNP vaccines that aim to trigger durable cross-protective immunity against the current and newly emerging variants.

Published
2024
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2. Employment of a high throughput functional assay to define the critical factors that influence vaccine induced cross-variant neutralizing antibodies for SARS-CoV-2

Author

Yue Gu, Bhuvaneshwari Shunmuganathan, Xinlei Qian, Rashi Gupta, Rebecca S. W. Tan, Mary Kozma, Kiren Purushotorman, Tanusya M. Murali, Nikki Y. J. Tan, Peter R. Preiser, Julien Lescar, Haziq Nasir, Jyoti Somani, Paul A. Tambyah, SCOPE Cohort Study Group, Kenneth G. C. Smith, Laurent Renia, Lisa F. P. Ng, David C. Lye, Barnaby E. Young, and Paul A. MacAry

Subjects
Medicine, Science
Abstract

Abstract The scale and duration of neutralizing antibody responses targeting SARS-CoV-2 viral variants represents a critically important serological parameter that predicts protective immunity for COVID-19. In this study, we describe the development and employment of a new functional assay that measures neutralizing antibodies for SARS-CoV-2 and present longitudinal data illustrating the impact of age, sex and comorbidities on the kinetics and strength of vaccine-induced antibody responses for key variants in an Asian volunteer cohort. We also present an accurate quantitation of serological responses for SARS-CoV-2 that exploits a unique set of in-house, recombinant human monoclonal antibodies targeting the viral Spike and nucleocapsid proteins and demonstrate a reduction in neutralizing antibody titres across all groups 6 months post-vaccination. We also observe a marked reduction in the serological binding activity and neutralizing responses targeting recently newly emerged Omicron variants including XBB 1.5 and highlight a significant increase in cross-protective neutralizing antibody responses following a third dose (boost) of vaccine. These data illustrate how key virological factors such as immune escape mutations combined with host demographic factors such as age and sex of the vaccinated individual influence the strength and duration of cross-protective serological immunity for COVID-19.

Published
2023
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3. Defining neutralization and allostery by antibodies against COVID-19 variants

Author

Nikhil Kumar Tulsian, Raghuvamsi Venkata Palur, Xinlei Qian, Yue Gu, Bhuvaneshwari D/O Shunmuganathan, Firdaus Samsudin, Yee Hwa Wong, Jianqing Lin, Kiren Purushotorman, Mary McQueen Kozma, Bei Wang, Julien Lescar, Cheng-I Wang, Ravindra Kumar Gupta, Peter John Bond, and Paul Anthony MacAry

Subjects
Science
Abstract

Abstract The changing landscape of SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. The functional activity of neutralizing antibodies is linked to their quaternary changes occurring as a result of antibody-Spike trimer interactions. Here, we reveal the conformational dynamics and allosteric perturbations linked to binding of novel human antibodies and the viral Spike protein. We identified epitope hotspots, and associated changes in Spike dynamics that distinguish weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan-Hu-1, Delta, and Omicron variants on differences in the antibody-induced conformational changes in Spike and illustrate how these render certain antibodies ineffective. Antibodies with similar binding affinities may induce destabilizing or stabilizing allosteric effects on Spike, with implications for neutralization efficacy. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19 and may assist in designing effective antiviral strategies.

Published
2023
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4. SHEAR saliva collection device augments sample properties for improved analytical performance

Author

Shang Wei Song, Rashi Gupta, Niharika Jothilingam, Xinlei Qian, Yue Gu, V Vien Lee, Yoann Sapanel, David Michael Allen, John Eu Li Wong, Paul MacAry, Dean Ho, and Agata Blasiak

Subjects
antigen rapid test, infectious diseases, point‐of‐care, saliva collection device, saliva‐based diagnostic, sample homogenizer, Chemical engineering, TP155-156, Biotechnology, TP248.13-248.65, Therapeutics. Pharmacology, RM1-950
Abstract

Abstract Despite being a convenient clinical substrate for biomonitoring, saliva's widespread utilization has not yet been realized. The non‐Newtonian, heterogenous, and highly viscous nature of saliva complicate the development of automated fluid handling processes that are vital for accurate diagnoses. Furthermore, conventional saliva processing methods are resource and/or time intensive precluding certain testing capabilities, with these challenges aggravated during a pandemic. The conventional approaches may also alter analyte structure, reducing application opportunities in point‐of‐care diagnostics. To overcome these challenges, we introduce the SHEAR saliva collection device that mechanically processes saliva, in a rapid and resource‐efficient way. We demonstrate the device's impact on reducing saliva's viscosity, improving sample's uniformity, and increasing diagnostic performance of a COVID‐19 rapid antigen test. Additionally, a formal user experience study revealed generally positive comments. SHEAR saliva collection device may support realization of the saliva's potential, particularly in large‐scale and/or resource‐limited settings for global and community diagnostics.

Published
2023
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5. A rapid simple point-of-care assay for the detection of SARS-CoV-2 neutralizing antibodies

Author

Patthara Kongsuphol, Huan Jia, Hoi Lok Cheng, Yue Gu, Bhuvaneshwari D/O Shunmuganathan, Ming Wei Chen, Sing Mei Lim, Say Yong Ng, Paul Ananth Tambyah, Haziq Nasir, Xiaohong Gao, Dousabel Tay, Seunghyeon Kim, Rashi Gupta, Xinlei Qian, Mary M. Kozma, Kiren Purushotorman, Megan E. McBee, Paul A. MacAry, Hadley D. Sikes, and Peter R. Preiser

Subjects
Medicine
Abstract

Kongsuphol et al. develop a paper-based, vertical flow assay to detect SARS-CoV-2 neutralizing antibodies. The point-of-care assay has comparable performance to lab-based tests and provides results in 10 min.

Published
2021
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6. Suppression of Speckle Noise in Digital Holography With Spatial and Temporal Domain Depolarization

Author

Tongyao Du, Yong Kong, Xinlei Qian, Wei Ding, and Zhenwei Wang

Subjects
Digital holography speckle noise, depolarization, quartz depolarizer, liquid crystal, Electrical engineering. Electronics. Nuclear engineering, TK1-9971
Abstract

Speckle noise in digital holography has a great influence on image quality, and one of the reasons for the formation of speckle noise is that the degree of coherence for the reference light and the object light is too high and unnecessary noise is introduced to the recorded hologram. In this paper, the spatial depolarization and the temporal domain depolarization are analyzed to reduce the speckle noise. The spatial depolarization utilizes the depolarization performance of the depolarizer. By adding a quartz depolarizer to the object light, the linearly polarized light in the object light becomes randomly polarized light, thereby reducing the degree of coherence with the reference light, realizing the suppression of speckle noise, and by utilizing the characteristics of pupil parameters towards the depolarization degree, it is to realize the control for the degree of coherence. The temporal domain depolarization uses two quarter-wave plates and adjustable liquid crystal to realize the depolarization superposition. By controlling the phase delay of the liquid crystal phase variable retarder, the multi-depolarization accumulation in a short time is realized, and the experimental results show that this method preserves the detail portion of the image while better removing speckle noise. Finally, the Non-Local Means filtering algorithm is used to make the reconstructed image smoother. The method proposed in this paper has great applicable value for improving the image quality of digital holography system.

Published
2020
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7. Switching Heavy Chain Constant Domains Denatures the Paratope 3D Architecture of Influenza Monoclonal Antibodies

Author

Moffat M. Malisheni, Cheng-Shoong Chong, Tanusya M. Murali, Kiren Purushotorman, Xinlei Qian, Alfred Laiman, Yee-Joo Tan, and Paul A. MacAry

Subjects
heavy chain constant domain, paratope, epitope, VR-analogous IgG variants, influenza, monoclonal Ab, Medicine
Abstract

Several human monoclonal Abs for treating Influenza have been evaluated in clinical trials with limited success despite demonstrating superiority in preclinical animal models including mice. To conduct efficacy studies in mice, human monoclonal Abs are genetically engineered to contain mouse heavy chain constant domain to facilitate the engagement of Fc-receptors on mouse immune effector cells. Although studies have consistently reported discrepancies in Ab effectiveness following genetic engineering, the structural and mechanistic basis for these inconsistencies remain uncharacterized. Here, we use homology modeling to predict variable region (VR) analogous monoclonal Abs possessing human IgG1, mouse IgG1, and mouse IgG2a heavy chain constant domains. We then examine predicted 3D structures for variations in the spatial location and orientation of corresponding paratope amino acid residues. By structurally aligning crystal structures of Fabs in complex with hemagglutinin (HA), we show that corresponding paratope amino acid residues for VR-analogous human IgG1, mouse IgG1, and mouse IgG2a monoclonal Abs interact differentially with HA suggesting that their epitopes might not be identical. To demonstrate that variations in the paratope 3D fine architecture have implications for Ab specificity and effectiveness, we genetically engineered VR-analogous human IgG1, human IgG4, mouse IgG1, and mouse IgG2a monoclonal Abs and explored their specificity and effectiveness in protecting MDCK cells from infection by pandemic H1N1 and H3N2 Influenza viruses. We found that VR-analogous monoclonal Abs placed on mouse heavy chain constant domains were more efficacious at protecting MDCK cells from Influenza virus infection relative to those on human heavy chain constant domains. Interestingly, mouse but not human heavy chain constant domains increased target breadth in some monoclonal Abs. These data suggest that heavy chain constant domain sequences play a role in shaping Ab repertoires that go beyond class or sub-class differences in immune effector recruitment. This represents a facet of Ab biology that can potentially be exploited to improve the scope and utilization of current therapeutic or prophylactic candidates for influenza.

Published
2022
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8. Specific Phase Modulation with Dynamic Variable Spectral Width of Nanosecond Optical Pulse in High-Power Lasers

Author

Xinlei Qian, Xiaochao Wang, Shouying Xu, Zhuli Xiao, Yue Wang, Shenlei Zhou, and Wei Fan

Subjects
high-power lasers, phase modulation, dynamic nanosecond spectral distribution, spectral smoothing dispersion, signal processing, Applied optics. Photonics, TA1501-1820
Abstract

High-power laser pulse transmitted by phase modulation with certain spectrum distribution can suppress the buildup of transverse stimulated Brillouin scattering (TSBS) in large aperture laser optics and smooth the speckle pattern illuminating the target by spectral smoothing dispersion (SSD). In this paper, based on the requirements of the double-cone ignition scheme including simultaneously realizing that the focal spot is variable at different times in size and the spatial intensity distribution is uniform, we propose a novel phase modulation technology with a rapid variable modulation index in the nanosecond scale instead of utilizing conventional constant amplitude sinusoidal curve. The relevant simulation results indicate that the proposed technology can realize the dynamic nanosecond spectral distribution and the trend correlates with the variety of modulation index. Particularly, we indirectly measure this rapid changeable spectral distribution based on the mapping relationship between frequency and time domain. We believe that the new technology is expected to meet the requirements of SSD and the dynamic focus simultaneously.

Published
2022
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9. SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

Author

Palur V Raghuvamsi, Nikhil K Tulsian, Firdaus Samsudin, Xinlei Qian, Kiren Purushotorman, Gu Yue, Mary M Kozma, Wong Y Hwa, Julien Lescar, Peter J Bond, Paul A MacAry, and Ganesh S Anand

Subjects
SARS-CoV-2, virus-host interactions, allostery, ACE2, HDXMS, spike, Medicine, Science, Biology (General), QH301-705.5
Abstract

The spike (S) protein is the main handle for SARS-CoV-2 to enter host cells via surface angiotensin-converting enzyme 2 (ACE2) receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, using amide hydrogen–deuterium exchange mass spectrometry and molecular dynamics simulations, we have mapped the S:ACE2 interaction interface and uncovered long-range allosteric propagation of ACE2 binding to sites necessary for host-mediated proteolysis of S protein, critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat [HR]) regions ~130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the prefusion state. Our findings provide a dynamics map of the S:ACE2 interface in solution and also offer mechanistic insights into how ACE2 binding is allosterically coupled to distal proteolytic processing sites and viral–host membrane fusion. Thus, protease docking sites flanking the S1/S2 cleavage site represent alternate allosteric hotspot targets for potential therapeutic development.

