Automated pattern-guided principal component analysis vs expert-based immunophenotypic classification of B-cell chronic lymphoproliferative disorders: a step forward in the standardization of clinical immunophenotyping

Immunophenotypic characterization of B-cell chronic lymphoproliferative disorders (B-CLPD) is becoming increasingly complex due to usage of progressively larger panels of reagents and a high number of World Health Organization (WHO) entities. Typically, data analysis is performed separately for each stained aliquot of a sample; subsequently, an expert interprets the overall immunophenotypic profile (IP) of neoplastic B-cells and assigns it to specific diagnostic categories. We constructed a principal component analysis (PCA)-based tool to guide immunophenotypic classification of B-CLPD. Three reference groups of immunophenotypic data files—B-cell chronic lymphocytic leukemias (B-CLL; n=10), mantle cell (MCL; n=10) and follicular lymphomas (FL; n=10)—were built. Subsequently, each of the 175 cases studied was evaluated and assigned to either one of the three reference groups or to none of them (other B-CLPD). Most cases (89%) were correctly assigned to their corresponding WHO diagnostic group with overall positive and negative predictive values of 89 and 96%, respectively. The efficiency of the PCA-based approach was particularly high among typical B-CLL, MCL and FL vs other B-CLPD cases. In summary, PCA-guided immunophenotypic classification of B-CLPD is a promising tool for standardized interpretation of tumor IP, their classification into well-defined entities and comprehensive evaluation of antibody panels

An Evolutionary Trade-Off between Protein Turnover Rate and Protein Aggregation Favors a Higher Aggregation Propensity in Fast Degrading Proteins

We previously showed the existence of selective pressure against protein aggregation by the enrichment of aggregation-opposing ‘gatekeeper’ residues at strategic places along the sequence of proteins. Here we analyzed the relationship between protein lifetime and protein aggregation by combining experimentally determined turnover rates, expression data, structural data and chaperone interaction data on a set of more than 500 proteins. We find that selective pressure on protein sequences against aggregation is not homogeneous but that short-living proteins on average have a higher aggregation propensity and fewer chaperone interactions than long-living proteins. We also find that short-living proteins are more often associated to deposition diseases. These findings suggest that the efficient degradation of high-turnover proteins is sufficient to preclude aggregation, but also that factors that inhibit proteasomal activity, such as physiological ageing, will primarily affect the aggregation of short-living proteins

Pharmacokinetic-Pharmacodynamic Modeling in Pediatric Drug Development, and the Importance of Standardized Scaling of Clearance.

Pharmacokinetic/pharmacodynamic (PKPD) modeling is important in the design and conduct of clinical pharmacology research in children. During drug development, PKPD modeling and simulation should underpin rational trial design and facilitate extrapolation to investigate efficacy and safety. The application of PKPD modeling to optimize dosing recommendations and therapeutic drug monitoring is also increasing, and PKPD model-based dose individualization will become a core feature of personalized medicine. Following extensive progress on pediatric PK modeling, a greater emphasis now needs to be placed on PD modeling to understand age-related changes in drug effects. This paper discusses the principles of PKPD modeling in the context of pediatric drug development, summarizing how important PK parameters, such as clearance (CL), are scaled with size and age, and highlights a standardized method for CL scaling in children. One standard scaling method would facilitate comparison of PK parameters across multiple studies, thus increasing the utility of existing PK models and facilitating optimal design of new studies

Biopharmaceutical considerations in paediatrics with a view to the evaluation of orally administered drug products – a PEARRL review.

Objectives: In this review, the current biopharmaceutical approaches for evaluation of oral formulation performance in paediatrics are discussed. Key findings: The paediatric gastrointestinal (GI) tract undergoes numerous morphological and physiological changes throughout its development and growth. Some physiological parameters are yet to be investigated, limiting the use of the existing in vitro biopharmaceutical tools to predict the in vivo performance of paediatric formulations. Meals and frequencies of their administration evolve during childhood and affect oral drug absorption. Furthermore, the establishment of a paediatric Biopharmaceutics Classification System (pBCS), based on the adult Biopharmaceutics Classification System (BCS), requires criteria adjustments. The usefulness of computational simulation and modeling for extrapolation of adult data to paediatrics has been confirmed as a tool for predicting drug formulation performance. Despite the great number of successful physiologically based pharmacokinetic models to simulate drug disposition, the simulation of drug absorption from the GI tract is a complicating issue in paediatric populations. Summary: The biopharmaceutics tools for investigation of oral drug absorption in paediatrics need further development, refinement and validation. A combination of in vitro and in silico methods could compensate for the uncertainties accompanying each method on its own

