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DSpace at MIT (83,054 recursos)
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MIT Open Access Articles

Mostrando recursos 1 - 20 de 16,347

1. Peptide Ligands for Pro-survival Protein Bfl-1 from Computationally Guided Library Screening - Dutta, Sanjib; Chen, T. Scott; Keating, Amy E.
Pro-survival members of the Bcl-2 protein family inhibit cell death by binding short helical BH3 motifs in pro-apoptotic proteins. Mammalian pro-survival proteins Bcl-x[subscript L], Bcl-2, Bcl-w, Mcl-1, and Bfl-1 bind with varying affinities and specificities to native BH3 motifs, engineered peptides, and small molecules. Biophysical studies have determined interaction patterns for these proteins, particularly for the most-studied family members Bcl-x[subscript L] and Mcl-1. Bfl-1 is a pro-survival protein implicated in preventing apoptosis in leukemia, lymphoma, and melanoma. Although Bfl-1 is a promising therapeutic target, relatively little is known about its binding preferences. We explored the binding of Bfl-1 to BH3-like...

2. Redox signaling via the molecular chaperone BiP protects cells against endoplasmic reticulum-derived oxidative stress - Wang, Jie; Pareja, Kristeen A; Sevier, Carolyn S; Kaiser, Chris
Oxidative protein folding in the endoplasmic reticulum (ER) has emerged as a potentially significant source of cellular reactive oxygen species (ROS). Recent studies suggest that levels of ROS generated as a byproduct of oxidative folding rival those produced by mitochondrial respiration. Mechanisms that protect cells against oxidant accumulation within the ER have begun to be elucidated yet many questions still remain regarding how cells prevent oxidant-induced damage from ER folding events. Here we report a new role for a central well-characterized player in ER homeostasis as a direct sensor of ER redox imbalance. Specifically we show that a conserved cysteine...

3. Mapping the Cellular Response to Small Molecules Using Chemogenomic Fitness Signatures - Spear, Eric D.; Kaiser, Chris
Genome-wide characterization of the in vivo cellular response to perturbation is fundamental to understanding how cells survive stress. Identifying the proteins and pathways perturbed by small molecules affects biology and medicine by revealing the mechanisms of drug action. We used a yeast chemogenomics platform that quantifies the requirement for each gene for resistance to a compound in vivo to profile 3250 small molecules in a systematic and unbiased manner. We identified 317 compounds that specifically perturb the function of 121 genes and characterized the mechanism of specific compounds. Global analysis revealed that the cellular response to small molecules is limited...

4. Systematic Identification of Culture Conditions for Induction and Maintenance of Naive Human Pluripotency - Theunissen, Thorold W.; Powell, Benjamin E.; Wang, Haoyi; Mitalipova, Maya; Faddah, Dina A.; Reddy, Jessica; Fan, Zi Peng; Maetzel, Dorothea; Ganz, Kibibi; Shi, Linyu; Lungjangwa, Tenzin; Imsoonthornruksa, Sumeth; Stelzer, Yonatan; Rangarajan, Sudharshan; D’Alessio, Ana; Zhang, Jianming; Gao, Qing; Dawlaty, Meelad M.; Young, Richard A.; Gray, Nathanael S.; Jaenisch, Rudolf; Faddah, Dina A.; Young, Richard A.
Embryonic stem cells (ESCs) of mice and humans have distinct molecular and biological characteristics, raising the question of whether an earlier, “naive” state of pluripotency may exist in humans. Here we took a systematic approach to identify small molecules that support self-renewal of naive human ESCs based on maintenance of endogenous OCT4 distal enhancer activity, a molecular signature of ground state pluripotency. Iterative chemical screening identified a combination of five kinase inhibitors that induces and maintains OCT4 distal enhancer activity when applied directly to conventional human ESCs. These inhibitors generate human pluripotent cells in which transcription factors associated with the...

5. Transcriptional profiling of cells sorted by transcript abundance - Klemm, Sandy; Semrau, Stefan; Wiebrands, Kay; Mooijman, Dylan; Jaenisch, Rudolf; van Oudenaarden, Alexander; Faddah, Dina A.
We have developed a quantitative technique for sorting cells on the basis of endogenous RNA abundance, with a molecular resolution of 10–20 transcripts. We demonstrate efficient and unbiased RNA extraction from transcriptionally sorted cells and report a high-fidelity transcriptome measurement of mouse induced pluripotent stem cells (iPSCs) isolated from a heterogeneous reprogramming culture. This method is broadly applicable to profiling transcriptionally distinct cellular states without requiring antibodies or transgenic fluorescent proteins.

