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MIT Open Access Articles

Mostrando recursos 181 - 200 de 27.634

  1. Variability in GRMHD Simulations of Sgr A* : Implications for EHT Closure Phase Observations

    Medeiros, Lia; Chan, Chi-kwan; Özel, Feryal; Psaltis, Dimitrios; Kim, Junhan; Marrone, Daniel P.; Sadowski, Aleksander B
    Closure phases along different baseline triangles carry a large amount of information regarding the structures of the images of black holes in interferometric observations with the Event Horizon Telescope. We use long time span, high cadence, GRMHD+radiative transfer models of Sgr A* to investigate the expected variability of closure phases in such observations. We find that, in general, closure phases along small baseline triangles show little variability, except in the cases when one of the triangle vertices crosses one of the small regions of low visibility amplitude. The closure phase variability increases with the size of the baseline triangle, as...

  2. Negative ion photoelectron spectroscopy of P[subscript 2]N[subscript 3]−: electron affinity and electronic structures of P[subscript 2]N[subscript 3]˙

    Hou, Gao-Lei; Chen, Bo; Hrovat, David A.; Borden, Weston Thatcher; Wang, Xue-Bin; Cummins, Christopher C; Transue, Wesley
    We report here a negative ion photoelectron spectroscopy (NIPES) and ab initio study of the recently synthesized planar aromatic inorganic ion P[subscript 2]N[subscript 3]−, to investigate the electronic structures of P[subscript 2]N[subscript 3]− and its neutral P[subscript 2]N[subscript 3]˙ radical. The adiabatic detachment energy of P[subscript 2]N[subscript 3]− (electron affinity of P[subscript 2]N[subscript 3]˙) was determined to be 3.765 ± 0.010 eV, indicating high stability for the P[subscript 2]N[subscript 3]− anion. Ab initio electronic structure calculations reveal the existence of five, low-lying, electronic states in the neutral P[subscript 2]N[subscript 3]˙ radical. Calculation of the Franck–Condon factors (FCFs) for each anion-to-neutral...

  3. Robust design of cognitive radio networks

    Lee, Hyang-Won; Modiano, Eytan H
    We develop a new framework for designing robust cognitive radio networks using white channels. Our framework assigns white channels to wireless links and provisions spare channel capacity that will used in the event of channel preemption. We characterize the optimal white channel assignment that minimizes the spare capacity while guaranteeing survivability against white channel preemptions.

  4. Scheduling multicast traffic with deadlines in wireless networks

    Kim, Kyu Seob; Li, Chih Ping; Modiano, Eytan H
    We consider the problem of transmitting multicast flows with hard deadlines over unreliable wireless channels. Every user in the network subscribes to several multicast flows, and requires a minimum throughput for each subscribed flow to meet the QoS constraints. The network controller schedules the transmissions of multicast traffic based on the instant feedback from the users. We characterize the multicast throughput region by analyzing its boundary points, each of which is the solution to a finite-horizon dynamic programming problem over an exponentially large state space. Using backward induction and interchange arguments, we show that the dynamic programming problems are solved...

  5. Computing Maximum Flow with Augmenting Electrical Flows

    Madry, Aleksander
    We present an Õ (m 7/10 U 1/7)-time algorithm for the maximum s-t flow problem (and the minimum s-t cut problem) in directed graphs with m arcs and largest integer capacity U. This matches the running time of the Õ (mU)10/7)- time algorithm of Madry [30] in the unit-capacity case, and improves over it, as well as over the Õ (m√n log U)-time algorithm of Lee and Sidford [25], whenever U is moderately large and the graph is sufficiently sparse. By well-known reductions, this also implies similar running time improvements for the maximum-cardinality bipartite b-matching problem. One of the advantages...

  6. Out-of-time-order correlation at a quantum phase transition

    Zhang, Pengfei; Fan, Ruihua; Zhai, Hui; Shen, Huitao
    Motivated by the recent studies of out-of-time-order correlation functions and the holographic duality, we propose the quantum critical point conjecture, which is stated as: For a many-body quantum system with a quantum phase transition, the Lyapunov exponent extracted from the out-of-time-order correlators will exhibit a maximum around the quantum critical region. We first demonstrate that the Lyapunov exponent is well defined in the one-dimensional Bose-Hubbard model with the help of the out-of-time-order correlation–Rényi-entropy theorem. We then support the conjecture by numerically computing the out-of-time-order correlators. We also compute the butterfly velocity, and propose an experiment protocol of measuring this correlator...