Resolving the inner parsec of the blazar J1924–2914 with the Event Horizon Telescope

Rest of authors: Ikeda, Shiro; Impellizzeri, C. M. Violette; Inoue, Makoto; James, David J.; Jannuzi, Buell T.; Jeter, Britton; Jiang, Wu; Jimenez-Rosales, Alejandra; Johnson, Michael D.; Joshi, Abhishek, V; Jung, Taehyun; Karami, Mansour; Karuppusamy, Ramesh; Kawashima, Tomohisa; Keating, Garrett K.; Kettenis, Mark; Kim, Dong-Jin; Kim, Jae-Young; Kim, Jongsoo; Kim, Junhan; Kino, Motoki; Koay, Jun Yi; Kocherlakota, Prashant; Kofuji, Yutaro; Koch, Patrick M.; Koyama, Shoko; Kramer, Carsten; Kramer, Michael; Kuo, Cheng-Yu; La Bella, Noemi; Lauer, Tod R.; Lee, Daeyoung; Lee, Sang-Sung; Leung, Po Kin; Levis, Aviad; Li, Zhiyuan; Lindahl, Greg; Lindqvist, Michael; Liu, Kuo; Liuzzo, Elisabetta; Lo, Wen-Ping; Lobanov, Andrei P.; Lonsdale, Colin; Mao, Jirong; Marchili, Nicola; Markoff, Sera; Marrone, Daniel P.; Marscher, Alan P.; Matsushita, Satoki; Matthews, Lynn D.; Medeiros, Lia; Menten, Karl M.; Michalik, Daniel; Mizuno, Izumi; Mizuno, Yosuke; Moran, James M.; Mueller, Cornelia; Mus, Alejandro; Musoke, Gibwa; Myserlis, Ioannis; Nadolski, Andrew; Nagai, Hiroshi; Nagar, Neil M.; Nakamura, Masanori; Narayan, Ramesh; Narayanan, Gopal; Natarajan, Iniyan; Nathanail, Antonios; Neilsen, Joey; Neri, Roberto; Ni, Chunchong; Noutsos, Aristeidis; Nowak, Michael A.; Oh, Junghwan; Okino, Hiroki; Olivares, Hector; Ortiz-Leon, Gisela N.; Oyama, Tomoaki; Ozel, Feryal; Palumbo, Daniel C. M.; Paraschos, Georgios Filippos; Park, Jongho; Parsons, Harriet; Patel, Nimesh; Pen, Ue-Li; Pietu, Vincent; Plambeck, Richard; PopStefanija, Aleksandar; Porth, Oliver; Potzl, Felix M.; Prather, Ben; Preciado-Lopez, Jorge A.; Psaltis, Dimitrios; Pu, Hung-Yi; Rao, Ramprasad; Rawlings, Mark G.; Raymond, Alexander W.; Rezzolla, Luciano; Ricarte, Angelo; Ripperda, Bart; Roelofs, Freek; Rogers, Alan; Ros, Eduardo; Romero-Canizales, Cristina; Roshanineshat, Arash; Rottmann, Helge; Roy, Alan L.; Ruiz, Ignacio; Ruszczyk, Chet; Rygl, Kazi L. J.; Sanchez, Salvador; Sanchez-Arguelles, David; Sanchez-Portal, Miguel; Sasada, Mahito; Satapathy, Kaushik; Savolainen, Tuomas; Schloerb, F. Peter; Schuster, Karl-Friedrich; Shao, Lijing; Shen, Zhiqiang; Small, Des; Sohn, Bong Won; SooHoo, Jason; Souccar, Kamal; Sun, He; Tazaki, Fumie; Tetarenko, Alexandra J.; Tilanus, Remo P. J.; Titus, Michael; Torne, Pablo; Trent, Tyler; Trippe, Sascha; van Bemmel, Ilse; van Langevelde, Huib Jan; van Rossum, Daniel R.; Vos, Jesse; Wagner, Jan; Ward-Thompson, Derek; Wardle, John; Weintroub, Jonathan; Wex, Norbert; Wharton, Robert; Wiik, Kaj; Witzel, Gunther; Wondrak, Michael; Wong, George N.; Wu, Qingwen; Yamaguchi, Paul; Yoon, Doosoo; Young, Andre; Young, Ken; Younsi, Ziri; Yuan, Feng; Yuan, Ye-Fei; Zensus, J. Anton; Zhang, Shuo; Zhao, Shan-Shan.The blazar J1924–2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center’s black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 μas resolution of the EHT. J1924–2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5–11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924–2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90° between 2.3 and 230 GHz. Linearly polarized intensity images of J1924–2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core.We thank the anonymous reviewer for their thoughtful and helpful comments. The Event Horizon Telescope Collaboration thanks the following organizations and programs: the Academy of Finland (projects 274477, 284495, 312496, 315721); the Agencia Nacional de Investigación y Desarrollo (ANID), Chile via NCN19_058 (TITANs) and Fondecyt 3190878, the Alexander von Humboldt Stiftung; an Alfred P. Sloan Research Fellowship; Allegro, the European ALMA Regional Centre node in the Netherlands, the NL astronomy research network NOVA and the astronomy institutes of the University of Amsterdam, Leiden University and Radboud University; the black hole Initiative at Harvard University, through a