Published
2021
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10. Suppression of Frequency Modulation to Amplitude Modulation Conversion with Modified Group Velocity Dispersion Compensation Device in the Front End of High-Power Lasers

Author

Xinlei Qian, Xiaochao Wang, Xinghua Lu, Tianyu Zhang, and Wei Fan

Subjects
dispersion compensation devices, lasers, frequency modulation, amplitude modulation, Technology, Engineering (General). Civil engineering (General), TA1-2040, Biology (General), QH301-705.5, Physics, QC1-999, Chemistry, QD1-999
Abstract

The group velocity dispersion (GVD) occurring in the front end of high-power lasers is one of the primary factors leading to the conversion of frequency modulation (FM) to amplitude modulation (AM). In this paper, we propose a modified, active, closed-loop feedback compensation device for GVD-induced FM–AM conversion, using a two-dimensional, electric, adjustable mirror mount and parallel grating pair to improve the long-term stability, efficiency of adjustment, and accuracy of compensation. Experimental results of a 12 h FM–AM depth test revealed that the depth varied between 2.28% and 5.22%. Moreover, we formulated a mathematical relationship between the dispersion parameters and temperature in optical fibers to analyze the intrinsic effect of temperature on FM–AM. The related simulation and experimental results consistently validated the quantitative relationship between the temperature and FM–AM depth.

Published
2022
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11. An anti-LpqH human monoclonal antibody from an asymptomatic individual mediates protection against Mycobacterium tuberculosis.

Author

Krishnananthasivam, Shivankari, Li, Hao, Bouzeyen, Rania, Shunmuganathan, Bhuvaneshwari, Purushotorman, Kiren, Liao, Xinlei, Du, Fengjiao, Friis, Claudia, Crawshay-Williams, Felicity, Boon, Low, Xinlei, Qian, Chan, Conrad, Sobota, Radoslaw, Kozma, Mary, Jo, Valeria, Wang, Guirong, Huang, Hairong, Floto, Andreas, Bifani, Pablo, MacAry, Paul, and Javid, Babak

Abstract

Tuberculosis (TB) is an airborne disease caused by Mycobacterium tuberculosis (Mtb). Whilst a functional role for humoral immunity in Mtb protection remains poorly defined, previous studies have suggested that antibodies can contribute towards host defense. Thus, identifying the critical components in the antibody repertoires from immune, chronically exposed, healthy individuals represents an approach for identifying new determinants for natural protection. In this study, we performed a thorough analysis of the IgG/IgA memory B cell repertoire from occupationally exposed, immune volunteers. We detail the identification and selection of a human monoclonal antibody that exhibits protective activity in vivo and show that it targets a virulence factor LpqH. Intriguingly, protection in both human ex vivo and murine challenge experiments was isotype dependent, with most robust protection being mediated via IgG2 and IgA. These data have important implications for our understanding of natural mucosal immunity for Mtb and highlight a new target for future vaccine development.

Published
2023

12. Author Correction: An anti-LpqH human monoclonal antibody from an asymptomatic individual mediates protection against Mycobacterium tuberculosis

Author

Krishnananthasivam, Shivankari, Li, Hao, Bouzeyen, Rania, Shunmuganathan, Bhuvaneshwari, Purushotorman, Kiren, Liao, Xinlei, Du, Fengjiao, Friis, Claudia Guldager Kring, Crawshay-Williams, Felicity, Boon, Low Heng, Xinlei, Qian, Chan, Conrad En Zuo, Sobota, Radoslaw, Kozma, Mary, Barcelli, Valeria, Wang, Guirong, Huang, Hairong, Floto, Andreas, Bifani, Pablo, Javid, Babak, and MacAry, Paul A.

Published
2023
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16. Single shot dendritic cell targeting SARS-CoV-2 vaccine candidate induces broad and durable systemic and mucosal immune responses

Author

Nicholas You Zhi Cheang, Peck Szee Tan, Kiren Purushotorma, Wee Chee Yap, Benson Yen Leong Chua, Kai Sen Tan, Kirsteen McInnes Tullett, Aileen Ying-Yan Yeoh, Caris Qi Hui Tan, Xinlei Qian, Douglas Jie Wen Tay, Irina Caminschi, Yee Joo Tan, Paul Anthony Macary, Chee Wah Tan, Mireille Hanna Lahoud, and Sylvie Alonso

Abstract

Current COVID-19 vaccines face certain limitations, which include waning immunity, immune escape by SARS-CoV-2 variants, limited CD8+cellular response, and poor induction of mucosal immunity. Here, we engineered a Clec9A-RBD antibody construct that delivers the Receptor Binding Domain (RBD) from SARS-CoV-2 spike protein to conventional type 1 dendritic cells (cDC1). We showed that single dose immunization with Clec9A-RBD induced high RBD-specific antibody titers with a strong T-helper 1 (TH1) isotype profile and exceptional durability, whereby antibody titers were sustained for at least 21 months post-vaccination. Uniquely, affinity maturation of the antibody response was observed over time, as evidenced by enhanced neutralization potency and breadth across the sarbecovirus family. Consistently and remarkably, RBD-specific T-follicular helper cells and germinal center B cells were still detected at 12 months post-immunization. Increased antibody-dependent cell-mediated cytotoxicity (ADCC) activity of the immune sera was also measured over time with comparable efficacy against ancestral SARS-CoV-2 and variants, including Omicron. Furthermore, Clec9A-RBD immunization induced a durable poly-functional TH1-biased cellular response that was strongly cross-reactive against SARS-CoV-2 variants, including Omicron, and with robust CD8+T cell signature. Lastly, Clec9A-RBD single dose systemic immunization primed effectively RBD-specific cellular and humoral mucosal immunity in lung. Taken together, Clec9A-RBD immunization has the potential to trigger robust and sustained, systemic and mucosal immune responses against rapidly evolving SARS-CoV2 variants.

Published
2023

17. Defining neutralization and allostery by antibodies against COVID-19 variants

Author

Nikhil Tulsian, Palur Raghuvamsi, Xinlei Qian, Yue Gu, Bhuvaneshwari D/O Shunmuganathan, Firdaus Samsudin, Yee Hwa Wong, Jianqing Lin, Kiren Purushotorman, Mary Kozma, BEI WANG, Julien Lescar, Cheng-I Wang, Ravindra Gupta, Peter Bond, and Paul MacAry

Abstract

The changing landscape of mutations in the SARS-CoV-2 Spike protein is linked to the emergence of variants, immune-escape and reduced efficacy of the existing repertoire of anti-viral antibodies. A major factor that contributes to the functional activity of the neutralizing antibodies are the intrinsic quaternary changes that occur as a result of antibody-Spike trimer interactions. In this study, we reveal the conformational dynamics and allosteric perturbations linked to binding of human monoclonal antibodies and the viral Spike protein. We identify epitope hotspots of known and novel antibodies, and associated changes in Spike dynamics that define weak, moderate and strong neutralizing antibodies. We show the impact of mutations in Wuhan, Delta, and Omicron variants of concern (VoCs) and differences observed in the antibody-induced conformational changes and illustrate how these render certain antibodies ineffective. Our comparative analyses of the antibody-footprints on Spike variants reveal how antibodies with similar binding affinities may induce destabilizing and stabilizing allosteric effects. These differences have important implications for neutralization efficacy and for developing new antibodies targeting emerging variants. Our results provide mechanistic insights into the functional modes and synergistic behavior of human antibodies against COVID-19, and provide a rationale to design effective antiviral strategies.

Published
2023

19. SHEAR Saliva Collection Device Augments Sample Properties for Improved Analytical Performance

Author

Shang Wei Song, Rashi Gupta, Jothilingam Niharika, Xinlei Qian, Yue Gu, V Vien Lee, Yoann Sapanel, David Michael Allen, John Eu Li Wong, Paul A MacAry, Dean Ho, and Agata Blasiak

Abstract

Despite human saliva representing a convenient and non-invasive clinical substrate for disease diagnosis and biomonitoring, its widespread utilization has been hampered by technical challenges. The non-Newtonian, heterogenous and highly viscous nature of clinical saliva samples complicate the development of automated fluid handling processes that are vital for accurate diagnoses. Furthermore, conventional saliva processing methods are either resource and/or time intensive precluding certain testing capabilities in low- and middle-income countries, with these challenges aggravated during a pandemic outbreak. The conventional approaches can also potentially alter analyte structure, reducing application opportunities in Point-of-Care diagnostics. To overcome these challenges, we introduce the SHEAR saliva collection device that preprocesses saliva for enhanced interfacing with downstream assays. We demonstrate the device’s impact on reducing saliva’s viscosity, improving sample uniformity and, increasing diagnostic performance of COVID-19 Rapid Antigen Tests. Importantly, in addition to reporting technical advances and to address downstream implementation factors, we conducted a formal user experience study, which resulted in generally positive comments. Effective implementation of this device could be of support to realize the potential of saliva, particularly in large-scale and/or resource-limited settings for global and community health diagnostics.

