Showing papers by "Massachusetts Institute of Technology published in 2008"

OpenFlow: enabling innovation in campus networks

Abstract: This whitepaper proposes OpenFlow: a way for researchers to run experimental protocols in the networks they use every day. OpenFlow is based on an Ethernet switch, with an internal flow-table, and a standardized interface to add and remove flow entries. Our goal is to encourage networking vendors to add OpenFlow to their switch products for deployment in college campus backbones and wiring closets. We believe that OpenFlow is a pragmatic compromise: on one hand, it allows researchers to run experiments on heterogeneous switches in a uniform way at line-rate and with high port-density; while on the other hand, vendors do not need to expose the internal workings of their switches. In addition to allowing researchers to evaluate their ideas in real-world traffic settings, OpenFlow could serve as a useful campus component in proposed large-scale testbeds like GENI. Two buildings at Stanford University will soon run OpenFlow networks, using commercial Ethernet switches and routers. We will work to encourage deployment at other schools; and We encourage you to consider deploying OpenFlow in your university network too

Science and technology for water purification in the coming decades

Abstract: One of the most pervasive problems afflicting people throughout the world is inadequate access to clean water and sanitation. Problems with water are expected to grow worse in the coming decades, with water scarcity occurring globally, even in regions currently considered water-rich. Addressing these problems calls out for a tremendous amount of research to be conducted to identify robust new methods of purifying water at lower cost and with less energy, while at the same time minimizing the use of chemicals and impact on the environment. Here we highlight some of the science and technology being developed to improve the disinfection and decontamination of water, as well as efforts to increase water supplies through the safe re-use of wastewater and efficient desalination of sea and brackish water.

Comprehensive genomic characterization defines human glioblastoma genes and core pathways

Abstract: Human cancer cells typically harbour multiple chromosomal aberrations, nucleotide substitutions and epigenetic modifications that drive malignant transformation. The Cancer Genome Atlas ( TCGA) pilot project aims to assess the value of large- scale multi- dimensional analysis of these molecular characteristics in human cancer and to provide the data rapidly to the research community. Here we report the interim integrative analysis of DNA copy number, gene expression and DNA methylation aberrations in 206 glioblastomas - the most common type of primary adult brain cancer - and nucleotide sequence aberrations in 91 of the 206 glioblastomas. This analysis provides new insights into the roles of ERBB2, NF1 and TP53, uncovers frequent mutations of the phosphatidylinositol- 3- OH kinase regulatory subunit gene PIK3R1, and provides a network view of the pathways altered in the development of glioblastoma. Furthermore, integration of mutation, DNA methylation and clinical treatment data reveals a link between MGMT promoter methylation and a hypermutator phenotype consequent to mismatch repair deficiency in treated glioblastomas, an observation with potential clinical implications. Together, these findings establish the feasibility and power of TCGA, demonstrating that it can rapidly expand knowledge of the molecular basis of cancer.

The CMS experiment at the CERN LHC

Abstract: The Compact Muon Solenoid (CMS) detector is described. The detector operates at the Large Hadron Collider (LHC) at CERN. It was conceived to study proton-proton (and lead-lead) collisions at a centre-of-mass energy of 14 TeV (5.5 TeV nucleon-nucleon) and at luminosities up to 10(34)cm(-2)s(-1) (10(27)cm(-2)s(-1)). At the core of the CMS detector sits a high-magnetic-field and large-bore superconducting solenoid surrounding an all-silicon pixel and strip tracker, a lead-tungstate scintillating-crystals electromagnetic calorimeter, and a brass-scintillator sampling hadron calorimeter. The iron yoke of the flux-return is instrumented with four stations of muon detectors covering most of the 4 pi solid angle. Forward sampling calorimeters extend the pseudo-rapidity coverage to high values (vertical bar eta vertical bar <= 5) assuring very good hermeticity. The overall dimensions of the CMS detector are a length of 21.6 m, a diameter of 14.6 m and a total weight of 12500 t.