grant (60477) from the John Templeton Foundation; the China Scholarship Council; Consejo Nacional de Ciencia y Tecnología (CONACYT, Mexico, projects U0004-246083, U0004- 259839, F0003-272050, M0037-279006, F0003-281692, 104497, 275201, 263356); the Delaney Family via the Delaney Family John A. Wheeler Chair at Perimeter Institute; Dirección General de Asuntos del Personal Académico-Universidad Nacional Autónoma de México (DGAPA-UNAM, projects IN112417 and IN112820); the European Research Council Synergy Grant “BlackHoleCam: Imaging the Event Horizon of Black Holes” (grant 610058); the Generalitat Valenciana postdoctoral grant APOSTD/2018/177 and GenT Program (project CIDEGENT/2018/021); MICINN Research Project PID2019-108995GB-C22; the Gordon and Betty Moore Foundation (grant GBMF-3561); the Istituto Nazionale di Fisica Nucleare (INFN) sezione di Napoli, iniziative specifiche TEONGRAV; the International Max Planck Research School for Astronomy and Astrophysics at the Universities of Bonn and Cologne; Joint Princeton/Flatiron and Joint Columbia/ Flatiron Postdoctoral Fellowships, research at the Flatiron Institute is supported by the Simons Foundation; the Japanese Government (Monbukagakusho: MEXT) Scholarship; the Japan Society for the Promotion of Science (JSPS) Grant-in- Aid for JSPS Research Fellowship (JP17J08829); the Key Research Program of Frontier Sciences, Chinese Academy of Sciences (CAS, grants QYZDJ-SSW-SLH057, QYZDJSSWSYS008, ZDBS-LY-SLH011); the Leverhulme Trust Early Career Research Fellowship; the Max-Planck-Gesellschaft (MPG); the Max Planck Partner Group of the MPG and the CAS; the MEXT/JSPS KAKENHI (grants 18KK0090, JP18K13594, JP18K03656, JP18H03721, 18K03709, 18H01245, 25120007); the Malaysian Fundamental Research Grant Scheme (FRGS) FRGS/1/2019/STG02/UM/02/6; the MIT International Science and Technology Initiatives (MISTI) Funds; the Ministry of Science and Technology (MOST) of Taiwan (105-2112-M-001-025-MY3, 106-2112-M-001-011, 106-2119- M-001-027, 107-2119-M-001-017, 107-2119-M- 001-020, 107-2119-M-110-005, 108-2112-M-001-048, and 109-2124-M-001-005); the National Aeronautics and Space Administration (NASA, Fermi Guest Investigator grant 80NSSC20K1567, NASA Astrophysics Theory Program grant 80NSSC20K0527, NASA NuSTAR award 80NSSC20K0645); the National Institute of Natural Sciences (NINS) of Japan; the National Key Research and Development Program of China (grant 2016YFA0400704, 2016YFA0400702); the National Science Foundation (NSF, grants AST-0096454, AST- 0352953, AST-0521233, AST-0705062, AST-0905844, AST- 0922984, AST-1126433, AST-1140030, DGE-1144085, AST- 1207704, AST-1207730, AST-1207752, MRI-1228509, OPP- 1248097, AST-1310896, AST-1555365,AST-1615796, AST- 1715061, AST-1716327, AST-1903847,AST-2034306); the Natural Science Foundation of China (grants 11573051, 11633006, 11650110427, 10625314, 11721303, 11725312, 11933007, 11991052, 11991053); a fellowship of China Postdoctoral Science Foundation (2020M671266); the Natural Sciences and Engineering Research Council of Canada (NSERC, including a Discovery Grant and the NSERC Alexander Graham Bell Canada Graduate Scholarships-Doctoral Program); the National Youth Thousand Talents Program of China; the National Research Foundation of Korea (the Global PhD Fellowship Grant: grants NRF- 2015H1A2A1033752, 2015- R1D1A1A01056807, the Korea Research Fellowship Program: NRF-2015H1D3A1066561, Basic Research Support Grant 2019R1F1A1059721); the Netherlands Organization for Scientific Research (NWO) VICI award (grant 639.043.513) and Spinoza Prize SPI 78-409; the New Scientific Frontiers with Precision Radio Interferometry Fellowship awarded by the South African Radio Astronomy Observatory (SARAO), which is a facility of the National Research Foundation (NRF), an agency of the Department of Science and Technology (DST) of South Africa; the Onsala Space Observatory (OSO) national infrastructure, for the provisioning of its