The capacity of the fecal microbiota from Malawian infants to ferment resistant starch

In Low and Middle-Income Countries (LMIC), weaning is associated with environmentally acquired and inflammation-associated enteric disorders. Dietary intake of high amylose maize starch (HAMS) can promote commensal fermentative bacteria and drive the production of short chain fatty acids (SCFAs). By stabilizing commensal gut microbiology, and stimulating the production of anti-inflammatory metabolites, HAMS supplementation might therefore influence enteric health. However, the extent to which the gut microbiota of LMIC infants are capable of fermenting HAMS is unclear. We assessed the capacity of the fecal microbiota from pre-weaning and weaning Malawian infants to ferment HAMS and produce SCFAs using an in vitro fermentation model. Fecal microbiota from both pre-weaning and weaning infants were able to ferment HAMS, as indicated by an increase in bacterial load and total SCFA concentration, and a reduction in pH. All of these changes were more substantial in the weaning group. Acetate production was observed with both pre-weaning and weaning groups, while propionate production was only observed in the weaning group. HAMS fermentation resulted in significant alterations to the fecal microbial community in the weaning group, with significant increases in levels of Prevotella, Veillonella, and Collinsella associated with propionate production. In conclusion, fecal microbiota from Malawian infants before and during weaning has the capacity to produce acetate through HAMS fermentation, with propionate biosynthetic capability appearing only at weaning. Our results suggest that HAMS supplementation might provide benefit to infants during weaning

Ribosomal Protein Mutations Induce Autophagy through S6 Kinase Inhibition of the Insulin Pathway

Mutations affecting the ribosome lead to several diseases known as ribosomopathies, with phenotypes that include growth defects, cytopenia, and bone marrow failure. Diamond-Blackfan anemia (DBA), for example, is a pure red cell aplasia linked to the mutation of ribosomal protein (RP) genes. Here we show the knock-down of the DBA-linked RPS19 gene induces the cellular self-digestion process of autophagy, a pathway critical for proper hematopoiesis. We also observe an increase of autophagy in cells derived from DBA patients, in CD34+ erythrocyte progenitor cells with RPS19 knock down, in the red blood cells of zebrafish embryos with RP-deficiency, and in cells from patients with Shwachman-Diamond syndrome (SDS). The loss of RPs in all these models results in a marked increase in S6 kinase phosphorylation that we find is triggered by an increase in reactive oxygen species (ROS). We show that this increase in S6 kinase phosphorylation inhibits the insulin pathway and AKT phosphorylation activity through a mechanism reminiscent of insulin resistance. While stimulating RP-deficient cells with insulin reduces autophagy, antioxidant treatment reduces S6 kinase phosphorylation, autophagy, and stabilization of the p53 tumor suppressor. Our data suggest that RP loss promotes the aberrant activation of both S6 kinase and p53 by increasing intracellular ROS levels. The deregulation of these signaling pathways is likely playing a major role in the pathophysiology of ribosomopathies

Reduced levels of two modifiers of epigenetic gene silencing, Dnmt3a and Trim28, cause increased phenotypic noise

Background: Inbred individuals reared in controlled environments display considerable variance in many complex traits but the underlying cause of this intangible variation has been an enigma. Here we show that two modifiers of epigenetic gene silencing play a critical role in the process.Results: Inbred mice heterozygous for a null mutation in DNA methyltransferase 3a (Dnmt3a) or tripartite motif protein 28 (Trim28) show greater coefficients of variance in body weight than their wild-type littermates. Trim28 mutants additionally develop metabolic syndrome and abnormal behavior with incomplete penetrance. Genome-wide gene expression analyses identified 284 significantly dysregulated genes in Trim28 heterozygote mutants compared to wild-type mice, with Mas1, which encodes a G-protein coupled receptor implicated in lipid metabolism, showing the greatest average change in expression (7.8-fold higher in mutants). This gene also showed highly variable expression between mutant individuals.Conclusions: These studies provide a molecular explanation of developmental noise in whole organisms and suggest that faithful epigenetic control of transcription is central to suppressing deleterious levels of phenotypic variation. These findings have broad implications for understanding the mechanisms underlying sporadic and complex disease in humans

First Sagittarius A* Event Horizon Telescope Results. I. The Shadow of the Supermassive Black Hole in the Center of the Milky Way