  7. Variable-Inverter-Rectifier-Transformer: A Hybrid Electronic and Magnetic Structure Enabling Adjustable High Step-Down Conversion Ratios

    Moon, Intae; Ranjram, Mike Kavian; Perreault, David J
    This paper proposes a hybrid electronic and magnetic structure that enables transformers with “fractional” and reconfigurable turns ratios (e.g. 12:0.5, 12:1, 12:2). This functionality is valuable in converters with wide operating voltage ranges and high step-up/down, as it offers a means to reduce copper loss within the transformer while also facilitating voltage doubling and quadrupling. We introduce the principle of operation of the structure and present models for its magnetic and electrical behaviour. An experimental prototype capable of accommodating a widely varying input (120-380[subscript Vdc]) and output (5, 9, 12V) validates the operating principle and modelling of the proposed structure...

  8. Oct1 and OCA-B are selectively required for CD4 memory T cell function

    Shakya, Arvind; Goren, Alon; Shalek, Alex; German, Cody N.; Snook, Jeremy; Kuchroo, Vijay K.; Yosef, Nir; Chan, Raymond C.; Williams, Matthew A.; Tantin, Dean; Regev, Aviv
    Epigenetic changes are crucial for the generation of immunological memory. Failure to generate or maintain these changes will result in poor memory responses. Similarly, augmenting or stabilizing the correct epigenetic states offers a potential method of enhancing memory. Yet the transcription factors that regulate these processes are poorly defined. We find that the transcription factor Oct1 and its cofactor OCA-B are selectively required for the in vivo generation of CD4⁺ memory T cells. More importantly, the memory cells that are formed do not respond properly to antigen reencounter. In vitro, both proteins are required to maintain a poised state at...

  9. Antiviral CD8⁺ T Cells Restricted by Human Leukocyte Antigen Class II Exist during Natural HIV Infection and Exhibit Clonal Expansion

    Ranasinghe, Srinika; Lamothe, Pedro A.; Soghoian, Damien Z.; Cole, Michael B.; Yosef, Nir; Jones, R. Brad; Donaghey, Faith; Nwonu, Chioma; Jani, Priya; Clayton, Gina M.; Crawford, Frances; White, Janice; Montoya, Alana; Power, Karen; Allen, Todd M.; Streeck, Hendrik; Kaufmann, Daniel E.; Picker, Louis J.; Kappler, John W.; Kazer, Samuel Weisgurt; Shalek, Alexander K; Walker, Bruce
    CD8⁺ T cell recognition of virus-infected cells is characteristically restricted by major histocompatibility complex (MHC) class I, although rare examples of MHC class II restriction have been reported in Cd4-deficient mice and a macaque SIV vaccine trial using a recombinant cytomegalovirus vector. Here, we demonstrate the presence of human leukocyte antigen (HLA) class II-restricted CD8⁺ T cell responses with antiviral properties in a small subset of HIV-infected individuals. In these individuals, T cell receptor β (TCRβ) analysis revealed that class II-restricted CD8⁺ T cells underwent clonal expansion and mediated killing of HIV-infected cells. In one case, these cells comprised 12% of circulating CD8⁺ T cells,...

  10. Initiation of Antiviral B Cell Immunity Relies on Innate Signals from Spatially Positioned NKT Cells

    Gaya, Mauro; Barral, Patricia; Burbage, Marianne; Aggarwal, Shweta; Montaner, Beatriz; Warren Navia, Andrew; Aid, Malika; Tsui, Carlson; Maldonado, Paula; Nair, Usha; Ghneim, Khader; Fallon, Padraic G.; Sekaly, Rafick-Pierre; Barouch, Dan H.; Bruckbauer, Andreas; Strid, Jessica; Batista, Facundo D.; Shalek, Alexander K
    B cells constitute an essential line of defense from pathogenic infections through the generation of class-switched antibody-secreting cells (ASCs) in germinal centers. Although this process is known to be regulated by follicular helper T (TfH) cells, the mechanism by which B cells initially seed germinal center reactions remains elusive. We found that NKT cells, a population of innate-like T lymphocytes, are critical for the induction of B cell immunity upon viral infection. The positioning of NKT cells at the interfollicular areas of lymph nodes facilitates both their direct priming by resident macrophages and the localized delivery of innate signals to...

  11. Two-photon imaging in mice shows striosomes and matrix have overlapping but differential reinforcement-related responses

    Bloem, Bernard; Huda, Rafiq; Sur, Mriganka; Graybiel, Ann M
    Striosomes were discovered several decades ago as neurochemically identified zones in the striatum, yet technical hurdles have hampered the study of the functions of these striatal compartments. Here we used 2-photon calcium imaging in neuronal birthdate-labeled Mash1- CreER;Ai14 mice to image simultaneously the activity of striosomal and matrix neurons as mice performed an auditory conditioning task. With this method, we identified circumscribed zones of tdTomato-labeled neuropil that correspond to striosomes as verified immunohistochemically. Neurons in both striosomes and matrix responded to reward-predicting cues and were active during or after consummatory licking. However, we found quantitative differences in response strength: striosomal...