Alternative Isoform Regulation in Human Tissue Transcriptomes

Abstract: Through alternative processing of pre-messenger RNAs, individual mammalian genes often produce multiple mRNA and protein isoforms that may have related, distinct or even opposing functions. Here we report an in-depth analysis of 15 diverse human tissue and cell line transcriptomes on the basis of deep sequencing of complementary DNA fragments, yielding a digital inventory of gene and mRNA isoform expression. Analyses in which sequence reads are mapped to exon-exon junctions indicated that 92-94% of human genes undergo alternative splicing, 86% with a minor isoform frequency of 15% or more. Differences in isoform-specific read densities indicated that most alternative splicing and alternative cleavage and polyadenylation events vary between tissues, whereas variation between individuals was approximately twofold to threefold less common. Extreme or 'switch-like' regulation of splicing between tissues was associated with increased sequence conservation in regulatory regions and with generation of full-length open reading frames. Patterns of alternative splicing and alternative cleavage and polyadenylation were strongly correlated across tissues, suggesting coordinated regulation of these processes, and sequence conservation of a subset of known regulatory motifs in both alternative introns and 3' untranslated regions suggested common involvement of specific factors in tissue-level regulation of both splicing and polyadenylation.

High-Thermoelectric Performance of Nanostructured Bismuth Antimony Telluride Bulk Alloys

Abstract: The dimensionless thermoelectric figure of merit (ZT) in bismuth antimony telluride (BiSbTe) bulk alloys has remained around 1 for more than 50 years. We show that a peak ZT of 1.4 at 100°C can be achieved in a p-type nanocrystalline BiSbTe bulk alloy. These nanocrystalline bulk materials were made by hot pressing nanopowders that were ball-milled from crystalline ingots under inert conditions. Electrical transport measurements, coupled with microstructure studies and modeling, show that the ZT improvement is the result of low thermal conductivity caused by the increased phonon scattering by grain boundaries and defects. More importantly, ZT is about 1.2 at room temperature and 0.8 at 250°C, which makes these materials useful for cooling and power generation. Cooling devices that use these materials have produced high-temperature differences of 86°, 106°, and 119°C with hot-side temperatures set at 50°, 100°, and 150°C, respectively. This discovery sets the stage for use of a new nanocomposite approach in developing high-performance low-cost bulk thermoelectric materials.

In Situ Formation of an Oxygen-Evolving Catalyst in Neutral Water Containing Phosphate and Co2+

Abstract: The utilization of solar energy on a large scale requires its storage. In natural photosynthesis, energy from sunlight is used to rearrange the bonds of water to oxygen and hydrogen equivalents. The realization of artificial systems that perform "water splitting" requires catalysts that produce oxygen from water without the need for excessive driving potentials. Here we report such a catalyst that forms upon the oxidative polarization of an inert indium tin oxide electrode in phosphate-buffered water containing cobalt (II) ions. A variety of analytical techniques indicates the presence of phosphate in an approximate 1:2 ratio with cobalt in this material. The pH dependence of the catalytic activity also implicates the hydrogen phosphate ion as the proton acceptor in the oxygen-producing reaction. This catalyst not only forms in situ from earth-abundant materials but also operates in neutral water under ambient conditions.

The impact of microRNAs on protein output

Abstract: MicroRNAs are endogenous ∼23-nucleotide RNAs that can pair to sites in the messenger RNAs of protein-coding genes to downregulate the expression from these messages. MicroRNAs are known to influence the evolution and stability of many mRNAs, but their global impact on protein output had not been examined. Here we use quantitative mass spectrometry to measure the response of thousands of proteins after introducing microRNAs into cultured cells and after deleting mir-223 in mouse neutrophils. The identities of the responsive proteins indicate that targeting is primarily through seed-matched sites located within favourable predicted contexts in 3′ untranslated regions. Hundreds of genes were directly repressed, albeit each to a modest degree, by individual microRNAs. Although some targets were repressed without detectable changes in mRNA levels, those translationally repressed by more than a third also displayed detectable mRNA destabilization, and, for the more highly repressed targets, mRNA destabilization usually comprised the major component of repression. The impact of microRNAs on the proteome indicated that for most interactions microRNAs act as rheostats to make fine-scale adjustments to protein output. MicroRNAs can regulate gene expression by either inhibiting translation of a messenger RNA, or inducing its degradation. While previous studies have measured regulation at the mRNA level, it was unknown how much regulation occurred at the protein level. Now two groups led by David Bartel and Nikolaus Rajewsky have used variants of the technique known as SILAC (stable isotope labelling with amino acids in cell culture) to measure proteome-wide changes in protein level as a function of expression of endogenous and exogenous microRNAs. They find that while microRNAs can directly repress the translation of hundreds of genes, additional indirect effects result in changes in expression of thousands of genes. Many of the changes observed are less than twofold in magnitude, however, indicating either directly or indirectly, microRNAs can act as rheostats to fine-tune protein synthesis to match the needs of the cell at any given time. In one of two studies, a technique known as SILAC is used to measure, on a large scale, changes in protein level as a function of expression of endogenous and exogenous miRNAs. It is found that although miRNAs directly repress the translation of hundreds of genes, additional indirect effects result in changes in expression of thousands of genes.

