Tuesday, July 28, 2015

 

 



Soy un nuevo usuario

Olvidé mi contraseña

Entrada usuarios

Lógica Matemáticas Astronomía y Astrofísica Física Química Ciencias de la Vida
Ciencias de la Tierra y Espacio Ciencias Agrarias Ciencias Médicas Ciencias Tecnológicas Antropología Demografía
Ciencias Económicas Geografía Historia Ciencias Jurídicas y Derecho Lingüística Pedagogía
Ciencia Política Psicología Artes y Letras Sociología Ética Filosofía
 

rss_1.0 Recursos de colección

DSpace at MIT (83,339 recursos)
This site is a university repository providing access to the publication output of the institution. Registered users can set up email alerts to notify them of newly added relevant content. A certain level of encryption and security is embedded in the site which may cause some users accessibility problems.

MIT Open Access Articles

Mostrando recursos 41 - 60 de 16,503

41. DISCOVERY AND COSMOLOGICAL IMPLICATIONS OF SPT-CL J2106-5844, THE MOST MASSIVE KNOWN CLUSTER AT z > 1 - Andersson, Karl; Bautz, Marshall W.
Using the South Pole Telescope (SPT), we have discovered the most massive known galaxy cluster at z>1, SPT-CL J2106-5844. In addition to producing a strong Sunyaev-Zel'dovich (SZ) effect signal, this system is a luminous X-ray source and its numerous constituent galaxies display spatial and color clustering, all indicating the presence of a massive galaxy cluster. Very Large Telescope and Magellan spectroscopy of 18 member galaxies shows that the cluster is at z = 1.132[+0.002 over –0.003]. Chandra observations obtained through a combined HRC-ACIS GTO program reveal an X-ray spectrum with an Fe K line redshifted by z = 1.18 ±...

42. Quantitative Determination of Technological Improvement from Patent Data - Benson, Christopher L.; Magee, Christopher L.
The results in this paper establish that information contained in patents in a technological domain is strongly correlated with the rate of technological progress in that domain. The importance of patents in a domain, the recency of patents in a domain and the immediacy of patents in a domain are all strongly correlated with increases in the rate of performance improvement in the domain of interest. A patent metric that combines both importance and immediacy is not only highly correlated (r = 0.76, p = 2.6*10[superscript -6]) with the performance improvement rate but the correlation is also very robust to...

43. Single-Walled Carbon Nanotube/Metalloporphyrin Composites for the Chemiresistive Detection of Amines and Meat Spoilage - Petty, Alexander R.; Liu, Sophie; Sazama, Graham Thomas; Swager, Timothy Manning
Chemiresistive detectors for amine vapors were made from single-walled carbon nanotubes by noncovalent modification with cobalt meso-arylporphyrin complexes. We show that through changes in the oxidation state of the metal, the electron-withdrawing character of the porphyrinato ligand, and the counteranion, the magnitude of the chemiresistive response to ammonia could be improved. The devices exhibited sub-ppm sensitivity and high selectivity toward amines as well as good stability to air, moisture, and time. The application of these chemiresistors in the detection of various biogenic amines (i.e. putrescine, cadaverine) and in the monitoring of spoilage in raw meat and fish samples (chicken, pork,...

44. Antibacterial Activity of and Resistance to Small Molecule Inhibitors of the ClpP Peptidase - Compton, Corey L.; Schmitz, Karl R.; Sauer, Robert T.; Sello, Jason K.
There is rapidly mounting evidence that intracellular proteases in bacteria are compelling targets for antibacterial drugs. Multiple reports suggest that the human pathogen Mycobacterium tuberculosis and other actinobacteria may be particularly sensitive to small molecules that perturb the activities of self-compartmentalized peptidases, which catalyze intracellular protein turnover as components of ATP-dependent proteolytic machines. Here, we report chemical syntheses and evaluations of structurally diverse β-lactones, which have a privileged structure for selective, suicide inhibition of the self-compartmentalized ClpP peptidase. β-Lactones with certain substituents on the α- and β-carbons were found to be toxic to M. tuberculosis. Using an affinity-labeled analogue of...