Published
2022

21. Brain charts for the human lifespan

Author

Armin Raznahan, Eric Courchesne, Andrea Parolin Jackowski, Kamen A. Tsvetanov, Cameron T. Ellis, R.C. Gur, Bin Bae J, Park Mtm, Pedro A. Valdes-Sosa, Simon N. Vandekar, Jacob W. Vogel, Juan Zhou, Machteld Marcelis, Kiho Im, Patricia Ellen Grant, Minhui Ouyang, Blesa Cabez M, Michael V. Lombardo, Sarah E. Morgan, James P. Boardman, Adamson C, Calhoun Vd, Delarue M, James H. Cole, Pichet Binette A, Roberto Toro, David H. Rowitch, Nynke A. Groenewold, Kevin M. Anderson, David T.W. Jones, Michael Schöll, Wang Ys, Aiden Corvin, R.E. Gur, Damien A. Fair, Gareth Ball, Herma Lina Schaare, Andrew Zalesky, Evdokia Anagnostou, Michael J. Meaney, Taki Y, Gareth J. Sullivan, Warrier, Petra E. Vértes, Chixiang Chen, Lisa T. Eyler, Wei Liao, Tomáš Paus, Jeremy A. Elman, Phillip McGuire, Hisham Ziauddeen, William S. Kremen, Etienne Vachon-Presseau, E.T. Bullmore, Christophe Tzourio, White, Hammill Cf, Mothersill D, Richard N. Henson, Jiang Qiu, Duncan E. Astle, Fabrice Crivello, Paul C. Fletcher, Chertavian C, Kim K, Jennifer Crosbie, Russell Schachar, Gabriel A. Devenyi, Manfred G. Kitzbichler, Tianye Jia, Trey Hedden, Sang Jae Lee, Ross D. Markello, Silke Kern, Ian M. Goodyer, Keith A. Johnson, Frauke Beyer, Bernard Mazoyer, A. Heinz, Sylvane Desrivières, Rosenberg, Gary Donohoe, Ong Mq, Alexander D. Edwards, Dan J. Stein, Nenad Medic, Zuo Xn, Travis T. Mallard, Peter Fonagy, Lindsay W. Victoria, Ingmar Skoog, Avram J. Holmes, Jason P. Lerch, Jed T. Elison, Jianfu Li, John H. Gilmore, Rosemary Holt, Caitlin K. Rollins, Carol E. Franz, Pedro Mario Pan, Saashi A Bedford, Yang N, Jonathan C Ipser, Richard A. I. Bethlehem, Tuulari Jj, Stolicyn A, Hua Huang, Bratislav Misic, Conor Liston, Ayub M, Lisa Ronan, Yeo Bt, Sophie Adler, Charles J. Lynch, Faith M. Gunning, Konrad Wagstyl, M. Mallar Chakravarty, John Suckling, Theodore D. Satterthwaite, Bharath Holla, Yap Seng Chong, Jinglei Lv, Jakob Seidlitz, Niall J Bourke, Xinlei Qian, Simon Baron-Cohen, Cynthia M. Ortinau, Deirel Paz Linares, Thyreau B, René S. Kahn, Aaron P. Schultz, Vanessa Cropley, Eric Westman, Mitchell Valdés-Sosa, Rik Ossenkoppele, André Zugman, Hasse Karlsson, Sylvia Villeneuve, Katja Heuer, Di Biase Ma, Margaret L. Westwater, Sofie L. Valk, David J. Sharp, Brigitte Landeau, Matthew Borzage, Kirsten A. Donald, Timothy Rittman, Richard Beare, Giovanni Abrahão Salum, Gunter Schumann, Ryuta Kawashima, Romero-Garcia R, John Blangero, Yun Hj, Russel T. Shinohara, Nicolas Crossley, Simon K. Warfield, Karen Pierce, George S. Alexopoulos, Katharine Dunlop, David C. Glahn, Francois Lalonde, Anqi Qiu, Lana Vasung, Gaël Chételat, Lídice Galán-García, Clifford R. Jack, Reisa A. Sperling, Anna Zettergren, Elizabeth Kelley, Arno Villringer, Andrea Mechelli, Benegal, Aaron Alexander-Bloch, Nicholas B. Turk-Browne, van Amelsvoort T, John D. Lewis, Heather C. Whalley, A. V. Witte, Zdenka Pausova, Joel T. Nigg, Heather J. Zar, Raymond J. Dolan, Christopher D. Smyser, Jay N. Giedd, Lena Palaniyappan, Ali Gholipour, Areces-Gonzalez A, Peter B. Jones, Jacqueline Hoare, Oskar Hansson, Linnea Karlsson, C Pantelis, Paly L, Bonnie Auyeung, Jorge Bosch-Bayard, Bethlehem, Richard [0000-0002-0714-0685], White, Simon [0000-0001-8642-7037], Astle, Duncan [0000-0002-7042-5392], Baron-Cohen, Simon [0000-0001-9217-2544], Henson, Rik [0000-0002-0712-2639], Jones, Peter [0000-0002-0387-880X], Kitzbichler, Manfred [0000-0002-4494-0753], Rittman, Timothy [0000-0003-1063-6937], Rowitch, David [0000-0002-0079-0060], Tsvetanov, Kamen A. [0000-0002-3178-6363], Westwater-Wozniak, Margaret [0000-0002-2918-0979], Ziauddeen, Hisham [0000-0003-4044-1719], Apollo - University of Cambridge Repository, British Academy, Autism Research Trust, National Institute of Mental Health (US), UK Research and Innovation, Medical Research Council (UK), National Institute for Health and Care Research (US), Wellcome Trust, University of Cambridge, Cambridge Biomedical Research Centre, University of Cambridge [UK] (CAM), University of Pennsylvania, Yale University [New Haven], Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), Physiopathologie et imagerie des troubles neurologiques (PhIND), Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Département de Neuroscience - Department of Neuroscience, Centre de Recherche Interdisciplinaire / Center for Research and Interdisciplinarity [Paris, France] (CRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Psychiatrie & Neuropsychologie, RS: MHeNs - R2 - Mental Health, MUMC+: MA Med Staf Spec Psychiatrie (9), Neurology, Amsterdam Neuroscience - Neurodegeneration, 3R-BRAIN, AIBL, Alzheimer’s Disease Neuroimaging Initiative, Alzheimer’s Disease Repository Without Borders Investigators, CALM Team, Cam-CAN, CCNP, COBRE, cVEDA, ENIGMA Developmental Brain Age Working Group, Developing Human Connectome Project, FinnBrain, Harvard Aging Brain Study, IMAGEN, KNE96, The Mayo Clinic Study of Aging, NSPN, POND, The PREVENT-AD Research Group, VETSA, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Auyeung, B.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Baron-Cohen, S.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bedford, S. A.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Holt, R.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Lombardo, M. V.] Univ Cambridge, Dept Psychiat, Autism Res Ctr, Cambridge, England, [Bethlehem, R. A. I.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Brain Mapping Unit, Cambridge, England, [Seidlitz, J.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Vogel, J. W.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. E.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Gur, R. C.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Jackowski, A. P.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Univ Penn, Dept Psychiat, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia, Dept Child & Adolescent Psychiat & Behav Sci, Philadelphia, PA 19104 USA, [Seidlitz, J.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Chertavian, C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. E.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Gur, R. C.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [Alexander-Bloch, A. F.] Childrens Hosp Philadelphia & Penn Med, Lifespan Brain Inst, Philadelphia, PA USA, [White, S. R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Goodyer, I. M.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Henson, R. N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Jones, P. B.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Kitzbichler, M. G.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Medic, N.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Morgan, S. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Romero-Garcia, R.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ronan, L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Suckling, J.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Vertes, P. E.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Warrier, V.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Westwater, M. L.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Ziauddeen, H.] Univ Cambridge, Dept Psychiat, Cambridge, England, [Bullmore, E. T.] Univ Cambridge, Dept Psychiat, Cambridge, England, [White, S. R.] Univ Cambridge, MRC Biostat Unit, Cambridge, England, [Vogel, J. W.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Satterthwaite, T. D.] Univ Penn, Lifespan Informat & Neuroimaging Ctr, Philadelphia, PA 19104 USA, [Anderson, K. M.] Yale Univ, Dept Psychol, New Haven, CT USA, [Ellis, C. T.] Yale Univ, Dept Psychol, New Haven, CT USA, [Turk-Browne, N. B.] Yale Univ, Dept Psychol, New Haven, CT USA, [Adamson, C.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Ball, G.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Beare, R.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Jackowski, A. P.] Murdoch Childrens Res Inst, Dev Imaging, Melbourne, Vic, Australia, [Adamson, C.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Beare, R.] Monash Univ, Dept Med, Melbourne, Vic, Australia, [Adler, S.] UCL Great Ormond St Inst Child Hlth, London, England, [Alexopoulos, G. S.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Anagnostou, E.] Univ Toronto, Dept Pediat, Toronto, ON, Canada, [Anagnostou, E.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Pierce, K.] Holland Bloorview Kids Rehabil Hosp, Toronto, ON, Canada, [Areces-Gonzalez, A.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Paz-Linares, D.] Univ Elect Sci & Technol China, MOE Key Lab NeuroInformat, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Areces-Gonzalez, A.] Univ Pinar del Rio Hermanos Saiz Montes de Oca, Pinar Del Rio, Cuba, [Astle, D. E.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Henson, R. N.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Whalley, H. C.] Univ Cambridge, MRC Cognit & Brain Sci Unit, Cambridge, England, [Auyeung, B.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Pausova, Z.] Univ Edinburgh, Sch Philosophy Psychol & Language Sci, Dept Psychol, Edinburgh, Midlothian, Scotland, [Ayub, M.] Queens Univ, Dept Psychiat, Ctr Neurosci Studies, Kingston, ON, Canada, [Ayub, M.] UCL, Mental Hlth Neurosci Res Dept, Div Psychiat, London, England, [Bae, J.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Ball, G.] Univ Melbourne, Dept Paediat, Melbourne, Vic, Australia, [Baron-Cohen, S.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge Lifetime Asperger Syndrome Serv CLASS, Cambridge, England, [Benegal, V.] Natl Inst Mental Hlth & Neurosci NIMHANS, Ctr Addict Med, Bengaluru, India, [Beyer, F.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Villringer, A.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Witte, A. V.] Max Planck Inst Human Cognit & Brain Sci, Dept Neurol, Leipzig, Germany, [Blangero, J.] Univ Texas Rio Grande Valley, South Texas Diabet & Obes Inst, Dept Human Genet, Edinburg, TX USA, [Blesa Cabez, M.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Boardman, J. P.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Sullivan, G.] Univ Edinburgh, MRC Ctr Reprod Hlth, Edinburgh, Midlothian, Scotland, [Borzage, M.] Univ Southern Calif, Childrens Hosp Los Angeles, Keck Sch Med, Fetal & Neonatal Inst,Div Neonatol,Dept Pediat, Los Angeles, CA 90007 USA, [Bosch-Bayard, J. F.] Montreal Neurol Inst, Ludmer Ctr Neuroinformat & Mental Hlth, McGill Ctr Integrat Neurosci, Montreal, PQ, Canada, [Bosch-Bayard, J. F.] McGill Univ, Montreal, PQ, Canada, [Chakravarty, M. M.] McGill Univ, Montreal, PQ, Canada, [Bourke, N.] Imperial Coll London, Dept Brain Sci, London, England, [Sharp, D.] Imperial Coll London, Dept Brain Sci, London, England, [Alexander-Bloch, A. F.] Imperial Coll London, Dept Brain Sci, London, England, [Bourke, N.] Dementia Res Inst, Care Res & Technol Ctr, London, England, [Calhoun, V. D.] Georgia State Univ, Triinst Ctr Translat Res Neuroimaging & Data Sci, Georgia Inst Technol, Atlanta, GA 30303 USA, [Calhoun, V. D.] Emory Univ, Atlanta, GA 30322 USA, [Chakravarty, M. M.] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Comp Brain Anat CoBrA Lab, Montreal, PQ, Canada, [Chen, C.] Univ Penn, Penn Stat Imaging & Visualizat Ctr, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA, [Shinohara, R. T.] Univ Penn, Penn Stat Imaging & Visualizat Ctr, Dept Biostat Epidemiol & Informat, Perelman Sch Med, Philadelphia, PA 19104 USA, [Chetelat, G.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Delarue, M.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Landeau, B.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Paly, L.] Normandie Univ, PhIND Physiopathol & Imaging Neurol Disorders, Inst Blood & Brain Caen Normandie, UNICAEN,INSERM,U1237, Caen, France, [Chong, Y. S.] Agcy Sci Technol & Res, Singapore Inst Clin Sci, Singapore, Singapore, [Chong, Y. S.] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Obstet & Gynaecol, Singapore, Singapore, [Cole, J. H.] UCL, Ctr Med Image Comp CMIC, London, England, [Cole, J. H.] UCL, Dementia Res Ctr DRC, London, England, [Corvin, A.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland, [Costantino, M.] Douglas Mental Hlth Univ Inst, Cerebral Imaging Ctr, Verdun, PQ, Canada, [Costantino, M.] McGill Univ, Undergrad Program Neurosci, Montreal, PQ, Canada, [Courchesne, E.] Univ Calif San Diego, Dept Neurosci, San Diego, CA 92103 USA, [Courchesne, E.] Univ Calif San Diego, Autism Ctr Excellence, San Diego, CA 92103 USA, [Crivello, F.] Univ Bordeaux, Inst Neurodegenerat Disorders, CNRS UMR5293, CEA, Bordeaux, France, [Mazoyer, B.] Univ Bordeaux, Inst Neurodegenerat Disorders, CNRS UMR5293, CEA, Bordeaux, France, [Cropley, V. L.] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia, [Di Biase, M. A.] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia, [Lv, J.] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia, [Zalesky, A.] Univ Melbourne, Melbourne Neuropsychiat Ctr, Melbourne, Vic, Australia, [Hammill, C. F.] Hosp Sick Children, Toronto, ON, Canada, [Schachar, R. J.] Hosp Sick Children, Toronto, ON, Canada, [Crossley, N.] Pontificia Univ Catolica Chile, Sch Med, Dept Psychiat, Santiago, Chile, [Crossley, N.] Kings Coll London, Dept Psychosis Studies, Inst Psychiat Psychol & Neurosci, London, England, [McGuire, P.] Kings Coll London, Dept Psychosis Studies, Inst Psychiat Psychol & Neurosci, London, England, [Crossley, N.] Inst Milenio Intelligent Healthcare Engn, Santiago, Chile, [Delorme, R.] Robert Debre Univ Hosp, AP HP, Child & Adolescent Psychiat Dept, Paris, France, [Delorme, R.] Inst Pasteur, Human Genet & Cognit Funct, Paris, France, [Desrivieres, S.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Social Genet & Dev Psychiat Ctr, London, England, [Devenyi, G. A.] Douglas Mental Hlth Univ Inst, McGill Dept Psychiat, Cerebral Imaging Ctr, Montreal, PQ, Canada, [Devenyi, G. A.] McGill Univ, Dept Psychiat, Montreal, PQ, Canada, [Di Biase, M. A.] Harvard Med Sch, Brigham & Womens Hosp, Dept Psychiat, Boston, MA 02115 USA, [Dolan, R.] UCL, Max Planck UCL Ctr Computat Psychiat & Ageing Res, London, England, [Dolan, R.] Wellcome Ctr Human Neuroimaging, London, England, [Wagstyl, K.] Wellcome Ctr Human Neuroimaging, London, England, [Donald, K. A.] Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Div Dev Paediat, Cape Town, South Africa, [Donald, K. A.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Groenewold, N. A.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Donohoe, G.] Natl Univ Ireland Galway, Sch Psychol, Ctr Neuroimaging Cognit & Genom NICOG, Galway, Ireland, [Dunlop, K.] Weill Cornell Med, Dept Psychiat, Weil Family Brain & Mind Res Inst, New York, NY USA, [Lynch, C.] Weill Cornell Med, Dept Psychiat, Weil Family Brain & Mind Res Inst, New York, NY USA, [Edwards, A. D.] Kings Coll London, Ctr Dev Brain, London, England, [Edwards, A. D.] Evelina London Childrens Hosp, London, England, [Edwards, A. D.] MRC Ctr Neurodev Disorders, London, England, [Elison, J. T.] Univ Minnesota, Mason Inst Dev Brain, Dept Pediat, Inst Child Dev, Minneapolis, MN USA, [Fair, D. A.] Univ Minnesota, Mason Inst Dev Brain, Dept Pediat, Inst Child Dev, Minneapolis, MN USA, [Feczko, E.] Univ Minnesota, Mason Inst Dev Brain, Dept Pediat, Inst Child Dev, Minneapolis, MN USA, [Ellis, C. T.] Haskins Labs Inc, New Haven, CT USA, [Elman, J. A.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genet Aging, La Jolla, CA 92093 USA, [Franz, C. E.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genet Aging, La Jolla, CA 92093 USA, [Kremen, W. S.] Univ Calif San Diego, Dept Psychiat, Ctr Behav Genet Aging, La Jolla, CA 92093 USA, [Eyler, L.] VA San Diego Healthcare, Desert Pacific Mental Illness Res Educ & Clin Ctr, San Diego, CA USA, [Eyler, L.] Univ Calif San Diego, Dept Psychiat, Los Angeles, CA USA, [Fletcher, P. C.] Univ Cambridge, Dept Psychiat, Cambridge Biomed Campus, Cambridge, England, [Fletcher, P. C.] Wellcome Trust MRC Inst Metab Sci, Cambridge Biomed Campus, Cambridge, England, [Fletcher, P. C.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England, [Jones, P. B.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England, [Suckling, J.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England, [Ziauddeen, H.] Cambridgeshire & Peterborough NHS Fdn Trust, Cambridge, England, [Fonagy, P.] UCL, Dept Clin Educ & Hlth Psychol, London, England, [Fonagy, P.] Anna Freud Natl Ctr Children & Families, London, England, [Galan-Garcia, L.] Cuban Ctr Neurosci, Havana, Cuba, [Valdes-Sosa, M. J.] Cuban Ctr Neurosci, Havana, Cuba, [Gholipour, A.] Boston Childrens Hosp, Computat Radiol Lab, Boston, MA USA, [Warfield, S. K.] Boston Childrens Hosp, Computat Radiol Lab, Boston, MA USA, [Giedd, J.] Univ Calif San Diego, Dept Child & Adolescent Psychiat, San Diego, CA 92103 USA, [Giedd, J.] Univ Calif San Diego, Dept Psychiat, San Diego, CA 92103 USA, [Gilmore, J. H.] Univ N Carolina, Dept Psychiat, Chapel Hill, NC 27515 USA, [Glahn, D. C.