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MIT Open Access Articles
Mostrando recursos 1 - 20 de 13,121
Probing nanoparticle translocation across the permeable endothelium in experimental atherosclerosis - Kim, YongTae; Lobatto, Mark E.; Kawahara, Tomohiro; Lee Chung, Bomy; Mieszawska, Aneta J.; Sanchez-Gaytan, Brenda L.; Fay, Francois; Senders, Max L.; Calcagno, Claudia; Becraft, Jacob Robert; Tun Saung, May; Gordon, Ronald E.; Stroes, Erik S. G.; Ma, Mingming; Farokhzad, Omid C.; Fayad, Zahi A.; Mulder, Willem J. M.; Langer, Robert
Therapeutic and diagnostic nanomaterials are being intensely studied for several diseases, including cancer and atherosclerosis. However, the exact mechanism by which nanomedicines accumulate at targeted sites remains a topic of investigation, especially in the context of atherosclerotic disease. Models to accurately predict transvascular permeation of nanomedicines are needed to aid in design optimization. Here we show that an endothelialized microchip with controllable permeability can be used to probe nanoparticle translocation across an endothelial cell layer. To validate our in vitro model, we studied nanoparticle translocation in an in vivo rabbit model of atherosclerosis using a variety of preclinical and clinical...
Morphological optimization for access to dual oxidants in biofilms - Kempes, Christopher P.; Okegbe, Chinweike; Mears-Clarke, Zwoisaint; Dietrich, Lars E. P.; Follows, Michael J.
A major theme driving research in biology is the relationship between form and function. In particular, a longstanding goal has been to understand how the evolution of multicellularity conferred fitness advantages. Here we show that biofilms of the bacterium Pseudomonas aeruginosa produce structures that maximize cellular reproduction. Specifically, we develop a mathematical model of resource availability and metabolic response within colony features. This analysis accurately predicts the measured distribution of two types of electron acceptors: oxygen, which is available from the atmosphere, and phenazines, redox-active antibiotics produced by the bacterium. Using this model, we demonstrate that the geometry of colony...
Reaction-based fluorescent sensor for investigating mobile Zn[superscript 2+] in mitochondria of healthy versus cancerous prostate cells - Chyan, Wen; Zhang, Daniel Y.; Lippard, Stephen J.; Radford, Robert J.
Chelatable, mobile forms of divalent zinc, Zn(II), play essential signaling roles in mammalian biology. A complex network of zinc import and transport proteins has evolved to control zinc concentration and distribution on a subcellular level. Understanding the action of mobile zinc requires tools that can detect changes in Zn(II) concentrations at discrete cellular locales. We present here a zinc-responsive, reaction-based, targetable probe based on the diacetyled form of Zinpyr-1. The compound, (6-amidoethyl)triphenylphosphonium Zinpyr-1 diacetate (DA-ZP1-TPP), is essentially nonfluorescent in the metal-free state; however, exposure to Zn(II) triggers metal-mediated hydrolysis of the acetyl groups to afford a large, rapid, and zinc-induced...
Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells - Chen, Qingfeng; Amaladoss, Anburaj; Ye, Weijian; Liu, Min; Dummler, Sara; Kong, Fang; Wong, Lan Hiong; Loo, Hooi Linn; Loh, Eva; Tan, Shu Qi; Tan, Thiam Chye; Chang, Kenneth T. E.; Dao, Ming; Suresh, Subra; Preiser, Peter R.; Chen, Jianzhu
Immunodeficient mouse–human chimeras provide a powerful approach to study host-specific pathogens, such as Plasmodium falciparum that causes human malaria. Supplementation of immunodeficient mice with human RBCs supports infection by human Plasmodium parasites, but these mice lack the human immune system. By combining human RBC supplementation and humanized mice that are optimized for human immune cell reconstitution, we have developed RBC-supplemented, immune cell-optimized humanized (RICH) mice that support multiple cycles of P. falciparum infection. Depletion of human natural killer (NK) cells, but not macrophages, in RICH mice results in a significant increase in parasitemia. Further studies in vitro show that NK...