LabelMe: A Database and Web-Based Tool for Image Annotation

Abstract: We seek to build a large collection of images with ground truth labels to be used for object detection and recognition research. Such data is useful for supervised learning and quantitative evaluation. To achieve this, we developed a web-based tool that allows easy image annotation and instant sharing of such annotations. Using this annotation tool, we have collected a large dataset that spans many object categories, often containing multiple instances over a wide variety of images. We quantify the contents of the dataset and compare against existing state of the art datasets used for object recognition and detection. Also, we show how to extend the dataset to automatically enhance object labels with WordNet, discover object parts, recover a depth ordering of objects in a scene, and increase the number of labels using minimal user supervision and images from the web.

Factors Affecting the Clearance and Biodistribution of Polymeric Nanoparticles

Abstract: Nanoparticle (NP) drug delivery systems (5−250 nm) have the potential to improve current disease therapies because of their ability to overcome multiple biological barriers and releasing a therapeutic load in the optimal dosage range. Rapid clearance of circulating nanoparticles during systemic delivery is a critical issue for these systems and has made it necessary to understand the factors affecting particle biodistribution and blood circulation half-life. In this review, we discuss the factors which can influence nanoparticle blood residence time and organ specific accumulation. These factors include interactions with biological barriers and tunable nanoparticle parameters, such as composition, size, core properties, surface modifications (pegylation and surface charge), and finally, targeting ligand functionalization. All these factors have been shown to substantially affect the biodistribution and blood circulation half-life of circulating nanoparticles by reducing the level of nonspecific uptake, de...

Spectral Hashing

Abstract: Semantic hashing[1] seeks compact binary codes of data-points so that the Hamming distance between codewords correlates with semantic similarity. In this paper, we show that the problem of finding a best code for a given dataset is closely related to the problem of graph partitioning and can be shown to be NP hard. By relaxing the original problem, we obtain a spectral method whose solutions are simply a subset of thresholded eigenvectors of the graph Laplacian. By utilizing recent results on convergence of graph Laplacian eigenvectors to the Laplace-Beltrami eigenfunctions of manifolds, we show how to efficiently calculate the code of a novel data-point. Taken together, both learning the code and applying it to a novel point are extremely simple. Our experiments show that our codes outperform the state-of-the art.

Transdermal drug delivery

Abstract: Transdermal drug delivery has made an important contribution to medical practice, but has yet to fully achieve its potential as an alternative to oral delivery and hypodermic injections. First-generation transdermal delivery systems have continued their steady increase in clinical use for delivery of small, lipophilic, low-dose drugs. Second-generation delivery systems using chemical enhancers, noncavitational ultrasound and iontophoresis have also resulted in clinical products; the ability of iontophoresis to control delivery rates in real time provides added functionality. Third-generation delivery systems target their effects to skin's barrier layer of stratum corneum using microneedles, thermal ablation, microdermabrasion, electroporation and cavitational ultrasound. Microneedles and thermal ablation are currently progressing through clinical trials for delivery of macromolecules and vaccines, such as insulin, parathyroid hormone and influenza vaccine. Using these novel second- and third-generation enhancement strategies, transdermal delivery is poised to significantly increase its impact on medicine.

Genome-wide association defines more than 30 distinct susceptibility loci for Crohn's disease

Abstract: Several risk factors for Crohn's disease have been identified in recent genome-wide association studies. To advance gene discovery further, we combined data from three studies on Crohn's disease (a total of 3,230 cases and 4,829 controls) and carried out replication in 3,664 independent cases with a mixture of population-based and family-based controls. The results strongly confirm 11 previously reported loci and provide genome-wide significant evidence for 21 additional loci, including the regions containing STAT3, JAK2, ICOSLG, CDKAL1 and ITLN1. The expanded molecular understanding of the basis of this disease offers promise for informed therapeutic development.