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA, [Im, K.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA, [Mathias, S. R.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA, [Rodrigue, A.] Boston Childrens Hosp, Dept Psychiat, Boston, MA USA, [Glahn, D. C.] Harvard Med Sch, Boston, MA 02115 USA, [Im, K.] Harvard Med Sch, Boston, MA 02115 USA, [Johnson, K. A.] Harvard Med Sch, Boston, MA 02115 USA, [Mathias, S. R.] Harvard Med Sch, Boston, MA 02115 USA, [Rodrigue, A.] Harvard Med Sch, Boston, MA 02115 USA, [Schultz, A. P.] Harvard Med Sch, Boston, MA 02115 USA, [Sperling, R. A.] Harvard Med Sch, Boston, MA 02115 USA, [Grant, P. E.] Harvard Med Sch, Fetal Neonatal Neuroimaging & Dev Sci Ctr, Boston Childrens Hosp, Div Newborn Med & Neuroradiol, Boston, MA 02115 USA, [Groenewold, N. A.] Univ Cape Town, SA MRC Unit Child & Adolescent Hlth, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa, [Zar, H. J.] Univ Cape Town, SA MRC Unit Child & Adolescent Hlth, Red Cross War Mem Childrens Hosp, Dept Paediat & Child Hlth, Cape Town, South Africa, [Gunning, F. M.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Victoria, L. W.] Weill Cornell Med, Dept Psychiat, Weill Cornell Inst Geriatr Psychiat, New York, NY USA, [Hammill, C. F.] Mouse Imaging Ctr, Toronto, ON, Canada, [Hansson, O.] Lund Univ, Dept Clin Sci Malmo, Clin Memory Res Unit, Malmo, Sweden, [Hansson, O.] Skane Univ Hosp, Memory Clin, Malmo, Sweden, [Hedden, T.] Icahn Sch Med Mt Sinai, Dept Neurol, New York, NY 10029 USA, [Hedden, T.] Harvard Med Sch, Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Boston, MA 02115 USA, [Heinz, A.] Charite Univ Med Berlin, Charite Campus Mitte, Berlin, Germany, [Heinz, A.] Free Univ Berlin, Charite Campus Mitte, Berlin, Germany, [Heinz, A.] Humboldt Univ, Dept Psychiat & Psychotherapy, Charite Campus Mitte, Berlin, Germany, [Heuer, K.] Max Planck Inst Human Cognit & Brain Sci, Dept Neuropsychol, Leipzig, Germany, [Heuer, K.] Univ Paris, Paris, France, [Toro, R.] Univ Paris, Paris, France, [Hoare, J.] Univ Cape Town, Dept Psychiat, Cape Town, South Africa, [Holla, B.] NIMHANS, Dept Integrat Med, Bengaluru, India, [Holla, B.] NIMHANS, Dept Psychiat, Accelerator Program Discovery Brain Disorders Usi, Bengaluru, India, [Holmes, A. J.] Yale Univ, Dept Psychol, New Haven, CT USA, [Villeneuve, S.] Yale Univ, Dept Psychol, New Haven, CT USA, [Holmes, A. J.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Villeneuve, S.] Yale Univ, Dept Psychiat, New Haven, CT 06520 USA, [Huang, H.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Ouyang, M.] Childrens Hosp Philadelphia, Radiol Res, Philadelphia, PA 19104 USA, [Huang, H.] Univ Penn, Dept Radiol, Perelman Sch Med, Philadelphia, PA 19104 USA, [Ipser, J.] Univ Cape Town, Dept Psychiat & Mental Hlth, Clin Neurosci Inst, Cape Town, South Africa, [Jack, C. R., Jr.] Mayo Clin, Dept Radiol, Rochester, MN USA, [Jones, D. T.] Mayo Clin, Dept Radiol, Rochester, MN USA, Univ Fed Sao Paulo, Dept Psychiat, Sao Paulo, Brazil, [Jackowski, A. P.] Natl Inst Dev Psychiat, Beijing, Peoples R China, [Jia, T.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Shanghai, Peoples R China, [Jia, T.] Fudan Univ, Minist Educ, Key Lab Computat Neurosci & Brain Inspired Intell, Shanghai, Peoples R China, [Jia, T.] Kings Coll London, Inst Psychiat Psychol & Neurosci, Ctr Populat Neurosci & Precis Med PONS, SGDP Ctr, London, England, [Johnson, K. A.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Schultz, A. P.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Sperling, R. A.] Massachusetts Gen Hosp, Dept Neurol, Harvard Aging Brain Study, Boston, MA 02114 USA, [Johnson, K. A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA, [Sperling, R. A.] Brigham & Womens Hosp, Dept Neurol, Ctr Alzheimer Res & Treatment, 75 Francis St, Boston, MA 02115 USA, [Johnson, K. A.] Massachusetts Gen Hosp, Dept Radiol, Boston, MA USA, [Jones, D. T.] Mayo Clin, Dept Neurol, Rochester, MN USA, [3R-BRAIN] Mayo Clin, Dept Neurol, Rochester, MN USA, [Kahn, R. S.] Icahn Sch Med Mt Sinai, Dept Psychiat, New York, NY 10029 USA, [Karlsson, H.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, L.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Dept Psychiat, Dept Clin Med, Turku, Finland, [Karlsson, H.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, L.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Tuulari, J. J.] Univ Turku, FinnBrain Birth Cohort Study, Turku Brain & Mind Ctr, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Turku, Finland, [Tuulari, J. J.] Turku Univ Hosp, Turku, Finland, [Karlsson, H.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, L.] Turku Univ Hosp, Ctr Populat Hlth Res, Turku, Finland, [Karlsson, H.] Univ Turku, Turku, Finland, [Karlsson, L.] Univ Turku, Turku, Finland, [Kawashima, R.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Taki, Y.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Thyreau, B.] Tohoku Univ, Inst Dev Aging & Canc, Aoba Ku, Sendai, Miyagi, Japan, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychol, Kingston, ON, Canada, [Kelley, E. A.] Queens Univ, Ctr Neurosci Studies, Dept Psychiat, Kingston, ON, Canada, [Kern, S.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Skoog, I.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Zettergren, A.] Univ Gothenburg, Neuropsychiat Epidemiol Unit, Dept Psychiat & Neurochem,Sahlgrenska Acad, Ctr Ageing & Hlth AGECAP,Inst Neurosci & Physiol, Gothenburg, Sweden, [Kern, S.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Skoog, I.] Sahlgrens Univ Hosp, Psychiat Cognit & Old Age Psychiat Clin, Reg Vastra Gotaland, Gothenburg, Sweden, [Kim, K. W.] Seoul Natl Univ, Dept Brain & Cognit Sci, Coll Nat Sci, Seoul, South Korea, [Kim, K. W.] Seoul Natl Univ, Bundang Hosp, Dept Neuropsychiat, Seongnam, South Korea, [Kim, K. W.] Seoul Natl Univ, Dept Psychiat, Coll Med, Seoul, South Korea, [Kim, K. W.] SNU MRC, Inst Human Behav Med, Seoul, South Korea, [Lalonde, F.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Raznahan, A.] NIMH, Sect Dev Neurogenom, Human Genet Branch, Bethesda, MD 20892 USA, [Lee, S.] Seoul Natl Univ, Coll Nat Sci, Dept Brain & Cognit Sci, Seoul, South Korea, [Lerch, J.] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada, [Lerch, J.] Univ Oxford, Nuffield Dept Clin Neurosci, FMRIB, Wellcome Ctr Integrat Neuroimaging, Oxford, England, [Lewis, J. D.] McGill Univ, Montreal Neurol Inst, Montreal, PQ, Canada, [Li, J.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liao, W.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Valdes-Sosa, P. A.] Univ Elect Sci & Technol China, Clin Hosp, Chengdu Brain Sci Inst, Chengdu, Peoples R China, [Liston, C.] Weill Cornell Med, Dept Psychiat, New York, NY USA, [Liston, C.] Weill Cornell Med, Brain & Mind Res Inst, New York, NY USA, [Lombardo, M. V.] Ist Italiano Tecnol, Ctr Neurosci & Cognit Syst UniTn, Lab Autism & Neurodev Disorders, Rovereto, Italy, [Lv, J.] Univ Sydney, Sch Biomed Engn, Sydney, NSW, Australia, [Lv, J.] Univ Sydney, Brain & Mind Ctr, Sydney, NSW, Australia, [Mallard, T. T.] Univ Texas Austin, Dept Psychol, Austin, TX 78712 USA, [Marcelis, M.] Maastricht Univ, Sch Mental Hlth & Neurosci, Dept Psychiat & Neuropsychol, EURON,Med Ctr, Maastricht, Netherlands, [Marcelis, M.] Inst Mental Hlth Care Eindhoven GGzE, Eindhoven, Netherlands, [Markello, R. D.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Misic, B.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Vasung, L.] McGill Univ, Montreal Neurol Inst, McConnell Brain Imaging Ctr, Montreal, PQ, Canada, [Mazoyer, B.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Douglas Mental Hlth Univ Inst, Ludmer Ctr Neuroinformat & Mental Hlth, Montreal, PQ, Canada, [Meaney, M. J.] Singapore Inst Clin Sci, Singapore, Singapore, [Mechelli, A.] Bordeaux Univ Hosp, Bordeaux, France, [Morgan, S. E.] Univ Cambridge, Dept Comp Sci & Technol, Cambridge, England, [Morgan, S. E.] Alan Turing Inst, London, England, [Vertes, P. E.] Alan Turing Inst, London, England, [Mothersill, D.] Natl Coll Ireland, Sch Business, Dept Psychol, Dublin, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Sch Psychol, Galway, Ireland, [Mothersill, D.] Natl Univ Ireland Galway, Ctr Neuroimaging & Cognit Genom, Galway, Ireland, [Mothersill, D.] Trinity Coll Dublin, Dept Psychiat, Dublin, Ireland, [Nigg, J.] Oregon Hlth & Sci Univ, Dept Psychiat, Sch Med, Portland, OR 97201 USA, [Ong, M. Q. W.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Qian, X.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Ortinau, C.] Washington Univ, Dept Pediat, St Louis, MO 63130 USA, [Ossenkoppele, R.] Vrije Univ Amsterdam, Alzheimer Ctr Amsterdam, Amsterdam UMC, Dept Neurol,Amsterdam Neurosci, Amsterdam, Netherlands, [Ossenkoppele, R.] Lund Univ, Clin Memory Res Unit, Lund, Sweden, [Palaniyappan, L.] Univ Western Ontario, Robarts Res Inst, London, ON, Canada, [Palaniyappan, L.] Univ Western Ontario, Brain & Mind Inst, London, ON, Canada, [Pan, P. M.] Fed Univ Sao Poalo UNIFESP, Dept Psychiat, Sao Poalo, Brazil, [Pan, P. M.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Zugman, A.] Natl Inst Dev Psychiat Children & Adolescents INP, Sao Poalo, Brazil, [Pantelis, C.] Univ Melbourne, Dept Psychiat, Melbourne Neuropsychiat Ctr, Carlton, Vic, Australia, [Pantelis, C.] Melbourne Hlth, Carlton, Vic, Australia, [Pantelis, C.] Univ Melbourne, Melbourne Sch Engn, Parkville, Vic, Australia, [Pantelis, C.] Florey Inst Neurosci & Mental Hlth, Parkville, Vic, Australia, [Park, M. M.] Western Univ, Schulich Sch Med & Dent, Dept Psychiat, London, ON, Canada, [Rollins, C. K.] Univ Montreal, Dept Psychiat, Fac Med, Montreal, PQ, Canada, [Rollins, C. K.] Univ Montreal, CHU St Justine, Montreal, PQ, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychiat, Toronto, ON, Canada, [Romero-Garcia, R.] Univ Toronto, Dept Psychol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Physiol, Toronto, ON, Canada, [Rosenberg, M. D.] Univ Toronto, Dept Nutr Sci, Toronto, ON, Canada, [Paz-Linares, D.] Cuban Neurosci Ctr, Havana, Cuba, [Pichet Binette, A.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Villeneuve, S.] McGill Univ, Fac Med, Dept Psychiat, Montreal, PQ, Canada, [Pichet Binette, A.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Villeneuve, S.] Douglas Mental Hlth Univ Inst, Montreal, PQ, Canada, [Qiu, J.] Southwest Univ, Sch Psychol, Chongqing, Peoples R China, [Qiu, A.] Natl Univ Singapore, N1 Inst Hlth, Dept Biomed Engn, Singapore, Singapore, [Rittman, T.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Tsvetanov, K. A.] Univ Cambridge, Dept Clin Neurosci, Cambridge, England, [Rollins, C. K.] Harvard Med Sch, Dept Neurol, Boston, MA 02115 USA, [Rollins, C. K.] Boston Childrens Hosp, Dept Neurol, Boston, MA USA, [Romero-Garcia, R.] Univ Seville, Dpto Fisiol Med & Biofis, Inst Biomed Sevilla IBiS HUVR CSIC, Seville, Spain, [Rosenberg, M. D.] Univ Chicago, Dept Psychol, 5848 S Univ Ave, Chicago, IL 60637 USA, [Rosenberg, M. D.] Univ Chicago, Inst Neurosci, Chicago, IL USA, [Rowitch, D. H.] Univ Cambridge, Dept Paediat, Cambridge, England, [Rowitch, D. H.] Univ Cambridge, Wellcome MRC Cambridge Stem Cell Inst, Cambridge, England, [Salum, G. A.] Univ Fed Rio Grande Sul UFRGS, Hosp Clin Porto Alegre, Dept Psychiat, Porto Alegre, RS, Brazil, [Salum, G. A.] Natl Inst Dev Psychiat INPD, Sao Paulo, Brazil, [Schaare, H. L.] Max Planck Inst Human Cognit & Brain Sci, Otto Hahn Grp Cognit Neurogenet, Leipzig, Germany, [Schaare, H. L.] Res Ctr Juelich, Inst Neurosci & Med INM 7 Brain & Behav, Julich, Germany, [Schultz, A. P.] Massachusetts Gen Hosp, Dept Radiol, Athinoula Martinos Ctr Biomed Imaging, Charlestown, MA USA, [Schumann, G.] Fudan Univ, Inst Sci & Technol Brain Inspired Intelligence, Ctr Populat Neurosci & Stratified Med PONS, Shanghai, Peoples R China, [Schumann, G.] Charite Campus Mitte, Dept Psychiat & Psychotherapy, Charite Mental Hlth, PONS Ctr, Berlin, Germany, [Scholl, M.] Univ Gothenburg, Wallenberg Ctr Mol & Translat Med, Gothenburg, Sweden, [Scholl, M.] Univ Gothenburg, Dept Psychiat & Neurochem, Gothenburg, Sweden, [Scholl, M.] UCL, Queens Sq Inst Neurol, Dementia Res Ctr, London, England, [Sharp, D.] UK Dementia Res Inst, Care Res & Technol Ctr, London, England, [Shinohara, R. T.] Univ Penn, Perelman Sch Med, Dept Radiol, Ctr Biomed Image Comp & Analyt, Philadelphia, PA 19104 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Neurol, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Pediat, St Louis, MO 63110 USA, [Smyser, C. D.] Washington Univ, Sch Med, Dept Radiol, St Louis, MO 63110 USA, [Stein, D. J.] Univ Cape Town, Dept Psychiat, SA MRC Unit Risk & Resilience Mental Disorders, Cape Town, South Africa, [Stein, D. J.] Univ Cape Town, Neurosci Inst, Cape Town, South Africa, [Stolicyn, A.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Whalley, H. C.] Univ Edinburgh, Ctr Clin Brain Sci, Div Psychiat, Edinburgh, Midlothian, Scotland, [Toro, R.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Inst Pasteur, Dept Neurosci, Paris, France, [Traut, N.] Univ Paris 05, Ctr Res & Interdisciplinar CRI, Paris, France, [Tsvetanov, K. A.] Univ Cambridge, Dept Psychol, Cambridge, England, [Turk-Browne, N. B.] Yale Univ, Wu Tsai Inst, New Haven, CT USA, [Tuulari, J. J.] Univ Turku, Dept Clin Med, Turku, Finland, [Tuulari, J. J.] Univ Turku, Turku Coll Sci Med & Technol, Turku, Finland, [Tzourio, C.] Univ Bordeaux, Bordeaux Populat Hlth Res Ctr, CHU Bordeaux, U1219,INSERM, Bordeaux, France, [Vachon-Presseau, E.] McGill Univ, Fac Dent Med & Oral Hlth Sci, Montreal, PQ, Canada, [Valdes-Sosa, P. A.] McGill Univ, Alan Edwards Ctr Res Pain AECRP, Montreal, PQ, Canada, [Valk, S. L.] Forschungszentrum Julich, Inst Neurosci & Med 7, Julich, Germany, [Valk, S. L.] Max Planck Inst Human Cognit & Brain Sci, Leipzig, Germany, [van Amelsvoort, T.] Maastricht Univ, Dept Psychiat & Neurosychol, Maastricht, Netherlands, [Vandekar, S. N.] Vanderbilt Univ, Dept Biostat, 221 Kirkland Hall, Nashville, TN 37235 USA, [Villeneuve, S.] Vanderbilt Univ, Med Ctr, Dept Biostat, Nashville, TN USA, [Villringer, A.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Witte, A. V.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Zuo, X. N.] Univ Leipzig, Clin Cognit Neurol, Med Ctr, Leipzig, Germany, [Wang, Y. S.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Yeo, B.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, State Key Lab Cognit Neurosci & Learning, Beijing, Peoples R China, [Wang, Y. S.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Yang, N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Zuo, X. N.] Beijing Normal Univ, IDG McGovern Inst Brain Res, Dev Populat Neuroscience Res Ctr, Beijing, Peoples R China, [Wang, Y. S.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Yang, N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Zuo, X. N.] Natl Basic Sci Data Ctr, Beijing, Peoples R China, [Wang, Y. S.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Yang, N.] Chinese Acad Sci, Res Ctr Lifespan Dev Brain & Mind, Inst Psychol, Beijing, Peoples R China, [Westman, E.] Karolinska Inst, Ctr Alzheimer Res, Dept Neurobiol Care Sci & Soc, Div Clin Geriatr, Stockholm, Sweden, [Witte, A. V.] Univ Leipzig, CRC 1052 Obes Mech, Fac Med, Leipzig, Germany, [Zhou, J. H.] Natl Univ Singapore, Dept Elect & Comp Engn, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Sleep & Cognit, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat MR Res, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, N1 Inst Hlth, Singapore, Singapore, [Yeo, B.] Natl Univ Singapore, Inst Digital Med, Singapore, Singapore, [Yun, H.] Natl Univ Singapore, Integrat Sci & Engn Programme ISEP, Singapore, Singapore, [Zar, H. J.] Univ Melbourne, Dept Biomed Engn, Melbourne, Vic, Australia, [Zhou, J. H.] Natl Univ Singapore, Yong Loo Lin Sch Med, Ctr Translat Magnet Resonance Res, Singapore, Singapore, [Ziauddeen, H.] Univ Cambridge, Wellcome Trust MRC Inst Metab Sci, Cambridge, England, [Zugman, A.] NIMH, NIH, Bethesda, MD 20892 USA, [Zugman, A.] Escola Paulista Med, Dept Psychiat, Sao Paulo, Brazil, [Zuo, X. N.] Nanning Normal Univ, Sch Educ Sci, Key Lab Brain & Educ, Nanning, Peoples R China, British Academy Postdoctoral fellowship, NIMH, UKRI Medical Research Council, NIHR Cambridge Biomedical Research Centre, NIHR Senior Investigator award, MRC research infrastructure award, Commonwealth Scientific and Industrial Research Organisation (CSIRO), and Ontario Brain Institute