Real-time, high-resolution study of nanocrystallization and fatigue cracking in a cyclically strained metallic glass - Wang, Cheng-Cai; Mao, Yun-Wei; Shan, Zhi-Wei; Dao, Ming; Li, Ju; Sun, Jun; Ma, Evan; Suresh, Subra
Metallic glasses (MGs) exhibit greater elastic limit and stronger resistance to plastic deformation than their crystalline metal counterparts. Their capacity to withstand plastic straining is further enhanced at submicrometer length scales. For a range of microelectromechanical applications, the resistance of MGs to damage and cracking from thermal and mechanical stress or strain cycling under partial or complete constraint is of considerable scientific and technological interest. However, to our knowledge, no real-time, high-resolution transmission electron microscopy observations are available of crystallization, damage, and failure from the controlled imposition of cyclic strains or displacements in any metallic glass. Here we present the...
Comprehensive analysis of imprinted genes in maize reveals allelic variation for imprinting and limited conservation with other species - Waters, Amanda J.; Bilinski, Paul; Eichten, Steven R.; Vaughn, Matthew W.; Ross-Ibarra, Jeffrey; Gehring, Mary; Springer, Nathan M.
In plants, a subset of genes exhibit imprinting in endosperm tissue such that expression is primarily from the maternal or paternal allele. Imprinting may arise as a consequence of mechanisms for silencing of transposons during reproduction, and in some cases imprinted expression of particular genes may provide a selective advantage such that it is conserved across species. Separate mechanisms for the origin of imprinted expression patterns and maintenance of these patterns may result in substantial variation in the targets of imprinting in different species. Here we present deep sequencing of RNAs isolated from reciprocal crosses of four diverse maize genotypes,...
Regulation of glutamate receptor internalization by the spine cytoskeleton is mediated by its PKA-dependent association with CPG2 - Loebrich, Sven; Djukic, Biljana; Tong, Zachary J.; Cottrell, Jeffrey R.; Turrigiano, Gina G.; Nedivi, Elly
A key neuronal mechanism for adjusting excitatory synaptic strength is clathrin-mediated endocytosis of postsynaptic glutamate receptors (GluRs). The actin cytoskeleton is critical for clathrin-mediated endocytosis, yet we lack a mechanistic understanding of its interaction with the endocytic process and how it may be regulated. Here we show that F-actin in dendritic spines physically binds the synaptic nuclear envelope 1 gene product candidate plasticity gene 2 (CPG2) in a PKA-dependent manner, and that this association is required for synaptic GluR internalization. Mutating two PKA sites on CPG2 disrupts its cytoskeletal association, attenuating GluR endocytosis and affecting the efficacy of synaptic transmission...
Highly expressed loci are vulnerable to misleading ChIP localization of multiple unrelated proteins - Teytelman, Leonid; Thurtle, Deborah M.; Rine, Jasper; van Oudenaarden, Alexander
Chromatin immunoprecipitation (ChIP) is the gold-standard technique for localizing nuclear proteins in the genome. We used ChIP, in combination with deep sequencing (Seq), to study the genome-wide distribution of the Silent information regulator (Sir) complex in Saccharomyces cerevisiae. We analyzed ChIP-Seq peaks of the Sir2, Sir3, and Sir4 silencing proteins and discovered 238 unexpected euchromatic loci that exhibited enrichment of all three. Surprisingly, published ChIP-Seq datasets for the Ste12 transcription factor and the centromeric Cse4 protein indicated that these proteins were also enriched in the same euchromatic regions with the high Sir protein levels. The 238 loci, termed ”hyper-ChIPable“, were...
MRI of the human brain at 130 microtesla - Inglis, Ben; Buckenmaier, Kai; SanGiorgio, Paul; Pedersen, Anders F.; Nichols, Matthew Alan; Clarke, John
We present in vivo images of the human brain acquired with an ultralow field MRI (ULFMRI) system operating at a magnetic field B[subscript 0] ∼ 130 μT. The system features prepolarization of the proton spins at B[subscript p] ∼ 80 mT and detection of the NMR signals with a superconducting, second-derivative gradiometer inductively coupled to a superconducting quantum interference device (SQUID). We report measurements of the longitudinal relaxation time T[subscript 1] of brain tissue, blood, and scalp fat at B[subscript 0] and B[subscript p], and cerebrospinal fluid at B[subscript 0]. We use these T[subscript 1] values to construct inversion recovery...
Simulation as an engine of physical scene understanding - Battaglia, Peter W.; Hamrick, Jessica B.; Tenenbaum, Joshua B.
In a glance, we can perceive whether a stack of dishes will topple, a branch will support a child’s weight, a grocery bag is poorly packed and liable to tear or crush its contents, or a tool is firmly attached to a table or free to be lifted. Such rapid physical inferences are central to how people interact with the world and with each other, yet their computational underpinnings are poorly understood. We propose a model based on an “intuitive physics engine,” a cognitive mechanism similar to computer engines that simulate rich physics in video games and graphics, but that...