Genome-scale DNA methylation maps of pluripotent and differentiated cells

Abstract: DNA methylation is essential for normal development and has been implicated in many pathologies including cancer. Our knowledge about the genome-wide distribution of DNA methylation, how it changes during cellular differentiation and how it relates to histone methylation and other chromatin modifications in mammals remains limited. Here we report the generation and analysis of genome-scale DNA methylation profiles at nucleotide resolution in mammalian cells. Using high-throughput reduced representation bisulphite sequencing and single-molecule-based sequencing, we generated DNA methylation maps covering most CpG islands, and a representative sampling of conserved non-coding elements, transposons and other genomic features, for mouse embryonic stem cells, embryonic-stem-cell-derived and primary neural cells, and eight other primary tissues. Several key findings emerge from the data. First, DNA methylation patterns are better correlated with histone methylation patterns than with the underlying genome sequence context. Second, methylation of CpGs are dynamic epigenetic marks that undergo extensive changes during cellular differentiation, particularly in regulatory regions outside of core promoters. Third, analysis of embryonic-stem-cell-derived and primary cells reveals that 'weak' CpG islands associated with a specific set of developmentally regulated genes undergo aberrant hypermethylation during extended proliferation in vitro, in a pattern reminiscent of that reported in some primary tumours. More generally, the results establish reduced representation bisulphite sequencing as a powerful technology for epigenetic profiling of cell populations relevant to developmental biology, cancer and regenerative medicine.

The Rag GTPases Bind Raptor and Mediate Amino Acid Signaling to mTORC1

Abstract: The multiprotein mTORC1 protein kinase complex is the central component of a pathway that promotes growth in response to insulin, energy levels, and amino acids and is deregulated in common cancers. We find that the Rag proteins--a family of four related small guanosine triphosphatases (GTPases)--interact with mTORC1 in an amino acid-sensitive manner and are necessary for the activation of the mTORC1 pathway by amino acids. A Rag mutant that is constitutively bound to guanosine triphosphate interacted strongly with mTORC1, and its expression within cells made the mTORC1 pathway resistant to amino acid deprivation. Conversely, expression of a guanosine diphosphate-bound Rag mutant prevented stimulation of mTORC1 by amino acids. The Rag proteins do not directly stimulate the kinase activity of mTORC1, but, like amino acids, promote the intracellular localization of mTOR to a compartment that also contains its activator Rheb.

An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumors

Abstract: Cancer cells possess traits reminiscent of those ascribed to normal stem cells. It is unclear, however, whether these phenotypic similarities reflect the activity of common molecular pathways. Here, we analyze the enrichment patterns of gene sets associated with embryonic stem (ES) cell identity in the expression profiles of various human tumor types. We find that histologically poorly differentiated tumors show preferential overexpression of genes normally enriched in ES cells, combined with preferential repression of Polycomb-regulated genes. Moreover, activation targets of Nanog, Oct4, Sox2 and c-Myc are more frequently overexpressed in poorly differentiated tumors than in well-differentiated tumors. In breast cancers, this ES-like signature is associated with high-grade estrogen receptor (ER)-negative tumors, often of the basal-like subtype, and with poor clinical outcome. The ES signature is also present in poorly differentiated glioblastomas and bladder carcinomas. We identify a subset of ES cell-associated transcription regulators that are highly expressed in poorly differentiated tumors. Our results reveal a previously unknown link between genes associated with ES cell identity and the histopathological traits of tumors and support the possibility that these genes contribute to stem cell-like phenotypes shown by many tumors.

The Microbial Engines That Drive Earth's Biogeochemical Cycles

Abstract: Virtually all nonequilibrium electron transfers on Earth are driven by a set of nanobiological machines composed largely of multimeric protein complexes associated with a small number of prosthetic groups. These machines evolved exclusively in microbes early in our planet's history yet, despite their antiquity, are highly conserved. Hence, although there is enormous genetic diversity in nature, there remains a relatively stable set of core genes coding for the major redox reactions essential for life and biogeochemical cycles. These genes created and coevolved with biogeochemical cycles and were passed from microbe to microbe primarily by horizontal gene transfer. A major challenge in the coming decades is to understand how these machines evolved, how they work, and the processes that control their activity on both molecular and planetary scales.

Nanoparticles in Medicine: Therapeutic Applications and Developments

Abstract: Nanotechnology is the understanding and control of matter generally in the 1-100 nm dimension range. The application of nanotechnology to medicine, known as nanomedicine, concerns the use of precisely engineered materials at this length scale to develop novel therapeutic and diagnostic modalities. Nanomaterials have unique physicochemical properties, such as ultra small size, large surface area to mass ratio, and high reactivity, which are different from bulk materials of the same composition. These properties can be used to overcome some of the limitations found in traditional therapeutic and diagnostic agents.