Subjects
631/378/2649, OpenPain Project, KNE96, Growth, Psychiatric-disorders, DISEASE, 3R-BRAIN, Brain charts, MRI Brain, OASIS-3, Disease, CCNP, 631/378/2571, UMN BCP, Multidisciplinary, medicine.diagnostic_test, PSYCHIATRIC-DISORDERS, article, Brain, Human brain, ASSOCIATION, Magnetic Resonance Imaging, Harvard Aging Brain Study, The Mayo Clinic Study of Aging, NSPN, medicine.anatomical_structure, GROWTH, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], ddc:500, BURDEN, WHITE-MATTER, FinnBrain, Harvard Aging Brain Study, Organization, Mri, MRI, medicine.medical_specialty, Concurrent validity, MODELS, Cam-CAN, Longevity, CALM Team, POND, Neuroimaging, Burden, ORGANIZATION, AIBL, The PREVENT-AD Research Group, VETSA, Cortical thickness, Association, Physical medicine and rehabilitation, FinnBrain, IMAGEN, KNE96, White-matter, medicine, Humans, ASRB, 631/378/1689, COBRE, business.industry, 631/378/2611, Brain morphometry, Neurosciences, Alzheimer’s Disease Repository Without Borders Investigators, Magnetic resonance imaging, Alzheimer’s Disease Neuroimaging Initiative, Anthropometry, Body Height, Brain growth, Birth, 59/57, Normative, IMAGEN, ENIGMA Developmental Brain Age working group, NSPN, business, CCNP, 3R-BRAIN, CORTICAL THICKNESS, Developing Human Connectome Project, ENIGMA Developmental Brain Age working group, The PREVENT-AD Research Group, VETSA, Bullmore, E.T
Abstract

Over the past few decades, neuroimaging has become a ubiquitous tool in basic research and clinical studies of the human brain. However, no reference standards currently exist to quantify individual differences in neuroimaging metrics over time, in contrast to growth charts for anthropometric traits such as height and weight1. Here we assemble an interactive open resource to benchmark brain morphology derived from any current or future sample of MRI data ( http://www.brainchart.io/ ). With the goal of basing these reference charts on the largest and most inclusive dataset available, acknowledging limitations due to known biases of MRI studies relative to the diversity of the global population, we aggregated 123,984 MRI scans, across more than 100 primary studies, from 101,457 human participants between 115 days post-conception to 100 years of age. MRI metrics were quantified by centile scores, relative to non-linear trajectories2 of brain structural changes, and rates of change, over the lifespan. Brain charts identified previously unreported neurodevelopmental milestones3, showed high stability of individuals across longitudinal assessments, and demonstrated robustness to technical and methodological differences between primary studies. Centile scores showed increased heritability compared with non-centiled MRI phenotypes, and provided a standardized measure of atypical brain structure that revealed patterns of neuroanatomical variation across neurological and psychiatric disorders. In summary, brain charts are an essential step towards robust quantification of individual variation benchmarked to normative trajectories in multiple, commonly used neuroimaging phenotypes., R.A.I.B. was supported by a British Academy Postdoctoral fellowship and by the Autism Research Trust. J. Seidlitz was supported by NIMH T32MH019112-29 and K08MH120564. S.R.W. was funded by UKRI Medical Research Council MC_UU_00002/2 and was supported by the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). E.T.B. was supported by an NIHR Senior Investigator award and the Wellcome Trust collaborative award for the Neuroscience in Psychiatry Network. A.F.A.-B. was supported by NIMH K08MH120564. Data were curated and analysed using a computational facility funded by an MRC research infrastructure award (MR/M009041/1) to the School of Clinical Medicine, University of Cambridge and supported by the mental health theme of the NIHR Cambridge Biomedical Research Centre.