Improved tumor oxygenation and survival in glioblastoma patients who show increased blood perfusion after cediranib and chemoradiation - Batchelor, Tracy T.; Gerstner, Elizabeth R.; Emblem, Kyrre E.; Duda, Dan G.; Kalpathy-Cramer, Jayashree; Snuderl, Matija; Ancukiewicz, Marek; Polaskova, Pavlina; Pinho, Marco C.; Jennings, Dominique; Plotkin, Scott R.; Chi, Andrew S.; Eichler, April F.; Dietrich, Jorg; Hochberg, Fred H.; Lu-Emerson, Christine; Iafrate, A. John; Ivy, S. Percy; Rosen, Bruce R.; Loeffler, Jay S.; Wen, Patrick Y.; Sorensen, A. Greg; Jain, Rakesh K.
Antiangiogenic therapy has shown clear activity and improved survival benefit for certain tumor types. However, an incomplete understanding of the mechanisms of action of antiangiogenic agents has hindered optimization and broader application of this new therapeutic modality. In particular, the impact of antiangiogenic therapy on tumor blood flow and oxygenation status (i.e., the role of vessel pruning versus normalization) remains controversial. This controversy has become critical as multiple phase III trials of anti-VEGF agents combined with cytotoxics failed to show overall survival benefit in newly diagnosed glioblastoma (nGBM) patients and several other cancers. Here, we shed light on mechanisms of...
Grammatical morphology as a source of early number word meanings - Almoammer, Alhanouf; Sullivan, Jessica; Donlan, Chris; Marusic, Franc; Zaucer, Rok; O'Donnell, Timothy John; Barner, David
How does cross-linguistic variation in linguistic structure affect children’s acquisition of early number word meanings? We tested this question by investigating number word learning in two unrelated languages that feature a tripartite singular-dual-plural distinction: Slovenian and Saudi Arabic. We found that learning dual morphology affects children’s acquisition of the number word two in both languages, relative to English. Children who knew the meaning of two were surprisingly frequent in the dual languages, relative to English. Furthermore, Slovenian children were faster to learn two than children learning English, despite being less-competent counters. Finally, in both Slovenian and Saudi Arabic, comprehension of...
Size homeostasis in adherent cells studied by synthetic phase microscopy - Sung, Yongjin; Tzur, Amit; Oh, Seungeun; Choi, Wonshik; Li, Victor; Dasari, Ramachandra Rao; Yaqoob, Zahid; Kirschner, Marc W.
The coupling of the rate of cell growth to the rate of cell division determines cell size, a defining characteristic that is central to cell function and, ultimately, to tissue architecture. The physiology of size homeostasis has fascinated generations of biologists, but the mechanism, challenged by experimental limitations, remains largely unknown. In this paper, we propose a unique optical method that can measure the dry mass of thick live cells as accurately as that for thin cells with high computational efficiency. With this technique, we quantify, with unprecedented accuracy, the asymmetry of division in lymphoblasts and epithelial cells. We can...
Direct transfer of graphene onto flexible substrates - Araujo, P. T.; Martins, Luiz G. P.; Song, Yi; Zeng, Tingying (Helen); Dresselhaus, Mildred; Kong, Jing; Araujo, Paulo T.
In this paper we explore the direct transfer via lamination of chemical vapor deposition graphene onto different flexible substrates. The transfer method investigated here is fast, simple, and does not require an intermediate transfer membrane, such as polymethylmethacrylate, which needs to be removed afterward. Various substrates of general interest in research and industry were studied in this work, including polytetrafluoroethylene filter membranes, PVC, cellulose nitrate/cellulose acetate filter membranes, polycarbonate, paraffin, polyethylene terephthalate, paper, and cloth. By comparing the properties of these substrates, two critical factors to ensure a successful transfer on bare substrates were identified: the substrate’s hydrophobicity and good...
Genetic topography of brain morphology - Chen, Chi-Hua; Fiecas, Mark; Gutierrez, E. D.; Panizzon, Matthew S.; Eyler, Lisa T.; Vuoksimaa, Eero; Thompson, Wesley K.; Fennema-Notestine, Christine; Hagler, Donald J., Jr.; Jernigan, Terry L.; Neale, Michael C.; Franz, Carol E.; Lyons, Michael J.; Fischl, Bruce; Tsuang, Ming T.; Dale, Anders M.; Kremen, William S.