We present the first Event Horizon Telescope (EHT) observations of Sagittarius A* (Sgr A*), the Galactic center source associated with a supermassive black hole. These observations were conducted in 2017 using a global interferometric array of eight telescopes operating at a wavelength of λ = 1.3 mm. The EHT data resolve a compact emission region with intrahour variability. A variety of imaging and modeling analyses all support an image that is dominated by a bright, thick ring with a diameter of 51.8 \ub1 2.3 μas (68% credible interval). The ring has modest azimuthal brightness asymmetry and a comparatively dim interior. Using a large suite of numerical simulations, we demonstrate that the EHT images of Sgr A* are consistent with the expected appearance of a Kerr black hole with mass ∼4 7 106 M☉, which is inferred to exist at this location based on previous infrared observations of individual stellar orbits, as well as maser proper-motion studies. Our model comparisons disfavor scenarios where the black hole is viewed at high inclination (i > 50\ub0), as well as nonspinning black holes and those with retrograde accretion disks. Our results provide direct evidence for the presence of a supermassive black hole at the center of the Milky Way, and for the first time we connect the predictions from dynamical measurements of stellar orbits on scales of 103-105 gravitational radii to event-horizon-scale images and variability. Furthermore, a comparison with the EHT results for the supermassive black hole M87* shows consistency with the predictions of general relativity spanning over three orders of magnitude in central mass

Multicenter evaluation of the clinical utility of laparoscopy-assisted ERCP in patients with Roux-en-Y gastric bypass

Background and Aims The obesity epidemic has led to increased use of Roux-en-Y gastric bypass (RYGB). These patients have an increased incidence of pancreaticobiliary diseases yet standard ERCP is not possible due to surgically altered gastroduodenal anatomy. Laparoscopic-ERCP (LA-ERCP) has been proposed as an option but supporting data are derived from single center small case-series. Therefore, we conducted a large multicenter study to evaluate the feasibility, safety, and outcomes of LA-ERCP. Methods This is retrospective cohort study of adult patients with RYGB who underwent LA-ERCP in 34 centers. Data on demographics, indications, procedure success, and adverse events were collected. Procedure success was defined when all of the following were achieved: reaching the papilla, cannulating the desired duct and providing endoscopic therapy as clinically indicated. Results A total of 579 patients (median age 51, 84% women) were included. Indication for LA-ERCP was biliary in 89%, pancreatic in 8%, and both in 3%. Procedure success was achieved in 98%. Median total procedure time was 152 minutes (IQR 109-210) with median ERCP time 40 minutes (IQR 28-56). Median hospital stay was 2 days (IQR 1-3). Adverse events were 18% (laparoscopy-related 10%, ERCP-related 7%, both 1%) with the clear majority (92%) classified as mild/moderate whereas 8% were severe and 1 death occurred. Conclusion Our large multicenter study indicates that LA-ERCP in patients with RYGB is feasible with a high procedure success rate comparable with that of standard ERCP in patients with normal anatomy. ERCP-related adverse events rate is comparable with conventional ERCP, but the overall adverse event rate was higher due to the added laparoscopy-related events

A Universal Power-law Prescription for Variability from Synthetic Images of Black Hole Accretion Flows

We present a framework for characterizing the spatiotemporal power spectrum of the variability expected from the horizon-scale emission structure around supermassive black holes, and we apply this framework to a library of general relativistic magnetohydrodynamic (GRMHD) simulations and associated general relativistic ray-traced images relevant for Event Horizon Telescope (EHT) observations of Sgr A*. We find that the variability power spectrum is generically a red-noise process in both the temporal and spatial dimensions, with the peak in power occurring on the longest timescales and largest spatial scales. When both the time-averaged source structure and the spatially integrated light-curve variability are removed, the residual power spectrum exhibits a universal broken power-law behavior. On small spatial frequencies, the residual power spectrum rises as the square of the spatial frequency and is proportional to the variance in the centroid of emission. Beyond some peak in variability power, the residual power spectrum falls as that of the time-averaged source structure, which is similar across simulations; this behavior can be naturally explained if the variability arises from a multiplicative random field that has a steeper high-frequency power-law index than that of the time-averaged source structure. We briefly explore the ability of power spectral variability studies to constrain physical parameters relevant for the GRMHD simulations, which can be scaled to provide predictions for black holes in a range of systems in the optically thin regime. We present specific expectations for the behavior of the M87* and Sgr A* accretion flows as observed by the EHT

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