Published
2022

22. Suppression of Speckle Noise in Digital Holography With Spatial and Temporal Domain Depolarization

Author

Yong Kong, Wei Ding, Xinlei Qian, Tongyao Du, and Wang Zhenwei

Subjects
General Computer Science, Holography, 02 engineering and technology, Degree of coherence, 01 natural sciences, law.invention, 010309 optics, 020210 optoelectronics & photonics, Optics, depolarization, law, 0103 physical sciences, 0202 electrical engineering, electronic engineering, information engineering, Depolarizer (optics), General Materials Science, liquid crystal, Digital holography speckle noise, quartz depolarizer, Group delay and phase delay, Physics, business.industry, General Engineering, Speckle noise, Depolarization, Noise, lcsh:Electrical engineering. Electronics. Nuclear engineering, business, lcsh:TK1-9971, Digital holography
Abstract

Speckle noise in digital holography has a great influence on image quality, and one of the reasons for the formation of speckle noise is that the degree of coherence for the reference light and the object light is too high and unnecessary noise is introduced to the recorded hologram. In this paper, the spatial depolarization and the temporal domain depolarization are analyzed to reduce the speckle noise. The spatial depolarization utilizes the depolarization performance of the depolarizer. By adding a quartz depolarizer to the object light, the linearly polarized light in the object light becomes randomly polarized light, thereby reducing the degree of coherence with the reference light, realizing the suppression of speckle noise, and by utilizing the characteristics of pupil parameters towards the depolarization degree, it is to realize the control for the degree of coherence. The temporal domain depolarization uses two quarter-wave plates and adjustable liquid crystal to realize the depolarization superposition. By controlling the phase delay of the liquid crystal phase variable retarder, the multi-depolarization accumulation in a short time is realized, and the experimental results show that this method preserves the detail portion of the image while better removing speckle noise. Finally, the Non-Local Means filtering algorithm is used to make the reconstructed image smoother. The method proposed in this paper has great applicable value for improving the image quality of digital holography system.

Published
2020

24. Mapping the allosteric effects that define functional activity of SARS-CoV-2 specific antibodies

Author

Nikhil K. Tulsian, Palur V. Raghuvamsi, Xinlei Qian, Gu Yue, Bhuvaneshwari D/O Shunmuganathan, Firdaus Samsudin, Wong Yee Hwa, Lin Jianqing, Kiren Purushotorman, Mary M. Kozma, Bei Wang, Julien Lescar, Cheng-I Wang, Ganesh S. Anand, Peter J. Bond, and Paul A. MacAry

Abstract

Previous studies on the structural relationship between human antibodies and SARS-CoV-2 have focused on generating static snapshots of antibody complexes with the Spike trimer. However, antibody-antigen interactions are dynamic, with significant binding-induced allosteric effects on conformations of antibody and its target antigen. In this study, we employ hydrogen-deuterium exchange mass spectrometry, in vitro assays, and molecular dynamics simulations to investigate the allosteric perturbations linked to binding events between a group of human antibodies with differential functional activities, and the Spike trimer from SARS-CoV-2. Our investigations have revealed key dynamic features that define weakly or moderately neutralizing antibodies versus those with strong neutralizing activity. These results provide mechanistic insights into the functional modes of human antibodies against COVID-19, and provide a rationale for effective antiviral strategies.TeaserDifferent neutralizing antibodies induce site-specific allosteric effects across SARS-CoV-2 Spike protein

Published
2021

25. A rapid simple point-of-care assay for the detection of SARS-CoV-2 neutralizing antibodies

Author

Hoi Lok Cheng, Peter R. Preiser, O Shunmuganathan, Hadley D. Sikes, Haziq Nasir, Patthara Kongsuphol, Mary M Kozma, Paul Ananth Tambyah, Bhuvaneshwari D, Megan E. McBee, Seunghyeon Kim, Xiaohong Gao, Say Yong Ng, Paul A. MacAry, Dousabel M Y Tay, Kiren Purushotorman, Rashi Gupta, Sing Mei Lim, Huan Jia, Xinlei Qian, Yue Gu, and Ming Wei Chen

Subjects
biology, Immunity, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), biology.protein, Medicine, Antibody, Vaccine efficacy, Cellulose binding, Virology, Virus, Herd immunity, Point of care
Abstract

Neutralizing antibodies (NAbs) prevent pathogens from infecting host cells. Detection of SARS-CoV-2 NAbs is critical to evaluate herd immunity and monitor vaccine efficacy against SARS-CoV-2, the virus that causes COVID-19. All currently available NAb tests are lab-based and time-intensive. We develop a 10 min cellulose pull-down test to detect NAbs against SARS-CoV-2 from human plasma. The test evaluates the ability of antibodies to disrupt ACE2 receptor—RBD complex formation. The simple, portable, and rapid testing process relies on two key technologies: (i) the vertical-flow paper-based assay format and (ii) the rapid interaction of cellulose binding domain to cellulose paper. Here we show the construction of a cellulose-based vertical-flow test. The developed test gives above 80% sensitivity and specificity and up to 93% accuracy as compared to two current lab-based methods using COVID-19 convalescent plasma. A rapid 10 min cellulose based test has been developed for detection of NAb against SARS-CoV-2. The test demonstrates comparable performance to the lab-based tests and can be used at Point-of-Care. Importantly, the approach used for this test can be easily extended to test RBD variants or to evaluate NAbs against other pathogens. In response to infections, the human body produces proteins called antibodies. Neutralizing antibodies (NAbs) are one type of such proteins that are capable of inactivating the target, such as the SARS-CoV-2 virus that causes COVID-19. Monitoring levels of NAb allows us to understand levels of protective immunity. However, current methods to measure NAb are laboratory-based and are not necessarily suitable for large scale NAb monitoring in a large population. We develop a rapid test to detect SARS-CoV-2 NAb in 10 min that can be operated outside a laboratory. Our test provides results that are comparable to lab-based tests, which require between 1 h and up to 2 days to get a result. Our test may be useful for large-scale monitoring of immunity, for example in populations that do not have routine access to a lab. Kongsuphol et al. develop a paper-based, vertical flow assay to detect SARS-CoV-2 neutralizing antibodies. The point-of-care assay has comparable performance to lab-based tests and provides results in 10 min.

Published
2021

26. Structure of the human metapneumovirus polymerase phosphoprotein complex

Author

Sarah L. Noton, Junhua Pan, Simon Lattmann, Tiong Han Yeo, Rachel Fearns, Tessa N. Cressey, Xinlei Qian, Abbas El Sahili, Julien Lescar, Huan Jia, Marian Kalocsay, and Barbara Ludeke

Subjects
Models, Molecular, Viral protein, viruses, medicine.disease_cause, Article, Cell Line, chemistry.chemical_compound, Human metapneumovirus, Transcription (biology), RNA polymerase, medicine, Animals, Amino Acid Sequence, Protein Structure, Quaternary, Polymerase, Ribonucleoprotein, Multidisciplinary, biology, Cryoelectron Microscopy, Phosphoproteins, RNA-Dependent RNA Polymerase, biology.organism_classification, Virology, chemistry, Phosphoprotein, biology.protein, Metapneumovirus, Viral genome replication, Protein Binding
Abstract

Respiratory syncytial virus (RSV) and human metapneumovirus (HMPV) cause severe respiratory diseases in infants and elderly adults1. No vaccine or effective antiviral therapy currently exists to control RSV or HMPV infections. During viral genome replication and transcription, the tetrameric phosphoprotein P serves as a crucial adaptor between the ribonucleoprotein template and the L protein, which has RNA-dependent RNA polymerase (RdRp), GDP polyribonucleotidyltransferase and cap-specific methyltransferase activities2,3. How P interacts with L and mediates the association with the free form of N and with the ribonucleoprotein is not clear for HMPV or other major human pathogens, including the viruses that cause measles, Ebola and rabies. Here we report a cryo-electron microscopy reconstruction that shows the ring-shaped structure of the polymerase and capping domains of HMPV-L bound to a tetramer of P. The connector and methyltransferase domains of L are mobile with respect to the core. The putative priming loop that is important for the initiation of RNA synthesis is fully retracted, which leaves space in the active-site cavity for RNA elongation. P interacts extensively with the N-terminal region of L, burying more than 4,016 A2 of the molecular surface area in the interface. Two of the four helices that form the coiled-coil tetramerization domain of P, and long C-terminal extensions projecting from these two helices, wrap around the L protein in a manner similar to tentacles. The structural versatility of the four P protomers—which are largely disordered in their free state—demonstrates an example of a ‘folding-upon-partner-binding’ mechanism for carrying out P adaptor functions. The structure shows that P has the potential to modulate multiple functions of L and these results should accelerate the design of specific antiviral drugs. A cryo-electron microscopy reconstruction shows the ring-shaped structure of the polymerase and capping domains of the L protein bound to a tetramer of phosphoprotein P of the human metapneumovirus.