45. Dual Molecular Signals Mediate the Bacterial Response to Outer-Membrane Stress - Sauer, Robert T.; Lima, Santiago; Guo, Monica S.; Chaba, Rachna; Gross, Carol A.
In Gram-negative bacteria, outer-membrane integrity is essential for survival and is monitored by the σ[superscript E] stress-response system, which initiates damage-repair pathways. One activating signal is unassembled outer-membrane proteins. Using biochemical and genetic experiments in Escherichia coli, we found that off-pathway intermediates in lipopolysaccharide transport and assembly provided an additional required signal. These distinct signals, arising from disruptions in the transport and assembly of the major outer-membrane components, jointly determined the rate of proteolytic destruction of a negative regulator of the σ[superscript E] transcription factor, thereby modulating the expression of stress-response genes. This dual-signal system permits a rapid response to...

46. miR-146a and miR-155 Delineate a MicroRNA Fingerprint Associated with Toxoplasma Persistence in the Host Brain - Cannella, Dominique; Brenier-Pinchart, Marie-Pierre; Braun, Laurence; van Rooyen, Jason M.; Bougdour, Alexandre; Bastien, Olivier; Behnke, Michael S.; Curt, Rose-Laurence; Sibley, L. David; Hakimi, Mohamed-Ali; Saeij, Jeroen; Curt, Aurelie; Pelloux, Herve
microRNAs were recently found to be regulators of the host response to infection by apicomplexan parasites. In this study, we identified two immunomodulatory microRNAs, miR-146a and miR-155, that were coinduced in the brains of mice challenged with Toxoplasma in a strain-specific manner. These microRNAs define a characteristic fingerprint for infection by type II strains, which are the most prevalent cause of human toxoplasmosis in Europe and North America. Using forward genetics, we showed that strain-specific differences in miR-146a modulation were in part mediated by the rhoptry kinase, ROP16. Remarkably, we found that miR-146a deficiency led to better control of parasite...

47. Asymmetric apportioning of aged mitochondria between daughter cells is required for stemness - Chen, Walter W.; Weinberg, Robert A.; Sabatini, David M.; Marjanovic, Nemanja; Zoncu, Roberto; Katajisto, Pekka; Dohla, Julia; Chaffer, Christine L.; Pentinmikko, Nalle; Iqbal, Sharif
By dividing asymmetrically, stem cells can generate two daughter cells with distinct fates. However, evidence is limited in mammalian systems for the selective apportioning of subcellular contents between daughters. We followed the fates of old and young organelles during the division of human mammary stemlike cells and found that such cells apportion aged mitochondria asymmetrically between daughter cells. Daughter cells that received fewer old mitochondria maintained stem cell traits. Inhibition of mitochondrial fission disrupted both the age-dependent subcellular localization and segregation of mitochondria and caused loss of stem cell properties in the progeny cells. Hence, mechanisms exist for mammalian stemlike...

48. Lysosomal amino acid transporter SLC38A9 signals arginine sufficiency to mTORC1 - Plovanich, M. E.; Jones, T. D.; Straub, C.; Sabatini, B. L.; Tsun, Zhi-Yang; Wang, Shuyu; Wolfson, Rachel Laura; Shen, Kuang; Wyant, Gregory Andrew; Yuan, Elizabeth D.; Jones, Tony D.; Chantranupong, Lynne; Comb, William; Wang, Tim; Bar-Peled, Liron; Zoncu, Roberto; Kim, Choah; Park, Jiwon; Sabatini, David M.
The mechanistic target of rapamycin complex 1 (mTORC1) protein kinase is a master growth regulator that responds to multiple environmental cues. Amino acids stimulate, in a Rag-, Ragulator-, and vacuolar adenosine triphosphatase–dependent fashion, the translocation of mTORC1 to the lysosomal surface, where it interacts with its activator Rheb. Here, we identify SLC38A9, an uncharacterized protein with sequence similarity to amino acid transporters, as a lysosomal transmembrane protein that interacts with the Rag guanosine triphosphatases (GTPases) and Ragulator in an amino acid–sensitive fashion. SLC38A9 transports arginine with a high Michaelis constant, and loss of SLC38A9 represses mTORC1 activation by amino acids,...