  12. Small molecule inhibition of apicomplexan FtsH1 disrupts plastid biogenesis in human pathogens

    Amberg-Johnson, Katherine; Ganesan, Suresh M; Lorenzi, Hernan A; Niles, Jacquin C; Yeh, Ellen; Hari, Sanjay B; Sauer, Robert T
    The malaria parasite Plasmodium falciparum and related apicomplexan pathogens contain an essential plastid organelle, the apicoplast, which is a key anti-parasitic target. Derived from secondary endosymbiosis, the apicoplast depends on novel, but largely cryptic, mechanisms for protein/lipid import and organelle inheritance during parasite replication. These critical biogenesis pathways present untapped opportunities to discover new parasite-specific drug targets. We used an innovative screen to identify actinonin as having a novel mechanism-of-action inhibiting apicoplast biogenesis. Resistant mutation, chemical-genetic interaction, and biochemical inhibition demonstrate that the unexpected target of actinonin in P. falciparum and Toxoplasma gondii is FtsH1, a homolog of a bacterial...

  13. Macrophage dysfunction initiates colitis during weaning of infant mice lacking the interleukin-10 receptor

    Redhu, Naresh S; Conaway, Evan A; Shouval, Dror S; Tsou, Amy; Goettel, Jeremy A; Biswas, Amlan; Field, Michael; Muller, Werner; Bleich, Andre; Li, Ning; Gerber, Georg K; Bry, Lynn; Snapper, Scott B; Horwitz, Bruce H; Bakthavatchalu, Vasudevan; Wang, Chuanwu; Fox, James G
    Infants with defects in the interleukin 10 receptor (IL10R) develop very early onset inflammatory bowel disease. Whether IL10R regulates lamina propria macrophage function during infant development in mice and whether macrophage-intrinsic IL10R signaling is required to prevent colitis in infancy is unknown. Here we show that although signs of colitis are absent in IL10R-deficient mice during the first two weeks of life, intestinal inflammation and macrophage dysfunction begin during the third week of life, concomitant with weaning and accompanying diversification of the intestinal microbiota. However, IL10R did not directly regulate the microbial ecology during infant development. Interestingly, macrophage depletion with...

  14. Erythropoietin signaling regulates heme biosynthesis

    Chung, Jacky; Wittig, Johannes G; Ghamari, Alireza; Maeda, Manami; Dailey, Tamara A; Bergonia, Hector; Kafina, Martin D; Coughlin, Emma E; Minogue, Catherine E; Hebert, Alexander S; Li, Liangtao; Kaplan, Jerry; Bauer, Daniel E; Orkin, Stuart H; Cantor, Alan B; Maeda, Takahiro; Phillips, John D; Coon, Joshua J; Pagliarini, David J; Dailey, Harry A; Paw, Barry H; Lodish, Harvey F
    Heme is required for survival of all cells, and in most eukaryotes, is produced through a series of eight enzymatic reactions. Although heme production is critical for many cellular processes, how it is coupled to cellular differentiation is unknown. Here, using zebrafish, murine, and human models, we show that erythropoietin (EPO) signaling, together with the GATA1 transcriptional target, AKAP10, regulates heme biosynthesis during erythropoiesis at the outer mitochondrial membrane. This integrated pathway culminates with the direct phosphorylation of the crucial heme biosynthetic enzyme, ferrochelatase (FECH) by protein kinase A (PKA). Biochemical, pharmacological, and genetic inhibition of this signaling pathway result...

  15. Epistatic mutations in PUMA BH3 drive an alternate binding mode to potently and selectively inhibit anti-apoptotic Bfl-1

    Ryan, Jeremy A; Letai, Anthony; Jenson, Justin Michael; Grant, Robert A; Keating, Amy E
    Overexpression of anti-apoptotic Bcl-2 family proteins contributes to cancer progression and confers resistance to chemotherapy. Small molecules that target Bcl-2 are used in the clinic to treat leukemia, but tight and selective inhibitors are not available for Bcl-2 paralog Bfl-1. Guided by computational analysis, we designed variants of the native BH3 motif PUMA that are > 150-fold selective for Bfl-1 binding. The designed peptides potently trigger disruption of the mitochondrial outer membrane in cells dependent on Bfl-1, but not in cells dependent on other anti-apoptotic homologs. High-resolution crystal structures show that designed peptide FS2 binds Bfl-1 in a shifted geometry,...