facilities/observational support (OSO receives funding through the Swedish Research Council under grant 2017-00648) the Perimeter Institute for Theoretical Physics (research at Perimeter Institute is supported by the Government of Canada through the Department of Innovation, Science and Economic Development and by the Province of Ontario through the Ministry of Research, Innovation and Science); the Spanish Ministerio de Economía y Competitividad (grants PGC2018-098915-B-C21, AYA2016-80889-P, PID2019-108995GB-C21); the State Agency for Research of the Spanish MCIU through the “Center of Excellence Severo Ochoa” award for the Instituto de Astrofísica de Andalucía (SEV-2017-0709); the Toray Science Foundation; the Consejería de Economía, Conocimiento, Empresas y Universidad of the Junta de Andalucía (grant P18-FR-1769), the Consejo Superior de Investigaciones Científicas (grant 2019AEP112); the US Department of Energy (USDOE) through the Los Alamos National Laboratory (operated by Triad National Security, LLC, for the National Nuclear Security Administration of the USDOE (Contract 89233218CNA000001); the European Unionʼs Horizon 2020 research and innovation program under grant agreement No 730562 RadioNet; ALMA North America Development Fund; the Academia Sinica; Chandra DD7- 18089X and TM6-17006X; the GenT Program (Generalitat Valenciana) Project CIDEGENT/2018/021. This work used the Extreme Science and Engineering Discovery Environment (XSEDE), supported by NSF grant ACI-1548562, and CyVerse, supported by NSF grants DBI-0735191, DBI-1265383, and DBI-1743442. XSEDE Stampede2 resource at TACC was allocated through TG-AST170024 and TG-AST080026N. XSEDE JetStream resource at PTI and TACC was allocated through AST170028. The simulations were performed in part on the SuperMUC cluster at the LRZ in Garching, on the LOEWE cluster in CSC in Frankfurt, and on the HazelHen cluster at the HLRS in Stuttgart. This research was enabled in part by support provided by Compute Ontario (http://computeontario.ca), Calcul Quebec (http://www.calculquebec.ca) and Compute Canada (http://www.computecanada.ca). We thank the staff at the participating observatories, correlation centers, and institutions for their enthusiastic support. This paper makes use of the following ALMA data: ADS/JAO.ALMA#2016.1.01154.V and ADS/JAO.ALMA2016.1.00413.V. ALMA is a partnership of the European Southern Observatory (ESO; Europe, representing its member states), NSF, and National Institutes of Natural Sciences of Japan, together with National Research Council (Canada), Ministry of Science and Technology (MOST; Taiwan), Academia Sinica Institute of Astronomy and Astrophysics (ASIAA; Taiwan), and Korea Astronomy and Space Science Institute (KASI; Republic of Korea), in cooperationwith the Republic of Chile. The Joint ALMA Observatory is operated by ESO, Associated Universities, Inc. (AUI)/NRAO, and the National Astronomical Observatory of Japan (NAOJ). The NRAO is a facility of the NSF operated under cooperative agreement by AUI. APEX is a collaboration between the Max- Planck-Institut für Radioastronomie (Germany), ESO, and the Onsala Space Observatory (Sweden). The SMA is a joint project between the SAO and ASIAA and is funded by the Smithsonian Institution and the Academia Sinica. The JCMT is operated by the East Asian Observatory on behalf of the NAOJ, ASIAA, and KASI, as well as the Ministry of Finance of China, Chinese Academy of Sciences, and the National Key R&D Program (No. 2017YFA0402700) of China. Additional funding support for the JCMT is provided by the Science and Technologies Facility Council (UK) and participating universities in the UK and Canada. The LMT is a project operated by the Instituto Nacional de Astrófisica, Óptica, y Electrónica (Mexico) and the University of Massachusetts at Amherst (USA). The IRAM 30 m telescope on Pico Veleta, Spain is operated by IRAM and supported by CNRS (Centre National de la Recherche Scientifique, France), MPG (Max-Planck- Gesellschaft, Germany) and IGN (Instituto Geográfico Nacional, Spain). The SMT is operated by the Arizona Radio Observatory, a part of the Steward Observatory of the University of Arizona, with financial support of operations from the State of Arizona and financial support for instrumentation development from the NSF. Support for SPT participation in the EHT is provided by the National Science Foundation through award OPP-1852617 to the University of Chicago. Partial support is also provided by the Kavli Institute of Cosmological Physics at the University of Chicago. The SPT hydrogen maser was provided on loan from the GLT, courtesy of ASIAA. The EHTC has received generous donations of FPGA chips from Xilinx Inc., under the Xilinx University Program. The EHTC has benefited from technology shared under open-source license by the Collaboration for Astronomy Signal Processing and Electronics Research (CASPER). The EHT project is grateful to T4Science and Microsemi for their assistance with Hydrogen Masers. This research has made use of NASAʼs Astrophysics Data System. We gratefully acknowledge the support provided by the extended staff of the ALMA, both from the inception of the ALMA Phasing Project through the observational campaigns of 2017 and 2018. We would like to thank A. Deller and W. Brisken for EHT-specific support with the use of DiFX. We acknowledge the significance that Maunakea, where the SMA and JCMT EHT stations are located, has for the indigenous Hawaiian people. We also thank Alexandra Elbakyan for her contributions to the open science initiative. This research has made use of data obtained with the Global Millimeter VLBI Array (GMVA), coordinated by the VLBI group at the Max-Planck-Institut für Radioastronomie (MPIfR). The GMVA consists of telescopes operated by MPIfR, IRAM, Onsala, Metsahovi, Yebes, the Korean VLBI Network, the Green Bank Observatory, and the Very Long Baseline Array (VLBA). The VLBA and the GBT are facilities of the National Science Foundation under cooperative agreement by Associated Universities, Inc. The data were correlated at the DiFX correlator of the MPIfR in Bonn, Germany. We thank the National Science Foundation (awards OISE-1743747, AST-1816420, AST-1716536, AST- 1440254, AST-1935980) and the Gordon and Betty Moore Foundation (GBMF-5278) for financial support of this work. Support for this work was also provided by the NASA Hubble Fellowship grant HST-HF2-51431.001-A awarded by the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., for NASA, under contract NAS5-26555.http://iopscience.iop.org/0004-637Xam2023Physic

Resolving the inner parsec of the blazar J1924-2914 with the event horizon telescope

Galaxie

Resolving the Inner Parsec of the Blazar J1924-2914 with the Event Horizon Telescope

The blazar J1924-2914 is a primary Event Horizon Telescope (EHT) calibrator for the Galactic center's black hole Sagittarius A*. Here we present the first total and linearly polarized intensity images of this source obtained with the unprecedented 20 mu as resolution of the EHT. J1924-2914 is a very compact flat-spectrum radio source with strong optical variability and polarization. In April 2017 the source was observed quasi-simultaneously with the EHT (April 5-11), the Global Millimeter VLBI Array (April 3), and the Very Long Baseline Array (April 28), giving a novel view of the source at four observing frequencies, 230, 86, 8.7, and 2.3 GHz. These observations probe jet properties from the subparsec to 100 pc scales. We combine the multifrequency images of J1924-2914 to study the source morphology. We find that the jet exhibits a characteristic bending, with a gradual clockwise rotation of the jet projected position angle of about 90 degrees between 2.3 and 230 GHz. Linearly polarized intensity images of J1924-2914 with the extremely fine resolution of the EHT provide evidence for ordered toroidal magnetic fields in the blazar compact core