6. Genome-wide binding of the CRISPR endonuclease Cas9 in mammalian cells - Wu, Xuebing; Cheng, Albert W; Chen, Sidi; Jaenisch, Rudolf; Zhang, Feng; Chiu, Anthony Chun-yin; Sharp, Phillip A.; Scott, David Arthur; Hsu, Patrick; Trevino, Alexandro E.; Konermann, Silvana M.; Kriz, Andrea J.; Dadon, Daniel Benjamin
Bacterial type II CRISPR-Cas9 systems have been widely adapted for RNA-guided genome editing and transcription regulation in eukaryotic cells, yet their in vivo target specificity is poorly understood. Here we mapped genome-wide binding sites of a catalytically inactive Cas9 (dCas9) from Streptococcus pyogenes loaded with single guide RNAs (sgRNAs) in mouse embryonic stem cells (mESCs). Each of the four sgRNAs we tested targets dCas9 to between tens and thousands of genomic sites, frequently characterized by a 5-nucleotide seed region in the sgRNA and an NGG protospacer adjacent motif (PAM). Chromatin inaccessibility decreases dCas9 binding to other sites with matching seed...

7. Antigen-specific B-cell receptor sensitizes B cells to infection by influenza virus - Dougan, Stephanie K.; Ashour, Joseph; Karssemeijer, Roos A.; Popp, Maximilian W.; Avalos, Ana M.; Barisa, Marta; Altenburg, Arwen F.; Ingram, Jessica R.; Cragnolini, Juan Jose; Guo, Chunguang; Alt, Frederick W.; Jaenisch, Rudolf; Ploegh, Hidde
Influenza A virus-specific B lymphocytes and the antibodies they produce protect against infection. However, the outcome of interactions between an influenza haemagglutinin-specific B cell via its receptor (BCR) and virus is unclear. Through somatic cell nuclear transfer we generated mice that harbour B cells with a BCR specific for the haemagglutinin of influenza A/WSN/33 virus (FluBI mice). Their B cells secrete an immunoglobulin gamma 2b that neutralizes infectious virus. Whereas B cells from FluBI and control mice bind equivalent amounts of virus through interaction of haemagglutinin with surface-disposed sialic acids, the A/WSN/33 virus infects only the haemagglutinin-specific B cells. Mere...

8. Basic Features of a Cell Electroporation Model: Illustrative Behavior for Two Very Different Pulses - Son, Reuben S.; Smith, Kyle C.; Gowrishankar, Thiruvallur R.; Vernier, P. Thomas; Weaver, James C.
Science increasingly involves complex modeling. Here we describe a model for cell electroporation in which membrane properties are dynamically modified by poration. Spatial scales range from cell membrane thickness (5 nm) to a typical mammalian cell radius (10 μ m), and can be used with idealized and experimental pulse waveforms. The model consists of traditional passive components and additional active components representing nonequilibrium processes. Model responses include measurable quantities: transmembrane voltage, membrane electrical conductance, and solute transport rates and amounts for the representative “long” and “short” pulses. The long pulse—1.5 kV/cm, 100 μ s—evolves two pore subpopulations with a valley...

9. Autophagy Is Required for Glucose Homeostasis and Lung Tumor Maintenance - Karsli-Uzunbas, Gizem; Guo, Jessie Yanxiang; Price, Sandy; Teng, Xin; Laddha, Saurabh V.; Khor, Sinan; Kalaany, Nada Y.; Jacks, Tyler E.; Chan, Chang S.; Rabinowitz, Joshua D.; White, Eileen
Macroautophagy (autophagy hereafter) recycles intracellular components to sustain mitochondrial metabolism that promotes the growth, stress tolerance, and malignancy of lung cancers, suggesting that autophagy inhibition may have antitumor activity. To assess the functional significance of autophagy in both normal and tumor tissue, we conditionally deleted the essential autophagy gene, autophagy related 7 (Atg7), throughout adult mice. Here, we report that systemic ATG7 ablation caused susceptibility to infection and neurodegeneration that limited survival to 2 to 3 months. Moreover, upon fasting, autophagy-deficient mice suffered fatal hypoglycemia. Prior autophagy ablation did not alter the efficiency of non–small cell lung cancer (NSCLC) initiation...