XORs in the air: practical wireless network coding

Abstract: This paper proposes COPE, a new architecture for wireless mesh networks. In addition to forwarding packets, routers mix (i.e., code) packets from different sources to increase the information content of each transmission. We show that intelligently mixing packets increases network throughput. Our design is rooted in the theory of network coding. Prior work on network coding is mainly theoretical and focuses on multicast traffic. This paper aims to bridge theory with practice; it addresses the common case of unicast traffic, dynamic and potentially bursty flows, and practical issues facing the integration of network coding in the current network stack. We evaluate our design on a 20-node wireless network, and discuss the results of the first testbed deployment of wireless network coding. The results show that using COPE at the forwarding layer, without modifying routing and higher layers, increases network throughput. The gains vary from a few percent to several folds depending on the traffic pattern, congestion level, and transport protocol.

Tools and tactics for the optical detection of mercuric ion.

Abstract: 9.2. Protein-Based Hg(II) Detectors 3467 9.3. Oligonucleotide-Based Hg(II) Detector 3467 9.4. DNAzyme-Based Hg(II) Detectors 3469 9.5. Antibody-Based Hg(II) Detector 3469 10. Mercury Detectors Based on Materials 3469 10.1. Soluble and Fluorescent Polymers 3469 10.2. Membranes, Films, and Fibers 3471 10.3. Micelles 3473 10.4. Nanoparticles 3473 11. Perspectives 3474 12. Addendum 3475 12.1. Small Molecules 3475 12.2. Biomolecules 3477 12.3. Materials 3477 13. List of Abbreviations 3477 14. Acknowledgments 3478 15. References 3478

Trends in U.S. Wage Inequality: Revising the Revisionists

Abstract: A recent “revisionist” literature characterizes the pronounced rise in U.S. wage inequality since 1980 as an “episodic” event of the first half of the 1980s driven by nonmarket factors (particularly a falling real minimum wage) and concludes that continued increases in wage inequality since the late 1980s substantially reflect the mechanical confounding effects of changes in labor force composition. Analyzing data from the Current Population Survey for 1963 to 2005, we find limited support for these claims. The slowing of the growth of overall wage inequality in the 1990s hides a divergence in the paths of upper-tail (90/50) inequality—which has increased steadily since 1980, even adjusting for changes in labor force composition—and lower-tail (50/10) inequality, which rose sharply in the first half of the 1980s and plateaued or contracted thereafter. Fluctuations in the real minimum wage are not a plausible explanation for these trends since the bulk of inequality growth occurs above the median ...

Constructing Inverse Probability Weights for Marginal Structural Models

Abstract: The method of inverse probability weighting (henceforth, weighting) can be used to adjust for measured confounding and selection bias under the four assumptions of consistency, exchangeability, positivity, and no misspecification of the model used to estimate weights. In recent years, several published estimates of the effect of time-varying exposures have been based on weighted estimation of the parameters of marginal structural models because, unlike standard statistical methods, weighting can appropriately adjust for measured time-varying confounders affected by prior exposure. As an example, the authors describe the last three assumptions using the change in viral load due to initiation of antiretroviral therapy among 918 human immunodeficiency virus-infected US men and women followed for a median of 5.8 years between 1996 and 2005. The authors describe possible tradeoffs that an epidemiologist may encounter when attempting to make inferences. For instance, a tradeoff between bias and precision is illustrated as a function of the extent to which confounding is controlled. Weight truncation is presented as an informal and easily implemented method to deal with these tradeoffs. Inverse probability weighting provides a powerful methodological tool that may uncover causal effects of exposures that are otherwise obscured. However, as with all methods, diagnostics and sensitivity analyses are essential for proper use.

Palladium-Catalyzed Suzuki-Miyaura Cross-coupling Reactions Employing Dialkylbiaryl Phosphine Ligands

Abstract: The cores of many types of polymers, ligands, natural products, and pharmaceuticals contain biaryl or substituted aromatic structures, and efficient methods of synthesizing these structures are crucial to the work of a broad spectrum of organic chemists. Recently, Pd-catalyzed carbon−carbon bond-forming processes, particularly the Suzuki−Miyaura cross-coupling reaction (SMC), have risen in popularity for this purpose. The SMC has many advantages over other methods for constructing these moieties, including mild conditions, high tolerance toward functional groups, the commercial availability and stability of its reagents, and the ease of handling and separating byproducts from its reaction mixtures. Until 1998, most catalysts for the SMC employed triarylphosphine ligands. More recently, new bulky and electron-rich phosphine ligands, which can dramatically improve the efficiency and selectivity of such cross-coupling reactions, have been introduced. In the course of our studies on carbon−nitrogen bond-formi...

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Abstract: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.