Published
2019

27. SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

Author

Firdaus Samsudin, Gu Yue, Wong Y Hwa, Peter J. Bond, Nikhil Kumar Tulsian, Palur Venkata Raghuvamsi, Ganesh S. Anand, Kiren Purushotorman, Mary M Kozma, Xinlei Qian, Julien Lescar, and Paul A. MacAry

Subjects
0301 basic medicine, medicine.medical_treatment, Structural Biology and Molecular Biophysics, ACE2, Plasma protein binding, 01 natural sciences, Mass Spectrometry, Biology (General), Furin, allostery, biology, 010304 chemical physics, medicine.diagnostic_test, Chemistry, General Neuroscience, General Medicine, Cell biology, Spike Glycoprotein, Coronavirus, Receptors, Virus, Medicine, Angiotensin-Converting Enzyme 2, Allosteric Site, hormones, hormone substitutes, and hormone antagonists, Research Article, Protein Binding, QH301-705.5, Proteolysis, Science, Allosteric regulation, Molecular Dynamics Simulation, Cleavage (embryo), General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Biochemistry and Chemical Biology, 0103 physical sciences, medicine, Humans, Amino Acid Sequence, Binding site, HDXMS, virus-host interactions, Protease, Binding Sites, General Immunology and Microbiology, SARS-CoV-2, Lipid bilayer fusion, COVID-19, spike, Virus Internalization, Heptad repeat, 030104 developmental biology, Structural biology, Docking (molecular), biology.protein, Biophysics, Other, Protein Processing, Post-Translational
Abstract

The Spike (S) protein is the main handle for SARS-CoV-2 to enter host cells through surface ACE2 receptors. How ACE2 binding activates proteolysis of S protein is unknown. Here, we have mapped the S:ACE2 interface and uncovered long-range allosteric propagation of ACE2 binding to sites critical for viral host entry. Unexpectedly, ACE2 binding enhances dynamics at a distal S1/S2 cleavage site and flanking protease docking site ~27 Å away while dampening dynamics of the stalk hinge (central helix and heptad repeat) regions ~ 130 Å away. This highlights that the stalk and proteolysis sites of the S protein are dynamic hotspots in the pre-fusion state. Our findings provide a mechanistic basis for S:ACE2 complex formation, critical for proteolytic processing and viral-host membrane fusion and highlight protease docking sites flanking the S1/S2 cleavage site, fusion peptide and heptad repeat 1 (HR1) as allosterically exposed cryptic hotspots for potential therapeutic development.One Sentence SummarySARS-CoV-2 spike protein binding to receptor ACE2 allosterically enhances furin proteolysis at distal S1/S2 cleavage sites

Published
2021

28. Author response: SARS-CoV-2 S protein:ACE2 interaction reveals novel allosteric targets

Author

Julien Lescar, Firdaus Samsudin, Palur Venkata Raghuvamsi, Paul A. MacAry, Wong Y Hwa, Ganesh S. Anand, Peter J. Bond, Kiren Purushotorman, Nikhil Kumar Tulsian, Xinlei Qian, Gu Yue, and Mary M Kozma

Subjects
Chemistry, Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Allosteric regulation, Computational biology
Published
2021

29. Smooth pulse recovery based on hybrid wavelet threshold denoising and first derivative adaptive smoothing filter

Author

Xinlei Qian, Xinghua Lu, Xiaochao Wang, and Wei Fan

Subjects
Nuclear and High Energy Physics, Smoothness, Computer science, Pulse (signal processing), Noise reduction, Filter (signal processing), 01 natural sciences, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, 010309 optics, Wavelet, Signal-to-noise ratio, Nuclear Energy and Engineering, Control theory, Modulation, Control system, 0103 physical sciences, 010306 general physics
Abstract

Based on the pulse-shaping unit in the front end of high-power laser facilities, we propose a new hybrid scheme in a closed-loop control system including wavelet threshold denoising for pretreatment and a first derivative adaptive smoothing filter for smooth pulse recovery, so as to effectively restrain the influence of electrical noise and FM-to-AM modulation in the time–power curve, and enhance the calibration accuracy of the pulse shape in the feedback control system. The related simulation and experiment results show that the proposed scheme can obtain a better shaping effect on the high-contrast temporal shape in comparison with the cumulative average algorithm and orthogonal matching pursuit algorithm combined with a traditional smoothing filter. The implementation of the hybrid scheme mechanism increased the signal-to-noise ratio of the laser pulse from about 11 dB to 30 dB, and the filtered pulse is smooth without modulation, with smoothness of about 98.8%.

Published
2021

30. Functional Evolution in Orthologous Cell-encoded RNA-dependent RNA Polymerases*

Author

Dina Amallia Darwis, Shashi Bhushan, Abbas El Sahili, Fursham M. Hamid, Yee Hwa Wong, Julien Lescar, Eugene V. Makeyev, Xinlei Qian, and School of Biological Sciences

Subjects
0301 basic medicine, RNA interference (RNAi), RNA-dependent RNA polymerase, Biology, Crystallography, X-Ray, Biochemistry, Evolution, Molecular, Fungal Proteins, 03 medical and health sciences, small RNAs, RNA polymerase I, protein evolution, Protein Structure, Quaternary, Molecular Biology, x-ray crystallography, Genetics, Neurospora crassa, fungi, Intron, RNA, Cell Biology, Non-coding RNA, RNA-Dependent RNA Polymerase, RNA silencing, 030104 developmental biology, RNA editing, RNA polymerase, Protein Multimerization, electron microscopy (EM), Small nuclear RNA
Abstract

Many eukaryotic organisms encode more than one RNA-dependent RNA polymerase (RdRP) that likely emerged as a result of gene duplication. Such RdRP paralogs often participate in distinct RNA silencing pathways and show characteristic repertoires of enzymatic activities in vitro. However, to what extent members of individual paralogous groups can undergo functional changes during speciation remains an open question. We show that orthologs of QDE-1, an RdRP component of the quelling pathway in Neurospora crassa, have rapidly diverged in evolution at the amino acid sequence level. Analyses of purified QDE-1 polymerases from N. crassa (QDE-1Ncr) and related fungi, Thielavia terrestris (QDE-1Tte) and Myceliophthora thermophila (QDE-1Mth), show that all three enzymes can synthesize RNA but the precise modes of their action differ considerably. Unlike their QDE-1Ncr counterpart favoring processive RNA synthesis, QDE-1Tte and QDE-1Mth produce predominantly short RNA copies via primer-independent initiation. Surprisingly, a 3.19 Å-resolution crystal structure of QDE-1Tte reveals a quasi-symmetric dimer similar to QDE-1Ncr. Further electron microscopy analyses confirm that QDE-1Tte occurs as a dimer in solution and retains this status upon interaction with a template. We conclude that divergence of orthologous RdRPs can result in functional innovation while retaining overall protein fold and quaternary structure. MOE (Min. of Education, S’pore) NMRC (Natl Medical Research Council, S’pore) Accepted version

Published
2016

31. Crystal structure of the periplasmic sensor domain of histidine kinase VbrK suggests indirect sensing of β-lactam antibiotics

Author

Boon Chong Goh, Julien Lescar, Yong Kang Chua, Martin Savko, Jianqing Lin, Xinlei Qian, and Peter C. Dedon

Subjects
Histidine Kinase, Size-exclusion chromatography, Crystallography, X-Ray, beta-Lactams, beta-Lactamases, 03 medical and health sciences, Bacterial Proteins, Structural Biology, Gene expression, Gene, 030304 developmental biology, 0303 health sciences, biology, Chemistry, Vibrio parahaemolyticus, 030302 biochemistry & molecular biology, Histidine kinase, Isothermal titration calorimetry, Periplasmic space, biology.organism_classification, Two-component regulatory system, Anti-Bacterial Agents, Periplasm, Biophysics, Protein Binding
Abstract

Bacterial two-component regulatory systems (TCS) play important roles in sensing environmental stimuli and responding to them by regulating gene expression. VbrK/VbrR, a TCS in Vibrio parahaemolyticus, confers resistance to β-lactam antibiotics through activating a β-lactamase gene. Its periplasmic sensor domain was previously suggested to detect β-lactam antibiotics by direct binding. Here, we report a crystal structure of the periplasmic sensing domain of VbrK (VbrKSD) using sulfur-based single-wavelength anomalous diffraction (S-SAD) phasing. Contrary to most bacterial sensor domains which form dimers, we show that VbrKSD is a monomer using size exclusion chromatography coupled with multi-angle light scattering. This observation is also supported by molecular dynamics simulations. To quantify the binding affinity of β-lactam antibiotics to VbrKSD, we performed isothermal titration calorimetry and other biophysical analyses. Unexpectedly, VbrKSD did not show any significant binding to β-lactam antibiotics. Therefore, we propose that the detection of β-lactam antibiotics by VbrK is likely to be indirect via an as yet unidentified mechanism.

Published
2020

32. Modified phase-generated carrier demodulation compensated for the propagation delay of the fiber

Author

Xinlei Qian, Tongyao Du, Yong Kong, Wang Zhenwei, and Wei Ding

Subjects
Physics, business.industry, Optical communication, Phase (waves), Propagation delay, Mach–Zehnder interferometer, Signal, Atomic and Molecular Physics, and Optics, Electronic, Optical and Magnetic Materials, Interferometry, Signal-to-noise ratio, Optics, Electronic engineering, Demodulation, Electrical and Electronic Engineering, Physical and Theoretical Chemistry, business
Abstract

In this paper, a modified phase generated carrier (PGC) demodulation technique based on Mach–Zehnder interferometer (MZI) is proposed, the related simulation and experiment results show that this technique can restrain the influence of the time delay between carrier signals and disturbance signals. Combined with 3×3 coupler, the modified PGC technique uses the two of three output signals as fundamental carrier frequency signal and second-harmonic carrier frequency signal by mathematical transformations, and another output is modulated signal, which enable the three signals output simultaneously from the interferometer. Meanwhile, in order to raise further the signal to noise ratio (SNR), the influences of differential-and-cross-multiplying (DCM) and Arctangent (ATAN) between the modified technique and the traditional technique, time delay, and laser sources with different line-width on demodulation effects are discussed. We believe this work will provide some new methods for the technological research in the field of fiber optical communication.

Published
2020

34. Alignment of the c-type cytochrome OmcS along pili of Geobacter sulfurreducens

Author

Ching Leang, Xinlei Qian, Mester, Tunde, and Lovley, Derek R.

Subjects
Iron bacteria -- Physiological aspects, Cytochromes -- Research, Electron transport -- Research, Iron oxides -- Chemical properties, Biological sciences
Abstract

Immunogold localization of the c-type cytochrome OmcS along pili of Geobacter sulfurreducens was explored to show that cytochrome OmcS required for Fe(III) oxide reduction by G. sulfurreducens is localized along the pili. The apparent spacing observed between OmcS molecules indicated that OmcS facilitated electron transfer from pili to Fe(III) oxides rather than promoting electron conduction along the length of the pili.

Published
2010

35. Purification and characterization of OmcZ, an outer-surface, octaheme c-type cytochrome essential for optimal current production by Geobacter sulfurreducens

Author

Inoue, Kengo, Xinlei Qian, Morgado, Leonor, Byoung-Chan Kim, Mester, Tunde, Izallalen, Mounir, Salgueiro, Carlos A., and Lovley, Derek R.

Subjects
Iron bacteria -- Genetic aspects, Iron bacteria -- Physiological aspects, Electron transport -- Analysis, Fuel cells -- Research, Biological sciences
Abstract

The c-type cytochrome OmcZ found in large and small forms in Geobacter sulfurreducens was characterized to gain insight into its role in current production in microbial fuel cells. The findings for the biochemical properties and extracellular localization of OmcZ confirmed the contribution of cytochrome OmcZ for promoting electron transfer in current-producing biofilms of G. sulfurreducens.

Published
2010

36. Evidence that OmcB and OmpB ofGeobacter sulfurreducensare outer membrane surface proteins

Author

Gemma Reguera, Tünde Mester, Derek R. Lovley, and Xinlei Qian

Subjects
Cytochrome, biology, Cell Membrane, Proteolytic enzymes, Cytochromes c, Immunogold labelling, Proteinase K, biology.organism_classification, Ferric Compounds, Microbiology, Microscopy, Electron, Transmission, Membrane protein, Biochemistry, Genetics, biology.protein, Biophysics, Geobacter, Bacterial outer membrane, Oxidation-Reduction, Molecular Biology, Geobacter sulfurreducens, Bacterial Outer Membrane Proteins, Peptide Hydrolases
Abstract

The c-type cytochrome (OmcB) and the multicopper protein (OmpB) required for Fe(III) oxide reduction by Geobacter sulfurreducens were predicted previously to be outer membrane proteins, but it is not clear whether they are positioned in a manner that permits the interaction with Fe(III). Treatment of whole cells with proteinase K inhibited Fe(III) reduction, but had no impact on the inner membrane-associated fumarate reduction. OmcB was digested by protease, resulting in a smaller peptide. However, immunogold labeling coupled with transmission electron microscopy did not detect OmcB, suggesting that it is only partially exposed on the cell surface. In contrast, OmpB was completely digested with protease. OmpB was loosely associated with the cell surface as a substantial portion of it was recovered in the culture supernatant. Immunogold labeling demonstrated that OmpB associated with the cell was evenly distributed on the cell surface rather than localized to one side of the cell like the conductive pili. Although several proteins required for Fe(III) oxide reduction are shown to be exposed on the outer surface of G. sulfurreducens, the finding that OmcB is also surface exposed is the first report of a protein required for optimal Fe(III) citrate reduction at least partially accessible on the cell surface.