10. Pareto-optimal phylogenetic tree reconciliation - Libeskind-Hadas, Ran; Wu, Yi-Chieh; Bansal, Mukul S.; Kellis, Manolis; Wu, Yi-Chieh
Motivation: Phylogenetic tree reconciliation is a widely used method for reconstructing the evolutionary histories of gene families and species, hosts and parasites and other dependent pairs of entities. Reconciliation is typically performed using maximum parsimony, in which each evolutionary event type is assigned a cost and the objective is to find a reconciliation of minimum total cost. It is generally understood that reconciliations are sensitive to event costs, but little is understood about the relationship between event costs and solutions. Moreover, choosing appropriate event costs is a notoriously difficult problem. Results: We address this problem by giving an efficient algorithm for...

11. Coherent Exciton Dynamics in Supramolecular Light-Harvesting Nanotubes Revealed by Ultrafast Quantum Process Tomography - Arias, Dylan H.; Eisele, Dorthe M.; Krich, Jacob J.; Bawendi, Moungi G.; Yuen, Joel; Steiner, Colby Peyton; Nelson, Keith Adam; Aspuru-Guzik, Alan
Long-lived exciton coherences have been recently observed in photosynthetic complexes via ultrafast spectroscopy, opening exciting possibilities for the study and design of coherent exciton transport. Yet, ambiguity in the spectroscopic signals has led to arguments against interpreting them in terms of exciton dynamics, demanding more stringent tests. We propose a novel strategy, quantum process tomography (QPT), for ultrafast spectroscopy and apply it to reconstruct the evolving quantum state of excitons in double-walled supramolecular light-harvesting nanotubes at room temperature from eight narrowband transient grating experiments. Our analysis reveals the absence of nonsecular processes, unidirectional energy transfer from the outer to the...

12. Beneficial bacteria stimulate host immune cells to counteract dietary and genetic predisposition to mammary cancer in mice - Lakritz, Jessica R.; Poutahidis, Theofilos; Levkovich, Tatiana; Chatzigiagkos, Antonis; Mirabal, Sheyla; Alm, Eric J.; Erdman, Susan E.; Varian, Bernard; Ibrahim, Yassin
Recent studies suggest health benefits including protection from cancer after eating fermented foods such as probiotic yogurt, though the mechanisms are not well understood. Here we tested mechanistic hypotheses using two different animal models: the first model studied development of mammary cancer when eating a Westernized diet, and the second studied animals with a genetic predilection to breast cancer. For the first model, outbred Swiss mice were fed a Westernized chow putting them at increased risk for development of mammary tumors. In this Westernized diet model, mammary carcinogenesis was inhibited by routine exposure to Lactobacillus reuteri ATCC-PTA-6475 in drinking water....

13. Dominant Role of Oncogene Dosage and Absence of Tumor Suppressor Activity in Nras-Driven Hematopoietic Transformation - Jacks, Tyler E.; Xu, Jin; Haigis, Kevin M.; Firestone, Ari J.; McNerney, Megan E.; Li, Qing; Davis, Elizabeth; Chen, Shann-Ching; Nakitandwe, Joy; Downing, James; Le Beau, Michelle M.; Shannon, Kevin
Biochemical properties of Ras oncoproteins and their transforming ability strongly support a dominant mechanism of action in tumorigenesis. However, genetic studies unexpectedly suggested that wild-type (WT) Ras exerts tumor suppressor activity. Expressing oncogenic Nras[superscript G12D] in the hematopoietic compartment of mice induces an aggressive myeloproliferative neoplasm that is exacerbated in homozygous mutant animals. Here, we show that increased Nras[superscript G12D] gene dosage, but not inactivation of WT Nras, underlies the aggressive in vivo behavior of Nras[superscript G12D over G12D] hematopoietic cells. Modulating Nras[superscript G12D] dosage had discrete effects on myeloid progenitor growth, signal transduction, and sensitivity to MAP-ERK kinase (MEK)...

14. Assessing the impact of typeface design in a text-rich automotive user interface - Reimer, Bryan; Dobres, Jonathan; Coughlin, Joseph F.; Matteson, Steve; Gould, David; Chahine, Nadine; Levantovsky, Vladimir; Mehler, Bruce L.
Text-rich driver–vehicle interfaces are increasingly common in new vehicles, yet the effects of different typeface characteristics on task performance in this brief off-road based glance context remains sparsely examined. Subjects completed menu selection tasks while in a driving simulator. Menu text was set either in a ‘humanist’ or ‘square grotesque’ typeface. Among men, use of the humanist typeface resulted in a 10.6% reduction in total glance time as compared to the square grotesque typeface. Total response time and number of glances showed similar reductions. The impact of typeface was either more modest or not apparent for women. Error rates for...