  16. High-Affinity Manganese Coordination by Human Calprotectin Is Calcium-Dependent and Requires the Histidine-Rich Site Formed at the Dimer Interface

    Hayden, Joshua A.; Brophy, Megan Brunjes; Cunden, Lisa Stephanie; Nolan, Elizabeth Marie
    Calprotectin (CP) is a transition metal-chelating antimicrobial protein of the calcium-binding S100 family that is produced and released by neutrophils. It inhibits the growth of various pathogenic microorganisms by sequestering the transition metal ions manganese and zinc. In this work, we investigate the manganese-binding properties of CP. We demonstrate that the unusual His₄ motif (site 2) formed at the S100A8/S100A9 dimer interface is the site of high-affinity Mn(II) coordination. We identify a low-temperature Mn(II) spectroscopic signal for this site consistent with an octahedral Mn(II) coordination sphere with simulated zero-field splitting parameters D = 270 MHz and E/D = 0.30 (E...

  17. Seq-Well: portable, low-cost RNA sequencing of single cells at high throughput

    Bryson, Bryan D; Butler, Andrew; Satija, Rahul; Fortune, Sarah; Love, J Christopher; Gierahn, Todd Michael; Wadsworth, Marc Havens; Hughes, Travis K.; Shalek, Alexander K
    Single-cell rna-seq can precisely resolve cellular states, but applying this method to low-input samples is challenging. here, we present seq-Well, a portable, low-cost platform for massively parallel single-cell rna-seq. barcoded mrna capture beads and single cells are sealed in an array of subnanoliter wells using a semipermeable membrane, enabling effcient cell lysis and transcript capture. We use seq-Well to profle thousands of primary human macrophages exposed to Mycobacterium tuberculosis.

  18. Single-cell analyses to tailor treatments

    Benson, Mikael; Shalek, Alexander K
    Single-cell RNA-seq could play a key role in personalized medicine by facilitating characterization of cells, pathways, and genes associated with human diseases such as cancer.

  19. The Human Cell Atlas

    Teichmann, Sarah A; Amit, Ido; Benoist, Christophe; Birney, Ewan; Bodenmiller, Bernd; Campbell, Peter; Carninci, Piero; Clatworthy, Menna; Clevers, Hans; Deplancke, Bart; Dunham, Ian; Eberwine, James; Eils, Roland; Enard, Wolfgang; Farmer, Andrew; Fugger, Lars; Göttgens, Berthold; Hacohen, Nir; Haniffa, Muzlifah; Hemberg, Martin; Kim, Seung; Klenerman, Paul; Kriegstein, Arnold; Lein, Ed; Linnarsson, Sten; Lundberg, Emma; Lundeberg, Joakim; Majumder, Partha; Marioni, John C; Merad, Miriam; Mhlanga, Musa; Nawijn, Martijn; Netea, Mihai; Nolan, Garry; Pe'er, Dana; Phillipakis, Anthony; Ponting, Chris P; Quake, Stephen; Reik, Wolf; Rozenblatt-Rosen, Orit; Sanes, Joshua; Satija, Rahul; Schumacher, Ton N; Shalek, Alex; Shapiro, Ehud; Sharma, Padmanee; Shin, Jay W; Stegle, Oliver; Stratton, Michael; Stubbington, Michael J T; Theis, Fabian J; Uhlen, Matthias; van Oudenaarden, Alexander; Wagner, Allon; Watt, Fiona; Weissman, Jonathan; Wold, Barbara; Xavier, Ramnik; Yosef, Nir; Regev, Aviv; Lander, Eric Steven
    The recent advent of methods for high-throughput single-cell molecular profiling has catalyzed a growing sense in the scientific community that the time is ripe to complete the 150-year-old effort to identify all cell types in the human body. The Human Cell Atlas Project is an international collaborative effort that aims to define all human cell types in terms of distinctive molecular profiles (such as gene expression profiles) and to connect this information with classical cellular descriptions (such as location and morphology). An open comprehensive reference map of the molecular state of cells in healthy human tissues would propel the systematic...

  20. Blood-brain-barrier spheroids as an in vitro screening platform for brain-penetrating agents

    Calligaris, David; Hornburg, Kalvis; Chiocca, E. Antonio; Agar, Nathalie Y. R.; Lawler, Sean E.; Cho, Choi-Fong; Wolfe, Justin; Fadzen, Colin M.; Pentelute, Bradley L.
    Culture-based blood-brain barrier (BBB) models are crucial tools to enable rapid screening of brain-penetrating drugs. However, reproducibility of in vitro barrier properties and permeability remain as major challenges. Here, we report that self-Assembling multicellular BBB spheroids display reproducible BBB features and functions. The spheroid core is comprised mainly of astrocytes, while brain endothelial cells and pericytes encase the surface, acting as a barrier that regulates transport of molecules. The spheroid surface exhibits high expression of tight junction proteins, VEGF-dependent permeability, efflux pump activity and receptor-mediated transcytosis of angiopep-2. In contrast, the transwell co-culture system displays comparatively low levels of BBB...

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