49. A Diverse Array of Cancer-Associated MTOR Mutations Are Hyperactivating and Can Predict Rapamycin Sensitivity - Sabatini, David M.; Grabiner, Brian C.; Nardi, Valentina; Birsoy, Kivanc; Possemato, Richard; Shen, Kuang; Sinha, Sumi; Jordan, Alexander; Beck, Andrew H.
Genes encoding components of the PI3K–AKT–mTOR signaling axis are frequently mutated in cancer, but few mutations have been characterized in MTOR, the gene encoding the mTOR kinase. Using publicly available tumor genome sequencing data, we generated a comprehensive catalog of mTOR pathway mutations in cancer, identifying 33 MTOR mutations that confer pathway hyperactivation. The mutations cluster in six distinct regions in the C-terminal half of mTOR and occur in multiple cancer types, with one cluster particularly prominent in kidney cancer. The activating mutations do not affect mTOR complex assembly, but a subset reduces binding to the mTOR inhibitor DEPTOR. mTOR...

50. The Sestrins Interact with GATOR2 to Negatively Regulate the Amino-Acid-Sensing Pathway Upstream of mTORC1 - Chantranupong, Lynne; Orozco, Jose M.; Scaria, Sonia M.; Bar-Peled, Liron; Spooner, Eric; Isasa, Marta; Gygi, Steven P.; Sabatini, David M.; Wolfson, Rachel Laura; Saxton, Robert Andrew; Scaria, Sonia M.; Sabatini, David M.
The mechanistic target of rapamycin complex 1 (mTORC1) kinase is a major regulator of cell growth that responds to numerous environmental cues. A key input is amino acids, which act through the heterodimeric Rag GTPases (RagA or RagB bound to RagC or RagD) in order to promote the translocation of mTORC1 to the lysosomal surface, its site of activation. GATOR2 is a complex of unknown function that positively regulates mTORC1 signaling by acting upstream of or in parallel to GATOR1, which is a GTPase-activating protein (GAP) for RagA or RagB and an inhibitor of the amino-acid-sensing pathway. Here, we find...

51. Inhibition of ATPIF1 Ameliorates Severe Mitochondrial Respiratory Chain Dysfunction in Mammalian Cells - Chen, Walter W.; Mihaylova, Maria M.; Snitkin, Harriet; Stasinski, Iwona; Yucel, Burcu; Bayraktar, Erol C.; Carette, Jan E.; Clish, Clary B.; Brummelkamp, Thijn R.; Sabatini, David D.; Sabatini, David M.; Birsoy, Kivanc; Chen, Walter W.; Sabatini, David M.
Mitochondrial respiratory chain disorders are characterized by loss of electron transport chain (ETC) activity. Although the causes of many such diseases are known, there is a lack of effective therapies. To identify genes that confer resistance to severe ETC dysfunction when inactivated, we performed a genome-wide genetic screen in haploid human cells with the mitochondrial complex III inhibitor antimycin. This screen revealed that loss of ATPIF1 strongly protects against antimycin-induced ETC dysfunction and cell death by allowing for the maintenance of mitochondrial membrane potential. ATPIF1 loss protects against other forms of ETC dysfunction and is even essential for the viability...

52. Metabolic determinants of cancer cell sensitivity to glucose limitation and biguanides - Possemato, Richard; Lorbeer, Franziska K.; Bayraktar, Erol C.; Thiru, Prathapan; Yucel, Burcu; Wang, Tim; Chen, Walter W.; Clish, Clary B.; Sabatini, David M.; Wang, Tim; Birsoy, Kivanc
As the concentrations of highly consumed nutrients, particularly glucose, are generally lower in tumours than in normal tissues, cancer cells must adapt their metabolism to the tumour microenvironment. A better understanding of these adaptations might reveal cancer cell liabilities that can be exploited for therapeutic benefit. Here we developed a continuous-flow culture apparatus (Nutrostat) for maintaining proliferating cells in low-nutrient media for long periods of time, and used it to undertake competitive proliferation assays on a pooled collection of barcoded cancer cell lines cultured in low-glucose conditions. Sensitivity to low glucose varies amongst cell lines, and an RNA interference (RNAi)...