Animal data show that cortical development is initially patterned by genetic gradients largely along three orthogonal axes. We previously reported differences in genetic influences on cortical surface area along an anterior-posterior axis using neuroimaging data of adult human twins. Here, we demonstrate differences in genetic influences on cortical thickness along a dorsal-ventral axis in the same cohort. The phenomenon of orthogonal gradations in cortical organization evident in different structural and functional properties may originate from genetic gradients. Another emerging theme of cortical patterning is that patterns of genetic influences recapitulate the spatial topography of the cortex within hemispheres. The genetic...
MicroRNA-134 activity in somatostatin interneurons regulates H-Ras localization by repressing the palmitoylation enzyme, DHHC9 - Chai, Sunghee; Cambronne, Xiaolu A.; Eichhorn, Stephen William; Goodman, Richard H.
MicroRNA-134 (miR-134) serves as a widely accepted model for microRNA function in synaptic plasticity. In this model, synaptic activity stimulates miR-134 expression, which then regulates dendrite growth and spine formation. By using a ratiometric microRNA sensor, we found, unexpectedly, that miR-134 activity in cortical neurons was restricted to interneurons. Using an assay designed to trap microRNA–mRNA complexes, we determined that miR-134 interacted directly with the mRNA encoding the palmitoylation enzyme, DHHC9. This enzyme is known to palmitoylate H-Ras, a modification required for proper membrane trafficking. Treatment with bicuculline, a GABA[subscript A] receptor antagonist, decreased DHHC9 expression in somatostatin-positive interneurons and...
Comprehensive experimental fitness landscape and evolutionary network for small RNA - Jimenez Zarco, Jose I.; Xulvi-Brunet, Ramon; Campbell, Gregory W.; Turk-MacLeod, Rebecca; Chen, Irene A.
The origin of life is believed to have progressed through an RNA world, in which RNA acted as both genetic material and functional molecules. The structure of the evolutionary fitness landscape of RNA would determine natural selection for the first functional sequences. Fitness landscapes are the subject of much speculation, but their structure is essentially unknown. Here we describe a comprehensive map of a fitness landscape, exploring nearly all of sequence space, for short RNAs surviving selection in vitro. With the exception of a small evolutionary network, we find that fitness peaks are largely isolated from one another, highlighting the...
Multiparametric approach for the evaluation of lipid nanoparticles for siRNA delivery - Alabi, Christopher A.; Love, Kevin T.; Sahay, Gaurav; Yin, Hao; Luly, Kathryn M.; Langer, Robert; Anderson, Daniel Griffith
Nanoparticle-mediated siRNA delivery is a complex process that requires transport across numerous extracellular and intracellular barriers. As such, the development of nanoparticles for efficient delivery would benefit from an understanding of how parameters associated with these barriers relate to the physicochemical properties of nanoparticles. Here, we use a multiparametric approach for the evaluation of lipid nanoparticles (LNPs) to identify relationships between structure, biological function, and biological activity. Our results indicate that evaluation of multiple parameters associated with barriers to delivery such as siRNA entrapment, pK[subscript a], LNP stability, and cell uptake as a collective may serve as a useful prescreening...
Ken Wilson: A scientific appreciation - Wilczek, Frank
This brief retrospective is an overview and celebration of Kenneth Wilson’s profound contributions to science, meant to be accessible to a broad scientific audience. Wilson’s lecture on receipt of the 1982 Nobel Prize gives a more technical and detailed description of his central work, including historical perspective and extensive references.
Human and natural influences on the changing thermal structure of the atmosphere - Santer, Benjamin D.; Painter, Jeffrey F.; Bonfils, Celine; Mears, Carl A.; Solomon, Susan; Wigley, Tom M. L.; Gleckler, Peter J.; Schmidt, Gavin A.; Doutriaux, Charles; Gillett, Nathan P.; Taylor, Karl E.; Thorne, Peter W.; Wentz, Frank J.
Since the late 1970s, satellite-based instruments have monitored global changes in atmospheric temperature. These measurements reveal multidecadal tropospheric warming and stratospheric cooling, punctuated by short-term volcanic signals of reverse sign. Similar long- and short-term temperature signals occur in model simulations driven by human-caused changes in atmospheric composition and natural variations in volcanic aerosols. Most previous comparisons of modeled and observed atmospheric temperature changes have used results from individual models and individual observational records. In contrast, we rely on a large multimodel archive and multiple observational datasets. We show that a human-caused latitude/altitude pattern of atmospheric temperature change can be identified...