15. Comparison of Grammar in Neurodevelopmental Disorders: The Case of Binding in Williams Syndrome and Autism With and Without Language Impairment - Perovic, Alexandra; Modyanova, Nadezhda N.; Wexler, Kenneth; Perovic, Aleksandra
This study investigates whether distinct neurodevelopmental disorders show distinct patterns of impairments in particular grammatical abilities and the relation of those grammatical patterns to general language delays and intellectual disabilities. We studied two disorders (autism and Williams syndrome [WS]) and two distinct properties (Principle A that governs reflexives and Principle B that, together with its associated pragmatic rule, governs pronouns) of the binding module of grammar. These properties are known to have markedly different courses of acquisition in typical development. We compare the knowledge of binding in children with autism with language impairment (ALI) and those with normal language (ALN)...

16. Tailoring Chimeric Ligands for Studying and Biasing ErbB Receptor Family Interactions - Krueger, Andrew T.; Kroll, Carsten; Sanchez, Edgar; Griffith, Linda G.; Imperiali, Barbara
Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away...

17. Two-Photon Fluorescence Spectroscopy and Imaging of 4-Dimethylaminonaphthalimide Peptide and Protein Conjugates - McLean, Alan M.; Socher, Elke; Varnavski, Oleg; Clark, Travis B.; Imperiali, Barbara; Goodson, Theodore
We report detailed photophysical studies on the two-photon fluorescence processes of the solvatochromic fluorophore 4-DMN as a conjugate of the calmodulin (CaM) and the associated CaM-binding peptide M13. Strong two-photon fluorescence enhancement has been observed which is associated with calcium binding. It is found that the two-photon absorption cross-section is strongly dependent on the local environment surrounding the 4-DMN fluorophore in the CaM conjugates, providing sensitivity between sites of fluorophore attachment. Utilizing time-resolved measurements, the emission dynamics of 4-DMN under various environmental (solvent) conditions are analyzed. In addition, anisotropy measurements reveal that the 4-DMN–S38C–CaM system has restricted rotation in the...

18. Biochemical evidence for an alternate pathway in N-linked glycoprotein biosynthesis - Larkin, Angelyn; Imperiali, Barbara; Chang, Michelle M.; Whitworth, Garrett E.
Asparagine-linked glycosylation is a complex protein modification conserved among all three domains of life. Herein we report the in vitro analysis of N-linked glycosylation from the methanogenic archaeon Methanococcus voltae. Using a suite of synthetic and semisynthetic substrates, we show that AglK initiates N-linked glycosylation in M. voltae through the formation of α-linked dolichyl monophosphate N-acetylglucosamine, which contrasts with the polyprenyl diphosphate intermediates that feature in both eukaryotes and bacteria. Notably, AglK has high sequence homology to dolichyl phosphate β-glucosyltransferases, including Alg5 in eukaryotes, suggesting a common evolutionary origin. The combined action of the first two enzymes, AglK and AglC,...

19. Ligand-Controlled Asymmetric Arylation of Aliphatic α-Amino Anion Equivalents - Zhu, Ye; Buchwald, Stephen Leffler
A palladium-catalyzed asymmetric arylation of 9-aminofluorene-derived imines using a chiral dialkylbiaryl phosphine as the supporting ligand has been developed. This transformation allows for enantioselective access to a diverse range of α-branched benzylamines.

20. High-Throughput Screening Platform for Engineered Nanoparticle-Mediated Genotoxicity Using CometChip Technology - Watson, Christa; Ge, Jing; Cohen, Joel; Pyrgiotakis, Georgios; Engelward, Bevin P.; Demokritou, Philip
The likelihood of intentional and unintentional engineered nanoparticle (ENP) exposure has dramatically increased due to the use of nanoenabled products. Indeed, ENPs have been incorporated in many useful products and have enhanced our way of life. However, there are many unanswered questions about the consequences of nanoparticle exposures, in particular, with regard to their potential to damage the genome and thus potentially promote cancer. In this study, we present a high-throughput screening assay based upon the recently developed CometChip technology, which enables evaluation of single-stranded DNA breaks, abasic sites, and alkali-sensitive sites in cells exposed to ENPs. The strategic microfabricated,...

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