53. The Adaptor Protein p66Shc Inhibits mTOR-Dependent Anabolic Metabolism - Lamming, Dudley W.; Sabatini, David M.; Soliman, Mohamed A.; Abdel Rahman, Anas M.; Birsoy, Kivanc; Pawling, Judy; Frigolet, Maria E.; Lu, Huogen; Fantus, I. George; Pasculescu, Adrian; Zheng, Yong; Dennis, James W.; Pawson, Tony
Adaptor proteins link surface receptors to intracellular signaling pathways and potentially control the way cells respond to nutrient availability. Mice deficient in p66Shc, the most recently evolved isoform of the Shc1 adaptor proteins and a mediator of receptor tyrosine kinase signaling, display resistance to diabetes and obesity. Using quantitative mass spectrometry, we found that p66Shc inhibited glucose metabolism. Depletion of p66Shc enhanced glycolysis and increased the allocation of glucose-derived carbon into anabolic metabolism, characteristics of a metabolic shift called the Warburg effect. This change in metabolism was mediated by the mammalian target of rapamycin (mTOR) because inhibition of mTOR with...

54. The TSC-mTOR pathway regulates macrophage polarization - Byles, Vanessa; Covarrubias, Anthony J.; Ben-Sahra, Issam; Lamming, Dudley W.; Sabatini, David M.; Manning, Brendan D.; Horng, Tiffany
Macrophages are able to polarize to proinflammatory M1 or alternative M2 states with distinct phenotypes and physiological functions. How metabolic status regulates macrophage polarization remains not well understood, and here we examine the role of mTOR (mechanistic target of rapamycin), a central metabolic pathway that couples nutrient sensing to regulation of metabolic processes. Using a mouse model in which myeloid lineage-specific deletion of Tsc1 (Tsc1[superscript Δ/Δ]) leads to constitutive mTOR complex 1 (mTORC1) activation, we find that Tsc1[superscript Δ/Δ] macrophages are refractory to IL-4-induced M2 polarization, but produce increased inflammatory responses to proinflammatory stimuli. Moreover, mTORC1-mediated downregulation of Akt signalling...

55. Rapamycin Doses Sufficient to Extend Lifespan Do Not Compromise Muscle Mitochondrial Content or Endurance - Ye, Lan; Widlund, Anne L.; Sims, Carrie A.; Lamming, Dudley W.; Guan, Yuxia; Davis, James G.; Sabatini, David M.; Harrison, David E.; Vang, Ole; Baur, Joseph A.
Rapamycin extends lifespan in mice, but can have a number of undesirable effects that may ultimately limit its utility in humans. The canonical target of rapamycin, and the one thought to account for its effects on lifespan, is the mammalian/mechanistic target of rapamycin, complex 1 (mTORC1). We have previously shown that at least some of the detrimental side effects of rapamycin are due to “off target” disruption of mTORC2, suggesting they could be avoided by more specific targeting of mTORC1. However, mTORC1 inhibition per se can reduce the mRNA expression of mitochondrial genes and compromise the function of mitochondria in...

56. Nutrients versus growth factors in mTORC1 activation - Efeyan, Alejo; Sabatini, David M.; Sabatini, David M.
Growth factors and nutrients regulate the mTORC1 [mammalian (or mechanistic) target of rapamycin complex 1] by different mechanisms. The players that link growth factors and mTORC1 activation have been known for several years and mouse models have validated its relevance for human physiology and disease. In contrast with the picture for growth factor signalling, the means by which nutrient availability leads to mTORC1 activation have remained elusive until recently, with the discovery of the Rag GTPases upstream of mTORC1. The Rag GTPases recruit mTORC1 to the outer lysosomal surface, where growth factor signalling and nutrient signalling converge on mTORC1 activation....