Published
2007

37. Biochemical characterization of purified OmcS, a c-type cytochrome required for insoluble Fe(III) reduction in Geobacter sulfurreducens

Author

Xinlei Qian, Tsutomu Arakawa, Derek R. Lovley, Crisjoe A. Joseph, Manju L. Sharma, Tünde Mester, Kengo Inoue, Carlos A. Salgueiro, Leonor Morgado, and Michael J. Maroney

Subjects
Circular dichroism, Cytochrome, Iron, Inorganic chemistry, Metal reduction, Biophysics, Humic substances, Cytochrome c Group, Heme, Redox, Biochemistry, 03 medical and health sciences, Electron transfer, chemistry.chemical_compound, C-type cytochrome, Geobacter sulfurreducens, 030304 developmental biology, chemistry.chemical_classification, 0303 health sciences, biology, Molecular mass, 030306 microbiology, Chemistry, Circular Dichroism, Cell Biology, Electron acceptor, biology.organism_classification, Molecular Weight, Kinetics, Solubility, Iron reduction, biology.protein, Geobacter, Oxidation-Reduction
Abstract

Previous studies with Geobacter sulfurreducens have demonstrated that OmcS, an abundant c-type cytochrome that is only loosely bound to the outer surface, plays an important role in electron transfer to Fe(III) oxides as well as other extracellular electron acceptors. In order to further investigate the function of OmcS, it was purified from a strain that overproduces the protein. Purified OmcS had a molecular mass of 47 015 Da, and six low-spin bis-histidinyl hexacoordinated heme groups. Its midpoint redox potential was −212 mV. A thermal stability analysis showed that the cooperative melting of purified OmcS occurs in the range of 65–82 °C. Far UV circular dichroism spectroscopy indicated that the secondary structure of purified OmcS consists of about 10% α-helix and abundant disordered structures. Dithionite-reduced OmcS was able to transfer electrons to a variety of substrates of environmental importance including insoluble Fe(III) oxide, Mn(IV) oxide and humic substances. Stopped flow analysis revealed that the reaction rate of OmcS oxidation has a hyperbolic dependence on the concentration of the studied substrates. A ten-fold faster reaction rate with anthraquinone-2,6-disulfonate (AQDS) (25.2 s− 1) was observed as compared to that with Fe(III) citrate (2.9 s− 1). The results, coupled with previous localization and gene deletion studies, suggest that OmcS is well-suited to play an important role in extracellular electron transfer.

Published
2010

38. Purification and characterization of OmcZ, an outer-surface, octaheme c-type cytochrome essential for optimal current production by Geobacter sulfurreducens

Author

Mounir Izallalen, Leonor Morgado, Derek R. Lovley, Byoung-Chan Kim, Xinlei Qian, Tünde Mester, Kengo Inoue, and Carlos A. Salgueiro

Subjects
Hot Temperature, Heme binding, Cytochrome, Stereochemistry, Bioelectric Energy Sources, Inorganic chemistry, Molecular Sequence Data, Heme, Applied Microbiology and Biotechnology, Electron Transport, chemistry.chemical_compound, Electricity, Sequence Analysis, Protein, Redox titration, Enzymology and Protein Engineering, Geobacter sulfurreducens, chemistry.chemical_classification, Binding Sites, Ecology, biology, Protein Stability, Cytochrome c, Cytochromes c, Electron acceptor, biology.organism_classification, Molecular Weight, chemistry, biology.protein, Geobacter, Oxidation-Reduction, Sequence Alignment, Food Science, Biotechnology, Protein Binding
Abstract

Previous studies have demonstrated that Geobacter sulfurreducens requires the c -type cytochrome OmcZ, which is present in large (OmcZ L ; 50-kDa) and small (OmcZ S ; 30-kDa) forms, for optimal current production in microbial fuel cells. This protein was further characterized to aid in understanding its role in current production. Subcellular-localization studies suggested that OmcZ S was the predominant extracellular form of OmcZ. N- and C-terminal amino acid sequence analysis of purified OmcZ S and molecular weight measurements indicated that OmcZ S is a cleaved product of OmcZ L retaining all 8 hemes, including 1 heme with the unusual c -type heme-binding motif CX 14 CH. The purified OmcZ S was remarkably thermally stable (thermal-denaturing temperature, 94.2°C). Redox titration analysis revealed that the midpoint reduction potential of OmcZ S is approximately −220 mV (versus the standard hydrogen electrode [SHE]) with nonequivalent heme groups that cover a large reduction potential range (−420 to −60 mV). OmcZ S transferred electrons in vitro to a diversity of potential extracellular electron acceptors, such as Fe(III) citrate, U(VI), Cr(VI), Au(III), Mn(IV) oxide, and the humic substance analogue anthraquinone-2,6-disulfonate, but not Fe(III) oxide. The biochemical properties and extracellular localization of OmcZ suggest that it is well suited for promoting electron transfer in current-producing biofilms of G. sulfurreducens .

Published
2010

39. Alignment of the c-Type Cytochrome OmcS along Pili of Geobacter sulfurreducens▿ †

Author

Derek R. Lovley, Ching Leang, Xinlei Qian, and Tünde Mester

Subjects
Ecology, Cytochrome, biology, Cytochrome c, Fimbria, Inorganic chemistry, Cytochromes c, Immunogold labelling, biology.organism_classification, Applied Microbiology and Biotechnology, Geomicrobiology, Ferric Compounds, Immunohistochemistry, Pilus, Electron transfer, Fimbriae, Bacterial, biology.protein, Biophysics, Geobacter, Microscopy, Immunoelectron, Geobacter sulfurreducens, Food Science, Biotechnology
Abstract

Immunogold localization revealed that OmcS, a cytochrome that is required for Fe(III) oxide reduction by Geobacter sulfurreducens , was localized along the pili. The apparent spacing between OmcS molecules suggests that OmcS facilitates electron transfer from pili to Fe(III) oxides rather than promoting electron conduction along the length of the pili.

Published
2010

40. Two putative c-type multiheme cytochromes required for the expression of OmcB, an outer membrane protein essential for optimal Fe(III) reduction in Geobacter sulfurreducens

Author

Byoung-Chan Kim, Maddalena V. Coppi, Derek R. Lovley, Xinlei Qian, and Ching Leang

Subjects
Cytochrome, Blotting, Western, Gene Expression, Microbiology, Ferric Compounds, Bacterial Proteins, Transcription (biology), Gene expression, RNA, Messenger, Molecular Biology, Geobacter sulfurreducens, biology, Cytochrome c, Cytochromes c, biology.organism_classification, Blotting, Northern, Enzymes and Proteins, RNA, Bacterial, Membrane protein, Biochemistry, Genes, Bacterial, biology.protein, Bacterial outer membrane, Geobacter, Oxidation-Reduction, Gene Deletion, Bacterial Outer Membrane Proteins
Abstract

Deletion of two homologous Geobacter sulfurreducens c -type cytochrome genes, omcG and omcH , decreased the rate of Fe(III) reduction and decreased the level of an outer membrane cytochrome critical for Fe(III) reduction, OmcB, without affecting its transcription. Expression of either gene restored Fe(III) reduction and OmcB expression, suggesting functional similarity.

Published
2006

41. Functional Evolution in Orthologous Cell-encoded RNA-dependent RNA Polymerases.

Author

Xinlei Qian, Hamid, Fursham M., El Sahili, Abbas, Darwis, Dina Amallia, Yee Hwa Wong, Bhushan, Shashi, Makeyev, Eugene V., and Lescar, Julien

Subjects
*RNA replicase, *EUKARYOTIC evolution, *CHROMOSOME duplication, *RNA interference, *NEUROSPORA crassa
Abstract

Many eukaryotic organisms encode more than one RNA-dependent RNA polymerase (RdRP) that probably emerged as a result of gene duplication. Such RdRP paralogs often participate in distinctRNAsilencing pathways and show characteristic repertoires of enzymatic activities in vitro. However, to what extent members of individual paralogous groups can undergo functional changes during speciation remains an open question. We show that orthologs of QDE-1, an RdRP component of the quelling pathway in Neurospora crassa, have rapidly diverged in evolution at the amino acid sequence level. Analyses of purified QDE-1 polymerases from N. crassa (QDE-1Ncr) and related fungi, Thielavia terrestris (QDE-1Tte) and Myceliophthora thermophila (QDE-1Mth), show that all three enzymes can synthesize RNA, but the precise modes of their action differ considerably. Unlike their QDE-1Ncr counterpart favoring processive RNA synthesis, QDE-1Tte and QDE-1Mth produce predominantly short RNA copies via primer-independent initiation. Surprisingly, a 3.19 Å resolution crystal structure of QDE-1Tte reveals a quasisymmetric dimer similar to QDE-1Ncr. Further electron microscopy analyses confirm that QDE-1Tte occurs as a dimer in solution and retains this status upon interaction with a template. We conclude that divergence of orthologous RdRPs can result in functional innovation while retaining overall protein fold and quaternary structure. [ABSTRACT FROM AUTHOR]

Published
2016
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42. Purification and Characterization of OmcZ, an Outer-Surface, Octaheme c-Type Cytochrome Essential for Optimal Current Production by Geobacter sulfurreducens.

Author

Kengo Inoue, Xinlei Qian, Morgado, Leonor, Byoung-Chan Kim, Tünde Mester, Izallalen, Mounir, Salgueiro, Carlos A., and Lovley, Derek R.

Subjects
*GRAM-negative bacteria, *MICROBIAL fuel cells, *CYTOCHROME c, *AMINO acid sequence, *OXIDATION-reduction reaction, *VOLUMETRIC analysis, *BIOFILMS, *CHARGE exchange, *MOLECULAR weights
Abstract

Previous studies have demonstrated that Geobacter sulfurreducens requires the c-type cytochrome OmcZ, which is present in large (OmcZL; 50-kDa) and small (OmcZS; 30-kDa) forms, for optimal current production in microbial fuel cells. This protein was further characterized to aid in understanding its role in current production. Subcellular-localizatiofl studies suggested that OmcZS was the predominant extracellular form of OmcZS. Nand C-terminal amino acid sequence analysis of purified OmcZ5 and molecular weight measurements indicated that OmcZS is a cleaved product of OmcZL retaining all 8 hemes, including 1 heme with the unusual c-type heme-binding motif CX14CH. The purified OmcZL was remarkably thermally stable (thermaldenaturing temperature, 94.2°C). Redox titration analysis revealed that the midpoint reduction potential of OmcZ5 is approximately -220 mV (versus the standard hydrogen electrode [SHE]) with nonequivalent heme groups that cover a large reduction potential range (-420 to -60 my). OmcZS transferred electrons in vitro to a diversity of potential extracellular electron acceptors, such as Fe(III) citrate, U(VI), Cr(VI), Au(III), Mn(IV) oxide, and the humic substance analogue anthraquinone-2,6-disulfonate, but not Fe(III) oxide. The biochemical properties and extracellular localization of OmcZ suggest that it is well suited for promoting electron transfer in current-producing biofilms of G. sulfurreducens. [ABSTRACT FROM AUTHOR]

Published
2010
Full Text
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43. Evidence that OmcB and OmpB of Geobacter sulfurreducens are outer membrane surface proteins.

Author

Xinlei Qian, Reguera, Gemma, Mester, Tünde, and Lovley, Derek R.

Subjects
*CELL membranes, *BIOMOLECULES, *MEMBRANE proteins, *PROTEOLYTIC enzymes, *TRANSMISSION electron microscopy, *CELLS, *BIOLOGICAL membranes, *ELECTRON microscopy, *PROTEINS
Abstract

The c-type cytochrome (OmcB) and the multicopper protein (OmpB) required for Fe(III) oxide reduction by Geobacter sulfurreducens were predicted previously to be outer membrane proteins, but it is not clear whether they are positioned in a manner that permits the interaction with Fe(III). Treatment of whole cells with proteinase K inhibited Fe(III) reduction, but had no impact on the inner membrane-associated fumarate reduction. OmcB was digested by protease, resulting in a smaller peptide. However, immunogold labeling coupled with transmission electron microscopy did not detect OmcB, suggesting that it is only partially exposed on the cell surface. In contrast, OmpB was completely digested with protease. OmpB was loosely associated with the cell surface as a substantial portion of it was recovered in the culture supernatant. Immunogold labeling demonstrated that OmpB associated with the cell was evenly distributed on the cell surface rather than localized to one side of the cell like the conductive pili. Although several proteins required for Fe(III) oxide reduction are shown to be exposed on the outer surface of G. sulfurreducens, the finding that OmcB is also surface exposed is the first report of a protein required for optimal Fe(III) citrate reduction at least partially accessible on the cell surface. [ABSTRACT FROM AUTHOR]

Published
2007
Full Text
View/download PDF

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