57. Characterization of Torin2, an ATP-Competitive Inhibitor of mTOR, ATM, and ATR - Sabatini, David M.; Liu, Qingsong; Xu, Chunxiao; Kirubakaran, Sivapriya; Zhang, Xin; Hur, Wooyoung; Liu, Yan; Kwiatkowski, Nicholas P.; Wang, Jinhua; Westover, Kenneth D.; Gao, Peng; Ercan, Dalia; Niepel, Mario; Thoreen, Carson C.; Kang, Seong A.; Patricelli, Matthew P.; Wang, Yuchuan; Tupper, Tanya; Altabef, Abigail; Kawamura, Hidemasa; Held, Kathryn D.; Chou, Danny M.; Elledge, Stephen J.; Janne, Pasi A.; Wong, Kwok-Kin; Gray, Nathanael S.
mTOR is a highly conserved serine/threonine protein kinase that serves as a central regulator of cell growth, survival, and autophagy. Deregulation of the PI3K/Akt/mTOR signaling pathway occurs commonly in cancer and numerous inhibitors targeting the ATP-binding site of these kinases are currently undergoing clinical evaluation. Here, we report the characterization of Torin2, a second-generation ATP-competitive inhibitor that is potent and selective for mTOR with a superior pharmacokinetic profile to previous inhibitors. Torin2 inhibited mTORC1-dependent T389 phosphorylation on S6K (RPS6KB1) with an EC[subscript 50] of 250 pmol/L with approximately 800-fold selectivity for cellular mTOR versus phosphoinositide 3-kinase (PI3K). Torin2 also exhibited...

58. Calorie restriction in humans inhibits the PI3K/AKT pathway and induces a younger transcription profile - Mercken, Evi M.; Crosby, Seth D.; Lamming, Dudley W.; JeBailey, Lellean; Krzysik-Walker, Susan; Villareal, Dennis T.; Capri, Miriam; Franceschi, Claudio; Zhang, Yongqing; Becker, Kevin; Sabatini, David M.; de Cabo, Rafael; Fontana, Luigi
Caloric restriction (CR) and down-regulation of the insulin/IGF pathway are the most robust interventions known to increase longevity in lower organisms. However, little is known about the molecular adaptations induced by CR in humans. Here, we report that long-term CR in humans inhibits the IGF-1/insulin pathway in skeletal muscle, a key metabolic tissue. We also demonstrate that CR induces dramatic changes of the skeletal muscle transcriptional profile that resemble those of younger individuals. Finally, in both rats and humans, CR evoked similar responses in the transcriptional profiles of skeletal muscle. This common signature consisted of three key pathways typically associated...

59. Young and old genetically heterogeneous HET3 mice on a rapamycin diet are glucose intolerant but insulin sensitive - Lamming, Dudley W.; Ye, Lan; Astle, Clinton M.; Baur, Joseph A.; Sabatini, David M.; Harrison, David E.
Rapamycin, an inhibitor of the mechanistic target of rapamycin (mTOR) signaling pathway, extends the life span of yeast, worms, flies, and mice. Interventions that promote longevity are often correlated with increased insulin sensitivity, and it therefore is surprising that chronic rapamycin treatment of mice, rats, and humans is associated with insulin resistance (J Am Soc Nephrol., 19, 2008, 1411; Diabetes, 00, 2010, 00; Science, 335, 2012, 1638). We examined the effect of dietary rapamycin treatment on glucose homeostasis and insulin resistance in the genetically heterogeneous HET3 mouse strain, a strain in which dietary rapamycin robustly extends mean and maximum life...

60. NailO: Fingernails as an Input Surface - Kao, Cindy Hsin-Liu; Dementyev, Artem; Paradiso, Joseph A.; Schmandt, Christopher M.
We present NailO, a nail-mounted gestural input surface. Using capacitive sensing on printed electrodes, the interface can distinguish on-nail finger swipe gestures with high accuracy (>92%). NailO works in real-time: we miniaturized the system to fit on the fingernail, while wirelessly transmitting the sensor data to a mobile phone or PC. NailO allows one-handed and always-available input, while being unobtrusive and discrete. Inspired by commercial nail stickers, the device blends into the user's body, is customizable, fashionable and even removable. We show example applications of using the device as a remote controller when hands are busy and using the system...

Página de resultados:
 

Busque un recurso